The association between malignancy and thromboembolism (TE) was first described more than 100 years ago as ‘migratory thrombophlebitis’, commonly found in patients with visceral cancer.1 Indeed, TE is a common complication in patients with cancer and the second most common cause of death among such patients.2

Although the association between TE and pancreatic cancer is well established, its effects on overall survival remain unclear. The results of studies conducted in Western countries generally support the notion that TE is associated with worse overall survival.3 4 For example, a recent large retrospective study in France demonstrated a statistically significant decrease in overall survival of 2.9 months among patients with TE, compared with patients who did not exhibit TE.3 In contrast, studies involving Asian populations tend to show similar overall survival in patients with and without TE.5 6 7 Furthermore, among the published retrospective studies concerning the incidence of TE in Asian patients with pancreatic cancer, very few data have focused on the impact of TE in Chinese patients with pancreatic cancer.

In this study, we aimed to investigate the incidence of TE among patients with pancreatic cancer in our centre, where >99% of patients are Chinese; explore risk factors associated with the development of TE; and assess the prognostic impact of TE.

This retrospective study included patients with a histological diagnosis of exocrine pancreatic cancer who were treated at the Department of Clinical Oncology of Prince of Wales Hospital in Hong Kong between 2010 and 2015; eligible patients were identified by a review of electronic medical records. If histological findings were unavailable because of the clinician’s decision to omit biopsy evaluation, patients were identified using clinical diagnoses based on radiological findings and substantial elevation of the level of serum marker carbohydrate antigen 19-9 (CA 19-9) (ie, >500 IU/mL). Patients were excluded if they had an atypical clinical presentation (eg, normal CA 19-9 level) or histological findings of non-exocrine pancreatic malignancies, such as neuroendocrine tumour or metastatic disease.

The following data were extracted from each patient’s electronic and physical medical records: (1) demographics (sex and age); (2) World Health Organization (WHO) performance status score (0: able to perform normal activities without restriction; 1: ambulatory and able to perform light work with limitations on strenuous activities; 2: ambulatory [>50% of waking hours] and capable of self-care but unable to perform any work activities; 3: symptomatic and in a chair or bed for >50% of the day but not bedridden; 4: completely disabled [bedridden] and unable to perform any self-care); (3) disease stage (according to the seventh edition of the American Joint Committee on Cancer tumour-node-metastasis staging system); (4) site of disease (head, neck, body, or tail); (5) CA 19-9 level at diagnosis; and (6) initial treatment (surgery, chemoradiotherapy, chemotherapy, or supportive care). Any occurrences of TE (venous, arterial, or both) were recorded from the time of diagnosis until death or last follow-up; the site of thrombosis (lung, lower limb, multiple, or other) and type of anticoagulation treatment were also recorded. After data entry, all patient data were verified by two authors (LL Chan and KY Lam) under the supervision of the corresponding author (SL Chan). Each patient’s survival status was last updated on 31 October 2019.

Patient factors (eg, age, sex, WHO performance status, and initial treatment), tumour-related factors (eg, histological diagnosis status, CA 19-9 level at diagnosis, stage, and site) and TE-related factors (eg, type and site) were summarised as numbers and percentages for categorical variables, and as medians and interquartile ranges for continuous variables. The Wilcoxon rank-sum test and Chi squared test were used to identify variables associated with the development of TE. Variables that displayed statistical significance in univariate analysis were included in multivariable analysis. Age and sex were included in multivariable analysis as adjustment variables because they are known risk factors for the development of TE in patients with cancer, as well as standard clinical variables commonly included in such analyses.8 9 10 Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were performed to evaluate the relationship between overall survival and TE. P values <0.05 were considered statistically significant. All analyses were performed with R version 3.5.1.11

In total, 365 patients (217 [59.5%] men and 148 [40.5%] women; median age, 65 years [interquartile range=57-72]) were included in the study; baseline characteristics are summarised in Table 1. Of these patients, 268 (73.4%) had WHO performance status score of 0 to 1, whereas 97 (26.6%) scored 2 to 4. Furthermore, 219 patients (60.0%) had a histologically confirmed diagnosis; the remaining 146 patients (40.0%) were diagnosed by radiological and serological modalities. In terms of tumour staging, 171 patients (46.8%) had stage I to III disease; 194 patients (53.2%) had stage IV disease. The tumour location was at the pancreatic head in 203 patients (55.6%) and other sites (neck, body, or tail) in 162 patients (44.4%). Initial treatment was surgery in 78 patients (21.4%), chemotherapy or chemoradiotherapy in 153 patients (41.9%), and supportive care in 134 patients (36.7%). Additional details are provided in Table 1.

