Original Article

Effects of primary granulocyte-colony stimulating factor prophylaxis on neutropenic toxicity and chemotherapy dose delivery in Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy: a retrospective cohort study

Hong Kong Med J 2022;28(6):438-46 | Epub 20 Oct 2022

https://doi.org/10.12809/hkmj219439

ORIGINAL ARTICLE

Effects of primary granulocyte-colony stimulating factor prophylaxis on neutropenic toxicity and chemotherapy dose delivery in Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy: a retrospective cohort study

Carol CH Kwok, MB, ChB¹; WH Wong, BSc, MSc¹; Landon L Chan, MB, ChB¹; Sabrina PY Wong, MB, BS, FCSHK²; F Wang, BMed, PhD³; Martin CS Wong, MD, MPH³; Shelly LA Tse, BMed, PhD³

¹ Department of Oncology, Princess Margaret Hospital, Hong Kong

² Department of Surgery, Princess Margaret Hospital, Hong Kong

³ JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong

Corresponding author: Dr Carol CH Kwok (kwokch@ha.org.hk)

Full paper in PDF

Abstract

Introduction: This study was performed to examine the effects of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on neutropenic toxicity, chemotherapy delivery, and hospitalisation among Chinese patients with breast cancer in Hong Kong.

Methods: This retrospective study included patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy from November 2007 to October 2013 at Princess Margaret Hospital. Data were collected regarding the usage of G-CSF prophylaxis; incidences of grade 3 or 4 neutropenia, febrile neutropenia, non-neutropenic fever, and infection; hospital admissions, and chemotherapy dose delivery. Patients who began to receive G-CSF prophylaxis during the first cycle of chemotherapy and continued such prophylaxis in subsequent cycles were regarded as the primary G-CSF prophylaxis group.

Results: In total, 231 female Chinese patients with breast cancer were included in the analysis. Overall, 193 (83.5%) patients received primary G-CSF prophylaxis. The demographics and tumour characteristics were comparable between patients with and without primary G-CSF prophylaxis. Primary G-CSF prophylaxis significantly reduced febrile neutropenia incidence from 31.6% to 14.5% (relative risk=0.45, 95% confidence interval=0.25-0.81). Primary G-CSF prophylaxis also significantly reduced the incidence of grade 3 or 4 neutropenia from 57.9% to 24.7% (relative risk=0.43, 95% confidence interval=0.30-0.62) and the incidence of febrile neutropenia–related hospital admission from 31.6% to 12.4% (P=0.025). Finally, it enabled more patients to receive adequate chemotherapy dose delivery.

Conclusion: Primary G-CSF prophylaxis effectively reduced the incidences of grade 3 or 4 neutropenia and febrile neutropenia, while enabling adequate chemotherapy dose delivery and reducing hospital admissions among Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy.

New knowledge added by this study

Primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with reduced neutropenic toxicity from adjuvant docetaxel plus cyclophosphamide (TC) chemotherapy.
Our 4-day G-CSF schedule helped to maintain the planned chemotherapy regimen and reduce the rate of hospital admission.

Implications for clinical practice or policy

Routine use of primary G-CSF prophylaxis enabled successful chemotherapy treatment and adequate chemotherapy dose delivery for patients with early breast cancer who received adjuvant TC chemotherapy.
Primary G-CSF prophylaxis could reduce hospital admissions for the management of febrile neutropenia; it may reduce in-patient bed occupancy and offset hospitalisation costs.
G-CSF prophylaxis can be extended to patients on all docetaxel-containing regimens of neoadjuvant and adjuvant chemotherapy.

[Abstract in Chinese]

Introduction

Adjuvant chemotherapy significantly improves disease-free survival and overall survival in patients with early breast cancer.1 For intermediate-risk patients who have axillary lymph node-negative early breast cancer,2 a common regimen comprises four cycles of doxorubicin plus cyclophosphamide. In 2009, Jones et al3 published a 7-year follow-up study of patients with stages I-III operable breast cancer in the United States; they reported that superior disease-free survival and overall survival could be achieved with four cycles of docetaxel plus cyclophosphamide (TC), compared with four cycles of doxorubicin plus cyclophosphamide. Since then, TC has been increasingly regarded as an alternative chemotherapy regimen to doxorubicin plus cyclophosphamide for patients with early-stage breast cancer. However, docetaxel causes significant myelotoxicity, characterised by high incidences of grade 3 or 4 neutropenia and febrile neutropenia (FN). Chemotherapy-induced neutropenia is a major type of toxicity that limits the dose of cancer therapy; FN is associated with substantial morbidity, mortality, and financial costs.4 Febrile neutropenia is considered a medical emergency, which often requires immediate hospitalisation and empirical administration of broad-spectrum antibiotics. Severe (grade 3 or 4) neutropenia or FN is the most common cause of dose reductions and/or cycle delays that lead to lower chemotherapy dose intensity; such changes may influence clinical outcomes, particularly when treatment is intended to be curative or to prolong survival.5 6

There is substantial evidence that granulocyte-colony stimulating factor (G-CSF) prophylaxis reduces the incidence of chemotherapy-associated FN in patients with diverse malignancies, including patients with breast cancer who are receiving chemotherapy and have moderately high/high FN risk; this prophylaxis can result in fewer chemotherapy dose reductions or delays.5 7 8 9 Current guidelines consistently recommend G-CSF prophylaxis during chemotherapy treatment for patients with cancer who have a high estimated risk of FN (ie, approximately 20%), as well as patients with cancer who have a history of FN.5 10 11 12 The administration of G-CSF should also be used to facilitate the maintenance of chemotherapy dose intensity for patients in whom reduced chemotherapy dose intensity or density is likely to cause a poor outcome (eg, patients receiving adjuvant or potentially curative treatment, or patients receiving treatment to prolong survival).5 10 12

We began using TC chemotherapy in 2007 at Princess Margaret Hospital, but we encountered a high incidence of FN. Our initial solution comprised dose reduction; after the first episode of FN, doses of chemotherapeutic agents were reduced by 10% to 25% in subsequent cycles. Then, G-CSF prophylaxis was administered if the second episode of FN occurred to avoid further dose reduction and to ensure delivery of planned chemotherapy; it was also intended to prevent the occurrence of further FN. This study was conducted to investigate the effects of primary G-CSF prophylaxis on neutropenic toxicity, chemotherapy delivery, and hospitalisation in patients with breast cancer if G-CSF was administrated from the first cycle of TC chemotherapy.

Methods

Patient selection

This retrospective cohort study was performed at Princess Margaret Hospital, Hong Kong. We reviewed the medical records of female Chinese patients with breast cancer who received adjuvant TC chemotherapy from November 2007 to October 2013. Exclusion criteria were as follows: previous receipt of chemotherapy, mixed TC and doxorubicin plus cyclophosphamide or other chemotherapy regimens; more than four cycles of TC; failure to complete four cycles of chemotherapy; and use of G-CSF after the occurrence of FN. Data were retrieved from the included patients’ out-patient and in-patient records, chemotherapy charts, and discharge summaries.

Tumour characteristics

Tumour staging, histological type, histological grade, lymphovascular invasion, oestrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 (HER2) status, and Ki67 status were extracted from each patient’s pathology report. Oestrogen and/or progesterone receptor statuses were considered positive if either percentage of immunohistochemical staining was ≥1% (ie, an H score of ≥50 or an Allred score of ≥3). The HER2 status was considered positive if the immunohistochemical score was 3, or if fluorescence in situ hybridisation showed HER2 gene amplification if immunohistochemical score was equivocal.

Docetaxel plus cyclophosphamide treatment protocol

Chemotherapy was initiated within 6 to 8 weeks after surgery. The chemotherapeutic regimen consisted of docetaxel 75 mg/m² and cyclophosphamide 600 mg/m² administered by intravenous infusion over 60 minutes and 30 minutes, respectively, on day 1 at 3-week intervals for four cycles; dexamethasone premedication and standard anti-emetic were administered during each cycle. In accordance with standard protocol in the Department of Oncology at Princess Margaret Hospital, patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. At baseline and before each cycle of chemotherapy, complete blood counts were performed, along with tests of renal and hepatic function. To proceed with treatment, patients were required to have a white blood cell count of ≥3 × 10⁹/L, an absolute neutrophil count (ANC) of ≥1.5 × 10⁹/L, and a platelet count of ≥100 × 10⁹/L. For patients with insufficient blood counts, chemotherapy was deferred for ≥1 week until counts reached the required levels. For patients with an elevated alanine transaminase level (ie, ≥1.5-fold above the upper limit of normal), the dose of docetaxel was reduced by 15%, in accordance with prescribing information. Complete blood counts were also checked at nadir (ie, the lowest white blood cell count or ANC recorded within 21 days of the first cycle of chemotherapy, typically on day 10 after chemotherapy) to assess the severity of neutropenia; based on blood count findings, chemotherapy dosage was adjusted (if necessary) in subsequent cycles. The dosage reduction ranged from 10% to 25% according to the occurrence of grade 4 neutropenia or FN in prior cycles. Hepatitis status was checked at baseline. Prophylactic antiviral therapy was administered to patients who had a positive test result for hepatitis B surface antigen.

Granulocyte-colony stimulating factor use

We suggested G-CSF prophylaxis (on a self-financed basis during the study period) to each patient who was scheduled to receive adjuvant TC, unless they had contra-indications mentioned in the prescribing information. The intent of G-CSF prophylaxis was to prevent the occurrence of FN, which would lead to cycle delay and chemotherapy dose reduction. We defined primary G-CSF prophylaxis as upfront use in the first chemotherapy cycle and continuation in subsequent cycles. The administration of G-CSF after an episode of FN during a previous chemotherapy cycle was considered secondary use; patients who received such treatment were excluded from the analysis, as indicated in the Patient selection subsection. Antibiotic treatment was administered to patients who showed grade 3 or 4 neutropenia at nadir.13 Neupogen (filgrastim) 30 MU was the form of G-CSF used during the study period; this treatment was administered subcutaneously from day 4 to day 7 of each chemotherapy cycle.

Febrile neutropenia and other adverse events

Febrile neutropenia was defined as a single reading of oral temperature ≥38.3°C or a sustained (≥1 h) oral temperature of ≥38.0°C, with either an ANC of <0.5 × 10⁹ cells/L or an ANC of <1.0 × 10⁹ cells/L and predicted decrease to <0.5 × 10⁹ cells/L over the next 48 hours.14 Haematological and other non-haematological adverse events were categorised and graded in accordance with the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 3.0); they were expressed as maximum toxicity per patient. Other adverse effects were reported as grade 3 or 4.

Hospital admission for chemotherapy-related toxicities

An admission was regarded as a single hospital admission that occurred between two consecutive chemotherapy cycles; admissions were recorded until 1 month after the final cycle of chemotherapy. If neutropenic fever was diagnosed or suspected, patients were admitted for isolation, sepsis tests, and antibiotic treatment; if patients refused admission, they were prescribed oral antibiotics. If indicated, patients were also admitted for treatment of chemotherapy-related adverse effects. Admissions were categorised according to the primary diagnosis at the time of admission.

Statistical analyses

Descriptive statistics were used to summarise baseline patient and tumour characteristics, chemotherapy delivery, and adverse events. The Chi squared test (or Fisher’s exact test) and Student’s t test (or Mann–Whitney U test) were used for comparisons of categorical and continuous variables, respectively. Multivariate logistic regression models were used to calculate the relative risk and 95% confidence interval for the occurrence of FN with primary G-CSF prophylaxis after adjustment for age.

The total percentage of planned doses received was calculated as the sum of the percentage of planned doses over four cycles divided by the number of cycles of chemotherapy administered. Dose intensity was calculated as the cumulative dose (mg/m²) divided by the total duration of chemotherapy (wk). Planned dose intensity was calculated as the planned cumulative dose (mg/m²) divided by the planned treatment duration (wk). Relative dose intensity was calculated as the ratio of delivered dose intensity to planned dose intensity. Chemotherapy dose delay was defined as a delay of ≥3 days from the planned treatment date. In all statistical analyses, P<0.05 was considered indicative of statistical significance. All data analyses were performed using SPSS software (Windows version 26.0; IBM Corp, Armonk [NY], United States).

Results

Baseline characteristics of patients according to primary granulocyte-colony stimulating factor prophylaxis status

During the initial review, 261 patients were identified and eight of them presented with synchronous bilateral breast cancer. In total, 30 patients were excluded from analysis for the following reasons: previous receipt of chemotherapy (n=2), mixed TC and doxorubicin plus cyclophosphamide or other chemotherapy regimens (eg, epirubicin plus cyclophosphamide, or cyclophosphamide plus methotrexate plus 5-fluorouracil) [n=14], or more than four cycles of TC (n=6); failure to complete four cycles of chemotherapy (n=3; 1 died of pneumonia, 1 discontinued chemotherapy after one cycle because of advanced age, and 1 discontinued chemotherapy after three cycles for unspecified reasons); and use of G-CSF after the occurrence of FN (n=5). Finally, 231 female Chinese patients with breast cancer were included in this study; 193 patients (83.5%) received primary G-CSF prophylaxis (Table 1). Age at diagnosis, body weight and height, body mass index, and menopausal and co-morbidity statuses were comparable between patients with and without primary G-CSF prophylaxis. The distributions of tumour stages, histological subtypes, histological grades, and molecular biomarker statuses were also similar between the two groups.

Table 1. Characteristics of patients with breast cancer, stratified according to primary granulocyte-colony stimulating factor prophylaxis status

Development of febrile neutropenia and other chemotherapy-related toxicities

In total, 106 patients (45.9%) had ≥1 episode of neutropenia; 69 patients (65.1%) developed grade 3 or 4 neutropenia (Table 2). Among patients with neutropenia, the incidences of FN were 40.0% (12/30) in the non-G-CSF group and 36.8% (28/76) in the G-CSF group. Compared with patients who did not receive G-CSF prophylaxis, primary G-CSF prophylaxis was associated with a lower incidence of FN (31.6% vs 14.5%) and a lower incidence of grade 3 or 4 neutropenia (57.9% vs 24.7%) [Table 2]; the relative risks were 0.45 (95% confidence interval=0.25-0.81) and 0.43 (95% confidence interval=0.30-0.62), respectively. However, G-CSF prophylaxis was not associated with reduced incidences of non-neutropenic fever and infection. The incidences of grade 3 or 4 chemotherapy-related toxicities other than neutropenia were very low among our patients. Only four episodes of grade 3 or 4 chemotherapy-related adverse events were observed (one episode of anaemia, one episode of non-neutropenic leukopenia, and two episodes of diarrhoea).

Table 2. Incidences of chemotherapy-related toxicities during docetaxel plus cyclophosphamide chemotherapy in patients with breast cancer, stratified according to primary granulocyte-colony stimulating factor prophylaxis status

Delivery of chemotherapy

Primary G-CSF prophylaxis helped to maintain the planned regimen of TC chemotherapy (Table 3). When compared with the non-G-CSF group, the proportion of patients who received the standard dose of TC was higher among patients in the G-CSF group (63.2% vs 74.6%); moreover, the proportion of patients with an overall dose deduction of >10% for docetaxel or cyclophosphamide was lower among patients in the G-CSF group (18.4% vs 14.0% and 13.2% vs 7.3%, respectively), although the difference was not statistically significant. However, compared with the non-G-CSF group, more patients in the G-CSF group experienced chemotherapy cycle delays (26.3% vs 56.5%). There were no significant differences in dose intensity or relative dose intensity for both docetaxel and cyclophosphamide between the G-CSF and non-G-CSF group (online supplementary Table 1).

Table 3. Delivery of docetaxel plus cyclophosphamide chemotherapy to patients with breast cancer, stratified according to primary granulocyte-colony stimulating factor prophylaxis status

Rate of hospital admission

Sixty patients had ≥1 hospital admission for a severe chemotherapy-related adverse event; 36 of these patients (60%) were diagnosed with FN. Compared with the non-G-CSF group, the hospital admission rate was lower in the primary G-CSF prophylaxis group, particularly in terms of admission for FN (31.6% vs 12.4%) [Table 4].

Table 4. Hospital admissions among patients with breast cancer, stratified according to primary granulocyte-colony stimulating factor prophylaxis status

Discussion

Primary granulocyte-colony stimulating factor prophylaxis reduced febrile neutropenia and severe neutropenia

To our knowledge, this is the first study to demonstrate an association between the use of a fixed schedule of G-CSF prophylaxis (days 4 to 7) and the reduction of neutropenia and FN incidences in patients with early-stage breast cancer who received adjuvant TC chemotherapy. Our study demonstrated that patients who received primary G-CSF prophylaxis were significantly more likely to maintain their planned regimen of chemotherapy and have a lower rate of hospital admission. These findings suggest that G-CSF prophylaxis can enhance treatment efficacy and conserve medical resources.

Chinese patients on docetaxel-based chemotherapy had higher incidences of neutropenia/febrile neutropenia

Our results are consistent with previous reports that the FN rate was higher among patients receiving TC chemotherapy in the absence of G-CSF.3 15 16 17 Rates of myelosuppression and neutropenia during docetaxel-based chemotherapy were higher in our Chinese patients compared with those in Caucasian patients in previous studies.18 19 20 In the original TC study, incidence of FN was only 5%.3 Inter-individual and inter-ethnic variations in pharmacokinetics and pharmacodynamics may be linked to variations in docetaxel toxicity.21 22 23

Four-day course of granulocyte-colony stimulating factor prophylaxis was effective

With regard to the schedule of G-CSF prophylaxis, international guidelines recommend initiation between 24 and 72 hours after the last day of chemotherapy, with continuation until sufficient and stable ANC recovery has been achieved after nadir.5 10 11 The optimal clinical benefits of filgrastim have been achieved with approximately 11 daily injections; ANC recovery typically requires 10 to 11 days.5 Therefore, the median recommended duration of daily filgrastim injections is 10 to 11 days.5 11 Nevertheless, the chemotherapy schedule varies in clinical practice.5 24 25 In a previous study, von Minckwitz et al8 found that daily G-CSF was most frequently administered at five to seven doses per cycle. We initiated G-CSF on day 4 in accordance with the recommendation (mentioned above) that G-CSF should be initiated between 24 and 72 hours after chemotherapy. According to the docetaxel prescribing information, a median of 7 days is needed to reach nadir; the median duration to reach severe neutropenia (<500 cells/mL) is also 7 days. Based on our previous experience concerning nadir, we examined complete blood counts from day 7 to day 11; we observed that the duration of neutrophil nadir for docetaxel was short and the ANC rapidly rebounded after day 10. Because the median neutrophil nadir of docetaxel typically occurs on day 7, the administration of G-CSF until day 7 would constitute the shortest duration of G-CSF injection; the increased neutrophil count as a result of G-CSF injection (due to the effect of G-CSF) would presumably have a protective effect during the expected neutrophil nadir period.

In this study, FN occurred after the first cycle in 28 of 193 (14.5%) patients who received primary G-CSF prophylaxis; all of those patients received G-CSF on days 4 to 7. It is important to consider whether this finding suggests that our G-CSF schedule was insufficient for FN prevention. Notably, there have been reports that the initial episode of neutropenia most frequently occurred during the first cycle in patients receiving cancer chemotherapy.6 25 26 The lower apparent risk after the first cycle presumably results from subsequent dose reductions and delays, or from the secondary use of a white blood cell growth factor.6 27 The high frequency of first-cycle FN has been proposed to emphasise the need for early (during the first cycle) initiation of G-CSF to reduce the risk of FN. A longer duration of G-CSF prophylaxis may further reduce the incidence of first-cycle FN, but this hypothesis requires further investigation.

Granulocyte-colony stimulating factor prophylaxis enabled adequate chemotherapy dose delivery

We found that primary G-CSF prophylaxis influenced the incidences of FN and FN-related hospitalisation and also enabled adequate chemotherapy dose delivery. Our findings were similar to the results reported by von Minckwitz et al8; however, their study involved a comparison of primary prophylaxis with long-acting pegfilgrastim to either no G-CSF treatment or any cycle of G-CSF/pegfilgrastim. In the group of patients who received G-CSF, the longer duration of chemotherapy might have offset the effect of the higher total percentage of scheduled chemotherapy doses on dose intensity and relative dose intensity. These findings were analogous to the findings in a Cochrane review, which showed CSF treatment did not help much in maintaining the planned chemotherapy schedules.9 Additionally, von Minckwitz et al8 reported that neutropenia prophylaxis influenced chemotherapy dose reductions (≥15%) but did not affect the incidence of chemotherapy dose delays (≥3 days). Similarly, in a study that evaluated the effect of pegfilgrastim during the first and subsequent cycles versus placebo, the proportion of patients who received their planned dose on time (defined as receiving ≥80% of the planned dose and no dose ≥3 days late) did not significantly differ between the two groups. The authors of the study concluded that no difference had been present because patients who developed FN were allowed to receive pegfilgrastim in subsequent cycles, which (because of study design) prevented the identification of a difference between the pegfilgrastim and placebo groups.26

Although the reduction of FN incidence is an important clinical outcome, G-CSF prophylaxis might facilitate the maintenance of chemotherapy dose intensity7; G-CSF has also been used as an adjunct to achieve moderate increases in dose intensity. Early clinical trials of patients with solid malignancies demonstrated a limited survival benefit for patients who received higher dose therapy.28 In clinical studies, dose-dense schedules (ie, with shortened treatment intervals) have shown increased survival, whereas the benefit in dose escalation studies has been less consistent.6 Notably, a meta-analysis showed that the receipt of primary G-CSF prophylaxis was associated with a modest reduction in all-cause mortality, compared with the absence of primary prophylaxis.29 Recently published meta-analyses confirm the survival benefit of dose-dense chemotherapy.29 30 These provide supporting evidence that ensuring chemotherapy dose intensity is an important consideration for treatment outcome which is particularly relevant in adjuvant chemotherapy settings. Further studies are awaited to assess the effects of chemotherapy dose delivery on survival outcomes in our patients with early breast cancer.

Our results showed that G-CSF prophylaxis reduced the rate of hospital admission for FN. Conventional management of FN involves hospital admission with intravenous administration of broad-spectrum antibiotics for 5 to 7 days. The mean length of hospitalisation for FN may exceed 1 week; patients must be placed in isolation rooms to undergo numerous diagnostic procedures and receive intravenous antibiotic support, and there is a need to consider the potential complications of such therapy (American Society of Clinical Oncology guideline 1994, 2000).31 The benefit of reducing the rate of hospital admission is that it can reduce demands on the resources of a public healthcare system with a limited number of in-patient beds. Additionally, the reduced rate of hospital admission can help to minimise disruption for patients and their families, thereby avoiding negative impacts on quality of life.

Study implications

The patients in this study received treatment from November 2007 to October 2013. Among the patients, 14.7% had luminal A–like breast cancer subtypes according to histopathological criteria (online supplementary Table 2); thus far, patients with such breast cancer subtypes have experienced minimal benefits from chemotherapy. With the increasing use of gene expression profiling as a personalised medicine approach for adjuvant chemotherapy in patients with hormone receptor–positive, HER2-negative breast cancers, the use of adjuvant chemotherapy has become increasingly selective for such patients; nevertheless, it remains important for patients with HER2-positive and triple-negative breast cancers. The TC regimen is an important type of adjuvant chemotherapy; it is recommended within the National Comprehensive Cancer Network guidelines. Because it is an anthracycline-free regimen, TC chemotherapy has been compared with anthracycline-containing regimens in some large, randomised trials; it has demonstrated excellent results.32 33 The TC regimen is considered an efficacious and less-toxic option in lower-risk patients, as well as patients with known cardiac disease or pre-existing risk factors for cardiac toxicity.32 33 Routine G-CSF prophylaxis has made adjuvant TC chemotherapy safer and more successful. Currently, the 4-day G-CSF schedule is widely used for patients in our hospital who receive other docetaxel-containing regimens, such as TCH (ie, trastuzumab, carboplatin, and docetaxel) and docetaxel 100 mg/m² regimens; the outcomes are generally positive.

Study limitations

First, this study used a retrospective cohort design and only included patients from a single centre. Thus, the overall sample size was moderate and the non-G-CSF group included a small number of patients. Moreover, because this was an observational study without randomisation, the number of patients who received G-CSF prophylaxis substantially differed from the number of patients who did not receive such prophylaxis. Our results require confirm in multicentre studies with diverse patient populations. Second, indication bias might have been present, such that patients who received G-CSF might constitute a distinct group, compared with patients who did not receive G-CSF. We suggested the use of primary G-CSF prophylaxis to each patient who was scheduled to receive adjuvant TC chemotherapy; most patients accepted this suggestion (193/231). Among 43 patients who did not receive G-CSF treatment at the first cycle of chemotherapy, only five received secondary administration of G-CSF, which indicated that cost was the main factor influencing receipt of primary G-CSF prophylaxis. Nevertheless, we used multivariate logistic regression models to adjust for potential confounding factors (eg, baseline differences between the two groups). Third, incomplete documentation of adverse effects might have influenced our findings because only significant adverse effects were recorded for most study participants. Febrile neutropenia and hospital admission were the major clinical outcomes recorded in medical records; therefore, medication-related adverse effects might have been neglected. Finally, because only short-term toxicity (ie, neutropenic toxicity) was examined in this study, the long-term effects of chemotherapy (eg, neurotoxicity) and G-CSF prophylaxis on quality of life should be addressed in future studies.

Conclusion

Our study demonstrated that the use of 4-day primary G-CSF prophylaxis can reduce neutropenic toxicity from adjuvant TC chemotherapy; it enables successful chemotherapy treatment and facilitates adequate chemotherapy dose delivery. Further studies are needed to assess the effects of primary G-CSF prophylaxis and chemotherapy dose delivery on survival outcomes in patients with breast cancer.

Author contributions

Concept or design: CCH Kwok, F Wang, SLA Tse.
Acquisition of data: CCH Kwok, SPY Wong.
Analysis or interpretation of data: WH Wong, CCH Kwok, SLA Tse, F Wang, LL Chan.
Drafting of the manuscript: CCH Kwok.
Critical revision of the manuscript for important intellectual content: CCH Kwok, F Wang, SLA Tse, MCS Wong.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

As the Editor-in-Chief and adviser of the journal, respectively, MCS Wong and SLA Tse were not involved in the peer review process. Other authors have disclosed no conflicts of interest.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

This study was approved by the Hong Kong Hospital Authority Kowloon West Cluster Research Ethics Committee (Ref: KW/EX-12-068 [53-03]). The requirement for informed consent was waived.

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31. Ozer H, Armitage JO, Bennett CL, et al. 2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 2000;18:3558-85. Crossref

32. Nitz U, Gluz O, Clemens M, et al. West German Study PlanB Trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol 2019;37:799-808. Crossref

33. Caparica R, Bruzzone M, Poggio F, Ceppi M, de Azambuja E, Lambertini M. Anthracycline and taxane-based chemotherapy versus docetaxel and cyclophosphamide in the adjuvant treatment of HER2-negative breast cancer patients: a systematic review and meta-analysis of randomized controlled trials. Breast Cancer Res Treat 2019;174:27-37. Crossref

Neonatal mortality in singleton pregnancies: a 20-year retrospective study from a tertiary perinatal unit in Hong Kong

Hong Kong Med J 2022;28(6):430-7 | Epub 29 Nov 2022

https://doi.org/10.12809/hkmj2210357

ORIGINAL ARTICLE

Neonatal mortality in singleton pregnancies: a 20-year retrospective study from a tertiary perinatal unit in Hong Kong

Genevieve PG Fung, MB BChir, MRCPCH¹; SL Lau, MB, ChB, MRCOG²; Annie SY Hui, MB, ChB, MRCOG²; Sani TK Wong, MB, ChB²; WT Tse, MB, ChB, MRCOG²; PC Ng, MD, FRCPCH¹; DS Sahota, PhD²; HS Lam, MD, FRCPCH¹; TY Leung, MD, FRCOG²

¹ Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong

² Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong

Corresponding author: Prof TY Leung (tyleung@cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: The global neonatal death (NND) rate has been declining in recent decades, but there are no comprehensive data concerning the characteristics of NNDs in Hong Kong. This study investigated the trends and aetiologies of NNDs among singleton pregnancies in Hong Kong.

Methods: This study included all cases of NND from singleton pregnancies in a tertiary hospital in Hong Kong between 2000 and 2019. The rates, clinical characteristics, and aetiologies of NND were compared between the first (2000-2009) and the second (2010-2019) decades.

Results: The NND rate decreased from 1.66/1000 livebirths (97 cases) in the first decade to 1.32/1000 livebirths (87 cases) in the second decade. Congenital or genetic abnormalities (82 cases) caused 44.6% of all NNDs. There was a significant reduction from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade (P=0.037). Other causes of NND were prematurity (69 cases; 37.5%), sepsis (16 cases; 8.7%), hypoxic-ischaemic encephalopathy (15 cases; 8.2%), and sudden infant death syndrome (2 cases; 1.1%). Gestational age-specific neonatal mortality for moderately preterm neonates (31-33 weeks of gestation) significantly decreased from 34.73/1000 in 2000-2009 to 8.63/1000 in 2010-2019 (P=0.001), but there were no significant changes in neonatal mortality for other gestations.