Among the 54 patients (14.8%) who developed TE, 32 (59.3%) had venous TE, 18 (33.3%) had arterial TE, and four (7.4%) had both. Lower limbs were the most common sites of thrombosis, with 55.6% of all thromboembolic events. Furthermore, three patients (5.6%) had pulmonary embolism. These findings are summarised in Table 2.

In univariate analysis, non-head pancreatic cancer (P=0.01) and stage IV disease (P=0.01) were significantly associated with TE. Other factors such as age at diagnosis, sex, WHO performance status, elevated CA 19-9 level at diagnosis, and initial treatment were not significantly associated with TE (Table 1). Multivariable analysis showed that stage IV disease was a significant risk factor (odds ratio=1.08, 95% confidence interval [CI]=1.00-1.17; P=0.046) [Table 3]. Median overall survival times in patients with and without TE were 4.88 months and 7.80 months, respectively (Fig 1); the difference between groups was not statistically significant (hazard ratio =1.08, 95% CI=0.80-1.49; P=0.58). Among patients with TE, median overall survival was not affected by anticoagulation treatment (no anticoagulation=4.77 months vs anticoagulation=5.63 months, hazard ratio=0.72, 95% CI=0.40-1.29; P=0.27) [Fig 2].

In the present study, approximately 15% of patients with pancreatic cancer developed TE. Lower limbs were the most frequent sites of TE, and venous TE was the most common type. In univariate analysis, both the site (non-head) and stage (IV) of disease were significantly associated with TE; multivariable analysis revealed that stage IV disease was a significant risk factor for TE.

There is considerable evidence of an association between pancreatic cancer and TE. In the first case series describing the relationship between TE and cancer, the incidence of TE was 60% in patients with pancreatic cancer, whereas it was 15% to 30% among patients with other malignancies.12 Several pathological processes have been implicated in this association.13 First, pancreatic cancer is characterised by high expression levels of tissue factor, which triggers the extrinsic coagulation pathway leading to thrombin formation. Second, the release of tumour-associated microvesicles promotes hypercoagulability and activates platelet aggregation. Third, the establishment of neutrophil extracellular traps secondary to neutrophil activation generates a matrix for platelet and tumour-associated microvesicle adhesion, resulting in blood clot formation.

Thromboembolism incidence of around 15% in our cohort is similar to that reported in other studies of Asian populations5 6 7 but lower than that in most Western populations (Table 4).3 4 14 The figures ranged from 20% to 40% in Western populations and 8% to 18% in Asian populations. Consistent with the findings in other studies of Asian populations, we observed no difference in overall survival between patients with and without TE. However, the literature suggests that, in Western populations, overall survival is affected by TE (Table 4).

Taken together, these findings support the hypothesis that TE incidences and outcomes are influenced by genetic and environmental differences between Western and Asian populations. For example, genetic variants in the clotting cascade (eg, factor V Leiden and thrombin gene G20210A) reportedly increase the risk of TE.15 These variants are much more prevalent in Western populations than in Asian populations.16 The resulting relative hypercoagulability may be one of the main reasons for the higher background incidence of TE in Western populations than in Asian populations.17 Another factor that may contribute to the difference in TE incidence between the two populations is obesity, an established risk factor for TE that is more common in Western populations.18

With respect to TE and pancreatic cancer prognosis, survival appears to be inherently longer in Western populations than in Asian populations (Table 4). Considering the aggressive nature of pancreatic cancer, it is possible that patients with shorter survival (eg, patients in Asian populations) do not live long enough to benefit from treatment of TE, whereas patients with longer survival (eg, patients in Western populations) experience a survival benefit from treatment of TE. Indeed, in a recent systematic review regarding the treatment outcomes of FOLFIRINOX and gemcitabine plus nab-paclitaxel in patients with pancreatic cancer, Lee et al19 showed that, compared with Asian populations, Western populations experienced a greater survival benefit from FOLFIRINOX (ie, standard treatment for metastatic pancreatic cancer) but a smaller survival benefit from gemcitabine plus nab-paclitaxel (which was not available to our patients during the present study). Therefore, a reasonable assumption is that anticoagulation can prolong survival in Western populations among patients treated with FOLFIRINOX. Further studies are needed to determine whether any subgroup of Asian patients with pancreatic cancer can benefit from the treatment of TE.

In univariate analysis, both non-head pancreatic cancer and metastatic disease were associated with the development of TE. However, in multivariable analysis, the association with non-head pancreatic cancer disappeared; metastatic disease was the sole risk factor for TE. This is not surprising—non-head pancreatic cancer is often detected at a late stage because clinical symptoms (eg, biliary obstruction) do not occur until the tumour becomes quite large. Therefore, the association of TE with non-head pancreatic cancer is mainly related to the advanced stage of disease. This finding is also consistent with the results of previous studies in which non-head pancreatic cancer was frequently detected at a later stage of disease.3 20

In the present study, we found that metastatic disease was a risk factor for TE, which is consistent with the results of previous studies.20 21 22 23 The underlying pathophysiological mechanisms involve multiple factors. For example, an advanced stage of disease is often associated with a higher tumour burden and bulky metastases, which can compress blood vessels and inhibit blood flow. Higher tumour burden can also affect WHO performance status, resulting in decreased mobility and bedridden status.

During the present study, most of our patients received low-molecular-weight heparin (LMWH) as treatment for cancer-associated TE, based on the results of the 2003 CLOT (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial in which LMWH demonstrated superior efficacy in preventing recurrent TE compared with coumarins (eg, warfarin) while maintaining a similar risk of bleeding.24 Recent studies have shown that direct oral anticoagulants (DOACs) such as edoxaban25 and apixaban26 are non-inferior to LMWH as secondary prophylaxis for TE with similar safety profiles. Accordingly, both LMWH and DOACs are valid options for the treatment of TE in patients with pancreatic cancer. This approach is consistent with the latest National Comprehensive Cancer Network 2021 guidelines.27 Although LMWH and DOACs demonstrate similar efficacy in preventing recurrent TE, other factors to consider in drug selection include baseline renal function, patient preference, ease of administration, risk of bleeding (eg, by tumour infiltration into the upper gastrointestinal tract), and availability of antidotes that can reverse anticoagulation.

Considering the overall poor prognosis of pancreatic cancer and the lack of an overall survival benefit associated with anticoagulation treatment of TE, factors such as quality of life should be considered when deciding whether to initiate or discontinue anticoagulation treatment. It is important to have clear discussions with patients regarding the risks and benefits of anticoagulation, particularly during the management of aggressive malignancies such as pancreatic cancer, where the life expectancy is often only months or weeks. Anticoagulation treatment, such as LMWH, may cause subcutaneous injection–related discomfort and carries an increased risk of bleeding, but the therapeutic effects of anticoagulation may relieve symptoms of TE (eg, calf swelling and dyspnoea). In a retrospective study of 128 patients with cancer-associated venous TE, Napolitano et al28 analysed the effects of anticoagulation on quality of life using the EORTC-C30 questionnaire; they found that long-term LMWH was not associated with worse quality of life. However, patients approaching the end of life often prefer to minimise their medication intake.29 In our clinic, we tend not to administer anticoagulation treatment if a patient’s life expectancy is <3 months or whose WHO status score is 3 to 4. This approach is consistent with the patient populations in recent clinical trials comparing the efficacies of DOACs and LMWH in the treatment of cancer-associated TE; patients with poor WHO performance status and short life expectancy were excluded from those trials.25 26

This study had a few limitations. First, its retrospective nature may have permitted bias related to missing data and the possibility of asymptomatic TE. However, TE tends to be symptomatic in patients with cancer; thus, it is unlikely that events were missed. Additionally, analyses of symptomatic TE are more relevant to real-world clinical practice. Second, the overall survival time of patients in the present study was worse than the survival times reported in randomised clinical trials of patients with metastatic pancreatic cancer.30 31 This discrepancy may have occurred because our study cohort was representative of real-world patients who more frequently have reduced liver function and worse WHO performance status. It may also be related to the absence of more effective chemotherapy (eg, nab-paclitaxel) during the study period.