Conclusions: The NND rate in Hong Kong is among the lowest worldwide. Neonatal deaths in our centre declined over the past two decades, mainly because of improvements in the prenatal diagnosis and treatment of congenital or genetic abnormalities, as well as an improved survival rate among moderately preterm neonates.

New knowledge added by this study

The rate of neonatal mortality among singleton pregnancies in Hong Kong decreased from 1.66/1000 livebirths in 2000-2009 to 1.32/1000 livebirths in 2010-2019.
The decline in the neonatal mortality rate mainly resulted from improvements in the prenatal diagnosis and treatment of congenital or genetic abnormalities, as well as an improved survival rate among moderately preterm neonates (31-33 weeks of gestation).

Implications for clinical practice or policy

Future improvements in the neonatal mortality rate should focus on in utero treatment, expanded carrier screening of genetic abnormalities, and the prevention of preterm birth and pre-eclampsia.

[Abstract in Chinese]

Introduction

Perinatal and neonatal mortality rates are important measures of the quality of medical care during pregnancy, childbirth, and the neonatal period. Although the global neonatal death (NND) rate has demonstrated a decreasing trend over the past 30 years, from 37/1000 livebirths to 17/1000 livebirths between 1990 and 2020,1 NND rates considerably vary among regions. According to the 2020 report by the World Health Organization, the NND rates were the highest in Africa (27/1000 livebirths), Eastern Mediterranean (25/1000 livebirths) and South-East Asia (18/1000 livebirths); the NND rates were the lowest in Americas (7/1000 livebirths), Western Pacific (5/1000 livebirths) and Europe (4/1000 livebirths).1 In Hong Kong, territory-wide statistics indicated NND rates of 1.2/1000 and 1.0/1000 livebirths in 2004 and 2014, respectively2; these rates are lower than the rates in most regions, according to the above report by the World Health Organization. However, there have been few in-depth studies concerning the trends and underlying causes of NND in Hong Kong. Our group recently published two epidemiological studies regarding singleton pregnancies in Hong Kong, which revealed a decreasing trend in the rate of stillbirths among singleton pregnancies from 3.61/1000 in 2000-2009 to 3.09/1000 in 2010-2019.3 The rate of perinatal mortality in multiple pregnancies also decreased from 5.52/1000 to 4.59/1000 during the same period.4 These improvements in mortality rates have mainly occurred because of advances in the prenatal diagnosis and management of fetal malformations and genetic diseases, as well as improvements in the antenatal management of multiple pregnancies. The present study investigated the trends of NNDs among singleton pregnancies in the largest tertiary perinatal centre in Hong Kong, as well as changes in the characteristics and aetiologies of NND over the past two decades, with the goal of improving perinatal care in Hong Kong.

Methods

Study setting

This retrospective study included all singleton pregnancies that delivered at the Prince of Wales Hospital from 1 January 2000 to 31 December 2019. The STROBE reporting guideline was followed when writing this manuscript. The Prince of Wales Hospital is affiliated with The Chinese University of Hong Kong and serves a large population of 1.7 million in the New Territories East region of Hong Kong; the hospital’s annual delivery rate is 6000 to 7000 (approximately one-sixth of the total births in all public hospitals in Hong Kong, and one-ninth of the total births in Hong Kong). Both the obstetric unit and the neonatal unit are the largest in Hong Kong. The neonatal unit is a Level III centre that consists of a 22-bed neonatal intensive care unit (NICU). The staff of the neonatal unit worked closely with the staff of the obstetric unit to manage high-risk deliveries from complicated pregnancies, as well as pregnancies that required fetal intervention after referral from other hospitals.

Perinatal and neonatal management

Complicated pregnancies were discussed in weekly perinatal meetings attended by the staff of both the obstetric unit and the neonatal unit; discussions of these pregnancies focused on management plans and the optimal timing of delivery. Relevant disciplines (eg, paediatric surgery, cardiology, neurosurgery, radiology, or otolaryngology) were included as appropriate. In cases where a specialist service outside of Prince of Wales Hospital (eg, cardiothoracic surgery) was anticipated after delivery, specialists from other centres were invited to participate in management planning. Active resuscitation was provided for all viable neonates delivered at ≥24 weeks. For extremely premature neonates with borderline viability (ie, delivered at 22-23 weeks of gestation), considering the high risks of mortality and long-term morbidity, comprehensive counselling was provided to affected families, which allowed them to select active resuscitation or no resuscitation at birth. In accordance with the departmental protocol, the paediatric unit was requested to prepare for rapid management of deliveries that involved specific maternal or fetal conditions (eg, prematurity, fetal distress, instrumental deliveries, and antenatally diagnosed severe congenital abnormalities). Neonates were managed in the NICU in accordance with the standard unit protocols and guidelines. These protocols were updated regularly according to the latest evidence-based consensus guidelines and recommendations established by clinicians in Hong Kong and other nations. In accordance with departmental guidelines, comprehensive investigations were performed to determine the cause of death in all cases of NND. All NNDs were referred for autopsy unless the cause of death was clearly identified (eg, trisomy 13 or 18 confirmed by genetic tests). If the cause of NND could not be identified, the case was reported to the coroner. If NND was caused by multiple pathologies, the most clinically significant pathology that contributed to death was selected for analysis.

Data collection and analysis

All cases of NND in livebirths of singleton pregnancies during the study period were retrieved using the Hospital Authority’s Clinical Data Analysis and Reporting System. Cases of NND in livebirths of multiple pregnancies were excluded. The included cases of NND were divided into two groups according to the decade of birth. The first group (ie, first decade) included cases of NND among singleton pregnancies that delivered between 1 January 2000 and 31 December 2009. The second group (ie, second decade) included cases of NND among singleton pregnancies that delivered between 1 January 2010 and 31 December 2019. Obstetric data including maternal demographics (maternal age, maternal illnesses, antenatal complications, and treatment) and birth history (gestation, mode of delivery, sex, birth weight, Apgar scores, and neonatal resuscitation) were collected from the Obstetric Specialty Clinical Information System. Neonatal data comprising neonatal diagnoses, interventions, and length of survival were retrieved from the Hospital Authority’s Clinical Management System. When further details were needed, individual case records were retrieved for analysis.

All NNDs were categorised as early NND (within 7 days after birth) or late NND (within 8-28 days after birth). Early, late, and total rates of NND, as well as baseline demographics, were compared between the two groups. Causes of death were divided into four main categories: prematurity, hypoxic-ischaemic encephalopathy (HIE), congenital abnormalities, and sepsis. Congenital abnormalities were defined by characteristic features on physical examination, confirmed by either genetic tests, diagnostic investigations, or autopsy. Sepsis was defined on the basis of positive cultures established using samples of blood, urine, cerebrospinal fluid, or tissue from the affected neonate. Hypoxic-ischaemic encephalopathy was diagnosed in accordance with criteria derived from international guidelines.5

Statistical analysis

The analysis was performed using data that overlapped with a previous study.3 Categorical variables were compared by the Chi squared test or Fisher’s exact test. The threshold of statistical significance was defined as a two-sided P value of <0.05. Data analysis was performed with the SPSS software (Windows version 22.0; IBM Corp, Armonk [NY], United States).

Results

Overall and gestational age-specific neonatal mortality

There were 124 281 livebirths from singleton pregnancies between 2000 and 2019 (Table 1). The number of livebirths increased by 12.7% from 58 442 in the first decade (2000-2009) to 65 839 in the second decade (2010-2019). There were 184 NNDs (1.48/1000 livebirths) between 2000 and 2019, including 97 in the first decade (1.66/1000 livebirths) and 87 in the second decade (1.32/1000 livebirths). Overall, there were 136 cases (73.9%) of early NND and 48 cases (26.1%) of late NND.

Table 1. Neonatal mortality in singleton pregnancies during 2000-2009 and 2010-2019

The maternal demographic characteristics of all singleton pregnancies during the study period were reported in our previous paper.3 The distribution of gestational age among all livebirths did not differ between the two decades (P=0.237) [Table 2]. The highest rate of NND (195.12/1000 livebirths) was observed in extremely preterm neonates (≤27 weeks of gestation) [Table 3]. The rate of NND decreased with increasing gestational age, such that NND rates were 48.42/1000, 20.13/1000, 4.98/1000, and 0.37/1000 for neonates delivered at gestational ages of 28-30 weeks, 31-33 weeks, 34-36 weeks, and ≥37 weeks, respectively. Compared with the first decade, there was a significant reduction (75.2%) in the rate of NND among neonates delivered at 31-33 weeks of gestation during the second decade (34.73/1000 vs 8.63/1000; P=0.001); however, there were no significant differences in the rates of NND among neonates in other gestational groups.

Table 2. Distribution of gestational age among all livebirths (including neonatal deaths) at time of delivery during 2000-2009 and 2010-2019

Table 3. Gestational age-specific neonatal mortality† during 2000-2009 and 2010-2019

Causes of neonatal death

The primary causes of NND in the two decades are shown in Table 4. Congenital or genetic abnormalities was the most common cause of NND (82 of 184; 44.6%) during the 20-year study period. Other common causes of NND were prematurity (69 cases; 37.5%), sepsis (16 cases; 8.7%), and HIE (15 cases; 8.2%) [Supplementary Fig].

Table 4. Causes of neonatal death in singleton pregnancies during 2000-2009 and 2010-2019

Chromosomal abnormalities caused 18.3% (15 of 82) of NNDs related to congenital or genetic abnormalities; all of these abnormalities were trisomy 13 or 18. Structural abnormalities caused 63.4% (52 of 82) of NNDs related to congenital or genetic abnormalities, and respiratory system abnormalities were the most common causes in both decades (22 cases). These respiratory system abnormalities included congenital diaphragmatic hernia (13 cases), pulmonary hypoplasia (5 cases), alveolar capillary dysplasia (2 cases), and tracheal stenosis or atresia (2 cases). The next most common causes were congenital cardiac abnormalities (8 cases), including transposition of the great arteries (2 cases), total anomalous pulmonary venous drainage (2 cases), endocardial cushion defect (2 cases), hypoplastic left heart syndrome (1 case), and congenital heart block (1 case); central nervous system abnormalities (8 cases), including anencephaly (3 cases), central nervous system malformation (4 cases), and brain tumour (1 case); and musculoskeletal abnormalities (7 cases), including fetal akinesia syndrome with arthrogryposis (3 cases), spinal muscular atrophy (2 cases), and skeletal dysplasia (2 cases). There were two cases of gastrointestinal abnormalities (volvulus and bowel atresia with meconium peritonitis), two cases of sacrococcygeal teratoma, two cases of multiple abnormalities, and one case of bilateral renal agenesis (a urogenital abnormality). There were also nine cases of haemoglobin Barts disease and six cases of idiopathic hydrops. There was a statistically significant decline in the rate of NND caused by congenital or genetic abnormalities, from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade (P=0.037).

There were no significant differences in the rates of NND caused by prematurity, sepsis, or HIE between the two decades. Cases of NND due to sepsis were mainly caused by Group B Streptococcus in the first decade and Escherichia coli in the second decade. The majority of HIE cases (67.7%) were related to acute intrapartum events, including placenta abruption (5 cases), uterine rupture (2 cases), vasa praevia (1 case), cord accident (1 case), and chorioamnionitis (1 case).

Discussion

The NND rate in our tertiary centre is consistent with the rate of 1.2/1000 livebirths in the territory-wide report2 and lower than the rates in many developed countries (eg, the United States, Australia, and nations located in Europe; neonatal mortality rates of 2-3/1000 livebirths).1 2 The global NND rate has been decreasing over the past two decades because of advances in perinatal care.2 Our overall NND rate decreased by 20%, from 1.66/1000 in the first decade to 1.32/1000 in the second decade. This decrease is mainly the result of a decrease in NNDs related to congenital or genetic disorders, as well as a decrease in NNDs among neonates delivered at 31-33 weeks of gestation.

Neonatal death due to congenital abnormalities

Similar to our previous report, which showed a reduction in the rate of congenital or genetic abnormality-related stillbirths,3 the present study showed that the rate of congenital or genetic abnormality-related NNDs decreased from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade. This decline was presumably because of improvements in antenatal screening and the early detection of lethal congenital abnormalities, which resulted in termination of pregnancy before 24 weeks of gestation. Universal first trimester combined screening for Down syndrome was implemented by the Hospital Authority in 2010.6 In 2011, non-invasive cell-free fetal DNA tests for common trisomies, as well as chromosomal microarrays for the diagnosis of chromosomal microdeletion syndromes, became available in the private sector.7 8 Expanded antenatal screening of inborn errors of metabolism was launched in the private sector in 2013; this expanded screening has gradually become available in the public sector since 2018.9 Although we expected a decline in the rate of trisomy-related NNDs after universal aneuploidy screening became available in 2011, there was an increase in the rate of trisomy 18–related NNDs (from 2 cases to 7 cases). A review of the individual cases revealed that the rate of trisomy 13–related NNDs decreased from six cases in the first decade to none in the second decade. Conversely, five of the seven cases of trisomy 18–related NND in the second decade were in pregnancies that had not received any screening; all of these five cases occurred during the period from 2010 to 2013. The other two cases of trisomy 18–related NND were diagnosed during prenatal screening, but the parents chose conservative management rather than termination of pregnancy. To further reduce mortality associated with hereditary genetic disorders such as spinal muscular atrophy and fetal akinesia syndrome (which caused NND in 5 cases), there is a need for expanded carrier screening of parents, particularly in families with a history of consanguineous marriage.10 11

The other main congenital abnormalities that caused NND in our cohort were cardiorespiratory and neuromusculoskeletal disorders, among which congenital diaphragmatic hernia was the most common. Although survival was common among neonates with mild to moderate congenital diaphragmatic hernia, neonates with severe congenital diaphragmatic hernia had a survival rate of 10% to 20% because of pulmonary hypoplasia. A recent large randomised controlled trial showed that fetoscopic endoluminal tracheal occlusion can improve the survival rate to 40% to 50%.12 In our unit, a baby survived after treatment with fetoscopic endoluminal tracheal occlusion in 2020.13 Pulmonary hypoplasia caused by hydrothorax or lung tumours can also be effectively and safely treated before birth with newly designed instruments such as the Somatex^® shunt for pleuro-amniotic shunting, and radiofrequency ablation of the tumour feeding artery, respectively.14 15 Fetal tumours such as sacrococcygeal teratoma, placental chorioangioma, and lung tumours remain challenging to manage because the rapid growth of tumours in utero increases the risk of preterm birth and leads to impaired neonatal cardiac function. We have demonstrated improvements in survival after in utero embolisation of chorioangioma using cyanoacrylate, and after in utero radiofrequency ablation of lung sequestration.15 16 Although spinal muscular atrophy has no cure, it can be prevented by accurate parental carrier screening using genomic technology and prenatal diagnosis.10

Neonatal death due to hydrops fetalis

The rate of idiopathic hydrops fetalis–related NND decreased from 5.2% in the first decade to 1.1% in the second decade. Advances in antenatal diagnostic techniques in recent years have identified the underlying causes of many conditions which may have previously been regarded as ‘idiopathic hydrops fetalis’.17 The early diagnosis of treatable conditions in the antenatal period can prevent the development of severe hydrops fetalis and subsequent NND.17 18 Intrauterine blood transfusion for fetal anaemia and anti-arrhythmic treatment19 has significantly reduced the rate of hydrops fetalis, resulting in improved survival and long-term outcomes.

Neonatal death due to prematurity

Our study showed a significant (75.2%) decrease in the rate of NND among moderately preterm neonates (31-33 weeks of gestation) from 34.73/1000 in 2000-2009 to 8.63/1000 in 2010-2019; however, the rate of NND did not change in other gestational groups (Table 3). The decrease in mortality among moderately preterm neonates could be attributed to the implementation of multiple approaches for the management of such neonates since 2010, including improved ventilation strategies with early extubation to non-invasive ventilation, new methods for surfactant administration (eg, the ‘less invasive surfactant administration’ method), and improvements in NICU care through continuous quality improvement programmes. The rate of NND among extremely preterm neonates (24-27 weeks of gestation) was 175-211/1000, which is comparable with the rates in other developed countries (139-326/1000).20 It is difficult to reduce the rate of NND among extremely preterm neonates. Research is ongoing regarding artificial placenta and womb technology, and the results may improve the survival of extremely preterm neonates in the future.21

The rate of prematurity-related NND can be reduced by preventing preterm delivery; however, this prevention remains a challenging goal. Although our overall preterm delivery rate of 7% is lower than the rates in other developed countries,1 22 it has remained at this level for the past two decades, and there has been no variations in gestation age-specific neonatal mortality among preterm categories. In a previous study, we demonstrated that measurements of cervical length can help to identify pregnant women who are at higher risk of preterm delivery, although the risk prediction values for Chinese women in Hong Kong are lower than the corresponding values for women in non-Asian countries.23 Additional methods to predict the onset of labour (eg, cervical elastography, immune markers, and genetic markers) should be explored to improve accuracy.24 25 Prophylactic progesterone is effective in reducing the risk of preterm delivery among women who have a short cervix.26 Although the use of a cervical ring pessary reportedly had a similar effect in a Spanish study,27 this result was not confirmed by a randomised controlled trial in Hong Kong28 or by subsequent meta-analysis.29 Pre-eclampsia is a common complication that requires medically induced preterm delivery. First trimester screening of pre-eclampsia, followed by prophylactic aspirin treatment in high-risk cases, is a proven strategy to effectively delay the onset of pre-eclampsia and the associated preterm births.29 Our recent study confirmed the accuracy of a screening programme for pre-eclampsia.30 Reductions in pre-eclampsia–related preterm births and mortality may be achieved by the implementation of a universal screening programme in the future.

Neonatal death due to hypoxic ischaemic encephalopathy

Despite advances in NICU management of HIE and the use of therapeutic hypothermia since 2011, the rate of HIE-related NND did not improve during the study period. Approximately 67% of HIE-related NNDs were caused by acute and unpredictable perinatal events such as cord prolapse, uterine rupture, vasa praevia, or placental abruption. We previously reported an infant death secondary to severe cerebral palsy as a result of prolonged shoulder dystocia, which occurred during the first study decade.31 Therefore, team-based training for the above perinatal events is needed to ensure that the obstetric team can respond appropriately and efficiently so that the risk of HIE and associated perinatal mortality can be reduced. During these situations that involved irreversible peripartum hypoxia, we showed that umbilical cord arterial pH decreased as the length of the bradycardia-to-delivery interval increased.31 32 33 With appropriate training, we were able to achieve a median bradycardia-to-delivery interval of 10 minutes and a median decision-to-delivery interval of 11 minutes,32 which was effective in preventing peripartum mortality. Furthermore, we showed that during umbilical cord prolapse, the knee-chest position is the most effective approach for relieving fetal compression of the prolapsed cord34; we also formulated an algorithm for acute resolution of cord prolapse.35 Shoulder dystocia is associated with macrosomia, but the optimal fetal weight cut-off for prophylactic elective caesarean delivery has not been established. Our previous study suggested a cut-off of 4.2 kg may help to prevent shoulder dystocia.36 With effective training and correct use of manoeuvres such as posterior arm delivery, we recently showed that the head-to-delivery interval can be shortened and the Apgar scores can be improved.37 38 We also proposed a modified posterior axillary sling technique to relieve severe shoulder dystocia.39

Neonatal death due to sepsis

The rate of severe sepsis-related NND is low and has been decreasing over the past two decades. Since the implementation of universal Group B Streptococcus screening and peripartum antibiotic prophylaxis in 2012, the rate of early onset Group B Streptococcus infection has significantly decreased from 1/1000 to 0.24/1000 births.40 Despite the reduced risk of neonatal Group B Streptococcus infection, recent reports have shown an increase in Escherichia coli–related early-onset neonatal sepsis.41 Clinicians should remain vigilant concerning the presence of chorioamnionitis and risk factors for sepsis.

To our knowledge, this is the largest and most comprehensive analysis of neonatal mortality during a 20-year period in Hong Kong. Nevertheless, there were a few limitations in this study. First, it was performed in a single large centre, rather than in a large segment of the population. Because the Prince of Wales Hospital is the main centre for fetal intervention in Hong Kong, many high-risk pregnancies are referred from adjacent hospitals, which may have led to an over-representation of complex cases and a bias towards worse outcomes. Second, some case details were not available for analysis because of the retrospective nature of the study. Third, our study excluded cases of NND among neonates with borderline viability (gestational age: 22-23 weeks and 6 days) because such NNDs are regarded as miscarriages based on the legal definition in Hong Kong. Although some parents of neonates with borderline viability requested resuscitation, the survival rate in this small group was zero according to a recent study in our centre.42 Finally, because the rate of NND is very low in Hong Kong, this study could have been strengthened by including data regarding the rates of major morbidities (eg, cerebral palsy). Nonetheless, our findings provide a basis for future territory-wide reviews of perinatal outcomes.

Conclusion

Hong Kong has one of the lowest rates of NND worldwide. The neonatal mortality in our centre has decreased from 1.66/1000 livebirths to 1.32/1000 livebirths over the past two decades, mainly because of improvements in the prenatal diagnosis and treatment of congenital or genetic abnormalities, as well as an improved survival rate among moderately preterm neonates. Future improvements should focus on in utero treatment, expanded carrier screening for genetic abnormalities, and the prevention of preterm birth and pre-eclampsia.

Author contributions

Concept or design: GPG Fung, TY Leung.
Acquisition of data: All authors.
Analysis or interpretation of data: GPG Fung, TY Leung.
Drafting of the manuscript: GPG Fung, TY Leung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

Ethical approval was obtained from the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref No.: CRE 2017.442).

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28. Hui SY, Chor CM, Lau TK, Lao TT, Leung TY. Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial. Am J Perinatol 2013;30:283-8. Crossref

29. Conde-Agudelo A, Romero R, Nicolaides KH. Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta-analysis. Am J Obstet Gynecol 2020;223:42-65.e2. Crossref

30. Chaemsaithong P, Pooh RK, Zheng M, et al. Prospective evaluation of screening performance of first trimester prediction models for preterm preeclampsia in Asian population. Am J Obstet Gynecol 2019;221:650.e1-16. Crossref

31. Leung TY, Stuart O, Sahota DS, Suen SS, Lau TK, Lao TT. Head-to-body delivery interval and risk of fetal acidosis and hypoxic ischaemic encephalopathy in shoulder dystocia: a retrospective review. BJOG 2011;118:474-9. Crossref

32. Leung TY, Chung PW, Rogers MS, Sahota DS, Lao TT, Chung TK. Urgent cesarean delivery for fetal bradycardia. Obstet Gynecol 2009;114:1023-8. Crossref

33. Wong L, Tse WT, Lai CY et al. Bradycardia-to-delivery interval and fetal outcomes in umbilical cord prolapse. Acta Obstet Gynecol Scand 2021;100:170-7. Crossref

34. Kwan AH, Chaemsaithong P, Wong L, et al. Transperineal ultrasound assessment of fetal head elevation by maneuvers used for managing umbilical cord prolapse. Ultrasound Obstet Gynecol 2021;58:603-8. Crossref

35. Wong L, Kwan AH, Lau SL, Sin WT, Leung TY. Umbilical cord prolapse: revisiting its definition and management. Am J Obstet Gynecol 2021;225:357-66. Crossref

36. Cheng YK, Lao TT, Sahota DS, Leung VK, Leung TY. Use of birth weight threshold for macrosomia to identify fetuses at risk of shoulder dystocia among Chinese populations. Int J Gynaecol Obstet 2013;120:249-53. Crossref

37. Chan EH, Lau SL, Leung TY. Changes in the incidence and management of shoulder dystocia over 20 years from a tertiary obstetric unit in Hong Kong. Hong Kong Med J. In press.

38. Leung TY, Stuart O, Suen SS, Sahota DS, Lau TK, Lao TT. Comparison of perinatal outcomes of shoulder dystocia alleviated by different type and sequence of manoeuvres: a retrospective review. BJOG 2011;118:985-90. Crossref

39. Kwan AH, Hui AS, Lee JH, Leung TY. Intrauterine fetal death followed by shoulder dystocia and birth by modified posterior axillary sling method: a case report. BMC Pregnancy Childbirth 2021;21:672. Crossref

40. Ma TW, Chan V, So CH, et al. Prevention of early onset group B streptococcal disease by universal antenatal culture-based screening in all public hospitals in Hong Kong. J Matern Fetal Neonatal Med 2018;31:881-7. Crossref

41. Stoll BJ, Puopolo KM, Hansen NI, et al. Early-onset neonatal sepsis 2015 to 2017, the rise of Escherichia coli, and the need for novel prevention strategies. JAMA Pediatr 2020;174:e200593. Crossref

42. Hon KL, Liu S, Chow JC, et al. Mortality and morbidity of extremely low birth weight infants in Hong Kong, 2010-2017: a single-centre review. Hong Kong Med J 2018;24:460-5. Crossref

THIRD bedside ultrasound protocol for rapid diagnosis of undifferentiated shock: a prospective observational study

Hong Kong Med J 2022 Oct;28(5):383-91 | Epub 29 Sep 2022

https://doi.org/10.12809/hkmj219648

ORIGINAL ARTICLE (HEALTHCARE IN MAINLAND CHINA)

THIRD bedside ultrasound protocol for rapid diagnosis of undifferentiated shock: a prospective observational study

P Geng, MD^{1 #}; B Ling, MM^{1 #}; Y Yang, MM¹; Joseph Harold Walline, MD²; Y Song, MM¹; M Lu, MD¹; H Wang, MM¹; Q Zhu, MM¹; D Tan, MD¹; J Xu, MD³

¹ Department of Emergency Medicine, Clinical Medical College of Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou, China

² Accident and Emergency Medicine Academic Unit, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong

³ Department of Emergency Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

^# The first two authors contributed equally to this work

Corresponding author: Dr D Tan (tandingyu1981@163.com)

Full paper in PDF

Abstract

Introduction: It is clinically challenging to differentiate the pathophysiological types of shock in emergency situations. Here, we evaluated the ability of a novel bedside ultrasound protocol (Tamponade/tension pneumothorax, Heart, Inferior vena cava, Respiratory system, Deep venous thrombosis/aorta dissection [THIRD]) to predict types of shock in the emergency department.

Methods: An emergency physician performed the THIRD protocol on all patients with shock who were admitted to the emergency department. All patients were closely followed to determine their final clinical diagnoses. The kappa index, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the initial diagnostic impression provided by the THIRD protocol, compared with each patient’s final diagnosis.

Results: In total, 112 patients were enrolled in this study. The kappa index between initial impression and final diagnosis was 0.81 (95% confidence interval=0.73-0.89; P<0.001). For hypovolaemic, cardiogenic, distributive, and obstructive types of shock, the sensitivities of the THIRD protocol were 100%, 100%, 93%, and 100%, respectively; the sensitivity for a ‘mixed’ shock aetiology was 86%. The negative predictive value of the THIRD protocol for all five types of shock was ≥96%.

Conclusion: Initial diagnostic judgements determined using the THIRD protocol showed favourable agreement with the final diagnosis in patients who presented with undifferentiated shock. The THIRD protocol has great potential for use as a bedside approach that can guide the rapid management of undifferentiated shock in emergency settings, particularly for patients with obstructive, hypovolaemic, or cardiogenic shock.

New knowledge added by this study

Differentiating shock types in emergency situations is clinically challenging. We sought to assess the ability of a novel bedside ultrasound protocol (Tamponade/tension pneumothorax, Heart, Inferior vena cava, Respiratory system, Deep venous thrombosis/aorta dissection [THIRD]) in predicting shock aetiology. Shock aetiology determined using the THIRD protocol showed acceptable agreement with the final diagnosis of shock in critically ill emergency department patients.
The THIRD protocol demonstrated very high negative predictive values when it was used to evaluate patients with hypovolaemic, cardiogenic, distributive, and obstructive shock.
The THIRD protocol showed least sensitivity for evaluation of mixed aetiology shock.

Implications for clinical practice or policy

Our findings support incorporation of the THIRD protocol into routine emergency department assessment of patients with undifferentiated shock to help guide early treatment.
Additional clinical assessments should be conducted to confirm a diagnosis of mixed shock made using the THIRD protocol.

[Abstract in Chinese]

Introduction

Undifferentiated shock is a common presenting condition in the emergency department (ED) which requires timely and effective interventions. The rapid and accurate differentiation of possible shock aetiologies is essential for reducing morbidity and mortality in critically ill patients with shock.1 Patients with undifferentiated shock in the ED often have an acute onset of severe illness, unstable vital signs, a limited medical history, and sparse physical examination findings.2 Point-of-care ultrasound (POCUS) has a crucial role in the management of undifferentiated shock because it is the only visual imaging tool that can provide real-time information concerning the key elements of haemodynamics.3 4 The use of POCUS in the ED has been rapidly increasing because it is safe, reliable, non-invasive, rapid, and repeatable at the bedside.5

The first ultrasound protocol for undifferentiated shock was published in 20046; since then, several additional protocols have been developed. The results of multiple studies have provided evidence that POCUS can help to differentiate the cause of hypotension, identify the most immediate life-threatening conditions, improve diagnostic certainty, and optimise treatment.7 8 The ‘Tamponade/tension pneumothorax, Heart, Inferior vena cava, Respiratory system, Deep venous thrombosis/aorta dissection’ (THIRD) bedside ultrasound protocol was published in 2017; it is the first POCUS protocol for undifferentiated shock in emergency medicine in mainland China.9 Compared with the ‘Rapid Ultrasound for Shock and Hypotension’ (RUSH) protocol, the THIRD protocol has been reported to significantly increase physician trainee self-confidence when diagnosing undifferentiated shock.10

The THIRD protocol is now widely accepted and regularly used by emergency physicians in China; to our knowledge, the protocol has not been validated in any studies thus far. This study was conducted to examine the effectiveness and accuracy of the THIRD protocol as an early and rapid bedside approach for the investigation of undifferentiated shock in emergency settings. We hypothesised that THIRD early diagnostic predictions would not demonstrate significant inconsistency with the final clinical diagnosis.

Methods

Enrolment

This single-centre prospective observational study enrolled patients with shock who presented to the emergency intensive care unit (EICU) section of the ED at a large, urban, tertiary teaching hospital between October 2017 and May 2019. The ED of the hospital has approximately 240 000 visits per year, and >800 patients annually are admitted to the 15-bed EICU for extended management. Shock was defined as acute circulatory failure which led to inadequate cellular oxygen utilisation.11 We established the enrolment criteria for this study based on clinical feasibility and previous literature12 13: (1) age >18 years and <95 years; (2) systolic blood pressure <90 mmHg or shock index (pulse/systolic blood pressure) >1.0, confirmed after ≥3 measurements during the first assessment; and (3) at least one of the following symptoms or signs of hypoperfusion: altered mental status (eg, syncope, delirium, or unresponsiveness), respiratory distress, oliguria, severe fatigue or discomfort, skin mottling, elevated blood lactate, and severe chest pain or abdominal pain. Patients with the following conditions were excluded from the study: (1) a pre-existing ‘hypotensive’ state recorded in past medical history or reported by the patient; (2) transfer from another hospital with a known diagnosis of shock type; and (3) no definite diagnosis of shock established during hospitalisation, despite plenary discussion of their clinical data.

Point-of-care ultrasound technique

The POCUS is routinely performed in all hemodynamically unstable patients in our EICU. In this study, an independent emergency physician with specific competence in emergency ultrasound performed the THIRD protocol evaluation upon patient arrival (Fig 1). The physician had completed a 20-hour emergency ultrasound workshop including the THIRD protocol and had 3 years of experience with >300 ultrasound examinations per year. The physician was unaware of the history of present illness or any other diagnostic test results; the pathophysiological diagnosis of shock was made based on ultrasound findings (Table 1). Ultrasound evaluation was performed with a Philips^® Sparq ultrasound device routinely used in the EICU. This ultrasound system contains a high-frequency 4-12 MHz linear probe, a 2-6 MHz curvilinear probe, and a 2-4 MHz cardiac probe.

Figure 1. THIRD protocol for bedside ultrasound evaluation of undifferentiated shock

Table 1. THIRD protocol: possible ultrasound findings in shock

The THIRD protocol is divided into the following five parts.

Tamponade or tension pneumothorax: First, the subcostal cardiac view is used to determine the presence of any pericardial effusion; then, evidence of right atrial or right ventricular diastolic collapse or cardiac oscillation is assessed to identify signs of pericardial tamponade-related shock. Second, the bilateral anterior thorax in the mid-clavicular lines is explored to identify pleural sliding, the ‘seashore’ sign, A lines, and B lines. If the above signs are not found and a ‘stratosphere’ sign or lung point is identified, tension pneumothorax–related obstructive shock is suspected.

Heart: The SMART (Size, Motivation, Aorta, Rhythm/rate, Tricuspid regurgitation) procedure is used to assess the heart size, shape, and wall motion; aortic diameter; presence of an aortic intimal flap; cardiac rhythm and rate; and presence of tricuspid regurgitation on the parasternal long-axis, parasternal short-axis, and apical four-chamber views. These assessments help to clarify the cause and type of shock with respect to cardiac function (Table 2).

Table 2. SMART procedure for focused cardiac ultrasound assessment

Inferior vena cava: The subcostal longitudinal acoustic window is used to localise the inferior vena cava. The diameter and respiratory variation rate of the inferior vena cava are measured to estimate central venous pressure, assess right heart function and overall blood volume, and evaluate indirect evidence of shock caused by hypovolaemia, right heart failure, pulmonary embolism, or pulmonary hypertension.

Respiratory system: Lung ultrasound assessment is performed using a symmetrical three-point technique to identify common lung ultrasound signs (eg, pleural fluid, pleural sliding, A lines, B lines, shred sign, and lung rockets). These signs are indicators of shock caused by lung consolidation, massive pleural effusion/haemorrhage, or other aetiologies such as pulmonary oedema.

Deep venous thrombosis or aortic dissection: The acoustic windows of the bilateral symmetrical inguinal areas and popliteal fossae are used to detect and assess the compressibility of the femoral veins and popliteal veins; these assessments facilitate the identification of deep vein thromboses. Because pulmonary emboli are commonly associated with deep venous thrombosis from the lower extremities, this ultrasound technique is an indirect test for shock caused by pulmonary emboli. Scans of the abdominal aorta in horizontal sections of the peritoneal trunk, superior mesenteric artery, and renal artery are then conducted to determine whether aortic dissection or aneurysm is present.

Clinical evaluation and final diagnosis

Upon admission to the EICU, the following information was recorded for all enrolled patients: demographic data, co-morbidities, APACHE II (acute physiology and chronic health evaluation II) score, need for mechanical ventilation, and physiological data (eg, mean arterial pressure, shock index, lactate level, and central venous oxygen saturation). All patients were closely followed to confirm their final diagnosis of shock. A panel of three board-certified physicians (D Tan, emergency physician; J Ye, radiologist; and J Zhang, cardiologist) established the diagnosis of shock type based on all relevant clinical data including history of present illness, signs, auxiliary examination results. Disagreements concerning diagnosis were resolved using a majority vote approach. Patients were excluded if their diagnosis could not be agreed upon by at least two physicians.

Statistical analysis

Statistical analysis was performed using SPSS (Windows version 21; IBM Corp., Armonk [NY], United States). Sample size calculations were performed prior to enrolment; to detect a protocol accuracy of >90% using the kappa method and considering an anticipated 10% rate of exclusion or dropout,14 at least 100 patients were required. Thus, we planned a sample size of >110 patients in this study. We calculated the kappa index between the diagnosis of shock type according to the THIRD protocol and the final diagnosis of shock. Additionally, we separately assessed the kappa agreement and reliability indices (sensitivity, specificity, positive predictive value [PPV] and negative predictive value [NPV])of the THIRD protocol for each type of shock. For this analysis, we excluded patients without a definite final diagnosis of shock type.

Results

Patient characteristics and final clinical diagnoses

In total, 120 patients were enrolled; eight patients were excluded prior to the analysis (two patients had a history of hypotension in their previous medical records, three patients were transferred from another hospital with a known diagnosis of shock type, and three patients did not have a definite final diagnosis of shock type) [Fig 2]. In the final sample size of 112 patients, 54% were men, with a mean age of 66.5 ± 13.5 years and a mean arterial pressure of 51.2 ± 10.9 mmHg at presentation to the EICU. The mean duration of a complete THIRD protocol evaluation was 9.1 ± 1.5 minutes. The baseline characteristics of enrolled patients are shown in Table 3. The final charted clinical diagnoses of the 112 patients are reported in Table 4.

Figure 2. Patient enrolment flowchart

Table 3. Baseline characteristics of enrolled patients (n=112)

Table 4. Final charted clinical diagnoses of 112 patients with symptomatic undifferentiated shock at presentation

The final clinical diagnoses of the 112 patients, based on chart assessment by the three auditors and the THIRD protocol evaluation results, are shown in Table 5. The most common type of shock in our study was distributive shock (36 patients, 32.1%). The kappa index for general agreement between final clinical diagnosis and the type of shock identified using the THIRD protocol was 0.81 (95% confidence interval=0.73-0.89; P<0.001) for all patients. Table 6 shows the kappa index, sensitivity, specificity, PPV, and NPV of the THIRD protocol for determining each type of shock among patients with definite final diagnoses.

Table 5. Prevalences of types of shock based on final clinical diagnosis and THIRD protocol evaluation

Table 6. Reliability indices and kappa agreement values of the THIRD protocol for each individual shock subtype

Hypovolaemic shock

Using the THIRD protocol, 32 patients had a diagnosis of hypovolaemic shock. The causes of hypovolaemic shock were traumatic bleeding (n=23), sepsis (n=2), acute gastrointestinal bleeding (n=3), cachexia (n=1), and pancreatitis (n=1). The remaining two patients included in the 32 patients were misdiagnosed with hypovolaemic shock based on their ultrasound findings, but the final clinical diagnoses were mixed shock (n=1) and distributive shock secondary to sepsis (n=1) [97.3% specificity and 95% PPV].

Cardiogenic shock

Using the THIRD protocol, 21 patients had a diagnosis of cardiogenic shock. Of them, 19 patients had a final clinical diagnosis of cardiogenic shock due to decompensated heart failure (n=8), acute myocardial infarction (n=7), and intoxication (n=4). The final clinical diagnosis for the remaining two patients was mixed aetiology shock (97.83% specificity and 90.9% PPV). The agreement between ultrasound findings and the final diagnosis was 92% (P<0.001) for cardiogenic shock.

Distributive shock

Using the THIRD protocol, 33 patients were diagnosed with distributive shock. Of them, 30 patients had a final clinical diagnosis of sepsis (concurrent pneumonia [n=26], concurrent cholangitis [n=2], concurrent urinary tract infections [n=2]) and three patients had a final clinical diagnosis of neurogenic aetiologies. Three other patients had a final clinical diagnosis of distributive shock, who were initially misdiagnosed using the THIRD protocol with hypovolaemic (n=1) and mixed aetiology shock (n=2). The agreement between ultrasound findings and the final diagnosis was 89% (P<0.001) for distributive shock.

Obstructive shock

Using the THIRD protocol, five patients were diagnosed with obstructive shock, and all five of them had a final clinical diagnosis of obstructive shock (cardiac tamponade [n=3], large, acute pulmonary embolism [n=2]). The agreement between ultrasound findings and the final diagnosis was 100% (P<0.001) for obstructive shock.

Mixed aetiology shock

Using the THIRD protocol, 21 patients were diagnosed with mixed aetiology shock. Of them, 19 had a final clinical diagnosis of mixed aetiology shock (sensitivity of 90.4%). The remaining two patients were misdiagnosed with mixed aetiology shock; the final clinical diagnosis was distributive shock (n=2). Three other patients had a final clinical diagnosis of mixed aetiology shock, who were initially misdiagnosed using the THIRD protocol with hypovolaemic (n=1) or cardiogenic shock (n=2). The THIRD protocol had the lowest agreement (82%, P<0.001) with the final diagnosis for mixed aetiology shock.

Discussion

In this prospective study, the primary diagnosis after implementation of the THIRD protocol in patients with undifferentiated shock was highly concordant with the final clinical diagnosis. The protocol was highly effective in guiding the rapid bedside management of undifferentiated shock in emergency settings, particularly for patients with obstructive, hypovolaemic, or cardiogenic shock.

Point-of-care ultrasound is the only tool available at the bedside that can rapidly reveal acute pathophysiology and establish key diagnoses to guide targeted interventions.15 As in other disciplines, POCUS has been commonly used in emergency medicine; it is an essential skill for emergency physicians. In mainland China, bedside ultrasound has been used in EDs since 2006, mainly for guidance during vascular puncture procedures and for the assessment of free intraperitoneal fluid.16 After a decade of rapid development, nearly half of EDs in China have dedicated bedside ultrasound equipment.17 The applications of POCUS have gradually expanded to undifferentiated hypotension, shortness of breath, chest pain, sepsis, and cardiac arrest, as well as other clinical manifestations.

To our knowledge, the THIRD protocol is the first ultrasound protocol for assessment of undifferentiated shock in mainland China, and this is the first study to validate the effectiveness and accuracy of the protocol. This study demonstrated favourable general agreement between the final clinical diagnosis of shock and the results of this early bedside ultrasound assessment (kappa=0.81). Similar to the RUSH protocol,13 the highest agreements were observed in patients with hypovolaemic, cardiogenic, and obstructive shock (kappa values of 0.92, 0.92, and 1.00, respectively). The NPVs for these shock types were all 100%, suggesting that the THIRD protocol can reliably exclude these types of shock. Clinically significant hypovolaemia, cardiac dysfunction, cardiac tamponade, pulmonary embolism, and tension pneumothorax are readily identifiable on ultrasound; the corresponding signs facilitate rapid diagnosis and ensure minimal delays in life-saving interventions for these conditions.4 18

The sensitivity, NPV, and kappa values of the THIRD protocol were lower for distributive or mixed shock than for the other three types of shock. Sepsis was the main cause of distributed shock in our study; high cardiac output with reduced vascular resistance is the main pathophysiological feature of this type of shock.19 A plausible explanation for this pathophysiological feature is that a hyperdynamic heart is not specific to distributive shock, and a decrease in vascular resistance lacks specific ultrasound signs. Our protocol had the least sensitivity and agreement for mixed aetiology shock. Considering this increased uncertainty, caution is advised when making a diagnosis of a ‘mixed’ type of shock.

Since its initial use in 2001 by Rose et al,20 POCUS has been increasingly used in the management of patients with undifferentiated shock in the ED. Furthermore, >15 ultrasound protocols for hypotension have been developed since 2001.7 These protocols consist of items such as echocardiography, transthoracic scanning, evaluation of the inferior vena cava and aorta, assessment of free fluid in the abdominal cavity, and detection of deep vein thrombosis. The overall goal of these protocols is to provide a comprehensive and practical approach for the classification of clinical syndromes that involve circulatory failure—syndromes which lack specificity and may have substantially different possible treatments—into four specific and manageable types of shock.

The RUSH protocol is one of the most frequently used POCUS protocols for undifferentiated shock.21 Multiple studies have shown that the kappa index of the RUSH protocol–based ultrasound diagnosis and the final clinical diagnosis is approximately 0.7.13 14 22 The RUSH protocol is used to find ultrasound abnormalities in three major aspects of a patient’s physiology, including ‘pump, tank, and pipe’.23 Unlike the RUSH protocol or other existing POCUS shock protocols (eg, ACES,24 UHP,20 or FATE25), each letter of the THIRD protocol represents a specific ultrasound assessment. The THIRD protocol is easy for clinicians to remember and can be used as a practical checklist for ultrasound examination during the management of patients with shock. This might explain why trainees had greater confidence and performance when using the THIRD protocol than when using the RUSH protocol in a training curriculum.10

There were some limitations in this study. First, we did not exclude certain patients, such as patients with traumatic injuries or gastrointestinal bleeding. However, trauma and gastrointestinal bleeding are common among patients who present to our ED, and the inclusion of these patients ensures that our shock assessment is consistent with real-world emergency settings. Second, we did not compare the THIRD protocol with other protocols, such as the RUSH protocol; thus, we cannot conclusively state whether the THIRD and RUSH protocols are equally effective. Third, we did not assess the impact of the THIRD protocol on subsequent treatment. In a previous study, 24.6% of patients had a statistically signiﬁcant change in their management after a POCUS protocol examination.12

In conclusion, this study demonstrated that the initial diagnostic judgements obtained using the THIRD protocol in the ED are consistent with the final diagnosis in patients who present with undifferentiated shock. The findings in this study encourage the incorporation of the THIRD protocol into routine ED assessment of patients with undifferentiated shock to help guide early interventions. The impact of the THIRD protocol on the outcomes of patients with shock, as well as comparisons of the effectiveness and accuracy of the THIRD protocol with other POCUS protocols, should be the focus of future studies.

Author contributions

Concept or design: P Geng, B Ling, J Xu, D Tan.
Acquisition of data: B Ling, Y Song, H Wang, Q Zhu, Y Yang, M Lu.
Analysis or interpretation of data: Y Song, H Wang, Q Zhu, Y Yang, M Lu.
Drafting of the manuscript: B Ling, JH Walline, D Tan, P Geng.
Critical revision of the manuscript for important intellectual content: D Tan, JH Walline, J Xu, P Geng.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

The authors declare that they have no competing interests.

Acknowledgement

We are grateful to J Ye and J Zhang for their contributions to establish the diagnosis of shock type in this study.

Funding/support

This work was supported by the Rui E Special Fund for Emergency Medicine Research (R2017003), the Yangzhou Science and Technology Development Plan (YZ2018090), the Yangzhou Phase III ‘Talent Cultivation Program’ Support Project (2018034), the Hospital-Level Support Project of Northern Jiangsu People’s Hospital (yzucms2018943), and the Hospital-Level Support Project of Northern Jiangsu People’s Hospital (fcjs201708, fcjs201842).

Ethics approval

This study protocol was approved by the Institutional Ethics Committee of Northern Jiangsu People’s Hospital (Ref: fcjs2017008). Written informed consent was obtained from all patients (or next of kin, if the patient was unable to provide informed consent). The study was registered in the Chinese Clinical Trial Registry (Ref: ChiCTR2000031072).

References

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18. Bernier-Jean A, Albert M, Shiloh AL, Eisen LA, Williamson D, Beaulieu Y. The diagnostic and therapeutic impact of point-of-care ultrasonography in the intensive care unit. J Intensive Care Med 2017;32:197-203. Crossref

19. Russell JA. Vasopressor therapy in critically ill patients with shock. Intensive Care Med 2019;45:1503-17. Crossref

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Vaginal delivery of second twins: factors predictive of failure and adverse perinatal outcomes

Hong Kong Med J 2022 Oct;28(5):376-82 | Epub 13 Sep 2022

https://doi.org/10.12809/hkmj198038

ORIGINAL ARTICLE

Vaginal delivery of second twins: factors predictive of failure and adverse perinatal outcomes

SL Mok, MB, BS, FHKAM (Obstetrics and Gynaecology); TK Lo, MB, BS, FHKAM (Obstetrics and Gynaecology)

Department Obstetrics and Gynaecology, Princess Margaret Hospital, Hong Kong

Corresponding author: Dr SL Mok (juliaslmok@yahoo.com.hk)

Full paper in PDF

Abstract

Introduction: This study was performed to explore factors associated with adverse perinatal outcomes for second twins and to identify predictive factors for successful vaginal delivery of the second twin after vaginal delivery of the first twin.

Methods: This 10-year retrospective study included 231 cases of twin pregnancies in which vaginal delivery of the second twin was attempted after vaginal delivery of the first twin. The relationships of obstetric characteristics with the composite adverse perinatal outcome of the second twin were analysed. Predictive factors for successful vaginal delivery of the second twin were also explored.

Results: Gestational age <32 weeks was the only independent risk factor for the composite adverse perinatal outcome and neonatal intensive care unit admission for the second twin. A longer inter-twin delivery interval was associated with greater risk of caesarean delivery of the second twin, but it did not increase the risk of an adverse perinatal outcome. Non-vertex presentation of the second twin at delivery was independently associated with caesarean delivery (9.0% vs 2.0%, P=0.03). For second twins in breech presentation, caesarean delivery was associated with the presence of less experienced birth attendants.

Conclusion: Among second twins born to mothers who had attempted vaginal delivery, adverse perinatal outcomes were mainly related to prematurity. The presence of more experienced birth attendants may contribute to successful vaginal delivery of the second twin, particularly for twins in non-vertex presentation.

New knowledge added by this study

Among second twins born to mothers who had attempted vaginal delivery, adverse perinatal outcomes were mainly related to prematurity, rather than actual mode of delivery.
An inter-twin delivery interval of >30 minutes alone did not increase the risk of an adverse perinatal outcome, although it increased the risk of caesarean delivery of the second twin.
For second twins in breech presentation, caesarean delivery was independently associated with a longer intertwin delivery interval (>30 minutes) and the presence of less experienced birth attendants.

Implications for clinical practice or policy

Our findings support vaginal delivery of the second twin when the first twin is delivered in cephalic presentation.
If monitoring of the second twin is possible and the findings are reassuring, obstetricians may consider a conservative approach, even 30 minutes after delivery of the first twin; emergency caesarean delivery should be readily available if necessary.

[Abstract in Chinese]

Introduction

Selection of the mode of delivery in a twin pregnancy is always challenging for obstetricians, although vaginal delivery is theoretically feasible for diamniotic twins if the first twin is in cephalic presentation.1 In the past 15 years, two cohort studies2 3 and a multicentre randomised trial4 concluded that when the first twin was in cephalic presentation, planned caesarean delivery did not significantly decrease or increase the risk of fetal/neonatal death or serious neonatal morbidity, compared with planned vaginal delivery. These findings suggest that vaginal delivery of twins is a safe and reasonable mode of delivery. However, attempts to deliver vaginally are not always successful, and the intrapartum risks of adverse outcomes for second twins should be carefully considered.

In a study of factors that were predictive of successful vaginal delivery, Easter et al5 found that the vaginal delivery rates of second twins in non-vertex presentation were comparable with the vaginal delivery rates of second twins in vertex presentation. Successful vaginal delivery was associated with higher parity. In the subgroup of second twins in non-vertex presentation, successful vaginal delivery was associated with the presence of more experienced birth attendants. The rates of neonatal morbidity and mortality were low in both groups, and they did not differ between groups. However, that study only included twins with gestational ages of ≥32 weeks.

In a study that examined caesarean delivery of the second twin after successful vaginal delivery of the first twin, Breathnach et al6 found that the most common indication for caesarean delivery of the second twin was malpresentation (transverse/shoulder/brow) or compound presentation. Second twins who were delivered by emergency caesarean section after vaginal delivery of the first twin had a perinatal morbidity rate of 29%, but there were only 14 such twins; thus, the sample size was insufficient for robust statistical analysis.

There is a need for additional information concerning factors predictive of successful vaginal delivery of the second twin, which will allow better case selection and avoid combined vaginal-caesarean delivery (ie, failed vaginal delivery of the second twin). To our knowledge, there have been few studies of these factors in Asian populations. Here, we examined the medical records of second twins born to mothers who had attempted vaginal delivery of twins in Hong Kong; we sought to identify factors that could affect the perinatal outcomes and predict failure of vaginal delivery in a predominantly Asian population. We also included deliveries of preterm gestations (23-32 weeks), which were not extensively investigated in previous studies.

Methods

This retrospective study focused on twin pregnancies that were delivered between 1 January 2006 and 31 December 2015 in Princess Margaret Hospital, a regional public hospital in Kowloon, Hong Kong. Inclusion criteria were vaginal delivery of the first twin at gestational viability or beyond. Exclusion criteria were miscarriage (delivery before gestational viability) or delivery of the first twin by elective or emergency caesarean section. Under Hong Kong law, 24 full weeks of gestation is generally regarded as the threshold of gestational viability. In exceptional cases, the threshold may be reduced to 23 weeks if, after full discussion with the obstetric and neonatal care teams, the parents demonstrate a strong preference for earlier initiation of active neonatal management.

Eligible cases were identified from the Obstetric Clinical Information System (OBSCIS); for each case, the mother’s demographic and clinical data were retrieved. The OBSCIS is a territory-wide electronic database that contains the prenatal, intrapartum, and postpartum information of all mothers who receive care in public hospitals in Hong Kong. Clinical information in the system is updated in a timely manner by each patient’s midwives and physicians before the patient is discharged from the hospital. Data entry integrity is continuously monitored by a dedicated information technology team within the Hospital Authority, and each obstetrics unit is asked to provide missing data promptly. Each infant’s clinical information was retrieved from the Electronic Patient Record, a comprehensive system that contains all health information (except obstetric records) of patients from birth to death and is shared by all public hospitals and out-patient clinics under the Hong Kong Hospital Authority.

The following maternal data were retrieved: age, parity, gestational age at delivery, chorionicity, and mode of delivery of the second twin. The following infant data were retrieved: birth weight, Apgar score, cord blood pH, delivery time, inter-twin delivery interval, presentation at delivery, and neonatal intensive care unit (NICU) admission status.

The primary outcome of the study was a composite adverse perinatal outcome that included any of the following: Apgar score <6 at 5 minutes after birth, cord blood pH <7, NICU admission, birth trauma, and presence of neonatal complications. For infants with a hospital stay of >28 days, complications until hospital discharge were included. The following complications were considered: respiratory morbidity, intracranial haemorrhage, hypoxic ischaemic encephalopathy, sepsis, metabolic disturbance, birth defects, and neonatal death. The secondary outcome was mode of delivery. Gestational age was established by the patient’s last menstrual period and verified by ultrasound in the first or early second trimester. Chorionicity was established by prenatal ultrasound and confirmed by placental histology after delivery. The likelihood of vaginal delivery may be adversely impacted by considerably larger second twin size, compared with the first twin. Breathnach et al6 found that the rate of caesarean section was higher if the first twin had ≥20% lower weight than the second twin. Therefore, clinically significant weight discordance was regarded as ≥20% in the present study, where weight discordance was defined as the weight difference between the second and first twin divided by the weight of first twin.

Vaginal deliveries of twins were managed in accordance with our labour ward protocol, which does not regard estimated fetal weight discordance as a contra-indication to vaginal delivery. All deliveries were attended by two physicians (as described below) and assisted by ≥2 midwives. Specialist supervision was recommended. In this context, a specialist is an obstetrician who has completed ≥6 years of postgraduate residency training and received accreditation as a Fellow of the Hong Kong College of Obstetricians and Gynaecologists (FHKCOG). Membership in the Royal College of Obstetricians and Gynaecologists (MRCOG) is a prerequisite for FHKCOG accreditation. When a specialist was unavailable (particularly at night), deliveries were conducted or supervised by an MRCOG-qualified physician. Paediatricians were present for all deliveries of second twins. Prenatal steroids (either betamethasone or dexamethasone depending on pharmacy availability and initial treatment at the referral unit) were administered in cases of delivery before 34 weeks of gestation. If necessary, oral nifedipine was used as a first-line tocolytic. Intravenous salbutamol was used as a second-line tocolytic until 2012; since 2013, atosiban has been used as a second-line tocolytic.

Statistical analysis was carried out using SPSS software (Windows version 17.0; SPSS Inc., Chicago [IL], United States). Categorical data were analysed by the Chi squared test or Fisher’s exact test, as appropriate. Among the factors that showed statistical significance in univariate analysis, binary logistic regression was used to identify factors that were independently predictive of vaginal delivery and adverse perinatal outcomes. P values <0.05 were considered statistically significant.

Results

During the 10-year study period, 47 595 deliveries were performed in Princess Margaret Hospital; 718 twin pairs were delivered. Among these twin pairs, 182 and 305 were delivered by elective and emergency caesarean section, respectively; they were excluded from the study. In the remaining 231 cases, the mothers delivered the first twin vaginally and intended to deliver the second twin vaginally. The second twins in this group of patients were included for analysis.

Table 1 shows the demographic and obstetric characteristics of the 231 cases, stratified according to the mode of delivery of the second twin. Emergency caesarean delivery was required in 10 cases (4.3%). Among the three second twins in vertex presentation, two were delivered by caesarean section because of second twin retention; the remaining twin was delivered by caesarean section because of fetal distress. Among the seven second twins in non-vertex presentation, the indications for caesarean delivery were second twin retention (two cases), fetal distress (four cases), and transverse lie (one case). Of the factors shown in Table 1, only an inter-twin delivery interval of >30 minutes and non-vertex presentation of the second twin at delivery were associated with the mode of delivery of the second twin. Logistic regression analysis showed that an inter-twin delivery interval of >30 minutes (odds ratio [OR]=26.952, 95% confidence interval [CI]=5.924-122.619) and non-vertex presentation of the second twin at delivery (OR=5.003, 95% CI=1.101-22.743) were independently associated with caesarean delivery of the second twin.

Table 1. Demographic and obstetric characteristics of 231 cases of twin pregnancies in which vaginal delivery of the second twin was attempted after vaginal delivery of the first twin

In subgroup analyses, we examined the relationships of the demographic and obstetric factors in Table 1 to determine their relationships with the mode of delivery for second twins in breech presentation. Univariate analysis revealed that only an inter-twin delivery interval >30 minutes and the presence of less experienced birth attendants were significantly associated with the mode of delivery. Logistic regression showed that an inter-twin delivery interval >30 minutes (OR=36.492, 95% CI=3.035-438.712) and the presence of less experienced birth attendants (OR=10.252, 95% CI=1.001-104.956) were independently associated with caesarean delivery of second twins in breech presentation.