In conclusion, this study demonstrated that the incidence of TE was around 15% in Chinese patients with pancreatic cancer. Notably, the presence of TE was not associated with worse overall survival, and metastatic disease increased the risk of TE.

Concept or design: LL Chan, KY Lam, SL Chan.
Acquisition of data: All authors.
Analysis or interpretation of data: LL Chan, DCM Lam, KY Lam, SL Chan.
Drafting of the manuscript: LL Chan, SL Chan.
Critical revision of the manuscript for important intellectual content: All authors.

The authors have no conflicts of interest to disclose.

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

This study protocol was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref No.: 2016.730). Informed patient consent was waived by the Committee due to the retrospective nature of the research.

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3. Frere C, Bournet B, Gourgou S, et al. Incidence of venous thromboembolism in patients with newly diagnosed pancreatic cancer and factors associated with outcomes. Gastroenterology 2020;158:1346-58.e4. Crossref

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12. Sproul EE. Carcinoma and venous thrombosis: the frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Am J Cancer. 1938;34:566-85.

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16. Jun ZJ, Ping T, Lei Y, Li L, Ming SY, Jing W. Prevalence of factor V Leiden and prothrombin G20210A mutations in Chinese patients with deep venous thrombosis and pulmonary embolism. Clin Lab Haematol 2006;28:111-6. Crossref

17. Wang KL, Yap ES, Goto S, Zhang S, Siu CW, Chiang CE. The diagnosis and treatment of venous thromboembolism in Asian patients. Thromb J 2018;16:4. Crossref

18. Yang G, De Staercke C, Hooper WC. The effects of obesity on venous thromboembolism: a review. Open J Prev Med 2012;2:499-509. Crossref

19. Lee YS, Lee JC, Kim JH, Kim J, Hwang JH. Pharmacoethnicity of FOLFIRINOX versus gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer: a systematic review and meta-analysis. Sci Rep 2021;11:20152. Crossref

20. Lee JC, Ro YS, Cho J, et al. Characteristics of venous thromboembolism in pancreatic adenocarcinoma in East Asian ethnics: a large population-based observational study. Medicine (Baltimore) 2016;95:e3472. Crossref

21. Dickmann B, Ahlbrecht J, Ay C, et al. Regional lymph node metastases are a strong risk factor for venous thromboembolism: results from the Vienna Cancer and Thrombosis Study. Haematologica 2013;98:1309-14. Crossref

22. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902-7. Crossref

23. Cronin-Fenton DP, Søndergaard F, Pedersen LA, et al. Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006. Br J Cancer 2010;103:947-53. Crossref

24. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53. Crossref

25. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-24. Crossref

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31. Vaccaro V, Sperduti I, Milella M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;365:768-9; author reply 769. Crossref

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease that affects premature infants.1 Infants born at low gestational age (GA) and/or low birth weight (BW) have a risk of ROP.2 Without timely intervention, severe ROP can progress to retinal detachment and blindness. Currently, ROP is one of the leading preventable causes of childhood blindness worldwide.3

Successful management of ROP relies on appropriate screening for early detection of high-risk disease, along with prompt treatment to prevent disease progression and visual loss. The United Kingdom (UK) Guidelines (published in 2008 by the Royal College of Paediatrics and Child Health, the Royal College of Ophthalmologists, and the British Association of Perinatal Medicine) recommend that all infants born at GA ≤31 weeks and 6 days or BW <1501 g undergo ROP screening.4 On the other hand, the United States (US) Guidelines (published in 2013 and 2018 by the American Academy of Pediatrics, American Academy of Ophthalmology, and American Association for Pediatric Ophthalmology and Strabismus) use narrower criteria; they recommend that all infants born at GA ≤30 weeks and 0 days or BW ≤1500 g undergo ROP screening.5 6

In Hong Kong, many hospitals use the UK screening criteria to guide ROP detection.7 8 9 Although the UK screening criteria are appropriate for ROP detection in many countries,10 11 12 they are not universally appropriate.13 14 15 16 17 18 In India14 15 19 and China,17 18 some infants with GA and BW above the UK screening thresholds also developed severe ROP requiring treatment. Thus, there is a need to understand the epidemiology of ROP in Hong Kong and evaluate the utility of current international guidelines for ROP detection in Hong Kong infants.