Perinatal outcomes of second twins are shown in Table 2. Univariate analysis revealed that the composite adverse perinatal outcome was only associated with gestational age <32 weeks (P<0.001; OR=12.1, 95% CI=2.738-53.481) [Table 3]. Similarly, gestational age <32 weeks was the only factor significantly associated with NICU admission (P<0.001; OR=6.420, 95% CI=2.073-19.878) [Table 4].

Table 2. Outcomes of second twins (n=231)

Table 3. Factors associated with the composite adverse perinatal outcome of the second twin

Table 4. Subgroup analysis of risk factors for neonatal intensive care unit admission

Among the 47 cases with delivery before 34 weeks of gestation, 27 completed steroid treatment before delivery. In 17 cases, delivery occurred before the completion of steroid treatment because of rapid labour that did not respond to tocolytics. Steroid treatment was not administered in three cases; two of these cases involved delivery before 24 weeks of gestation, which is the threshold for beginning steroid treatment in our hospital. In the third case, the mother was admitted in advanced labour. Completion or non-completion of steroid treatment was not associated with the composite adverse perinatal outcome (25/27 vs 18/20, P=0.753).

Discussion

To our knowledge, this is the first study in Hong Kong concerning the short-term composite adverse perinatal outcomes of second twins in cases where vaginal delivery was attempted. Our approach enabled simultaneous consideration of multiple outcome parameters. The inclusion of additional clinical information until hospital discharge for infants with prolonged hospital stay (>28 days) allowed a more comprehensive assessment of outcomes. Notably, cases of gestation <32 weeks were included; there are minimal published data for this group of infants because they have been excluded from many large trials. Additionally, we examined the effects of birth attendant experience and birth timing.

Perinatal outcomes

Prior to this study, there were two analyses of twin deliveries in a predominantly Asia population, both from Hong Kong. The first analysis mainly focused on patient preference regarding the mode of delivery; it also included few vaginal deliveries (35 cases).7 The second analysis, reported by Tang et al,8 was performed in the same obstetric unit as the first analysis; it reviewed neonatal and maternal outcomes after an increase in the rate of vaginal delivery of twins. The authors did not find any significant differences in neonatal morbidities between the vaginal delivery group and the elective caesarean delivery group. However, there were fewer successful vaginal deliveries of ≥1 twin (72 cases) and the effect of inter-twin delivery interval was not evaluated.

In this study, the main factor that affected the composite adverse perinatal outcome was gestational age; complications were mainly related to prematurity. Similarly, NICU admission was mainly related to complications of prematurity, rather than complications of vaginal delivery. There were no statistically significant differences in adverse perinatal outcomes, even for twins who were not delivered in cephalic presentation. Thus, non-cephalic presentation alone should not be considered sufficient to recommend caesarean delivery for twin pregnancies.

A study in Hong Kong by Leung et al,9 published in 2002, showed that all umbilical cord blood gas parameters in the second twin were significantly associated with the inter-twin delivery interval. The risk of severe fetal acidosis was 27% if the second twin was not delivered ≤30 minutes after delivery of the first twin, but the outcomes of second twins were not analysed. In our study, an inter-twin delivery interval of >30 minutes alone did not increase the risk of short-term adverse perinatal outcomes, although it increased the risk of caesarean delivery of the second twin. Schneuber et al10 also reported similar findings in their series, which suggested that an increased inter-twin delivery interval was not associated with adverse fetal outcomes. If monitoring of the second twin is possible and the findings are reassuring, obstetricians may thus consider a conservative approach, even 30 minutes after delivery of the first twin; however, emergency caesarean delivery should be readily available if necessary.

Our study also showed no increase in adverse perinatal outcomes for infants who were delivered after midnight. In general, delivery of twins in daytime or early evening is preferable because additional staff are present, and those staff are often more experienced. Therefore, when there are no indications for urgent delivery, the usual practice in our unit is to begin labour induction for twin pregnancies in the early morning. Deliveries after midnight usually follow spontaneous labour and are thus unplanned. However, such deliveries are supervised by the most senior on-call obstetrician (MRCOG-qualified or FHKCOG-accredited) during the intrapartum period.

Delivery of non-cephalic second twin

The vaginal delivery of second twins in non-cephalic presentation is challenging. Our findings showed a higher rate of caesarean delivery for second twins in non-cephalic presentation (9.0% vs 2.0%, P=0.03). In a large cohort study using the World Health Organization Global Survey dataset, Vogel et al11 showed that caesarean rates were 6.2% and 0.9% for second twins in non-cephalic and cephalic presentation, respectively. Another study by Kong et al12 revealed the caesarean delivery rates of second twins were 4.7% in cephalic presentation, 11.1% in breech presentation, and up to 90% in transverse lie. In both of these studies, analyses were conducted based on the presentation of the second twin at the onset of labour; their findings were consistent with our results. The presence of more experienced obstetricians who are able to perform artful manoeuvres (ie, internal podalic version and external cephalic version) can increase the likelihood of successful vaginal delivery of the second twin. Regular training and rehearsal of the vaginal delivery of twins is important for obstetricians to maintain their skills.

Caesarean section of second twin

In our study, caesarean delivery of the second twin was necessary in 4.3% of cases, which is similar to or lower than the proportions in other series.6 8 13 14 Regardless of whether the second twin was delivered by caesarean section, there were no significant increases in short-term adverse perinatal outcomes; however, this mode of delivery is less favourable for mothers. These results are contrary to the findings by Breathnach et al,6 in which the perinatal morbidity rate was 29% among second twins delivered by emergency caesarean section after vaginal delivery of the first twin. A systematic review by Rossi et al15 also showed a higher rate of morbidity in second twins after caesarean delivery (19.8% vs 9.5% after vaginal delivery). Thus, combined vaginal-caesarean delivery of twins should be avoided whenever possible.

In the present study, the presence of a larger second twin (≥20% weight discordance) did not significantly increase the risk of caesarean delivery. The second twin was larger in only 12 cases (5.2%). We suspect that many other cases with a larger second twin were scheduled for caesarean delivery without a trial of vaginal delivery. Decisions concerning the mode of delivery are affected by the estimated fetal weight, fetal presentation, and whether the mother has a history of successful vaginal delivery. Various factors must be carefully considered in each case.

Limitations

There were some limitations in this study. First, the retrospective design may have resulted in missing data or incomplete data collection. This is not a large problem because clinical information in the OBSCIS and the Electronic Patient Record is required to be updated when each patient is discharged from the hospital; therefore, these systems are reliable sources of patient data. Nevertheless, some information was not retrievable, such as the presentation of the second twin at the time of first twin delivery and whether birth attendant manoeuvres were necessary to deliver the second twin. Second, the non-randomised analysis might have led to selection bias concerning the mode of delivery, such that low-risk cases were over-represented in the study. The number of second twins delivered by caesarean section was small; a larger trial is needed to more comprehensively evaluate such cases.

Conclusion

Among second twins born to mothers who had attempted vaginal delivery, we found that adverse perinatal outcomes were mainly related to prematurity, rather than actual mode of delivery. For all second twins, an inter-twin delivery interval <30 minutes was associated with a higher rate of vaginal delivery; for second twins in breech presentation, the presence of more experienced birth attendants was also associated with a higher rate of vaginal delivery. Overall, the risk of caesarean delivery of the second twin was low. Our findings in a predominantly Asian population in Hong Kong support vaginal delivery of the second twin when the first twin is delivered in cephalic presentation.

Author contributions

This study was planned and designed by both authors. Both authors also jointly performed the data analysis. TK Lo provided leadership and supervision, while SL Mok wrote and managed the manuscript. Both authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

Both authors have disclosed no conflicts of interest.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

This study was approved by the Kowloon West Cluster Research Ethics Committee (Ref KW/EX-17-154 (118-02)). The requirement for patient informed consent was waived because this was a retrospective review of medical records that did not involve patient participation.

References

1. Monson M, Silver RM. Multifetal gestation: mode of delivery. Clin Obstet Gynecol 2015;58:690-702. Crossref

2. Peaceman AM, Kuo L, Feinglass J. Infant morbidity and mortality associated with vaginal delivery in twin gestations. Am J Obstet Gynecol 2009;200:462.e1-6. Crossref

3. Fox NS, Silverstein M, Bender S, Klauser CK, Saltzman DH, Rebarber A. Active second-stage management in twin pregnancies undergoing planned vaginal delivery in a U.S. population. Obstet Gynecol 2010;115:229-33. Crossref

4. Barrett JF, Hannah ME, Hutton EK, et al. A randomized trial of planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med 2013;369:1295-305.Crossref

5. Easter SR, Lieberman E, Carusi D. Fetal presentation and successful twin vaginal delivery. Am J Obstet Gynecol 2016;214:116.e1-10.Crossref

6. Breathnach FM, McAuliffe FM, Geary M, et al. Prediction of safe and successful vaginal twin birth. Am J Obsetet Gynecol 2011;205:237.e1-7. Crossref

7. Liu AL, Yung WK, Yeung HN, et al. Factors influencing the mode of delivery and associated pregnancy outcomes for twins: a retrospective cohort study in a public hospital. Hong Kong Med J 2012:18:99-107.

8. Tang HT, Liu AL, Chan SY, et al. Twin pregnancy outcomes after increasing the rate of vagina twin delivery: retrospective cohort study in a Hong Kong regional obstetrics unit. J Maternal Fetal Neonatal Med 2016;29:1094-100. Crossref

9. Leung TY, Tam WH, Leung TN, Lok IH, Lau TK. Effect of twin-to-twin delivery interval on umbilical cord blood gas in the second twins. BJOG 2002;109:63-7. Crossref

10. Schneuber S, Magnet E, Haas J, et al. Twin-to-twin delivery time: neonatal outcome of second twin. Twin Res Hum Genet 2011;14:573-9. Crossref

11. Vogel JP, Holloway E, Cuesta C, Carroli G, Souza JP, Barrett J. Outcomes of non-vertex second twins, following vertex vaginal delivery of first twin: a secondary analysis of the WHO Global Survey on maternal and perinatal health. BMC Pregnancy Childbirth 2014;14:55. Crossref

12. Kong CW, To WW. The predicting factors and outcomes of caesarean section of the second twin. J Obstet Gynaecol 2017;37:709-13. Crossref

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14. Persad VL, Baskett TF, O’Connell CM, Scott HM. Combined vaginal-cesarean delivery of twin pregnancies. Obstet Gynecol 2001;98:1032-7. Crossref

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Behavioural adaptations and responses to obstetric care among pregnant women during an early stage of the COVID-19 pandemic in Hong Kong: a cross-sectional survey

Hong Kong Med J 2022 Oct;28(5):367-75 | Epub 1 Aug 2022

https://doi.org/10.12809/hkmj209032

ORIGINAL ARTICLE

Behavioural adaptations and responses to obstetric care among pregnant women during an early stage of the COVID-19 pandemic in Hong Kong: a cross-sectional survey

PW Hui, MD, FRCOG; Mimi TY Seto, MB, BS, MRCOG; KW Cheung, MB, BS, MRCOG

Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong

Corresponding author: Dr PW Hui (apwhui@hku.hk)

Full paper in PDF

Abstract

Introduction: This study evaluated behavioural adaptations and responses to obstetric care among pregnant women during an early stage of the coronavirus disease 2019 (COVID-19) pandemic.

Methods: This cross-sectional survey included pregnant women who received obstetric care from 27 May 2020 to 16 June 2020 in a university-affiliated hospital in Hong Kong. Responses were collected with respect to obstetric appointment scheduling, workplace changes, mask-wearing practices, travel and quarantine experiences, obstetric service adjustments, and visiting arrangements. Regression analysis was used to compare the effects of patient characteristics on their responses.

Results: In total, 1000 surveys were distributed; 733 pregnant women provided complete survey responses. Among obstetric-related appointments in public hospitals, 16% were postponed or cancelled by pregnant women; such changes were most frequent among women beyond 24 weeks of gestation, women who had previous deliveries, and women who had a history of mental illness. The practice of working from home imposed psychological stress and negatively impacted the pregnancy experience in 4.5% of women. Childbirth companionship was regarded as an important service by 88.1% of women; only 4.2% agreed with its suspension. Obstetric service adjustments had the greatest impact on Chinese women and nulliparous women.

Conclusions: The findings provide an overview of how pregnant women adapted during an early stage of the COVID-19 pandemic. Women adjusted obstetric service attendance, began working from home, and wore masks. Women’s expectations did not match changes in childbirth companionship and peripartum services. Hospital administrators should consider psychological impacts on pregnant women when implementing service adjustments.

New knowledge added by this study

Pregnant women, especially women who had previous deliveries and a history of mental illness, were more likely to postpone or cancel obstetric appointments during an early stage of the coronavirus disease 2019 (COVID-19) pandemic.
While working from home improved the overall pregnancy experience for most women, it caused psychological stress and had a negative influence in 4.5% of respondents.
Childbirth companionship was considered important by 88.1% of the respondents; only 4.2% of respondents fully accepted its suspension.

Implications for clinical practice or policy

Obstetricians and policy makers should be aware of mismatches in the expectations of pregnant women concerning childbirth companionship and peripartum services; infection control should be balanced with peripartum needs.
Obstetric service adjustments had the greatest impact on Chinese women and nulliparous women.

[Abstract in Chinese]

Introduction

Coronavirus disease 2019 (COVID-19) has had substantial psychosocial impacts worldwide and caused major behavioural changes. In 2020, increased stress and anxiety levels were reported in countries with major disease spread.1 2 3 4 5 6 Pregnancy is considered a risk factor for COVID-19 because of relative maternal immunosuppression; there is also a risk of vertical transmission.7 8 9 10 11 Importantly, behavioural changes have been recognised among pregnant women.4 The pandemic situation could potentially disrupt obstetric care for pregnant women.8 Thus, it is important to study how the pandemic has affected obstetric care and pregnancy experiences.

Considering the severe adult respiratory syndrome (SARS) outbreaks in 2002 to 2003 in Hong Kong, a serious alert level was announced on 4 January 2020 in response to the emergence of novel coronavirus pneumonia in Wuhan, China.12 13 This was escalated to an emergency alert level on 25 January 2020. Corresponding policies were imposed in public hospitals with each alert announcement. In obstetric units, husbands and partners were no longer allowed to accompany pregnant women for labour and delivery. No visiting was allowed for mothers or babies staying with their mothers in postnatal wards. All antenatal exercise classes, antenatal seminars, hospital tours, and postnatal classes were suspended. Many workplaces for women and their partners shifted to working from home. These changes were coupled with suspensions of schools and non-urgent community services. The infection continued to spread worldwide; the COVID-19 pandemic was recognised by the World Health Organization on 11 March 2020. On 20 March 2020, the first case of COVID-19 in a pregnant woman was confirmed in Hong Kong. The local government subsequently restricted travel with additional quarantine measures and mandated social distancing in late March 2020.12 This study was conducted in the middle of 2020 to examine how pregnant women responded to changes in obstetric care and alterations in the workplace during an early stage of the COVID-19 pandemic; it also investigated their adaptations to the practices of mask wearing and social distancing.

Methods

This prospective questionnaire survey was conducted in the obstetric unit of a university-affiliated tertiary public hospital in Hong Kong from 27 May 2020 to 16 June 2020 in English (online supplementary Table 1) and Traditional Chinese (online supplementary Table 2). Pregnant women were invited to participate in an online questionnaire upon admission to obstetric wards or attendance to obstetric clinics; each invitation was provided by a midwife (in an obstetric ward) or a designated research assistant (in an obstetric clinic). Clinic sessions included an antenatal check-up, ultrasound scan, and screenings for gestational diabetes and Group B streptococcus. The survey was administered to all women who could read either Chinese or English. Each woman received an information leaflet containing an introduction of the project, a description of key events related to COVID-19 from January 2020 to March 2020, and a QR code linked to an online survey. The participants could begin the survey by scanning the QR code, selecting the language, and providing their consent.

The survey was developed by the authors and tailored to address issues related to the impacts of COVID-19 on obstetric services. Prior to this study, the survey content was validated by local consultant obstetricians and midwives; it consisted of demographic data collection and questions that involved five domains. These domains were related to obstetric appointment scheduling, workplace changes, mask-wearing practices, travel and quarantine experiences, and adjustments to birth companionship and visiting hours since the first novel coronavirus alerts were announced in January 2020. Concerning obstetric appointment scheduling, participants were asked whether their appointments had been postponed or rescheduled from a public hospital to a private hospital. Concerning workplace changes, participants were asked whether they and/or their partners had begun to work from home; they were then asked to describe the impact of the change on their pregnancy experience. Concerning mask-wearing practices, participants were asked about their pattern and type of mask use. With respect to travel and quarantine, participants were asked whether they had travelled because of COVID-19 risk; they were also asked about their experiences with COVID-19 testing and quarantine. Regarding the importance of birth companionship and visiting hours, as well as the acceptance of service adjustments and relief measures, participants were asked to rate their opinions of these factors using a visual analogue scale of 0 to 100, with 100 as very important or strongly accepted.

Women with gestational age ≤24 weeks were regarded as the early gestational group, while women with gestational age >24 weeks and women in the postnatal period were regarded as the late gestational group. The COVID-19 alert was announced by the Hong Kong government on 4 January 2020, slightly more than 20 weeks prior to the commencement of this study. Women in the early gestational group conceived after the date of COVID-19 alert announcement, while women in the late gestational group were already pregnant on the announcement date. Statistical analysis was performed using SPSS software (Windows version 26.0; IBM Corp, Armonk [NY], United States). The distributions of continuous variables were checked for normality. Analysis of variance and t test assessments were used for normally distributed variables, while the Mann-Whitney U test was used for non-normally distributed variables. Categorical variables were evaluated by the Chi squared test or Fisher’s exact test. Regression analysis was performed to examine the effects of marital status, ethnic background, parity, and mental illness on the behaviours of pregnant women regarding antenatal appointment rescheduling and their opinions of obstetric service adjustments. A value of P<0.05 was considered significant.

Results

In total, 1000 information leaflets were distributed to 200 women in obstetric wards and 800 women in out-patient clinics. In all, 890 responses were registered online, including 878 women who consented to participate and 12 women who did not consent. Among women who agreed to participate, 145 did not finish the survey; thus, 733 completed responses were available for analysis.

Table 1 shows the basic demographic characteristics of the participants. Women aged 31 to 35 years constituted nearly half (48.8%) of the respondents. The largest gestational age-group was 25 to 30 weeks (24.3%). With the exception of influenza and pertussis vaccination histories, other background characteristics were comparable between early and late gestational groups.

Table 1. Participant characteristics

Obstetric appointment scheduling

Among 2583 patient appointments, 417 (16.1%) were postponed or cancelled by pregnant women. Over half (56.1%) of these were rescheduled to a private hospital. The rate of postponement or cancellation was higher for regular antenatal visits (20.3%) and lower for foetal anomaly scans (13.6%) [Table 2]. Multivariate analysis showed that women in the late gestational group (odds ratio [OR]=2.66; 95% confidence interval [CI]=1.68-4.19; P<0.001) and women with mental illness (OR=2.20; 95% CI=1.09-4.43; P=0.03) were more likely to postpone or cancel regular antenatal appointments, while nulliparous women (OR=0.67; 95% CI=0.46-0.99; P=0.04) were less likely to make such changes (Table 3). No significant associations of demographic characteristics with ultrasound and investigation appointments (blood test, screening of Down’s syndrome, or Group B streptococcus colonisation) were identified.

Table 2. Arrangement of obstetric appointments after COVID-19 alert

Table 3. Multivariate analysis of factors affecting the antenatal appointment scheduling pattern

Working from home

As shown in Table 4, there were 542 (73.9%) working women in this study; more than half of them began working from home after the COVID-19 alert announcement. Compared with their husbands/partners, significantly more women were working from home (29.6% vs 52.8%; P<0.05). Among women working from home, this work pattern facilitated obstetric appointment attendance for 46.5% (133/286) of the women and 43.5% (87/200) of their husbands/partners. There was a tendency for decreased omission of antenatal appointments among women working at home, compared with women working in usual workplaces, although the differences were not statistically significant for any type of appointment (antenatal check-up 6.6% vs 6.7%, P=0.10; anomaly scan 3.7% vs 8.0%, P=0.09; obstetric scan 3.5% vs 6.6%, P=0.22; obstetric investigations 5.1% vs 8.3%, P=0.30).

Table 4. Work patterns, and effect of work patterns on antenatal appointment attendance

Overall pregnancy experience

Among the 131 women who reported that both they and their husbands/partners worked from home, 107 (81.7%) reported a better overall pregnancy experience. Among the 224 women who reported that they or their husbands/partners worked from home, 139 (62.1%) felt this work arrangement had made their overall pregnancy experience better while 13 (5.8%) felt this had made their experience worse. A significantly greater proportion of respondents reported a much better overall pregnancy experience when both they and their husbands/partners were working from home than when either they or their husbands/partners were working from home (50.4% vs 31.7%; P=0.001). In contrast, suspension of school and community services had more negative impacts on pregnancy experience (Table 5).

Table 5. Effect of work pattern, school suspension, and community service suspension on overall pregnancy experience

More time to spend at home was selected by 80.1% (197/246) of the respondents as a beneficial effect of working from home on their pregnancy experience (online supplementary Table 3). Among 18 women who had a worse pregnancy experience because of working from home, more psychological stress was chosen by 13 (72.2%) women as one of the underlying reasons. Five (27.8%) women reported greater conflict with their husbands/partners because of working from home (online supplementary Table 4).

Mask-wearing practices

The mean proportion of mask-wearing time was significantly greater in clinical areas (97.2% for hospitals and 97.0% for clinics) than in outdoor areas (89.3%) and at home (4.1%, P<0.05). Over 90% of respondents always wore masks in clinical areas; 63.8% always wore masks outdoors, and 0.8% always wore masks at home. Among all women in the study, surgical masks were most commonly used; N95 masks were used by 55 (7.5%) women in hospitals and 32 (4.4%) women in clinics (online supplementary Table 5).

Travel and quarantine experiences

Since the announcement of the COVID-19 alert, 6.8% (50/733) of respondents had travelled abroad because of COVID-19 risk in Hong Kong; 13.4% (98/733) of respondents had returned to Hong Kong because of COVID-19 risk abroad. Additionally, 31 (4.2%) women had been quarantined and 26 (3.5%) women had lived with household members during home quarantine. Coronavirus disease 2019 testing had been performed in 3.7% of all respondents. Moderate to marked emotional disturbance related to personal quarantine experience was reported by 64.5% (20/31) of the women (online supplementary Table 6).

Adjustments of birth companionship and visiting hours

Husband/partner companionship during childbirth was regarded as the most important obstetric service, followed by visiting hours for pregnant women and neonates. Childbirth companionship was considered important by 88.1% of the respondents; only 4.2% of the respondents fully accepted its suspension. In contrast, suspension of hospital tours was fully accepted by 27.0% of the respondents (online supplementary Fig). Univariate analysis showed that marital status, ethnicity, parity, and history of mental illness were factors that influenced opinions of obstetric service importance and acceptance of service suspension. Regression analysis showed that being married was strongly associated with greater perceived importance of childbirth companionship (B=10.51; 95% CI=5.77-15.24) and visiting hours for mothers (B=5.14; 95% CI=0.35-9.94). Chinese women had the greatest perceived importance of visiting arrangements for both mothers and babies; they had the least acceptance of suspension of those services. Nulliparity was only factor significantly associated with the perceived importance of antenatal exercise (B=23.41; 95% CI=19.00-27.82), antenatal seminars (B=28.72; 95% CI=24.41-33.03), hospital tours (B=20.03; 95% CI=14.97-25.09), and postnatal breastfeeding classes (B=25.96; 95% CI=21.59-30.33) [Table 6].

Table 6. Multivariate analysis of obstetric service importance and acceptance of service suspension

Discussion

Summary

To our knowledge, this is the first study of the behavioural adaptations and responses to obstetric care among pregnant women during an early stage of the COVID-19 pandemic in Hong Kong, a city which previously experienced SARS outbreaks in 2002-2003. Approximately 16% of obstetric-related appointments in public hospitals were postponed or cancelled by pregnant women because of COVID-19, but only 56% of these appointments were rescheduled in private hospitals. Women who had previous deliveries and a history of mental illness were more likely adjust their appointments. Working from home during the COVID-19 pandemic improved the overall pregnancy experience in most respondents. However, approximately 5% of women reported negative impacts on their pregnancy experiences, primarily because of psychological stress. Concerning obstetric services, nearly 90% of the women considered childbirth companionship to be important; <5% of the women fully accepted its suspension. More than 80% of the respondents regarded visiting for mothers and newborns as very important aspect of the overall pregnancy experience. Obstetric service adjustments had the greatest impact on Chinese women and nulliparous women.

Antenatal care

Delays in seeking medical attention for acute medical conditions such as cardiac and cerebrovascular events were reported in 2020.14 15 16 Importantly, failure to attend scheduled antenatal care can lead to adverse outcomes.17 18 Women in the late gestational group were already pregnant on the date of the COVID-19 alert announcement; they might have reported more adjustments to obstetric appointments. Additionally, their shifts in obstetric care and avoidance of in-hospital stays in public hospitals might be reflected by the reduced delivery rate.19 Because of their previous pregnancy experience, multiparous women might have been more likely to modify antenatal appointments. In contrast, women with mental illness require greater antenatal care and psychosocial support.20 The establishment of virtual clinics for online assessment without exposing pregnant women to COVID-19 risk in clinical areas offers an important alternative.21 To establish such clinics, antenatal protocols must be revised to incorporate virtual visits when ultrasounds, physical examinations, and obstetric investigations are unnecessary. Pregnant women would also require stable internet access, as well as foetal doppler and blood pressure monitoring equipment.

Working from home

Prior to and during the survey period, no complete lockdowns were instituted in Hong Kong, although working from home was encouraged. In this study, slightly more than half of working women were working from home after the COVID-19 alert. There is a need to consider safety for women who reported greater conflict with their husband/partner while working from home. Increased domestic violence was observed during the early stages of the COVID-19 pandemic; greater relationship friction and household conflict could be contributing factors.22 Public policy should be revised to facilitate the identification of women in need of conflict assistance when physical and psychosocial support may be limited because of physical isolation and the suspension of community services.9 23

Behavioural adaptations

In this study, >90% of pregnant women reported wearing a mask in clinical areas, although <10% reported wearing an N95 mask in hospitals. Our finding of 90% mask usage in clinical areas was much greater than the 31.8% observed among the general public in Taiwan in 2020.3 While the high rate of mask use could represent compliance with hospital policies regarding mandatory mask use and heightened awareness of self-protection in pregnant women, the use of N95 masks might also indicate a fear of contacting COVID-19 in public hospitals where confirmed cases were managed. Additionally, >20% of the women either travelled abroad or returned to Hong Kong because of COVID-19 risk. The history of SARS outbreaks in Hong Kong might have led to increased caution from the initial announcement of the COVID-19 alert. Travel during pregnancy and changes in delivery plans are important decisions. In 2020, a study in China showed that women were generally more anxious than men with respect to COVID-19; greater perceived susceptibility and severity of COVID-19 were also associated with greater anxiety.5 Obstetric decision-making and the implementation of preventive measures have been associated with antenatal anxiety secondary to the COVID-19 pandemic.3 8 Quarantine can lead to widespread and long-lasting adverse psychological sequelae.24 In 2020, anxiety levels were significantly higher among people who personally knew at least one person with COVID-19.1 In our cohort, moderate to marked emotional disturbance was reported by two-thirds of women who had undergone quarantine and one-third of women who had been living with household members during home quarantine. There is a need for supportive counselling to be provided to this susceptible group of women.

Expectations of childbirth companionship and peripartum services

Women’s expectations did not match changes in peripartum services and childbirth companionship; these mismatches were greatest in married women. Childbirth companionship provides multiple types of physical and psychological support.25 Women of Chinese ethnicity exhibited the greatest disagreement with suspension of visiting hours. The principle of “doing the month” in Chinese culture promotes maternal rest with nutritious supplements; thus, visits during the postpartum period are regarded as essential convalescence for mothers and babies.26 In Hong Kong, a greater proportion of women had a higher Edinburg Postpartum Depression Scale score upon suspension of childbirth companionship and visiting hours after announcement of the COVID-19 alert.19 In 2020, a similar effect on the Edinburg Postpartum Depression Scale score was observed in a Turkish population.27 Importantly, the Comprehensive Child Development Service in public obstetric units provides a programme for the identification, follow-up, and counselling of women at risk of postpartum depression; this programme constitutes critical support during stressful periods, such as the COVID-19 pandemic.

Strengths and limitations

Likely because many women of reproductive age living in Hong Kong remember the SARS outbreaks in 2002-2003, a notable strength was that the present study provided a useful assessment of adaptations and responses to a similar disease (COVID-19). Such valuable information can improve the understanding of behaviour among pregnant women in places that encounter further waves of COVID-19 transmission.

The merit of this survey was that the online questionnaire format allowed respondents to complete the questionnaire remotely and at their preferred speed. The responses were automatically captured in a database, which minimised entry errors and potential transmission of COVID-19. However, this questionnaire format is limited to patients with electronic access and does not permit the involvement of an interviewer to explain the questions. The use of convenience sampling in a single centre might also have introduced bias and limited the generalisability of the findings to the general population.

An additional limitation was that only women who continued antenatal follow-up or delivered in our public hospital were included in the present study. The delivery rate for January to April decreased by 13% in 2020, compared with the same period in 2019, despite a similar number of delivery bookings.17 This phenomenon was observed across all public hospitals in Hong Kong, indicating that pregnant women might have chosen to deliver in private hospitals instead. There is no standalone maternity hospital in Hong Kong; all maternity units are housed within general hospitals that admit patients with COVID-19. We suspect that this situation might have led some pregnant women to deliver in private hospitals where they perceived the risk of COVID-19 to be lower.

The final limitation was that the survey was conducted during a non-peak period of COVID-19 transmission in 2020. Childbirth companionship was resumed 2 days prior to the survey period; companions were required to complete an assessment of fever, travel, occupational exposure, contact history, and clustering phenomenon. Thus, the practices might have differed and the overall fear of disease might have been less intense, compared with a peak period of COVID-19 transmission. Furthermore, the retrospective nature of this study might have introduced recall bias, which we attempted to minimise by providing a timeline of key events concerning COVID-19 in the information leaflet. However, the initial response of the general public to COVID-19 might have been exaggerated because accurate disease information was limited during the early stages of the pandemic; the performance of a questionnaire study during a non-peak period might have helped to gather less exaggerated data concerning the behaviour of pregnant women. Further prospective longitudinal studies can address how women respond in different phases of the COVID-19 pandemic.

Conclusion

This study demonstrated the adaptations and responses of pregnant women to the COVID-19 pandemic in Hong Kong. The women in this study adjusted their obstetric appointments, began to work from home, and practised protective measures to reduce their risk of disease. While the overall pregnancy experience was mostly improved by working from home, women reported emotional disturbance because of the pandemic. Expectations of obstetric services remained high, particularly for Chinese women and nulliparous women. Obstetricians and policymakers should attempt to balance infection control and the peripartum needs of pregnant women when modifying childbirth companionship policies. Particular attention to nulliparous women is needed because they demonstrated higher levels of disagreement with the suspension of antenatal and postnatal educational programmes.

Author contributions

Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: PW Hui.
Drafting of the manuscript: PW Hui.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Acknowledgement

The authors thank Ms WK Choi for her assistance with creation of the online survey and Mr G Chu for his assistance with participant recruitment.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

The research has been approved by Institutional Review Board of The University of Hong Kong/Hospital Authority West Cluster (Ref UW 20-387).

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9. Thapa SB, Mainali A, Schwank SE, Acharya G. Maternal mental health in the time of the COVID-19 pandemic. Acta Obstet Gynecol Scand 2020;99:817-8. Crossref

10. Wu Y, Zhang C, Liu H, et al. Perinatal depressive and anxiety symptoms of pregnant women along with COVID-19 outbreak in China. Am J Obstet Gynecol 2020;223:240.e1-9.

11. Westgren M, Pettersson K, Hagberg H, Acharya G. Severe maternal morbidity and mortality associated with COVID-19: the risk should not be downplayed. Acta Obstet Gynecol Scand 2020;99:815-6. Crossref

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14. Metzler B, Siostrzonek P, Binder RK, Bauer A, Reinstadler SJ. Decline of acute coronary syndrome admissions in Austria since the outbreak of COVID-19: the pandemic response causes cardiac collateral damage. Eur Heart J 2020;41:1852-3. Crossref

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Models to predict prognosis in older patients with heart failure complicated by pre-frailty and frailty: a pilot prospective cohort study

Hong Kong Med J 2022 Oct;28(5):356-66 | Epub 22 Sep 2022

https://doi.org/10.12809/hkmj209103

ORIGINAL ARTICLE

Models to predict prognosis in older patients with heart failure complicated by pre-frailty and frailty: a pilot prospective cohort study

Takuya Umehara, PT, PhD^1,2; Nobuhisa Katayama, PT³; Akinori Kaneguchi, PT, PhD¹Yoshitaka Iwamoto, PT, PhD⁴; Miwako Tsunematsu, RN, PhD⁵; Masayuki Kakehashi, PhD, DSc⁵

¹ Department of Rehabilitation, Faculty of Rehabilitation, Hiroshima International University, Higashi-Hiroshima, Japan

² Department of Rehabilitation, Saiseikai Kure Hospital, Kure, Japan

³ Department of Rehabilitation, Kure Kyosai Hospital, Kure, Japan

⁴ Department of Neuromechanics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

⁵ Department of Health Informatics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Corresponding author: Dr T Umehara (start.ume0421@gmail.com)

Full paper in PDF

Abstract

Introduction: There are no clinical prediction models to predict the prognosis of pre-frailty or frailty in patients with heart failure. We aimed to develop prediction models for the prognosis of pre-frailty and frailty in older patients with heart failure using the classification and regression tree (CART) method; we then tested the predictive accuracies of the developed models.

Methods: Patients with pre-frailty or frailty at admission were divided into improved and non-improved groups. The CART method was used to establish two models: A, which predicted the presence or absence of pre-frailty improvement during hospitalisation; and B, which predicted the presence or absence of frailty improvement during hospitalisation.

Results: Patients with heart failure complicated by pre-frailty (n=28) or frailty (n=156) were included. In model A, the accuracy of predicting pre-frailty improvement was high; the best predictor was single-leg standing time at admission, followed by left ventricular ejection fraction at admission. In model B, the accuracy of predicting frailty improvement was moderate; the best predictor was hand grip strength at admission, followed by estimated glomerular filtration rate at admission, haemoglobin level at admission, and change in single-leg standing time during hospitalisation. The areas under the receiver operating characteristic curves of the CART models were 0.96 and 0.84 in models A and B, respectively.

Conclusion: Although conditions at admission may predict the improvement of pre-frailty and frailty during hospitalisation, cardiac rehabilitation that improves single-leg standing time may help to improve frailty, particularly when conditions at admission are poor.

New knowledge added by this study

We developed prediction models for the prognosis of pre-frailty and frailty in older patients with heart failure using classification and regression tree methods.
Single-leg standing time at admission was the best predictor of pre-frailty improvement, whereas hand grip strength at admission was the best predictor of frailty improvement.
Change in single-leg standing time during hospitalisation was also a predictor of frailty improvement.

Implications for clinical practice or policy

Improvements in physical function can help to manage frailty in older patients with heart failure, particularly when conditions at admission are poor.
Cardiac rehabilitation to prolong single-leg standing time is necessary to improve frailty, particularly when conditions at admission are poor.

[Abstract in Chinese]

Introduction

Heart failure is a major public health problem that has been shown to increase with age, such that incidence rates rapidly increase after 80 years of age.1 Among older patients with heart failure, 18% to 54% show signs of frailty, a state of reduced physical and cognitive function that results in weakness.2 There are some overlapping symptoms between heart failure and frailty; they interact to accelerate the vicious cycle of frailty.3 One study showed that frail patients with cardiovascular disease had a 7-year survival rate of 12%, which was much lower than the survival rate in non-frail patients with cardiovascular disease (43%).4 Moreover, frailty among patients with heart failure has been associated with poor prognosis5 and reduced cardiac output capacity.6 Pre-frailty is the first step towards frailty; approximately 34.6% to 46.1% of individuals with pre-frailty progress to frailty in Japan.7 Therefore, improvements in frailty and pre-frailty are important considerations in the care of older patients with heart failure.

Age,8 nutrition,9 walking speed,9 heart function,8 and grip strength10 have been shown to influence frailty improvement among older patients with heart failure. However, the predictive accuracies of such factors remain unknown. Moreover, a combination of the predictors has been suggested to increase their predictive accuracy,11 although this hypothesis has not yet been tested. Additionally, nutrition,12 physical function,12 and quality of life12 have been reported to influence pre-frailty improvement among community-dwelling older individuals. To our knowledge, there are no reports of factors that influence pre-frailty improvement among patients with heart failure.

In this study, we used the classification and regression tree (CART) method,13 which facilitates the establishment of clinical prediction models that can identify the best combinations of medical signs, symptoms, and other findings to predict prognoses or treatment outcomes.13 Several clinical prediction models have been developed using the CART method to predict mortality in patients with heart failure.14 15 However, no clinical prediction models have been established to predict the prognosis of patients with heart failure complicated by pre-frailty and frailty.

Here, we aimed to use the CART method to develop models that could predict the prognosis of older patients with heart failure complicated by pre-frailty and frailty, then confirm the predictive accuracies of those models.

Methods

Study design

This pilot prospective cohort study followed the STROBE reporting guidelines. All included patients provided written informed consent to participate in the study. Identifying information was not collected to protect each patient’s privacy. This study was performed in accordance with the Declaration of Helsinki.

Setting

Recruitment, follow-up, and data collection were performed at two acute hospitals (Saiseikai Kure Hospital, Kure, Japan; Kure Kyosai Hospital, Kure, Japan) between July 2018 and December 2019. Potential participants were recruited by therapists at the rehabilitation department.

Patients

This study included patients who met the following inclusion criteria: age ≥65 years; hospitalisation for the treatment of heart failure; and presence of pre-frailty or frailty. The exclusion criteria were complications during hospitalisation and/or severe dementia (defined as a revised Hasegawa’s Dementia Scale score ≤9).

Intervention

Cardiac rehabilitation was performed by physical or occupational therapists to improve physical condition, restore walking ability during hospitalisation, and expand the activities of daily living. Rehabilitation programmes were established by physical or occupational therapists in accordance with physicians’ orders. Initially, aerobic exercises and resistance training programmes were provided according to each patient’s physical condition. Exercise intensity was determined using multiple indices, including target heart rate (convenient method: resting heart rate + 20 bpm), talk test, and Borg scale (11-13) for the chest and lower limbs. The type of exercise was modified (ie, duration extended and load increased) with consideration of each patient’s symptoms and haemodynamics. If necessary, functional exercises (eg, neuromuscular facilitation, joint range of motion, and muscle strengthening exercises), exercises for activities of daily living, and psychological support were implemented for patients and their families. Exercises for activities of daily living were customised according to the functions that each patient needed for discharge. Overall, the duration and frequency of intervention were 30 minutes to 1 hour per day and 5 days per week, respectively.

Variables

Variables included demographic and clinical characteristics, frailty assessment results, and physical function. Demographic characteristics included age, sex, body mass index, living arrangement (with family members or alone), New York Heart Association class, medical history (eg, heart failure, coronary artery disease, valvular disease, hypertension, diabetes mellitus, dyslipidaemia, atrial fibrillation, chronic renal dysfunction, and/or stroke), cognitive function assessed using the revised Hasegawa’s Dementia Scale, Life-Space Assessment score, interval from admission to initiation of cardiac rehabilitation, interval from admission to rehabilitation room entry, and length of hospital stay. Hasegawa’s Dementia Scale scores of 21-30, 15-20, 10-14, and ≤9 were regarded as normal, suspected dementia, mild to moderate dementia, and severe dementia, respectively.16 The Life-Space Assessment developed by Baker et al17 was used to evaluate life-space mobility. Up to 120 points were assigned based on the degree of independence in each life-space level during the month prior to the assessment; higher scores were considered indicative of broader life-space and/or greater independence.

Clinical characteristics included blood data, cardiac function, and pharmacotherapy. Blood data included the Geriatric Nutritional Risk Index, brain natriuretic peptide level, estimated glomerular filtration rate (eGFR), and haemoglobin (Hb) level. Cardiac function was evaluated using left ventricular ejection fraction (LVEF), as determined by echocardiography. Pharmacotherapy data included whether patients were receiving dopamine, dobutamine, noradrenaline, phosphodiesterase III inhibitor, or diuretics.

Frailty was assessed using the following five conditions based on the Cardiovascular Health Study (CHS) Index: slow gait speed, weakness, exhaustion, low activity, and weight loss.18 Slow gait speed was defined as <1.0 m/s. Weakness was assessed using maximum grip strength according to sex-specific cut-offs (<26 and <18 kg for men and women, respectively). Exhaustion was assessed using the question “During the past 2 weeks, have you felt tired without a specific reason?” A positive response to this question (ie, “yes”) was considered indicative of exhaustion. Physical activity was evaluated using the question “Do you engage in low levels of physical activity to improve your health?” A negative response to this question (ie, “no”) was considered indicative of a low activity level. Weight loss was assessed using the question “Have you lost 2 kg or more in the past 6 months?” A positive answer to this question was considered indicative of weight loss. There are various criteria for assessing frailty; Fried’s frailty phenotype model18 and the accumulated deficit model established by Mitnitski et al19 are well known. The CHS criteria and the Frailty Index were developed based on the above frailty phenotype model and accumulated deficit model, respectively. Furthermore, a Japanese version of the CHS criteria (J-CHS) has been established,20 and its validity has been confirmed.21 Thus, we selected the J-CHS to assess frailty. Patients with none of the above conditions were considered non-frail (robust), patients with one to two conditions were considered pre-frail, and patients with three conditions or more were considered frail.22

Physical function was assessed using the Short Physical Performance Battery score, 10-metre walk time, single-leg standing time, and hand grip strength. Patients performed the Short Physical Performance Battery test in the following sequence, in accordance with the National Institute on Aging protocol: standing balance tests, gait test (4 m), and chair stand test (five repetitions). The sum of the three test components comprised the final Short Physical Performance Battery score, which ranged from 0 to 12; a score of 12 indicated optimal lower extremity function.23 24 Moreover, 10-m walk time was measured at a comfortable walking speed to assess walking ability. The 10-m walk test has demonstrated high validity and reliability in multiple populations, including healthy older individuals and patients with stroke, neurological disorders, or orthopaedic dysfunction.25 26 Measurements were performed twice at an interval of 30 s; the smaller value was used to indicate walking ability. Standing balance was evaluated by measuring single-leg standing time, which reflects the ability to maintain the body’s centre of gravity within its base of support. A stopwatch was used to measure the duration that a patient could stand on one leg with their eyes open and hands on their waist, without any assistance or falling. A second trial was performed if the result of the first trial was <60 s.27 Hand grip strength (kg) was measured using a digital hand grip strength dynamometer (TKK-5101; Takei Scientific Instruments, Tokyo, Japan or 12B3X00030; Tsutsumi Works, Chiba, Japan). Accordingly, patients were asked to squeeze the dynamometer with maximum effort during two trials for each hand. The maximum value (rounded to the nearest 0.1 kg) for either the left or right hand was used for subsequent analyses.28

Demographic and clinical characteristics were assessed upon admission or each time, whereas cognitive function and Life-Space Assessment were assessed during the first physical therapy session. Frailty and physical function were assessed upon initial entry into the rehabilitation room and at discharge. The amount of change in physical function (discharge−initial) was calculated.

Bias

To reduce selection bias, outcomes were selected based on the methods of previous studies.16 17 18 19 20 21 22 23 24 25 26 27 28 To reduce measurement bias, the first author (T Umehara) was not involved in participant enrolment or data collection. Patients received explanations about the purpose of the study but did not receive information concerning the hypothesis tested.

Statistical analysis

Classification and regression tree analysis29 was used to predict the primary outcomes. Patients with pre-frailty at admission were categorised into an improved group and a non-improved group: patients who were non-frail at discharge were assigned to the improved group, whereas patients who were pre-frail or frail were assigned to the non-improved group. Similarly, patients with frailty at admission were categorised into an improved group and a non-improved group: patients who were non-frail or pre-frail at discharge were assigned to the improved group, whereas patients who were frail were assigned to the non-improved group. Binary trees were used to recursively split predictor variables based on answers to yes/no questions for each variable. All statistical distributions were considered without limitation to linear relationships between outcome variables and predictor variables. These algorithms have been used to develop prediction models in various fields.30 31 32 The CART method with the Gini index was used for the following models: A, which predicted the presence or absence of pre-frailty improvement during hospitalisation; and B, which predicted the presence or absence of frailty improvement during hospitalisation. Pre-frailty or frailty improvement was the dependent variable, whereas demographic and clinical characteristics, pharmacotherapy, and amount of change in physical function were the independent variables. The accuracies of the CART models were evaluated using the area under the receiver operating characteristic curve (AUROC). The method proposed by Delong et al33 was used to identify optimal cut-off points. Subsequently, the sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated. To assess model validity, cross-validation was performed as follows: the sample was divided into 10 subgroups and the model developed from nine subgroups was used to test the 10th subgroup; this was repeated for all 10 combinations and the rates of misclassification were averaged. Model validity was considered high when the misclassification rates were similar before and after cross-validation. The accuracies of the CART models were evaluated using the AUROC developed from each method. The maximum Youden index (sensitivity + specificity − 1) was defined as the optimal cut-off point. All statistical analyses were performed using SPSS (Windows version 23.0; IBM Corp, Armonk [NY], United States) and the significance level was set at 5%.

Sample size

Sample size calculations were conducted using MedCalc statistical software, version 19.2 (MedCalc Software bvba, Ostend, Belgium). Before plotting an AUROC, the following values were established: statistical significance (P<0.05), alpha (0.05), statistical power (0.80), and the AUROC value to be included in the null hypothesis (0.5). The AUROC could distinguish between non-predictive (AUROC<0.5), less predictive (0.5<AUROC^lt;0.7), moderately predictive (0.7<AUROC<0.9), highly predictive (0.9<AUROC<1), and perfectly predictive (AUROC=1).34 In this study, an AUROC value of 0.7 was considered indicative of superior statistical discrimination. The frailty improvement ratio (ie, positive/negative ratio) considerably varied among previous studies.35 36 37 Therefore, the positive/negative ratio used here was set at 1:1-5. Moreover, a large sample size was needed to allow for the possibility of stratified analysis. Thus, 62 to 120 patients with frailty were required: 20-31 and 31-100 in the improved and non-improved groups, respectively.

Results

Figure 1 shows the flowchart of patient recruitment. Among the 30 patients with pre-frailty, two with severe dementia were excluded; 28 patients were included in the analysis. Among the 161 patients with frailty, five with severe dementia were excluded; 156 patients were included in the analysis. The patient characteristics are summarised in Tables 1 and 2 (patients with pre-frailty and patients with frailty, respectively).

Figure 1. Flowchart depicting the recruitment of older patients with heart failure complicated by pre-frailty and frailty

Table 1. Characteristics of patients with pre-frailty

Table 2. Characteristics of patients with frailty

Figure 2 shows CART model A, which predicted the presence or absence of pre-frailty improvement during hospitalisation. Among the 28 patients with pre-frailty, seven experienced improvements. Single-leg standing time at admission was identified as the best single discriminator for pre-frailty improvement (≤4.4 or >4.4 s). Among patients with single-leg standing time of >4.4 s at admission, the next predictor was LVEF (≤36.8% or >36.8%). Our CART analysis resulted in the establishment of three terminal nodes. The terminal node with the highest probability of a favourable outcome (pre-frailty improvement) was defined as rank 1, whereas the terminal node with the lowest probability of a favourable outcome was defined as rank 3. Based on the AUROC (95% confidence interval [CI]), this CART model had an accuracy of 0.96 (95% CI=0.89-1.00), with an optimal cut-off point of rank 1 (sensitivity: 85.7%, specificity: 95.2%, PLR: 18.0, and NLR: 0.15). The misclassification rates before and after cross-validation were 7.1% and 28.6%, respectively.

Figure 2. Model to predict the presence or absence of pre-frailty improvement during hospitalisation

Figure 3 shows CART model B, which predicted the presence or absence of frailty improvement during hospitalisation. Among the 156 patients with frailty, 57 experienced improvements. Hand grip strength at admission was identified as the best single discriminator for frailty improvement (≤16.8 or >16.8 kg). Among patients with hand grip strength of >16.8 kg at admission, the next predictor was eGFR (≤27.0 or >27.0 mL/min/1.73 m²). Among patients with hand grip strength of ≤16.8 kg at admission, the next predictor was eGFR (≤83.5 or >83.5 mL/min/1.73 m²). Among patients with eGFR ≤83.5 mL/min/1.73 m², the next predictor was Hb level (≤14.3 or >14.3 g/dL). Among patients with Hb level ≤14.3 g/dL, the next predictor was change in single-leg standing time (≤4.9 or >4.9 s). Our CART analysis resulted in the establishment of six terminal nodes. The terminal node with the highest probability of a favourable outcome (frailty improvement) was defined as rank 1, whereas the terminal node with the lowest probability of a favourable outcome was defined as rank 6. Based on the AUROC (95% CI), this CART model had an accuracy of 0.84 (95% CI=0.78-0.91), with an optimal cut-off point of rank 4 (sensitivity: 70.1%, specificity: 86.9%, PLR: 5.3, and NLR: 0.3). The misclassification rates before and after cross-validation were 19.2% and 35.3%, respectively.

Figure 3. Model to predict the presence or absence of frailty improvement during hospitalisation

Discussion

Model A predicted pre-frailty improvement with high accuracy; it identified single-leg standing time at admission as the best predictor, followed by LVEF. Notably, changes in physical function during hospitalisation were not identified as predictors. These results suggest that conditions at admission strongly influence pre-frailty improvement during hospitalisation; moreover, improvement can be expected among patients with good physical function (single-leg standing time >4.4 s) and cardiac function (LVEF >36.8%) at admission. To our knowledge, no study has examined the factors that influence pre-frailty improvement among patients with heart failure. However, one study found that physical function, nutrition, and quality of life were factors that influenced pre-frailty improvement among community-dwelling older individuals.12 The above findings suggest that although physical function is a common factor that influences pre-frailty improvement among older patients with heart failure and community-dwelling older individuals, cardiac function specifically influences pre-frailty improvement among patients with heart failure.

Model B predicted frailty improvement with moderate accuracy; it identified hand grip strength at admission as the best predictor, followed by eGFR, Hb level, and change in single-leg standing time during hospitalisation. Thus, frailty improvement can be expected among patients with good hand grip strength and/or renal function at admission. However, the cut-off values for eGFR, an index of renal function, considerably differed between patients with good (>16.8 kg) and poor (≤16.8 kg) hand grip strength (27 and 83.5 mL/min/1.73 m², respectively). A previous study also showed that older patients with heart failure who had higher hand grip strength were more likely to experience frailty improvement.10 Although no association has been identified between renal function and frailty, renal function is known to influence improvements in exercise capacity among patients with heart failure.38 Moreover, our results showed that, despite the presence of poor physical and renal function at admission, patients with a high Hb level (>14.3 g/dL) were likely to improve from frailty. Although there is no published literature concerning an association between Hb level and frailty, a low Hb level has been shown to cause fatigability,39 40 which is one of the criteria for assessing frailty using the CHS. Furthermore, the Hb level reportedly influences improvements in exercise capacity among patients with heart failure.38

Despite poor hand grip strength, weak renal function, and a low Hb level at admission, frailty improvement was observed in most patients whose single-leg standing time during hospitalisation was >4.9 s. In previous studies that sought to predict frailty improvement among older patients with heart failure, investigators mostly focused on conditions at admission without considering changes during hospitalisation.41 The present results indicate that, despite the presence of poor conditions at admission, patients can recover from frailty by improving physical function during hospitalisation; therefore, rehabilitation is essential during hospitalisation. Resistance training is known to improve single-leg standing time among older individuals.42 Thus, we recommend cardiac rehabilitation, including resistance training, to improve frailty among older patients with heart failure.

The clinical implications of our findings are as follows. Thus far, no algorithms have been established concerning pre-frailty and frailty improvements in older patients with heart failure. Using the CART method, we developed models that could predict the prognosis of older patients with heart failure complicated by pre-frailty and frailty. These models will provide useful information for patients and caregivers. Many of the factors extracted in this study were only assessed at the time of initial rehabilitation. Thus, the prognoses of patients with pre-frailty and patients with frailty can be inferred (to some extent) at the time of initial rehabilitation. Additionally, an increase in single-leg standing time during hospitalisation was associated with frailty improvement. For older patients with heart failure who show signs of frailty, interventions to increase single-leg standing time may help to improve frailty. The PLR and NLR were used to assess the diagnostic performances of the CART models; these parameters revealed that both model A (pre-frailty) and model B (frailty) had good performance. However, our data should be interpreted cautiously because of the small number of patients with pre-frailty.

There were several notable weaknesses and limitations in this study. First, the sample size was limited; the numbers of patients with pre-frailty and frailty were 28 and 156, respectively. Therefore, this study should be regarded as a pilot prospective cohort study. Despite the moderate to high accuracies of models A and B, more large-scale studies are needed to enhance the generalisability of our results. Second, three aspects of frailty exist, namely physical, social, and mental frailty; mental frailty was not considered in this study. A previous study reported that patients with multifaceted frailty, including physical, mental, and social frailty, had worse prognoses compared with patients who had physical frailty alone.5 Therefore, additional studies are needed to develop models that predict improvements in multifaceted frailty, including mental frailty. Third, interventions were customised for each patient; they were not uniform. However, physical therapists in both study hospitals received 2 weeks of training in cardiac rehabilitation, and the methods of cardiac rehabilitation were standardised as much as possible. Fourth, we used the J-CHS to measure frailty; the use of this tool to assess patients with heart failure is potentially controversial. The J-CHS was developed for older adults and has been used in multiple studies.7 21 Additionally, the reliability and validity of this tool have been confirmed.21 We thus consider this use of the J-CHS to be appropriate. Fifth, this study was performed in an unblinded manner, and we could not completely rule out the potential for bias. However, to reduce the measurement bias, the first author (T Umehara) was not involved in participant enrolment or data collection. Sixth, a selection bias might have been present because patients were only recruited at two hospitals in Japan. Caution is needed when generalising our results, particularly to patients in other countries.

Conclusion

By using the CART method, we developed moderately to highly accurate prediction models for pre-frailty and frailty improvement among older patients with heart failure. Model A, which predicted pre-frailty improvement, showed that patients with good single-leg standing time and cardiac function at admission are likely to experience pre-frailty improvement. Furthermore, Model B, which predicted frailty improvement, showed that patients with good hand grip strength, excellent renal function, and/or a high Hb level at admission are likely to experience frailty improvement. Notably, despite the presence of poor conditions at admission, frailty improvement may occur in patients who show improvement in single-leg standing time during hospitalisation. Overall, our results suggest that cardiac rehabilitation to prolong single-leg standing time is necessary to improve frailty, particularly when conditions at admission are poor.

Author contributions

Concept or design: All authors.
Acquisition of data: T Umehara and N Katayama.
Analysis or interpretation of data: T Umehara, M Tsunematsu, M Kakehashi.
Drafting of the manuscript: T Umehara, A Kaneguchi and Y Iwamoto.
Critical revision of the manuscript for important intellectual content: T Umehara, A Kaneguchi, Y Iwamoto.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Acknowledgement

We thank Y Yamamoto, M Ota, Y Nakashima, W Kawakami, and M Iwanaga (Kure Kyosai Hospital, Kure, Japan), as well as S Nagao, Y Kawabata, and D Tomiyama (Saiseikai Kure Hospital, Kure, Japan) for their support in data collection.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

The study was approved by the Ethics Committees of Saiseikai Kure Hospital (Ref 127) and Kure Kyosai Hospital (Ref 31-17). Patients provided written informed consent to participate.

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Perinatal mortality rate in multiple pregnancies: a 20-year retrospective study from a tertiary obstetric unit in Hong Kong

Hong Kong Med J 2022 Oct;28(5):347-56 | Epub 5 Sep 2022

https://doi.org/10.12809/hkmj2210153

ORIGINAL ARTICLE CME

Perinatal mortality rate in multiple pregnancies: a 20-year retrospective study from a tertiary obstetric unit in Hong Kong

SL Lau, MB, ChB, MRCOG¹; Sani TK Wong, MB, ChB¹; WT Tse, MB, ChB, MRCOG¹; Genevieve PG Fung, MB BChir, MRCPCH²; Hugh Simon Lam, MD, FRCPCH²; Daljit Singh Sahota, PhD; TY Leung, MD, FRCOG¹

¹ Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong

² Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong

Corresponding author: Prof TY Leung (tyleung@cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: Multiple pregnancies have become more common, but their perinatal mortality rate remains higher than the rate among singleton pregnancies. This retrospective study investigated the prevalence and causes of perinatal mortality among multiple pregnancies in Hong Kong.

Methods: All multiple pregnancies in a university tertiary obstetric unit between 2000 and 2019 were reviewed, and the medical records of cases complicated by stillbirth and neonatal death were identified. The causes of perinatal mortality were determined based on clinical assessment and laboratory results, then compared between the first (2000-2009) and second (2010-2019) decades.

Results: The prevalence of multiple pregnancies increased from 1.41% in the first decade to 1.91% in the second decade (P<0.001). Compared with the first decade, the second decade had a lower stillbirth rate (14.72 vs 7.68 [both per 1000 births]; P=0.026), late neonatal death rate (4.78 vs 1.16 [both per 1000 livebirths]; P=0.030), and total mortality rate (25.32 vs 13.82 [both per 1000 births]; P=0.006). The decline in stillbirth rate was related to improvements in antenatal care and treatment. The decline in the late neonatal death rate was related to a reduction in preterm birth before 34 weeks (18.5% vs 15.2%; P=0.006), as well as an improvement in the mortality rate in the subgroup of 31-33 weeks (19.23 vs 0 [both per 1000 livebirths]; P=0.035).