In the Early Treatment for Retinopathy of Prematurity study,20 type 1 ROP was defined as: (1) zone I, any stage of ROP, with plus disease; (2) zone I, stage 3 ROP, without plus disease; or (3) zone II, stage 2 or 3 ROP, with plus disease. Type 1 ROP requires treatment.4 6 Although it is important not to miss any infants who develop type 1 ROP requiring treatment, it is also important to avoid unnecessarily screening a large number of infants because the ROP screening procedure is painful and distressful for premature infants; it can lead to oxygen desaturation, tachycardia, and apnea.2 21 22 There is also a need to limit the systemic absorption of dilating eye drops that may cause adverse events.23 24 An effective strategy would reduce the number of infants unnecessarily screened without missing any cases of severe ROP requiring treatment. This study was conducted to determine whether the UK or the US screening criteria are more appropriate for Hong Kong, in terms of sensitivity for detecting type 1 ROP and the number of infants requiring screening.

In this retrospective cohort study, we reviewed the medical records of all premature infants who underwent ROP screening between 1 January 2009 and 31 December 2018 in Prince of Wales Hospital, Hong Kong. During the study period, all infants born at GA ≤31 weeks and 6 days or BW <1501 g (ie, UK screening criteria) underwent ROP screening. Infants with GA and BW above the UK screening threshold who had a high risk of ROP because of an unstable clinical course also underwent ROP screening at the request of the attending neonatologist. Analyses were performed to determine the numbers of ROP and type 1 ROP cases that would have been detected and missed if the US screening criteria (GA ≤30 weeks & 0 days or BW ≤1500 g) had been used.

All infants who underwent ROP screening in Prince of Wales Hospital were included. Infants were excluded if they died or were transferred to other institutions before completion of ROP screening without a known ROP outcome. Data were recorded concerning GA, BW, most severe ROP stage, any treatment, and treatment outcome. ROP findings were classified in accordance with the International Classification of ROP25 (Table 1). Treatment was indicated for infants with type 1 ROP. If the ROP stage differed between eyes in an individual infant, the more severe ROP stage was used for analysis.

The primary outcome measure was the sensitivity of the US screening criteria, compared with the UK screening criteria, for detection of type 1 ROP. The secondary outcome measure was the number of infants requiring screening.

R software (R version 3.6.1) was used for statistical analysis. All demographic data were expressed as medians and interquartile ranges (IQRs).

Of the 857 infants who underwent ROP screening in the study period, 61 were excluded because they died or were transferred to other hospitals before the completion of ROP screening. Thus, the remaining 796 infants (404 boys [50.8%] and 392 girls [49.2%]) were included in the study. The median GA was 30 weeks and 2 days (IQR=7 weeks & 3 days; range, 23 weeks & 4 days to 37 weeks & 4 days), and the median BW was 1320 g (IQR=471; range, 470-2550).

In total, 238 infants (29.9%) developed ROP, including 38 infants (4.8%) who developed type 1 ROP requiring treatment. The median GA and BW of infants who developed ROP were 27 weeks and 4 days (IQR=3 weeks & 0 days; range, 23 weeks & 4 days to 35 weeks & 5 days) and 943 g (IQR=366; range, 470-2550), respectively. The median GA and BW of infants who developed type 1 ROP were 26 weeks and 0.5 days (IQR=2 weeks & 2.5 days; range, 23 weeks & 4 days to 32 weeks & 0 days) and 781 g (IQR=315; range, 510-1240), respectively. Among the infants who developed type 1 ROP requiring treatment, 81.6% were extremely preterm (GA <28 weeks) infants and 100% were extremely low BW (<1000 g) infants. Of the treated infants, 13 had stage 2 ROP and 25 had stage 3 ROP. No infants had stage 4 or 5 ROP.