Conclusion: Although the prevalence of multiple pregnancies increased during the study period, the corresponding total perinatal mortality rate improved by 45.4%.

New knowledge added by this study

The prevalence of multiple pregnancies increased from 1.41% in 2000-2009 to 1.91% in 2010-2019, but the total perinatal mortality rate decreased by 45.4% (from 25.32 per 1000 births to 13.82 per 1000 births).
The stillbirth rate decreased from 14.72 per 1000 births to 7.68 per 1000 births because of close antenatal ultrasonographic monitoring, as well as fetal intervention including fetoscopic laser coagulation.
The late neonatal death rate decreased from 4.78 per 1000 births to 1.16 per 1000 births because of a reduction in the rate of preterm deliveries before 34 weeks of gestation, as well as improvements in intensive neonatal care that increased the survival rate for babies delivered at 31-33 weeks of gestation.

Implications for clinical practice or policy

Designated regular ultrasonography examinations and antenatal clinical examinations, beginning in the first trimester, are essential for reducing perinatal mortality in multiple pregnancies (particularly when a monochorionic placenta is present).
Territory-wide monitoring of perinatal mortality is needed to maintain the standard of perinatal care in Hong Kong.

[Abstract in Chinese]

Introduction

The global prevalence of multiple pregnancies has been increasing since the introduction of assisted reproductive technology in 1978.1 However, the risk of perinatal mortality is four-fold to seven-fold higher in twin pregnancies than in singleton pregnancies; this risk is further increased in triplet and quadruplet pregnancies.2 3 In particular, multiple pregnancies with a monochorionic (MC) component are at greater risk, compared with multiple pregnancies that lack a MC component.4 5 Preterm deliveries, selective fetal growth restriction, twin-to-twin transfusion syndrome (TTTS), and congenital anomalies are responsible for the higher rate of perinatal mortality in multiple pregnancies.2 6 7 8 In the UK, the Confidential Enquiry into Maternal and Child Health and Perinatal Mortality Surveillance Report for Births showed that the stillbirth (SB) rate for twin pregnancies had decreased from 17.58 per 1000 total births in 2000 to 6.16 per 1000 total births in 2016, whereas the SB rate for singleton pregnancies remained unchanged. Moreover, the neonatal mortality for twin pregnancies decreased from 23.2 to 5.34 per 1000 livebirths for the same period of time.9 10 These changes can presumably be attributed to the 2011 implementation of national guidelines in the UK11 concerning structured and more intensive antenatal monitoring; the guidelines emphasise the use of ultrasonography to determine chorioamnionicity and clarify the gestational age prior to delivery in uncomplicated multiple pregnancies.12

To our knowledge, no Hong Kong–specific data are available regarding the trends and causes of perinatal mortality in multiple pregnancies. We recently reported the improvement of perinatal mortality in singleton pregnancies at a tertiary centre in Hong Kong between 2000 and 2019.13 In the present study, we aimed to assess changes in the rates of perinatal mortality in multiple pregnancies, their underlying causes, and trends between 2000 and 2019 in the same obstetric unit, which is a referral centre for complicated multiple pregnancies.

Methods

Study setting

This study comprised a sub-analysis of our retrospective investigation of perinatal mortality in Prince of Wales Hospital, Hong Kong, over a 20-year period from 1 January 2000 to 31 December 2019, with a focus on multiple pregnancies. The hospital serves a population of approximately 1.7 million in the New Territories East region of Hong Kong, with an annual delivery rate of around 6000-7000 (approximately one-sixth of all births in all public hospitals, and one-ninth of all births in Hong Kong). Furthermore, the obstetric unit is a tertiary centre that receives complicated multiple pregnancies referred from other hospitals; it also serves as a maternal fetal medicine training centre accredited by both The Royal College of Obstetricians and Gynaecologists (RCOG; https://www.rcog.org.uk) and The Hong Kong College of Obstetricians and Gynaecologists (HKCOG; www.hkcog.org.hk). The STROBE reporting guideline was followed when writing this manuscript.

Data collection and analysis

Records of all multiple pregnancies delivered at the study hospital were retrieved from the hospital database. Multiple pregnancies were defined as pregnancies in which >1 fetus remained alive in utero by 24 weeks of gestation. Thus, the final pregnancy order was defined according to the number of live fetuses at 24 weeks. For example, if a twin was lost before 24 weeks of gestation because of spontaneous in utero death or fetal reduction, such that only one fetus remained alive at 24 weeks, the pregnancy was considered singleton. In contrast, if a twin was lost at 26 weeks of gestation and the co-twin was delivered at 37 weeks, the pregnancy was considered a twin pregnancy with one in utero fetal death. Because the delivery of a dead fetus might have been deferred until the delivery of its live co-fetus, the definition of the time of in utero fetal death or SB was based on the timing of death, rather than the timing of delivery. Stillbirth was defined as fetal death that occurred at or after 24 weeks of gestation; late SB was defined as fetal death that occurred at or after 28 weeks. Neonatal death (NND) was defined as the death of a livebirth and was subcategorised into early (death within 7 days after birth) and late (death between 8 and 28 days after birth).

Statistical analysis

The SB rate was calculated as the number of SBs divided by the total number of births (SBs and livebirths after 24 weeks). Early, late, and total (early plus late) NND rates were calculated as the number of NNDs in a specific period divided by the total number of livebirths (excluding SBs). The perinatal mortality rate was calculated as the sum of SBs and early NNDs divided by the total number of births. Continuous variables were compared by independent samples t tests or the Mann-Whitney U test for parametric and non-parametric data, respectively. For comparisons of risk factors, 95% confidence intervals of the differences or odds ratios were included. Categorical variables were compared by the Chi squared test or Fisher’s exact test, as appropriate. The level of significance was set at a two-sided P value of <0.05. Data analysis was performed with SPSS (Windows version 22.0; IBM Corp, Armonk [NY], United States).

Results

Multiple pregnancy types, prevalences, and mortalities

During the 20-year study period, there were 2126 multiple pregnancies, including 2077 (97.7%) twin pregnancies, 48 (2.26%) triplet pregnancies, and one (0.05%) quadruplet pregnancy; the quadruplet pregnancy was quadrachorionic quadra-amniotic. Among the twin pregnancies, 1377 (66.3%) were dichorionic-diamniotic, 670 (32.3%) were monochorionic-diamniotic, and 21 (1.0%) were monochorionic-monoamniotic; chorioamnionicity in the remaining nine (0.4%) was unknown. Among the triplet pregnancies, 25 (52.1%) were trichorionic-triamniotic; the remaining 23 (47.9%) triplet pregnancies had ≥1 MC component, including 14 dichorionic-triamniotic, seven monochorionic-triamniotic, one monochorionic-diamniotic, and one dichorionic-diamniotic. Thus, among 4302 total births from multiple pregnancies, 1451 (33.7%) were from 714 pregnancies with a MC component, 2833 (65.9%) [including the quadruplets] were from 1403 pregnancies without a MC component, and 18 (0.4%) were from the nine twin pregnancies of uncertain chorioamnionicity.

The prevalence of multiple pregnancies increased from 1.41% (837 per 59 469 pregnancies) in the first decade to 1.91% (1289 per 67 316 pregnancies) in the second decade (P<0.001). This change was caused by increases in both MC multiple pregnancies (from 309 [0.52%] to 405 [0.60%]) and non-MC multiple pregnancies (from 519 [0.87%] to 884 [1.31%]) between the first and second decades; the increase in non-MC multiple pregnancies was greater. The nine twin pregnancies with unknown chorioamnionicity were all delivered in the first decade.

Overall, there were 45 SBs, 23 early NNDs, and 11 late NNDs during the study period (Table 1). Among the 45 SBs in multiple pregnancies, 21 (46.7%) occurred between 24 and 27 weeks of gestation, whereas 24 (53.3%) occurred thereafter; the late SB rate was 5.71 per 1000 births. Forty-three SBs (10.35 per 1000 births) occurred in twin pregnancies (including five double SBs: four pairs of monochorionic-diamniotic twins and one pair of dichorionic diamniotic twins), whereas two SBs (13.89 per 1000 births) occurred in triplet pregnancies; these SB rates did not significantly differ. Furthermore, there were 28 NNDs (6.81 per 1000 births) in twin pregnancies and six NNDs (42.25 per 1000 births) in triplet pregnancies; the NND rate was significantly higher in triplet pregnancies (P=0.001). Therefore, the total mortality rate (17.09 per 1000 births vs 55.56 per 1000 births; P=0.005) and the perinatal mortality rate (14.93 per 1000 births vs 41.67 per 1000 births; P=0.025) were both higher in triplet pregnancies (Table 1). There were no instances of perinatal mortality in the only case of quadruplet pregnancy or in the nine twin pregnancies of unknown chorioamnionicity.

Table 1. Rates of stillbirth, NND, and perinatal mortality in multiple pregnancies, compared between 2000-2009 and 2010-2019, and compared among orders of pregnancy

Among the twin pregnancies, the MC group had significantly higher rates of SB (18.81 per 1000 births vs 6.17 per 1000 births; P<0.001) compared with the non-MC group, but the early, late and total NND rates did not differ between groups. Overall, the MC twin group had higher rates of total mortality (28.94 per 1000 births vs 11.26 per 1000 births; P<0.001) and perinatal mortality (24.60 per 1000 births vs 10.17 per 1000 births; P<0.001), compared with the non-MC twin group. Among the triplet pregnancies, the MC group also had significantly higher rates of total NND (88.24 per 1000 births vs 0; P=0.011) and total mortality (101.45 per 1000 births vs 13.33 per 1000 births; P=0.028) [Table 2].

Table 2. Rates of stillbirth, NND, and perinatal mortality, compared among twin and triplet pregnancies with and without a monochorionic component

Changes in stillbirth and neonatal death rates during the study period

The following rates were significantly lower in the second decade, compared with the first decade: overall SB (14.72 per 1000 births vs 7.68 per 1000 births; P=0.026), late NND (4.78 per 1000 births vs 1.16 per 1000 births; P=0.030), perinatal mortality (20.61 per 1000 births vs 12.67 per 1000 births; P=0.041) and total mortality (25.32 per 1000 births vs 13.82 per 1000 births; P=0.006) [Table 1]. Notably, the rates of early NND and total NND did not significantly differ between decades. In the non-MC group, the following rates were significantly lower in the second decade: overall SB (12.39 per 1000 births vs 2.81 per 1000 births; P=0.004), early NND (7.72 per 1000 births vs 1.69 per 1000 births; P=0.023), and total NND (9.65 per 1000 births vs 2.25 per 1000 births; P=0.016). No differences between decades were observed in the MC group (Table 2).

Details of stillbirths in multiple pregnancies

The maternal characteristics associated with SBs in multiple pregnancies are shown in Supplementary Table 1 of the Appendix. Compared with the livebirth group (excluding cases with NND), mothers in the SB group were significantly younger (30.3 ± 6.6 years vs 32.7 ± 5.3 years; P=0.004) and the proportion of mothers aged ≥35 years was lower (17.5% vs 38.5%; P=0.007). Maternal characteristics were comparable between the two groups in terms of ethnicity, booking status, parity, and body mass index. The prevalences of all medical diseases were also comparable.

Table 3 and the Supplementary Figure a show the respective incidences and distribution of the causes of SB among multiple pregnancies. The most common cause was fetal growth restriction (13; 28.9%), followed by TTTS [7; 15.5%]. Other causes of SB included pre-eclampsia/hypertension (3; 6.7%), congenital and genetic abnormalities (3; 6.7%), chorioamnionitis (3; 6.7%), other maternal medical diseases (2; 4.4%), cord-related pathology/accident (1; 2.2%), and placental pathologies (1; 2.2%). There were 12 (26.7%) unexplained SBs throughout the study period, although the rate was significantly lower in the second decade (2; 10%) than in the first decade (10; 40%, P=0.002); otherwise, there were no other substantial differences in the causes of SB between the first and second decades. The causes of SB differed between MC and non-MC groups: fetal growth restriction (9; 33.3%) [P=0.014] and TTTS (7; 25.9%) [P=0.001] were the two most common causes of SB in MC multiple pregnancies. Whereas one-third of SBs in the non-MC group were unexplained, fetal growth restriction (4; 22.2%), congenital and genetic abnormalities (2; 11.1%), chorioamnionitis (2; 11.1%), and pre-eclampsia/hypertension (2; 11.1%) were common causes in the non-MC group.

Table 3. Causes of stillbirth among multiple pregnancies with and without a monochorionic component, compared between 2000-2009 and 2010-2019

Details of neonatal deaths in multiple pregnancies

The distribution of gestational ages at NND is shown in Table 4. In the ‘31 to 33 weeks’ group, the overall NND rate was significantly higher in the first decade (19.23 per 1000 births) than in the second decade (0 per 1000 births; P=0.035). In the ‘24 to 27 weeks’ group, the NND rate was significantly higher among triplet pregnancies (545.45 per 1000 births) than among twin pregnancies (215.38 per 1000 births; P=0.031). Preterm birth before 34 weeks of gestation in multiple pregnancies was significantly higher in the first decade (18.5%) than in the second decade (15.2%; P=0.006).

Table 4. Distributions of gestational age at livebirth and neonatal death, compared among multiple pregnancies

Regarding the causes of NND in multiple pregnancies, prematurity (23; 67.6%) was the most common cause, followed by congenital and genetic abnormalities (8; 23.6%), birth asphyxia (2; 5.9%), and sepsis (1; 2.9%) [Table 5 and Supplementary Fig b]. There were no significant differences in the incidences of various causes of NND between the first and second decades. However, a greater proportion of NNDs in the MC group was caused by prematurity, compared with the non-MC group (11.24 per 1000 births vs 2.49 per 1000 births; P=0.001) [Table 5].

Table 5. Causes of neonatal death among multiple pregnancies with and without a monochorionic component, compared between 2000-2009 and 2010-2019

Changes in maternal demographics during the study period

Between the first and second decades, there were several statistically significant trends in maternal demographics, including a higher maternal age in the second decade (31.6 ± 5.3 years vs 33.3 ± 5.2 years; P<0.001), as well as greater proportions of mothers aged ≥35 years (29.7% vs 43.4%; P<0.001) and ≥40 years (4.8% vs 8.0%; P=0.004). The overall mean booking body mass index was significantly lower in the second decade (23.1 ± 3.7 kg/m² vs 22.7 ± 3.3 kg/m²; P=0.011). The prevalence of non-booked cases was also significantly lower in the second decade (11.2% vs 4.7%; P<0.001). Women of Chinese ethnicity remained the predominant group (96.9% vs 94.9%), but there was an increase in the proportion of deliveries by women of Southeast Asian ethnicity (1.3% vs 4.3%; P<0.001). The proportions of nulliparous women were similar (63.9% vs 67%; P=0.150). In the second decade, there were higher prevalences of chronic hypertension (0% vs 1.1%; P=0.006) and pre-eclampsia/gestational hypertension (8.5% vs 11.2%; P=0.043), as well as an increase in the rate of caesarean delivery (65.0% vs 81.0%; P<0.001). Other differences in the prevalences of medical diseases are summarised in Supplementary Table 2 of the Appendix.

Discussion

Changes in the types of multiple pregnancies and their perinatal mortality rates

To our knowledge, this is the first large study concerning the epidemiology and patterns of perinatal mortality in multiple pregnancies during a 20-year period in Hong Kong. In the second decade, there were significantly more non-MC twin pregnancies, compared with the first decade; this was mainly because of the widespread use of artificial reproductive technology. However, there was no change in the number of non-MC triplet or quadruplet pregnancies; this finding was presumably related to changes in artificial reproductive technology practices that restricted the number of embryo transfers, controlled ovulation induction, and implemented fetal reduction (ie, from higher order pregnancies to twin pregnancies).14 The probability of a spontaneous MC twin pregnancy is generally stable (~1 in 300).15 The increased prevalence of MC twin pregnancies in this cohort is presumably related to the increased number of referrals received by the obstetric unit involved in this study, which is a specialised centre for the treatment of complicated twin pregnancies via fetoscopic laser coagulation of anastomoses or radiofrequency ablation of umbilical vessels for selective fetal reduction.14 16 17 18 19 Embryos produced by artificial reproductive technology also have a higher probability of spitting and forming MC multiple pregnancies.20 Compared with the perinatal mortality in singleton pregnancies during the same period, which we previously reported,13 the respective perinatal mortality rates in twin pregnancies and triplet pregnancies were 3.6-fold and 10.0-fold higher (4.16 in 1000 births [singleton] vs 14.93 in 1000 births [twin] vs 41.67 in 1000 births [triplet]; P<0.05). The total perinatal mortality rate in twin pregnancies was 45.4% lower in the second decade than in the first decade (25.32 per 1000 births [2000-2009] vs 13.82 per 1000 births [2010-2019]). This difference was considerably larger than the 15.2% reduction we previously observed in singleton pregnancies (4.54 per 1000 births [2000-2009] vs 3.85 per 1000 births [2010-2019]).13

Changes in the stillbirth rates

The improvement in perinatal mortality in multiple pregnancies was a combined effect of reductions in SB and late NND. Compared with SB rates in twin and triplet pregnancies in the same obstetric unit between 1988 and 1992,21 the SB rate for twin pregnancies substantially decreased from 23.2 per 1000 births (1988-1992) to 14.9 per 1000 births (2000-2009) and 7.53 per 1000 births (2010-2019). The SB rate for triplet pregnancies also substantially decreased from 66.7 per 1000 births (1988-1992) to 15.2 per 1000 births (2000-2009) and 12.8 per 1000 births (2010-2019). Our findings are comparable to results from the UK, where the national SB rate in twin pregnancies decreased from 17.58 per 1000 births (2000) to 6.16 per 1000 births (2016).22

The decline in SB rates since 1990 can be attributed to improvements in care, including the introduction of fetoscopic laser coagulation for TTTS (in 2002)17 18 and the establishment of a specialised multiple pregnancy clinic with a standard protocol for close ultrasonographic monitoring (in the late 2000s). The establishment of this clinic ensured better care for these high-risk multiple pregnancies; the additional monitoring allowed earlier recognition of complications and greater access to timely treatment.23 However, the effect of radiofrequency ablation of the umbilical vessels for selective fetal reduction, introduced in 2011, was not revealed in this study because many multiple pregnancies were regarded as singleton pregnancies after fetal reduction.14 16 19 24

In the second decade, the proportion of non-MC multiple pregnancies increased from 62.6% [1049/(1049+627)] to 68.4% [1780/(1780+824)]; this also reduced the overall perinatal mortality rate. Furthermore, non-MC multiple pregnancies had lower rates of total mortality (11.31 in 1000 births vs 32.39 in 1000 births; P<0.001), perinatal mortality (10.25 in 1000 births vs 26.88 in 1000 births; P<0.001), and SB (6.36 in 1000 births vs 18.61 in 1000 births; P<0.001), compared with MC multiple pregnancies. This is consistent with findings from the UK, where the SB rates were 3-5 in 1000 births (dichorionic twin pregnancies) and 18-26 in 1000 births (MC twin pregnancies) during the period of 2013-2016.

Comparison with singleton pregnancies

Notably, approximately half of the SBs in multiple pregnancies occurred between 24 and 27 weeks of gestation, whereas only 25% of SBs in singleton pregnancies occurred in this range of gestational ages.13 This difference suggests that the underlying diseases associated with SB were more severe (with earlier onset) in multiple pregnancies than in singleton pregnancies. When comparing the aetiologies of SB between singleton and multiple pregnancies, the multiple pregnancies group had higher rates of SB caused by fetal growth restriction (3.04 in 1000 births vs 0.49 in 1000 births), pre-eclampsia/ hypertension (0.70 in 1000 births vs 0.19 in 1000 births), other maternal medical diseases (0.47 in 1000 births vs 0.11 in 1000 births), and TTTS (specific to MC multiple pregnancies). In the second decade, the proportion of unexplained SBs in multiple pregnancies was significantly lower than in the first decade (40% [2000-2009] vs 10% [2010-2019]); this change was not observed in singleton pregnancies (33.3% [2000-2009] vs 39.1% [2010-2019]). We presumed that the difference was mainly related to the close monitoring provided in multiple pregnancies.

Whereas SBs in singleton pregnancies were associated with older maternal age and obesity, SBs in multiple pregnancies were associated with significantly younger maternal age, compared with livebirths in multiple pregnancies. Moreover, the proportion of mothers aged ≥35 years was significantly lower among multiple pregnancies with SBs than among multiple pregnancies with livebirths. This difference presumably can be attributed to the younger age of mothers with MC multiple pregnancies compared with mothers who had non-MC multiple pregnancies; moreover, a greater proportion of non-MC multiple pregnancies were produced by artificial reproductive technology.

Changes in neonatal death rates

As in singleton pregnancies, prematurity was the most common cause of NND in multiple pregnancies.13 There was a significantly lower rate of preterm birth before 34 weeks of gestation in multiple pregnancies during the second decade (15.2%) than in the first decade (18.5%; P=0.006); accordingly, the rates of late NND and total NND were lower in the second decade. After stratification according to gestational age at birth, the NND rate was significantly higher in triplet pregnancies than in twin pregnancies among deliveries between 24 and 27 weeks of gestation. However, the NND rate did not significantly differ between singleton pregnancies (197.53 per 1000 births) and twin pregnancies (215.38 per 1000 births; P=0.743). Thus, there is an unclear effect of order of pregnancy on the NND rate in extreme preterm births; the degree of prematurity is the main factor that affects the NND rate.

The rate of caesarean delivery was significantly lower in the first decade than in the second decade (65.0% vs 81.0%; P<0.001). This difference was mainly related to an increase in the elective caesarean delivery rate for multiple pregnancies (23.7% vs 42.5%); the emergency caesarean delivery rate was similar between the first and second decades (41.3% vs 38.5%). Women with the first twin in cephalic presentation and overall stable condition were offered a trial of vaginal delivery and elective caesarean delivery. Because there is a generally consistent probability that the first fetus is in cephalic presentation, the higher rate of elective caesarean delivery was mainly related to patient choice and preference.

Strengths and limitations

This is the first large analysis of the prevalence and causes of SB and NND among multiple pregnancies in Hong Kong. Most data regarding chorioamnionicity, gestational age at SB, and basic maternal demographics are complete and accurate. The 20-year study period also allowed comparisons between the first and second decades. However, because our obstetric unit is the major referral centre for complicated MC cases, the number of MC cases in this study was higher than the number of cases in a nearby obstetric unit (0.6% vs 0.4% of all pregnancies); moreover, total perinatal mortality was higher in our obstetric unit (32.77 per 1000 births during 2010-2019 [Table 2], vs 19 per 1000 births during 2011-2018).25 Notably, the analysis by the other obstetric unit excluded MC triplet pregnancies, monoamniotic twin pregnancies, and cases complicated by TTTS or lethal anomalies, all of which carried a high risk of perinatal mortality.25 Furthermore, clinical practices might have changed during the 20-year study period, potentially influencing the classification of causes of SB. For example, the change from karyotyping to chromosomal microarray may have led to additional genetic disease diagnoses.26 Additionally, some multiple pregnancies were reduced to singleton pregnancies, either spontaneously or by medical intervention, before 24 weeks of gestation; these pregnancies were regarded as singleton pregnancies. Therefore, the effect of fetal reduction in these cases was unclear. Finally, although this large cohort provided extensive data concerning perinatal mortality among multiple pregnancies in Hong Kong, the dataset was insufficient for statistical evaluation of rare events. Nonetheless, these findings provide a basis for a territory-wide review of perinatal outcomes in multiple pregnancies.

Conclusion

The prevalence of multiple pregnancies increased from 1.41% in 2000-2009 to 1.91% in 2010-2019, but the total perinatal mortality rate decreased from 25.32 per 1000 births to 13.82 per 1000 births. This change in the total perinatal mortality rate was related to reductions in the rates of SB and NND, which resulted from improvements in antenatal care and neonatal intensive care.

Author contributions

Concept or design: SL Lau, TY Leung.
Acquisition of data: All authors.
Analysis or interpretation of data: SL Lau, STK Wong, WT Tse, TY Leung.
Drafting of the manuscript: SL Lau, TY Leung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

Ethical approval was obtained from the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref CRE 2017.442).

References

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3. Sherer DM. Adverse perinatal outcome of twin pregnancies according to chorionicity: review of the literature. Am J Perinatol 2001;18:23-37. Crossref

4. Hack KE, Derks JB, Elias SG, et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. BJOG 2008;115:58-67. Crossref

5. Lewi L, Jani J, Blickstein I, et al. The outcome of monochorionic diamniotic twin gestations in the era of invasive fetal therapy: a prospective cohort study. Am J Obstet Gynecol 2008;199:514.e1-8. Crossref

6. Lee YM, Wylie BJ, Simpson LL, D’Alton ME. Twin chorionicity and the risk of stillbirth. Obstet Gynecol 2008;111:301-8. Crossref

7. Ananth CV, Chauhan SP. Epidemiology of twinning in developed countries. Semin Perinatol 2012;36:156-61. Crossref

8. Manktelow BN, Smith LK, Seaton SE, et al; on behalf of the MBRRACE-UK collaboration. MBRRACE-UK perinatal mortality surveillance report. UK perinatal deaths for births from January to December 2014. Available from: https://www.npeu.ox.ac.uk/assets/downloads/mbrraceuk/ reports/MBRRACE-UK-PMS-Report-2014.pdf. Accessed 1 Mar 2022.

9. Healthcare Quality Improvement Partnership Ltd. MBRRACE-UK. Perinatal mortality surveillance report 2018. Available from: https://www.hqip.org.uk/ resource/mbrrace-uk-perinatal-mortality-surveillancereport- 2018/. Accessed 1 Mar 2022.

10. Healthcare Quality Improvement Partnership Ltd. CMACE and CEMACH reports. Stillbirth, neonatal and post-neonatal mortality 2002-2003 from CEMACH. Available from: https://www.hqip.org.uk/resource/cmace-and-cemach-reports/. Accessed 1 Mar 2022.

11. National Collaborating Centre for Women’s and Children’s Health (UK). Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. London: RCOG Press; 2011.

12. Khalil A, Giallongo E, Bhide A, Papageorghiou AT, Thilaganathan B. Reduction in twin stillbirth following implementation of NICE guidance. Ultrasound Obstet Gynecol 2020;56:566-71. Crossref

13. Wong ST, Tse WT, Lau SL, Sahota DS, Leung TY. Stillbirth rate in singleton pregnancies: a 20-year retrospective study from a public obstetric unit in Hong Kong. Hong Kong Med J 2022;28:285-93. Crossref

14. Tse WT, Law LW, Sahota DS, Leung TY, Cheng YK. Triplet pregnancy with fetal reduction: experience in Hong Kong. Hong Kong Med J 2017;23:326-32. Crossref

15. Sperling L, Kiil C, Larsen LU, et al. Naturally conceived twins with monochorionic placentation have the highest risk of fetal loss. Ultrasound Obstet Gynecol 2006;28:644-52. Crossref

16. Ting YH, Poon LC, Tse WT, et al. Outcomes of radiofrequency ablation for selective fetal reduction before vs at or after 16 gestational weeks in complicated monochorionic pregnancy. Ultrasound Obstet Gynecol 2021;58:214-20. Crossref

17. Lau TK, Leung TY, Fung TY, Leung TN. Treatment of twin-twin transfusion syndrome by fetoscopic laser photocoagulation. Chin Med J (Engl) 2004;117:1431-4.

18. Yang X, Leung TY, Ngan Kee WD, Chen M, Chan LW, Lau TK. Fetoscopic laser photocoagulation in the management of twin-twin transfusion syndrome: local experience from Hong Kong. Hong Kong Med J 2010;16:275-81.

19. Lu J, Ting YH, Law KM, Lau TK, Leung TY. Radiofrequency ablation for selective reduction in complicated monochorionic multiple pregnancies. Fetal Diagn Ther 2013;34:211-6. Crossref

20. Saravelos SH, Zhang T, Chung JP, et al. Monochorionic quadramniotic and triamniotic pregnancies following single embryo transfers: two case reports and a review of the literature. J Assist Reprod Genet 2016;33:27-32. Crossref

21. Lau TK, Li CY. A perinatal audit of stillbirths in a teaching hospital in Hong Kong. Aust N Z J Obstet Gynaecol 1994;34:416-21. Crossref

22. Kurinczuk JJ, Draper ES, Field DJ, et al. Experiences with maternal and perinatal death reviews in the UK—the MBRRACE-UK programme. BJOG 2014;121 Suppl 4:41-6. Crossref

23. Pan M, Chen M, Leung TY, Sahota DS, Ting YH, Lau TK. Outcome of monochorionic twin pregnancies with abnormal umbilical artery Doppler between 16 and 20 weeks of gestation. J Matern Fetal Neonatal Med 2012;25:277-80.Crossref

24. Ting YH, Lao TT, Law KM, Cheng YK, Lau TK, Leung TY. Pseudoamniotic band syndrome after in-utero intervention for twin-to-twin transfusion syndrome: case reports and literature review. Fetal Diagn Ther 2016;40:67-72. Crossref

25. Yu FN, Mak AS, Chan NM, Siu KL, Ma TW, Leung KY. Prospective risk of stillbirth and neonatal complications for monochorionic diamniotic and dichorionic diamniotic twins after 24 weeks of gestation. J Obstet Gynaecol Res 2021;47:3127-35. Crossref

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Utilisation of village clinics in Southwest China: evidence from Yunnan Province

Hong Kong Med J 2022 Aug;28(4):306–14 | Epub 8 Aug 2022

https://doi.org/10.12809/hkmj209153

ORIGINAL ARTICLE (Healthcare in Mainland China)

Utilisation of village clinics in Southwest China: evidence from Yunnan Province

Y Shi, PhD¹; S Song, MA¹; L Peng, MA¹; J Nie, PhD¹; Q Gao, PhD¹; H Shi, PhD²; DE Teuwen, MD³; H Yi, PhD^4,5

¹ Center for Experimental Economics in Education, Shaanxi Normal University, Xi’an, China

² Business Department Center of Red Cross Society of China, Beijing, China

³ Ghent University Hospital, Department of Neurology, Ghent, Belgium

⁴ China Center for Agricultural Policy, School of Advanced Agricultural Sciences, Peking University, Beijing, China

⁵ Institute for Global Health and Development, Peking University, Beijing, China

Corresponding author: Dr Q Gao (gqiufeng820@163.com)

Full paper in PDF

Abstract

Introduction: Primary healthcare in rural China is underutilised, especially in village clinics in Southwest China. The aim of this study was to explore any relationships among the ethnicity of the healthcare provider, the clinical competence of the healthcare provider, and the utilisation of village clinics in Southwest China.

Methods: This cross-sectional survey study involved 330 village healthcare providers from three prefectures in Yunnan Province in 2017. Multiple logistic regressions were adopted to investigate the utilisation of primary healthcare among different ethnic healthcare providers.

Results: Primary healthcare utilisation was higher in village clinics where healthcare providers were Han Chinese than those where healthcare providers were ethnic minority (151 vs 101, P=0.008). The logistic regression analysis showed that clinical competence was positively associated with the utilisation of primary healthcare (odds ratio [OR]=1.49, 95% confidence interval [CI]=1.12-2.00; P=0.007) and that inadequate clinical competence of ethnic minority health workers may lead to a lag in the utilisation of primary healthcare (OR=0.45, 95% CI=0.23-0.89; P=0.022).

Conclusion: Our results confirm differences in the utilisation of primary healthcare in rural Yunnan Province among healthcare providers of different ethnicities. Appropriate enhancements of clinical competence could be conducive to improving the utilisation of primary healthcare, especially among ethnic minority healthcare providers.

New knowledge added by this study

The results of our study confirmed that differences exist in the utilisation of primary healthcare in rural Yunnan Province among different ethnic minority healthcare providers.
Significant differences in clinical competence were observed between ethnic minority and Han Chinese majority healthcare providers.
The underdeveloped clinical competence of ethnic minority healthcare providers likely contributes to the difference in utilisation of village clinics.

Implications for clinical practice or policy

Proper enhancements for ethnic minority providers could be conducive to improving their clinical competence.
More involvement from the government and adequate in-service training for ethnic minority healthcare providers could help improve the utilisation of primary healthcare.

[Abstract in Chinese]

Introduction

For rural residents, who account for approximately 41% of China’s population, primary healthcare is the main source of medical care.1 To meet their healthcare needs, China promoted a tiered medical system in 2015 to encourage people to fully utilise primary healthcare.2 3 Nevertheless, while the government invests various resources, primary healthcare in rural areas remains underused.4 5 6 From 2015 to 2018, the total number of out-patient visits in rural primary healthcare institutions decreased from 2.90 billion to 2.70 billion, while the number of hospital visits increased from 3.10 billion to 3.60 billion.7

Disparity exists in the utilisation of primary healthcare across different regions of China. Compared with rural residents in eastern China, the utilisation of primary healthcare among those in western China is relatively low.8 9 The lack of medical resources and sparseness of the land in western China contributes to the inconvenience of accessing primary healthcare among rural residents.10 11 12 In addition to the difference between eastern and western China, differences in the utilisation of primary healthcare exists among the provinces in western China.11 Although many studies have reported on the utilisation of primary healthcare in Southwest China, most have focused on the perspective of rural residents while neglecting the importance of providers, who play important roles in primary healthcare.3 4 Therefore, research concerning village healthcare providers in Southwest China could be conducive to understanding the utilisation of primary healthcare.

Southwest China is home to more ethnic minority village healthcare providers than other areas in China.11 To investigate village healthcare providers in Southwest China, the ethnicity of providers, which may be linked to the utilisation of healthcare, is a factor that cannot be ignored. Previous studies have illustrated that ethnic minority providers are more likely to attract patients from the same ethnicity, and this finding has been attributed to the patients’ preference instead of the capability of minority providers.13 14 Existing studies were mainly conducted outside China or were related to providers who performed traditional Chinese medicine.13 14 15 Therefore, knowledge regarding whether differences exist in the utilisation of primary healthcare among Chinese ethnic minority providers and Han Chinese majority providers is limited.

Clinical competence may influence the utilisation of healthcare and serves as a practical way to measure a doctor’s working performance and quality.16 17 Some studies in China have shown that the ethnicity of medical students might be related to their future clinical competence.18 19 20 21 22 Studies conducted in Southwest China confirmed the underdeveloped clinical competence of village providers, but most studies failed to distinguish the ethnicity of the healthcare providers.23 24 25 26 Whether ethnic minority healthcare providers in rural areas of China have underdeveloped clinical competence remains unclear.

Considering the above, the purpose of the present study was to investigate the utilisation of primary healthcare in western China. In particular, the aims were to clarify whether the ethnicity of healthcare providers affects utilisation of primary healthcare; whether there are differences in clinical competence among different ethnic groups; and whether clinical competence of healthcare providers affects utilisation of primary healthcare.

Methods

Study design, setting and sampling method

This study was a cross-sectional survey conducted in three prefectures (ie, prefecture-level cities) in Yunnan Province, an economically developing area in Southwest China. In 2017, the per capita gross domestic product in Yunnan Province was US$5068, which is lower than the national average (US$8777).27 The total population in Yunnan Province was 47.71 million, and the proportion of the rural population in Yunnan Province was 53.31%, which is much higher than the overall proportion of rural population in China (41.48%).27 The three prefectures included in our study have a total rural population of 6.50 million, accounting for 20.00% of the total rural population in Yunnan Province.

To investigate the utilisation of primary healthcare in rural China, we conducted a cross-sectional study in 330 village clinics (VCs), representing the first tiers of China’s three-tiered rural health system.4 In summary, we selected a random sample of 330 healthcare providers from three prefectures in three steps (Fig). First, we selected 10 counties (in three prefectures) at random, after excluding three urban counties and 13 counties with a minority population greater than 20%. Second, we used probability proportional to size sampling to randomly select 330 VCs proportional to the number of VCs in each county. Finally, we asked each clinic to list all staff serving in the clinic and describe their responsibilities. Considering the measurement of different types of medical practitioners, we excluded healthcare providers other than Western medicine practitioners (ie, traditional Chinese medicine practitioners or those responsible for public health services only). Then, we randomly selected one of the remaining village healthcare providers as our sample.

Figure. Flowchart of participants in this study

Data collection

The data collection was carried out in July 2017 by trained investigators. The survey consisted of a clinic form administered to the head of the VC and a clinician form administered to providers in each clinic verbally.

The clinic form (Supplementary Table 1) was used to collect basic information regarding the VCs, including the number of equipment per clinic, whether the drugs sold by the clinics met the zero price difference of medicine (a policy requires no mark-ups above the cost of drugs),6 the number of clinics within 5 km, the number of out-patient visits per clinic, and the number of providers per clinic.

The clinician form (Supplementary Table 2) consisted of two parts. The first part was used to obtain information regarding the provider’s demographics, working time allocation and income. This part included age, sex, ethnicity, basic salary, local residence (whether he/she was born and raised in the sample village), and time spent performing public health services. The second part was used to obtain detailed information on the providers’ in-service training participation in 2016 (the year before the survey year) and their clinical competence, including education level, certificate in rural medicine or higher, length of experience, and medical study.

Assessment of the utilisation of village clinics

The primary healthcare system provides generalist clinical care and basic public health services.1 China has promoted the three-tiered healthcare system to improve the use of primary healthcare. In rural China, the three-tiered healthcare system consists of VCs, township health centres, and county hospitals. Township health centres and VCs play a role in primary healthcare, and VCs mainly provide out-patient services under common clinical conditions. To assess the utilisation of VCs, the investigators asked the heads of the VCs to estimate (on average) the total number of out-patient visits during the previous month. The utilisation of the VCs was calculated using data related to the total number of out-patient visits, intramuscular injection visits, intravenous infusion visits, and number of healthcare providers in the clinics. Specifically, the utilisation of VCs in our research is measured on a per-provider basis. Thus, the utilisation of VCs equals the total number of out-patient visits divided by the number of healthcare providers.

Measurement of the providers’ clinical competence

Providers’ clinical competence is the quality of healthcare providers pertaining to medical knowledge, treatment quality, medical experience, medical study background, and medical training.28 In our study, we evaluated the providers’ clinical competence in the following dimensions: education above college level (measured medical knowledge); attainment of certificates in rural medicine or higher (measured treatment quality); length of experience (measured medical experience); participation in medical studies (measured medical study background); and completion of in-service training (measured medical training).

In clinical competence, multiple characteristics are often correlated; multicollinearity is a limitation of applying a multiple logistic regression analysis to measure clinical competence. A principal component analysis is often used to address this issue by transforming the data into one or two dimensions that serve as a summary of the characteristics, such as constructing an index.29 Therefore, we constructed the Clinical Competence Index to assess the overall clinical competence of the providers using a principal component analysis approach.

Statistical methods

To explore the relationships between the healthcare providers and the utilisation of VCs, we used a multiple logistic regression. We conducted three types of regressions, and the outcome variable was out-patient visits per doctor. In the first regression, we measured the relationship between the village providers’ ethnicity and the utilisation of VCs. In the second regression, we included only the variables measuring the providers’ clinical competence. This relationship might vary across different ethnicities, and a heterogeneity analysis is needed. In the third regression, we performed a heterogeneity analysis by including the interaction term ‘Clinical Competence Index ethnic minority providers’ to measure the providers’ clinical competence and its relationship with the utilisation of VCs across different ethnicities.

In each regression mentioned above, we assessed the correlations with a fixed set of facility-level and provider-level characteristics. These characteristics included the number of equipment per clinic, whether the drugs sold by the clinics met the zero price difference of medicine, the number of clinics within 5 km, the percentage of minority residents in the town, the providers’ sex, salary, local residency, and time spent providing public health services. Notably, in all regressions, we also controlled for county-fixed effects.

All statistical analyses were performed using Stata version 15.0 statistical software (Stata Corp, College Station [TX], United States). The results with a P value <0.05 were considered statistically significant.

Results

Characteristics and the utilisation of village clinics

The questionnaire surveys were sent to 330 VCs and 330 healthcare providers, and valid results were obtained from all (participation rate 100%). There were no significant differences in terms of the amount of clinic equipment (P=0.395) and the implementation of the zero price difference of medicine (P=0.396) among the VCs (Table 1). However, the proportion of minority residents in the towns significantly differed with type of VCs (P<0.001). We also found that VCs where Han Chinese providers worked faced more competition, as the number of clinics within 5 km of these clinics was significantly higher than that for clinics where ethnic minority providers worked (P=0.002). The average number of healthcare providers in the VCs was 2.79. There was a significant difference in the number of providers across clinics (P=0.016), and this difference was mainly due to the number of providers who treat patients (P=0.044). Among the 330 VCs, mean number of out-patient visits per doctor was 146. The results indicate that the Han Chinese providers conducted a significantly higher average number of out-patient visits than the ethnic minority providers (151 vs 101; P=0.008) [Table 1]. In addition, we documented intramuscular injection visits and intravenous infusion visits. There was also a significant difference between the ethnic minority and Han Chinese majority providers in intravenous infusion visits (P=0.023), but no significant difference was found in intramuscular injection visits (P=0.834).

Table 1. Facility characteristics and the utilisation of village clinics

Characteristics of the providers and their clinical competence

Most healthcare providers were male (64.5%), and 81.8% of providers were local residents (Table 2). The mean ± standard deviation annual salary of all providers was US$926±399, with no significant difference between the ethnic minority and Han Chinese majority providers (P=0.327). More than half of the healthcare providers devoted close to 60% of their work time to providing public health services (P=0.577).

Table 2. Healthcare provider characteristics

Among the 330 providers, 26.4% had a college degree or higher, and the proportion among the Han Chinese providers was similar to that (26.4%) among the ethnic minority providers (25.7%, P=0.927) [Table 2]. In total, 91.9% of the Han Chinese providers were confirmed to have at least certificates in rural medicine; however, the proportion was 74.3% among the ethnic minority providers (P=0.001). In addition, the length of experience of the Han Chinese providers was significantly higher than that of the ethnic minority providers (P=0.013). The proportion of full-time medical studies conducted by all providers was 52.7%, and more ethnic minority providers than Han Chinese providers received in-service medical training (P=0.085).

Determinants of the utilisation of village clinics

The ethnicity of the providers was negatively associated with the utilisation of VCs (odds ratio [OR]=0.53, 95% confidence interval [CI]=0.29-0.96; P=0.037) [Table 3]; the providers’ clinical competence was positively associated with the utilisation of VCs (OR=1.49, 95% CI=1.12-2.00; P=0.007) [Table 3]. To better examine this relationship, we performed a heterogeneity analysis (Table 4). The results suggest that ethnic minority providers were likely to have underdeveloped clinical competence, which could further limit the utilisation of VCs (OR=0.45, 95% CI=0.23-0.89; P=0.022) [Table 4]. We also measured the determinants of intravenous infusion visits, and the results suggest that the providers’ clinical competence (OR=1.43, 95% CI=1.16-1.77; P=0.001) [Supplementary Table 4] was associated with the utilisation of VCs.

Table 3. Logistic regression model of the utilisation of village clinics among 330 providers (n=330)

Table 4. Logistic regression model of the utilisation of VCs among 330 providers (n=330)

Discussion

The data enabled an analysis of the utilisation of primary healthcare in rural areas in Southwest China. In general, there are three key findings in this study. First, we found significant differences between Han Chinese and ethnic minority providers in the utilisation of VCs. Second, compared with Han Chinese providers, ethnic minority providers in our sample had poorer clinical competence in two dimensions (possession of rural physician certificate or length of experience). Finally, our results indicate that underdeveloped clinical competence is a factor responsible for the lower utilisation of VCs among ethnic minority providers.

Our survey data show that the average number of out-patient visits in the sampling VCs is 146 per month per doctor, which is lower than the number of out-patient visits in eastern China (188 per month per doctor, 2017).9 Consistent with previous studies, we believe that the inconvenience of accessing primary healthcare among rural residents contributes to this difference.23 Compared with Yunnan Province (116 per month per doctor, 2017), the utilisation of VCs in the sampling area was higher.9 Based on our investigation, the high utilisation of VCs in the sampling area could be explained by both the population density and local economic development. According to the China Statistical Yearbook, the rural residents in the three prefectures we studied accounted for 20.00% of the total rural residents in Yunnan Province, which is quite large compared with the rate in other regions.30 The gross domestic product of the sampling area is also relatively high in Yunnan Province.27

However, the number of out-patient visits to VCs where the main providers are ethnic minorities is significantly lower than that of VCs where the main providers are Han Chinese individuals. Previous studies have shown that patients visiting providers of their own race were more satisfied and deliberately chose providers of their own race because of personal preference and language issues.13 14 In contrast to these studies, we excluded the preference and language issues of patients. First, their studies were generally conducted in large hospitals with many providers, but the average number of providers in our sampled VCs was approximately two, limiting the patients’ choices. Second, regarding language, most (81.8%) providers in our study were local residents who were fluent in the local dialect. These providers rarely have communication problems with their patients. After the above exclusions, an investigation of the characteristics of different ethnic providers was performed. Consistent with previous studies, there was no significant difference in provider characteristics and income, and the amount of clinic equipment and implementation of zero price difference of the medicine did not differ.19 20

Furthermore, we find significant differences between ethnic minority and Han Chinese village providers in their clinical competence. As a crucial aspect of primary healthcare services in rural China, village providers are obligated to provide qualified medical services, which require abundant clinical competence.31 32 However, based on our evidence, even if rural patients in Southwest China were asked to follow the instructions of policymakers and seek care primarily in VCs, they would visit higher-level facilities with a relatively high cost considering the local providers’ poor clinical competence. In fact, this type of situation is already very common in rural China.3 16 25

Under such circumstances, our findings imply that the difference in the utilisation of VCs might be related to ethnic minority providers’ underdeveloped clinical competence. Despite the small number of previous studies, the current evidence is consistent with the main findings.1 24 On the one hand, early studies suggested that the quality of health providers limited the utilisation of primary healthcare.3 4 16 On the other hand, ethnic minority providers usually experience less supportive learning environments during their medical studies, which might help explain the lag in their clinical competence.33 34 35 Therefore, we believe that uniformly improving the clinical competence of village providers, especially that of ethnic minority village providers, is conducive to improving the utilisation of primary healthcare.1 36

The Government of the People’s Republic of China understands the benefits of improving the clinical competence of village providers. A series of human resource policies for health launched in 2010 had a positive impact in rural China.37 Among these policies, the encouragement of external training for healthcare providers has been proven effective and necessary.36 38 39 In-service training for village providers could help these providers be informed of the latest knowledge and skills to manage diseases, which could significantly improve the quality of their medical services.36 The government has implemented actions to encourage the training of ethnic minorities since 2009.40 Thus, the appropriate introduction of re-education and more medical training should be adopted among ethnic minority providers.

Considering previous studies with analyses based mainly on the utilisation of healthcare from the patient perspective, our study might be the first investigation to examine healthcare providers’ ethnicity and clinical competence.10 11 32 In addition, our quantitative data include a rich set of detailed information of VCs regarding out-patient visits and providers’ clinical competence. We hope that our findings offer key insights into the utilisation of primary healthcare in rural China.

Our study has two main limitations. First, the participants in this study were recruited from rural Southwest China, so unavoidably, the nationwide validity of our findings is limited. Second, the results were limited by the cross-sectional nature of the study, and no causal effect between the providers’ clinical competence and the utilisation of primary healthcare was detected. Future research could investigate how different ethnic providers influence the utilisation of VCs and seek to adopt multiple measures to reduce bias in investigations.

Conclusions

In conclusion, this study reveals differences in the utilisation of primary healthcare between ethnic minority providers and Han Chinese providers at VCs in rural areas in Southwest China. Notably, the results indicate that higher clinical competence is more likely to drive the utilisation of VCs. We believe that the results of this study provide compelling evidence that ethnic minority healthcare providers in Southwest China require further enhancement with respect to their clinical competence.

Author contributions

Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

As an adviser of the journal, Y Shi was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

Funding/support

H Yi received funding for this study from the Health and Hope Fund of the Business Development Center of the Red Cross Society of China and UCB of Belgium. Y Shi received funding from 111 Project (Grant number B16031), and Q Gao received funding from Innovation Capability Support Program of Shaanxi (Grant number 2022KRM007). The funders had no role in study design, data collection/analysis/interpretation, or manuscript preparation.

Ethics approval

The study was approved by the Peking University Institutional Review Board (Ref IRB 00001052-17033). The board approved the verbal consent procedure. Informed consent from all respondents as a requirement for completing the survey.

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Rapid antigen test during a COVID-19 outbreak in a private hospital in Hong Kong

Hong Kong Med J 2022 Aug;28(4):300–5 | Epub 17 Mar 2022

https://doi.org/10.12809/hkmj219559

ORIGINAL ARTICLE

Rapid antigen test during a COVID-19 outbreak in a private hospital in Hong Kong

Jonpaul ST Zee, FRCPath, FHKAM (Medicine)^1,2; Chris TL Chan, BSc (Hons) (UK), PhD (HK)¹; Alex CP Leung, MMedsc (HKU)¹; Bella PW Yu, MNurs²; Jhan Raymond L Hung, MNurs²; Queenie WL Chan, BScN, FHKAN (Medicine-Infection Control)²; Edmond SK Ma, MD (HK), FRCPath¹; KH Lee, MMed Sc (HKU), FHKAM (Community Medicine)³; CC Lau, MB, BS, FHKAM (Emergency Medicine)³; Raymond WH Yung, MB, BS, FHKCPath^1,2,3

¹ Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong

² Infection Control Team, Hong Kong Sanatorium & Hospital, Hong Kong

³ Hospital Administration, Hong Kong Sanatorium & Hospital, Hong Kong

Corresponding author: Dr Jonpaul ST Zee (jonpaul.st.zee@hksh.com)

Full paper in PDF

Abstract

Introduction: In response to two nosocomial clusters of coronavirus disease 2019 (COVID-19) in our hospital, we adopted a series of strict infection control measures, including regular rapid antigen test (RAT) screening for high-risk patients, visitors, and healthcare workers. We evaluated the diagnostic performance of a locally developed RAT, the INDICAID COVID-19 Rapid Antigen Test (Phase Scientific, Hong Kong), using respiratory samples from both symptomatic and asymptomatic individuals.

Methods: Real-time reverse-transcription polymerase chain reaction (rRT-PCR)–confirmed deep throat saliva (DTS) and pooled nasopharyngeal swab and throat swab (NPS/TS) samples collected from 1 November to 30 November 2020 were tested by INDICAID. Screening RATs were performed on asymptomatic healthcare workers during a 16-week period (1 December 2020 to 22 March 2021).

Results: In total, 20 rRT-PCR-confirmed samples (16 DTS, four pooled NPS/TS) were available for RAT. Using the original sample, RAT results were positive in 17/20 samples, indicating 85% sensitivity (95% confidence interval [CI]=62.11%-96.79%). Negative RAT results were associated with higher cycle threshold (Ct) values. For samples with Ct values <25, the sensitivity was 100%. Of the 49801 RATs collected from healthcare workers, 33 false positives and one rRT-PCR-confirmed case were detected. The overall specificity was 99.93% (95% CI=99.91%-99.95%). The positive and negative predictive values were 2.94% (95% CI=2.11%-4.09%) and 100%, respectively.

Conclusions: The INDICAID COVID-19 RAT demonstrated good sensitivity for specimens with high viral loads and satisfactory specificity for low-risk, asymptomatic healthcare workers.

New knowledge added by this study

Rapid antigen tests (RATs) are simple and rapid; they have high sensitivity for specimens with high viral loads. When RATs were applied as point-of-care tests, using specimens intended analysis by for real-time reverse-transcription polymerase chain reaction (rRT-PCR), infected patients could be identified before molecular results were available.
The use of RATs to regularly screen asymptomatic high-risk patients, visitors, and healthcare workers during a coronavirus disease 2019 outbreak led to successful control of the nosocomial outbreak and prevented further entry of community-acquired infections into the hospital.
The use of screening RATs and the establishment of a registration system for patient visitors led to minimal laboratory service disruption; visitation policies were maintained without reducing infection control measures.

Implications for clinical practice or policy

RATs are appropriate for the screening of individuals with recent exposure or early symptoms because of their high sensitivities for specimens with high viral loads.
RATs can be used in conjunction with rRT-PCR in outbreak situations to allow the rapid triage and isolation of infected individuals before confirmatory rRT-PCR results are available.
Regular RAT screening for asymptomatic high-risk patients, visitors, and healthcare workers is useful for preventing nosocomial outbreaks while causing minimal disturbances to laboratory services and visitation policies.

[Abstract in Chinese]

Introduction

Rapid diagnosis of coronavirus disease 2019 (COVID-19) is crucial, particularly during an outbreak situation when the segregation and immediate isolation of infected individuals are critical. This is because up to half of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are asymptomatic; moreover, infection transmission can be greater during the pre-symptomatic phase than during the symptomatic phase, leading to silent transmission.1 2 The ideal diagnostic test should be easy to perform and interpret; it should also have a rapid turnaround time. Despite higher costs and greater technical demands, the detection of unique viral sequences (eg, E, RdRP, N, and S genes) by nucleic acid amplification tests such as real-time reverse-transcription polymerase chain reaction (rRT-PCR) remains the ‘gold standard’ for diagnosis because of superior sensitivity and specificity.3 Although most contemporary automated PCR platforms are capable of integrated sample preparation, amplification, and software-assisted result interpretation, most such tests require approximately 1 hour to perform; this duration excludes specimen transportation time from the bedside or the field to the laboratory, as well as time for preparation by laboratory personnel. In contrast, rapid antigen tests (RATs; ie, immunochromatographic membrane assays), commonly known as lateral flow assays, are gaining popularity. Rapid antigen tests are rapid, easily deployable in the field without the need for specialised equipment, and relatively inexpensive; they require only minimal training for performance and subsequent interpretation of the results. Despite their lower sensitivities, several antigen-based diagnostic tests have received in vitro diagnostics emergency use authorisations from the United States Food and Drug Administration4 and are considered valuable for reducing transmission through the early detection of highly infectious cases and facilitation of contact tracing.5

Since the first local case of COVID-19 were confirmed on 4 February 2020, Hong Kong has experienced four waves of COVID-19 surges with over 11 000 cases reported. The fourth wave, which began in late October/early November, primarily comprised multiple clusters of locally acquired infections that involved food premises, construction sites, nursing homes, and dancing/singing venues.6 In November 2020, two clusters of nosocomial transmission of COVID-19 were found in a private ward and the renal dialysis unit of Hong Kong Sanatorium & Hospital. In both clusters, the source of nosocomial infection could be traced back to visitors and relatives of patients who belonged to the largest local COVID-19 cluster–the dancing/singing cluster. As a precautionary measure against future transmission, the hospital subsequently adopted a strict registration policy for patient visitors. Each patient could register a maximum of three visitors; each patient visitor was required to undergo RATs at 3-day intervals. Single RATs were required for other hospital visitors, including technicians and contractors who remained in clinical areas for >1 hour. In addition to the mandatory pre-admission PCR screening for all in-patients, PCR was repeated at 7-day intervals for long-term in-patients. For haemodialysis and oncology patients who required frequent visits, RATs were required at 3-day intervals or before each haemodialysis session, in addition to a weekly PCR test. Single RATs were also required for out-patient visits that involved mask-off procedures, such as dental procedures, rhinoscopy, lung function tests, or gastroscopy. In this study, we evaluated the diagnostic performance of the INDICAID COVID-19 Rapid Antigen Test (Phase Scientific, Hong Kong) using respiratory samples submitted by patients and staff members.

Methods

Clinical specimens

The rRT-PCR-confirmed SARS-CoV-2-positive respiratory specimens, including posterior pharyngeal saliva (ie, deep throat saliva; DTS) and pooled nasopharyngeal swab and throat swab (NPS/TS), submitted to our laboratory during 1 to 30 November 2020 were subjected to additional RATs. Deep throat saliva specimens were self-collected, in accordance with instructions from local health authorities.7 8 A video with detailed instructions was shown to all patients before the collection of their DTSs in a well-ventilated area with a hand-washing facility. Each DTS was spit into an empty sterile container, which was then double-bagged and submitted to the designated collection point in our hospital. The NPS/TS specimens were collected by healthcare workers in full personal protection equipment using a Dryswab™ PurFlock^® (Medical Wire, United Kingdom) for nasal swabbing and a flocked swab (Taizhou Sun Trine Biotechnology Co, Ltd, Taizhou City, China) for throat swabbing. Both swabs were submerged in the same viral transport medium (Biologix, Shandong, China), then double bagged and immediately transferred to the laboratory. Nasal swabs collected for the screening of asymptomatic hospital staff members from 1 December 2020 to 22 March 2021 were included for analysis. Nasal swabs were collected by healthcare workers using swabs provided by the RAT manufacturer. Each swab was inserted 2.5 cm into each nostril, twisted for 5 seconds, and then swirled in buffer solution at least 20 times.

Severe acute respiratory syndrome coronavirus 2 detection by nucleic acid amplification test

Deep throat saliva specimens (approximately 500 µL) from patients were mixed in a 1:1 (v/v) ratio with Sputasol (Oxoid, England), vortexed for 1 minute to reduce viscosity, and spun for 1 minute. An approximately 300-µL aliquot of the mixture was transferred to the Xpert^® Xpress SARS-CoV-2 cartridge. Nucleic acid amplification tests of DTS and pooled NPS/TS were performed in accordance with the manufacturer’s protocol.