In total, 795 infants underwent ROP screening in accordance with the UK screening criteria. One infant had a GA above the UK screening threshold; however, the infant continued to undergo screening because he was only 1 day older than the screening threshold, and the attending neonatologist concluded that he had a risk of ROP. The UK screening criteria detected all cases of ROP (n=238) and type 1 ROP requiring treatment (n=38) [Table 2].

If the US screening criteria had been used, the number of infants receiving ROP screening would have decreased to 627 (21.1% reduction compared with the UK screening criteria) [Table 2]. The use of the US screening criteria would have detected 234 cases of ROP (98.3% of cases detected using the UK criteria, 234/238) and 38 cases of type 1 ROP (100% of cases detected using the UK criteria, 38/38) [Table 2]. Of the 168 infants who would not have been screened using the US screening criteria, only 4 of them (2.4%) had developed ROP (Table 3) and all cases were mild (maximum stage 1 only); all affected infants displayed spontaneous resolution of ROP without the need for treatment. No cases of type 1 ROP were missed by the US screening criteria (ie, 100% sensitivity) [Table 4].

This study showed that if the US screening criteria had been used, instead of the UK screening criteria, the number of infants screened in our population would have decreased by 21.1% without missing any case of type 1 ROP requiring treatment. The number of ROP cases that would have been missed was very small (n=4), and all cases were mild (maximum stage 1).

Previous studies showed that many hospitals in Hong Kong follow the UK screening criteria for ROP screening7 8 9,26,27; consistent with our findings, the reported incidences of ROP and type 1 ROP in Hong Kong were 16% to 28%7 8 9 and 3.4% to 3.8%,7 8 9 respectively. In the present study, type 1 ROP mainly developed in extremely preterm infants with a median GA of 26 weeks and 0.5 days (IQR=2 weeks & 2.5 days), suggesting that low GA was an important predictor of type 1 ROP in our population. Because the GA criterion is lower in the US screening criteria (≤30 weeks & 0 days) than in the UK screening criteria (≤31 weeks & 6 days), the US screening criteria may be more appropriate for Hong Kong.

Our findings were also consistent with the results of a study conducted in another hospital in Hong Kong7; in that study, 12.4% of infants would not have required ROP screening if the US screening criteria had been used, rather than the UK criteria, none of those infants would have developed ROP. Our results suggest similar outcomes in different hospitals across Hong Kong.

In a study conducted in Shanghai in mainland China, the screening thresholds were GA of 34 weeks and BW of 2000 g. The mean GA and BW of infants requiring ROP treatment were 29.3 weeks (range, 24-35) and 1331 g (range, 750-2550), respectively17; these infants were more mature and heavier than the infants in our study. The Shanghai study showed that 9% of severe ROP cases requiring treatment would have been missed if the UK screening criteria were used; 26% would have been missed if the US screening criteria were used.17 Another study conducted in Beijing in mainland China showed that 17% of treatment-requiring ROP cases would have been missed if the UK screening criteria were used; 21% would have been missed if the US screening criteria were used.18 Therefore, despite sharing the same Chinese ethnicity, infants with severe ROP differed in maturity between Hong Kong and mainland China. This discrepancy could be the result of variations in comorbidities, perinatal risk factors, standard of neonatal healthcare, and level of supplemental oxygen therapy used. Long oxygen duration, mechanical ventilation, and high level of supplemental oxygen are known risk factors for ROP.2 Therefore, the results of our study are not generalisable to regions outside of Hong Kong.