Rapid antigen test

The INDICAID COVID-19 Rapid Antigen Test is an immunochromatographic membrane assay intended for the qualitative detection of SARS-CoV-2 nucleocapsid antigens in nasal swab and NPS samples. The SARS-CoV-2-specific monoclonal antibodies and a control antibody are immobilised at the test line (T) region and control line (C) region of a nitrocellulose membrane in a plastic cassette. Monoclonal anti-SARS-CoV-2 antibodies conjugated with red colloidal gold particles are used to detect the SARS-CoV-2 antigen. In accordance with the test protocol, the collected nasal swab or NPS was swirled 20 times in the buffer solution; three drops of the buffer solution were then applied to the sample well. When the SARS-CoV-2 antigen was present, it bound to the antibody-gold conjugate to form an immunocomplex. The immunocomplex then travelled across the strip via capillary action and bound to the SARS-CoV-2 antibodies at the test line (T), forming a visible red line. The test result was intended to be read between 20 and 25 minutes after sample application to the well. The result was considered invalid if the control line was invisible (Fig). The result was considered false positive if a subsequent PCR result was negative, or the positive band was not reproducible upon repeated assessment with a new INDICAID kit.

Figure. Left: valid negative result with a control band (C). Right: valid positive result (cycle threshold value 17) with a positive band (T) and a control band (C)

For RATs using DTS specimens, a 50-µL aliquot of Sputasol-treated DTS was mixed with 100 µL of INDICAID buffer. An approximately 100-µL aliquot of the mixture was then transferred to the sample well of the INDICAID kit.

For RATs using pooled NPS/TS specimens, a 50-µL aliquot of viral transport medium was added to the INDICAID buffer solution; a 100-µL aliquot of the mixture was then transferred to the sample well of the INDICAID kit.

Data analysis

To evaluate RAT sensitivity, we calculated the proportion of rRT-PCR-confirmed SARS-CoV-2-positive respiratory specimens that were correctly identified as positive by the RAT. Nasal swabs from asymptomatic hospital staff were used for evaluation of the RAT false positive rate, specificity, positive predictive value, and negative predictive value. Statistical tests were performed using MedCalc^® (https://www.medcalc.org/).

Results

In total, 20 PCR positive samples (16 DTS, four pooled NPS/TS) were available for further testing by RAT (Table 1). These specimens belonged to 18 symptomatic or asymptomatic patients who attended the hospital’s out-patient department and two hospital staff members who had positive screening results during contact tracing of a nosocomial cluster of COVID-19. Using the original sample, RATs yielded positive results in 17 samples, demonstrating 85% sensitivity (95% confidence interval [CI]=62.11%-96.79%). Negative RAT results were associated with higher cycle threshold (Ct) values. For samples with Ct values <25 (Xpert Xpress SARS-CoV-2), the sensitivity was 100%.

Table 1. Correlation between INDICAID result and cycle threshold (Ct) value of 20 SARS-CoV-2-positive samples

In total, 49 801 RAT screenings were performed on asymptomatic healthcare workers during 16 weeks from 1 December 2020 to 22 March 2021 (Table 2). In all, 33 false positives and one PCR-confirmed case were detected during this period. In the first week of hospital-wide staff screening, all specimens with positive RAT results exhibited negative PCR results. Importantly, these false positives were not reproducible by a repeat RAT, and many of them were caused by delays in reading the results (>25 min). Therefore, staff members were subsequently advised to strictly adhere to the manufacturer’s instructions; PCR was not performed unless a repeat RAT also yielded positive results. We also ensured that the healthcare workers with positive screening results were asymptomatic and did not have any recent exposure to confirmed cases; otherwise, rRT-PCR was performed. The reported false positive rate greatly decreased in subsequent weeks. The false positive rate of INDICAID was approximately 1/1509 tests in our cohort. The overall specificity was 99.93% (95% CI=99.91%-99.95%). The positive predictive value was 2.94% (95% CI=2.11%-4.09%), while the negative predictive value was 100%.

Table 2. Number of rapid antigen tests (INDICAID), false positive rate, and specificity when performed on asymptomatic healthcare workers during a 16-week period (1 December 2020 to 22 March 2021)

A staff member from the Engineering and Maintenance Department exhibited positive RAT results during his pre-symptomatic period in March 2021. He subsequently exhibited positive rRT-PCR results (Ct values of approximately 20) and developed mild upper respiratory tract symptoms. This staff member had no known exposure to a confirmed COVID-19 case but had received physiotherapy in the hospital during the incubation period. He did not have any direct patient contact. His close contacts, including co-workers who shared the same workspace and his attending physiotherapist, were offered immediate screening. All of his close contacts were quarantined, but no secondary cases were identified.

Discussion

The RAT used in this study was a SARS-CoV-2 antigen lateral flow assay with a reported detection limit of 140 TCID50/swab; it has positive and negative percent agreements of 96% (95% CI=86.3%-99.5%) and 100% (95% CI=92.9%-100%), respectively, when performed on contrived samples near the test’s limit of detection (2xLoD) and simulated negative matrix. Although the manufacturer does not specifically recommend the use of DTS and pooled NPS/TS specimens, our evaluation showed a satisfactory sensitivity for these samples, particularly for samples with high viral loads (100% sensitivity for Ct values <25). The INDICAID test specificity was high; however, the positive predictive value was only 2.94% (95% CI=2.11%-4.09%). This finding was presumably caused by low disease prevalence in our cohort because all RATs were performed on asymptomatic healthcare workers without exposure history.

In a Cochrane review of five studies regarding SARS-CoV-2 RATs, their sensitivities considerably varied (mean, 56.2%; 95% CI=29.5%-79.8%), while their specificities were consistently high (mean, 99.5%; 95% CI=98.1%-99.9%).9 The World Health Organisation recommends the use of SARS-CoV-2 RATs for screening to support outbreak investigations and contact tracing for rapid isolation of positive cases; they should also be used in communities with widespread transmission where the nucleic acid amplification test capacity is limited, although such tests should meet the minimum performance requirements of ≥80% sensitivity and ≥97% specificity. Moreover, a negative RAT result should be considered presumptive and insufficient for removal of a contact from quarantine requirements.10 The European Centre for Disease Prevention and Control has higher performance requirements of ≥90% sensitivity and ≥97% specificity for SARS-CoV-2 RATs. The positive predictive value of any clinical test could be influenced by the pretest probability. Therefore, both the World Health Organisation and the European Centre for Disease Prevention and Control do not recommend the use of SARS-CoV-2 RATs on asymptomatic individuals without contact history and in low prevalence communities (eg, <10%).5 10 The United States Centers for Disease Control and Prevention has provided an antigen test algorithm that focuses on pretest probability: a negative RAT result should be confirmed by a nucleic acid amplification test in situations where the pretest probability is high, while a negative antigen test could indicate the absence of SARS-CoV-2 infection in an asymptomatic individual who had no known exposure to a COVID-19 case within the previous 14 days.11

Rapid antigen test sensitivity is higher during the early course of infection (5-7 days after symptom onset) when both viral load and infectivity are at their peaks.9 10 12 13 14 A negative RAT result is insufficient to rule out infection, although it is associated with lower infectivity. In a field evaluation of the Panbio™ COVID-19 Ag Rapid Test Device for symptomatic patients (n=412) attending primary healthcare centres, SARS-CoV-2 could not be cultured from specimens that yielded rRT-PCR+/RAT– results (n=11); the authors of the study concluded that patients with RT-PCR-proven COVID-19 and negative RAT results were unlikely to be infectious.15 Because of their timeliness and simplicity, RATs provide added value for contact tracing and patient triage. Considering the limitations of RATs, we used them as screening tools for people who were at highest risk of SARS-CoV-2 transmission, such as immunocompromised oncology and renal failure patients who attended out-patient chemotherapy and haemodialysis treatment centres, as well as out-patients who underwent mask-off procedures. Our frequent screening approach constituted an attempt to compensate for the moderate sensitivity of the RAT. The scale of screening in our hospital was very large and could only be achieved by a point-of-care test that permitted decentralised testing (ie, at the site of clinical encounter); this allowed minimal impact to our daily laboratory operation.

Among the 49 801 RATs performed for weekly staff screening during the 16-week study period, only one PCR-confirmed case was detected. Although the cost-effectiveness has not been determined, the early case detection could have prevented a major nosocomial outbreak and service disruption affecting the Engineering and Maintenance Department and the Physiotherapy Department.

To control the fourth wave of COVID-19 in Hong Kong, authorities repeatedly enforced lockdowns within communities containing multiple cases of COVID-19; this facilitated mandatory testing of all residents in those communities. When respiratory samples were collected for complementary RAT and PCR assessments, positive results could be obtained before molecular results were available. Rapid antigen tests allowed rapid specimen triage and the preliminary isolation of individuals with presumptive positive results. This type of dual-track testing was also used during screening of a local community outbreak (personal communication). In addition to the screening function, RATs have been utilised by some laboratories for secondary rapid confirmation of positive rRT-PCR results.

Our study had several limitations. First, we could not evaluate the diagnostic sensitivity of the INDICAID test using the recommended types of specimens (ie, nasal swab and NPS) because most of our patient samples were DTS and pooled NPS/TS. Second, asymptomatic infections with viral loads below the INDICAID detection limit could have been missed because no parallel rRT-PCR analyses were conducted. Third, the effects of mutant SARS-CoV-2 strains on the INDICAID detection limit were not evaluated.

In conclusion, RATs are rapid and simple point-of-care tools that can shorten the COVID-19 testing turnaround time; they can be used in many different strategies. Our study showed that the INDICAID COVID-19 RAT has good sensitivity for specimens with high viral loads and satisfactory specificity for low-risk, asymptomatic healthcare workers.

Author contributions

Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: JST Zee.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

As an epidemiology adviser of the journal, ESK Ma was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

Acknowledgement

The authors acknowledge the excellent work and contributions by staff members at the Clinical Pathology Laboratory, Infection Control Team, and Audit Office of Quality and Safety Division of Hong Kong Sanatorium & Hospital.

Funding/support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

This study obtained ethics approval (RC-2021-08) from the Research Ethics Committee of the Hong Kong Sanatorium & Hospital Medical Group.

References

1. Ren R, Zhang Y, Li Q, et al. Asymptomatic SARS-CoV-2 infections among persons entering China from April 16 to October 12, 2020. JAMA 2021;325:489-92. Crossref

2. Li F, Li YY, Liu MJ, et al. Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study. Lancet Infect Dis 2021;21:617-28. Crossref

3. World Health Organization. Diagnostic testing for SARS-CoV-2 Interim guidance, 11 September 2020. Available from: https://apps.who.int/iris/handle/10665/334254. Accessed 11 Sep 2020.

4. US Food and Drug Administration. In vitro diagnostics EUAs. Available from: https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euas. Accessed 6 May 2021.

5. European Centre for Disease Prevention and Control. Options for the use of rapid antigen tests for COVID-19 in the EU/EEA and the UK. 19 November 2020. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/Options-use-of-rapid-antigen-tests-for-COVID-19.pdf. Accessed 6 May 2021.

6. Liu Y, Gu Z, Liu J. Uncovering transmission patterns of COVID-19 outbreaks: a region-wide comprehensive retrospective study in Hong Kong. EClinicalMedicine 2021;36:100929. Crossref

7. Centre for Health Protection, Department of Health, Hong Kong SAR Government. Information sheet on deep throat saliva (DTS) collection. Available from: https://www.chp.gov.hk/files/pdf/information_sheet_on_dts_en.pdf. Accessed 6 May 2021.

8. Hospital Authority, Hong Kong SAR Government. Patient information sheet on deep throat saliva collection. Available from: https://www.ha.org.hk/haho/ho/cc/Information_sheet_en_txt.pdf. Accessed 6 May 2021.

9. Dinnes J, Deeks JJ, Adriano A, et al. Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev 2020;(8):CD013705. Crossref

10. World Health Organization. SARS-CoV-2 antigen-detecting rapid diagnostic tests: an implementation guide. Available from: https://www.who.int/publications/i/item/9789240017740. Accessed 6 May 2021.

11. US Centers for Disease Control and Prevention. Using antigen tests. Available from: https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html. Accessed 16 Dec 2020.

12. Li D, Li J. Immunologic testing for SARS-CoV-2 infection from the antigen perspective. J Clin Microbiol 2021;59:e02160-20. Crossref

13. Prince-Guerra JL, Almendares O, Nolen LD, et al. Evaluation of Abbott BinaxNOW rapid antigen test for SARS-CoV-2 infection at two community-based testing sites—Pima County, Arizona, November 3-17, 2020. MMWR Morb Mortal Wkly Rep 2021;70:100-5. Crossref

14. Kohmer N, Toptan T, Pallas C, et al. The comparative clinical performance of four SARS-CoV-2 rapid antigen tests and their correlation to infectivity in vitro. J Clin Med 2021;10:328. Crossref

15. Albert E, Torres I, Bueno F, et al. Field evaluation of a rapid antigen test (Panbio™ COVID-19 Ag Rapid Test Device) for COVID-19 diagnosis in primary healthcare centres. Clin Microbiol Infect 2021;27:472.e7-10. Crossref

Effects of strict public health measures on seroprevalence of anti–SARS-CoV-2 antibodies during pregnancy

Hong Kong Med J 2022 Aug;28(4):294–9 | Epub 28 Jan 2022

https://doi.org/10.12809/hkmj219653

ORIGINAL ARTICLE

Effects of strict public health measures on seroprevalence of anti–SARS-CoV-2 antibodies during pregnancy

Hillary HY Leung, MB, BS, BSc¹; Christy YT Kwok, BMBS¹; Daljit S Sahota, BEng, PhD¹; Maran BW Leung, PhD¹; Grace CY Lui, MB, ChB (Hons), PDipID²; Susanna SS N, g, MB, ChB, FHKAM (Medicine)³; WC Leung, MB, BS, MD (HKU)⁴; Paul KS Chan, MB, BS, MD (CUHK)²; Liona CY Poon, MB, BS, MD (Res) (University of London)¹

¹ Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong

² Division of Infectious Diseases, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

³ Division of Respiratory Diseases, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

⁴ Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong

Corresponding author: (liona.poon@cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: A substantial number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic throughout the course of infection. Nearly half of pregnant women with coronavirus disease 2019 (COVID-19) are asymptomatic upon diagnosis; these cases are not without risk of maternal morbidity. Here, we investigated the seroprevalence of anti–SARS-CoV-2 antibodies in an unselected sample of pregnant women in Hong Kong.

Methods: This prospective cohort study included pregnant women who presented for routine Down syndrome screening (DSS) between November 2019 and October 2020; all women subsequently delivered at the booking hospitals. Serum antibodies against SARS-CoV-2 were analysed using a qualitative serological assay in paired serum samples taken at DSS and delivery for all participants.

Results: In total, 1830 women were recruited. Six women (0.33%) were seropositive at the DSS visit; this seropositivity persisted until delivery. Of the six women, none reported relevant symptoms during pregnancy; one reported a travel history before DSS and one reported relevant contact history. The interval between sample collections was 177 days (range, 161-195). Among women with epidemiological risk factors, 1.79% with travel history, 50% with relevant contact history, and 0.77% with community SARS-CoV-2 testing history, were seropositive.

Conclusion: The low seroprevalence in this study suggests that strict public health measures are effective for preventing SARS-CoV-2 transmission. However, these measures cannot be maintained indefinitely. Until a highly effective therapeutic drug targeting SARS-CoV-2 becomes available, vaccination remains the best method to control the COVID-19 pandemic.

New knowledge added by this study

The seroprevalence of severe acute respiratory syndrome coronavirus 2 (anti–SARS-CoV-2) antibodies in an unselected sample of pregnant women in Hong Kong was low.
Public health measures are effective for limiting the transmission of SARS-CoV-2.
Anti–SARS-CoV-2 antibodies persist for at least 6 months.

Implications for clinical practice or policy

Serological testing could be utilised at antenatal screening to confirm the presence of anti–SARS-CoV-2 antibodies, preferably acquired through vaccination; such antibodies would provide some protection for the pregnant woman and her baby during the remaining portion of the pregnancy.

[Abstract in Chinese]

Introduction

A substantial number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain completely asymptomatic throughout the course of infection.1 In a recent prospective observational study of maternal and neonatal complications among 2130 pregnant women with and without SARS-CoV-2 infection, 44% of pregnant women diagnosed with coronavirus disease 2019 (COVID-19) were asymptomatic upon diagnosis. Despite this asymptomatic status, they exhibited increased risks of maternal morbidity (relative risk=1.24; 95% confidence interval=1.00-1.52) and pre-eclampsia (relative risk=1.63; 95% confidence interval=1.01-2.63), compared with pregnant women who had not been diagnosed with COVID-19.2 In a retrospective cohort study conducted in Spain, 3.1% of 759 pregnant women exhibited anti–SARS-CoV-2 antibodies and had been asymptomatic throughout pregnancy.3 Serological testing may serve as a useful tool to identify pregnant women who have recovered from a recent asymptomatic SARS-CoV-2 infection; this information can help guide the management of potential future complications.

Before the imposition of strict border control, a large number of people travelled between Hong Kong and the rest of the world each day. Pregnant women could have been infected without their knowledge because of asymptomatic or very mild disease. Furthermore, pregnancy symptoms can mask some COVID-19 symptoms, particularly if the COVID-19 symptoms are mild.4 In this study, we invited women who had undergone Down syndrome screening (DSS) since November 2019 to ascertain the seroprevalence of anti–SARS-CoV-2 antibodies in an unselected sample of pregnant women in Hong Kong. The findings were expected to provide insights concerning the asymptomatic infection rate among pregnant women.

Methods

This prospective cohort study included pregnant women who presented for routine DSS and underwent routine blood sample collection at 11 to 13 weeks of gestation between November 2019 and October 2020. All participants delivered at Kwong Wah Hospital or Prince of Wales Hospital, Hong Kong; the last delivery occurred in March 2021. Eligibility criteria included consent to serum storage for future research purposes and intention to deliver at the booking hospital. Eligible women who attended the booking hospital for delivery were invited to participate in the study. Women who delivered elsewhere, experienced pregnancy termination or miscarriage, or received a diagnosis of COVID-19 before the study were excluded. Women who agreed to participate in the study were asked to provide written informed consent for blood collection at delivery. Symptoms of COVID-19 throughout the pregnancy were evaluated at recruitment and at delivery.

Serum antibodies against SARS-CoV-2 were analysed using a qualitative serological assay. Qualitative detection of anti–SARS-CoV-2 antibodies (immunoglobulin G [IgG] and immunoglobulin M [IgM]) directed against the nucleocapsid protein (N-protein) of the virus was performed using the Elecsys Anti–SARS-CoV-2 assay (Roche, United States) on a Cobas^®e411 analyser. The result was provided as a cut-off index (COI). A positive anti–SARS-CoV-2 antibody result was defined as COI >=1.0. Individuals who had recovered from COVID-19 were recruited as positive control cases (COI >=1.0); individuals who had negative SARS-CoV-2 test results were recruited as negative control cases (COI <1.0) to ensure quality control in the anti–SARS-CoV-2 immunoassay.

Positive results based on qualitative detection of anti–SARS-CoV-2 antibodies were subsequently confirmed by quantitative measurements of IgG and IgM antibodies against the SARS-CoV-2 spike protein by using enzyme-linked immunosorbent assays (ImmunoDiagnostics Limited, Hong Kong). All tests were performed in duplicate, in accordance with the manufacturer’s instructions. Results were interpreted as negative when the optical density was <0.2 and as positive when the optical density was >=0.2. For samples with positive results, anti–spike protein concentrations (ng/mL) were calculated.

Continuous variables were expressed as medians (interquartile ranges or ranges). Categorical variables were summarised as counts and percentages. SPSS Statistics (Windows version 26.0; IBM Corp, Armonk [NY], United States) was used for data analyses.

The STROBE reporting guidelines were used during the preparation of this manuscript.

Results

In total, 3219 consecutive pregnant women were approached; 306 declined participation and 1083 were excluded, including two with laboratory-confirmed SARS-CoV-2 infection, 69 who experienced miscarriage or pregnancy termination, and 1012 who planned delivery elsewhere. Thus, 1830 women were recruited to the study and provided written informed consent to participate. In total, 1810 (98.9%) women were Chinese, and 852 (46.6%) women were nulliparous. The median (interquartile range) maternal weight, height and age were 55.5 kg (50.3-62.5), 159 cm (155-163) and 33.0 years (30.2-36.4), respectively.

In total, six women (0.33%) were seropositive (COI >=1) at the DSS visit; this seropositivity persisted until delivery. Among these six women, one exhibited both anti–SARS-CoV-2 IgG and IgM antibodies; the IgM antibodies were undetectable at delivery. The remaining seropositive women exhibited only anti–SARS-CoV-2 IgG antibodies at both visits. All six of these women reported no relevant symptoms during pregnancy. Among the six women, one reported a travel history before her first DSS and one reported relevant contact history. The median COIs were 2.465 (interquartile range=1.430-3.178) and 1.680 (interquartile range=1.145-2.350) at DSS and delivery, respectively. The interval between sample collections was 177 days (range, 161-195). The COI at delivery was lower by a median of 31.8% (range, 12.0-35.1), compared with the COI at the DSS visit.

Characteristics of the study sample are presented in the Table. Fifty six women reported a travel history during pregnancy; one (1.79%) was seropositive at both visits. Two women reported relevant contact history during pregnancy; one (50.0%) was seropositive at both visits. Forty two women reported relevant symptoms during pregnancy; all were seronegative at both visits. Of the 1788 asymptomatic women, six (0.34%) were seropositive at both visits. In all, 259 women reported undergoing community SARS-CoV-2 testing during pregnancy; all tested negative. Among these 259 women, two (0.77%) were seropositive at both visits.

Table. Characteristics of the study sample

Discussion

Our findings demonstrated a low seroprevalence (0.33%) of anti–SARS-CoV-2 antibodies in an unselected sample of pregnant women in Hong Kong. Among women with risk factors for SARS-CoV-2 infection, 1.79% and 50% with a travel history and relevant contact history, respectively, were seropositive. This finding suggests that targeted serological testing of pregnant women with a positive epidemiological link is useful for identifying women who have recovered from asymptomatic SARS-CoV-2 infection. A limitation of this study was that we relied on recruited individuals to recall COVID-19 symptoms throughout pregnancy, using only two recall time points: recruitment and delivery. This aspect may have introduced recall bias, particularly when COVID-19 symptoms could be non-specific and overlap with pregnancy symptoms. However, this limitation presumably did not have a large effect on the results because the seroprevalence of anti–SARS-CoV-2 antibody found in our unselected sample of pregnant women was very low. With a population of over 7 million, Hong Kong has largely been successful in controlling the transmission of SARS-CoV-2. Only 11 981 confirmed or probable cases have been recorded since the beginning of the epidemic.5 Thus, it is reasonable that the number of asymptomatic SARS-CoV-2 infections has also been low; this low number of asymptomatic infections has led to a low seroconversion rate in pregnant women.

Compared with other seroprevalence studies in pregnant women, the seroprevalence recorded in our study was substantially lower. The seroprevalence rates were 14% and 21% in Barcelona6 and southern Madrid3 (both in Spain), respectively. The low seroprevalence of anti–SARS-CoV-2 antibodies recorded in our study is presumably related to the implementation of a series of infection control strategies, including strict border control, mandatory quarantine for inbound travellers, mask wearing, and meticulous contact tracing. Hong Kong has learnt from its prior experience combating the SARS (severe acute respiratory syndrome) outbreak in 2003; accordingly, it implemented serious control measures early during the current epidemic. The Figure outlines the timeline of public health measures implemented during the first three waves of the epidemic in Hong Kong. By the end of March 2020, Hong Kong had closed its border to all incoming non-residents arriving from overseas and stopped transits through the city. All returning residents were subject to mandatory quarantine for 14 days; the quarantine period was extended to 21 days in December 2020. Locally, temporary closures of gyms, karaoke venues, clubs, and bars were periodically enforced, depending on the incidence of COVID-19. Dine-in service was forbidden from 6:00 pm to 5:00 am for several months, beginning in mid-July 2020. Mask wearing in public indoor areas and public transportation was also mandatory at that time. Notably, all seropositive cases in this study were first identified at the DSS visit between February 2020 and July 2020. This suggests that the seropositive cases acquired their infections during the first two waves of the epidemic; the implementation of stricter control measures by the local government during the third wave might have led to a lower transmission rate of asymptomatic infection among pregnant women, resulting in a lack of seroconversion during that period. Moreover, pregnant women are presumably more careful about social distancing and compliant with public health regulations. It would be useful to compare our seroprevalence results with the findings in other countries where strict measures were also implemented, such as Australia and New Zealand.

Figure. Timeline of public health measures during the first three waves of the COVID-19 epidemic in Hong Kong

The humoral immune response is characterised by the production of virus-specific neutralising antibodies. Regardless of whether patients are symptomatic, IgG or IgM seroconversion has been observed in 65% to 100% of patients after infection with SARS-CoV-2.7 8 9 10 We previously demonstrated that 75% of pregnant women with laboratory-confirmed SARS-CoV-2 infection were seropositive at delivery.11 In addition to the strict control measures mentioned above, the low seroprevalence recorded in our study might have been related to undetectable antibody levels at the time of specimen collection—the timing of blood sample collection might not have been compatible with antibody detection. However, this is unlikely to have affected the findings among the large number of pregnant women in this study. A longitudinal study conducted in Wuhan, China, demonstrated that the median times from the first virus-positive test result to IgG or IgM seroconversion were 7 and 14 days in asymptomatic and symptomatic patients, respectively.12 In the asymptomatic cohort, all patients underwent seroconversion within 14 days from the first positive reverse transcriptase–polymerase chain reaction result.12 While waning immunity was observed at 5 months after infection,13 two studies showed that the antibody levels remained high and detectable at 8 months after infection.14 15 This finding is consistent with our results that the antibodies persisted until delivery in all women who had demonstrated seroconversion at the DSS visit. Because the two blood samples in this study were collected approximately 6 months apart, the timing of specimen collection was presumably adequate to identify most women who had contracted SARS-CoV-2 and developed detectable levels of antibodies.

Concerns regarding the usefulness of serological testing have been raised because of the uncertain onset and duration of humoral immunity; our study demonstrated a very low seroconversion yield in an unselected sample of pregnant women. Because of the ongoing vaccination programme, it is increasingly difficult to distinguish people who have acquired humoral immunity through natural infection from people who have acquired humoral immunity through vaccination. While the strict public health measures in Hong Kong have significantly reduced community transmission of SARS-CoV-2, these measures cannot be maintained indefinitely. The adverse effects of prolonged social distancing measures on the economy, education, mental health, and well-being of the population are immeasurable. There is increasing evidence that the COVID-19 mRNA vaccines are safe and effective; thus, pregnant women and women planning to become pregnant are encouraged to undergo vaccination at the earliest opportunity because pregnancy is a risk factor for severe COVID-19–related complications (eg, intensive care unit admission, invasive ventilation requirement, and death).16 17 The risk of preterm birth is also greater among pregnant women with COVID-19, compared with pregnant women who do not have COVID-19.18 19 20 Our study has demonstrated that anti–SARS-CoV-2 antibodies found at DSS persist until delivery. This result suggests that the presence of anti–SARS-CoV-2 antibodies in early pregnancy, preferably acquired through vaccination, would provide some protection for the pregnant woman and her baby during the remaining portion of the pregnancy.

Until a highly effective therapeutic drug targeting SARS-CoV-2 becomes readily available, mass vaccination remains the best solution to control the COVID-19 pandemic, avoid further lockdowns, and allow a return to “normal” pre–COVID-19 life, as well as saving lives. Our study highlights the importance of a successful vaccination campaign.

Author contributions

Concept or design: LCY Poon, DS Sahota.
Acquisition of data: HHY Leung, CYT Kwok, WC Leung, DS Sahota, MBW Leung, GCY Lui, SSS Ng.
Analysis or interpretation of data: HHY Leung, CYT Kwok, LCY Poon.
Drafting of the manuscript: HHY Leung, CYT Kwok, LCY Poon, DS Sahota.
Critical revision of the manuscript for important intellectual content: HHY Leung, CYT Kwok, LCY Poon, DS Sahota, SSS Ng, PKS Chan.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

LCY Poon has received speaker fees and consultancy payments from Roche Diagnostics and Ferring Pharmaceuticals. She has also received in-kind contributions from Roche Diagnostics. Other authors have disclosed no conflict of interest.

Acknowledgement

We thank Lijia Chen, Tracy CY Ma, Maggie Mak, Ching-man Mak, Angela ST Tai, Jeffery Ip, Phyllis Ngai, Andrea Chan, and Lisa LS Chan for making substantial contributions by involving in study coordination and patient recruitment.

Funding/support

This work was supported by Roche Diagnostic, United States, which provided reagents for the qualitative detection of anti– SARS-CoV-2 antibodies.

Ethics approval

Approval for the study was obtained from the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (CREC Ref No. 2020.214). Patients provided written informed consent to participate in the study; this included consent for serum storage for research purposes.

Trial registration

The study is registered with ClinicalTrials.gov (Ref NCT04465474).

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