There is evidence that the UK and the US screening criteria are not appropriate for many low- and middle-income countries.15 19 28 29 In North India, 17% of severe ROP cases would have been missed if the US screening criteria were used; 22% would have been missed if the UK screening criteria were used.15 In South India, 8% of treatment-requiring ROP cases would have been missed if the US screening criteria were used; all of these cases were aggressive posterior ROP.19 In Saudi Arabia, 35% of infants older than the UK screening threshold developed ROP; one infant developed severe ROP (stage 3).28 In Turkey, severe ROP developed in 3.8% of infants born at ≥32 weeks and 6.5% of infants born at ≥1500 g.29

Although it is important not to miss any severe ROP cases, it is also preferable to avoid missing mild ROP cases because the detection of early ROP (even mild cases) can influence decisions regarding systemic management (eg, level of supplemental oxygen), thereby reducing the rate of ROP progression. In the present study, only four cases of mild ROP would have been missed by the US screening criteria; this number was very small, compared with the 168 infants (21.1%) who could have been excluded from screening. The number of screened infants required to detect one additional case of ROP was 42 (ie, 168/4). Considering that few mild ROP cases were missed in exchange for the exclusion of a large number of infants from screening, we conclude that it is acceptable and appropriate to use the US screening criteria for ROP screening in Hong Kong.

There are several benefits to reducing the number of infants screened without compromising the detection of severe ROP. First, this modified approach minimises unnecessary stress and the potential for ROP screening-related adverse events among infants. Previous studies revealed significant elevation of blood pressure, increase in pulse rate, and decrease in oxygen saturation, which persisted after ROP screening.30 A significant increase in the number of apnoea events was also observed after screening.31 Approximately half of infants develop bradycardia from the oculocardiac reflex caused by scleral depression during screening.32 Second, this modified approach can reduce hospital expenses. The estimated cost of ROP screening is approximately US$230 per infant in the US33 and US$198.9 per infant in India.34 Third, the approach can reduce the length of hospitalisation related to delays in the completion of ROP screening.35 Finally, it may minimise unnecessary parental stress and anxiety. For example, one study showed that parents of infants undergoing ROP screening had significantly higher anxiety and depression scores compared with the general population.36

In recent decades, several ROP prediction models have been developed to improve screening sensitivity and specificity, including WINROP,37,38 ROPScore,39 CHOP ROP,40 41 CO-ROP,42 STEP-ROP, 43 and G-ROP.44 45 However, these prediction models have many limitations. First, they require the collection of postnatal data such as postnatal weight gain and insulin-like growth factor 1 level, which may not be available to ophthalmologists. Second, the mechanisms by which these predictive factors would interact to affect ROP outcome are not fully understood. Third, these models were all derived from Western countries and may not be appropriate for Asian populations.46 Finally, none of these models have been validated in Hong Kong. Considering our findings in the present study, we suggest narrowing the GA screening criterion to ≤30 weeks and 0 days, consistent with the US screening criteria; this simple and straightforward approach avoids the need for calculations required by prediction models.

This study had several limitations. First, its retrospective design hindered the assessment of other risk factors (eg, supplemental oxygen level and comorbidities) that may affect ROP outcomes. Second, because of the retrospective design, we could not determine whether the use of a narrower GA screening criterion would reduce the number of screenings in real-world clinical practice. A prospective cohort study is needed to confirm our findings. Third, although the G-ROP screening criteria are more sensitive and specific than the current US screening criteria for populations in the US,44 45 we could not evaluate the suitability of G-ROP criteria in our population because we lacked data concerning postnatal weight gain. Finally, data were missing regarding infants who died or were transferred to other hospitals without a known ROP outcome. Despite these limitations, our findings are robust because the present study revealed consistent results when the same screening practices were applied to a large number of infants over a study period of 10 years.

Compared with the UK screening criteria, the US screening criteria appeared to be more appropriate for our population because they could greatly reduce the number of infants screened without compromising sensitivity for the detection of type 1 ROP. Thus, we suggest narrowing the GA criterion for consistency with the US screening criteria during ROP screening in Hong Kong. A prospective cohort study is needed to further explore the impact of changes to the screening criteria.

Concept or design: LPL Iu, WWK Yip.
Acquisition of data: LPL Iu, LTY Cheung, THM Wu.
Analysis or interpretation of data: LPL Iu, WWK Yip, JYC Lok.
Drafting of the manuscript: LPL Iu.
Critical revision of the manuscript for important intellectual content: WWK Yip, JYC Lok, M Ho, AL Young.

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.

All authors have disclosed no conflicts of interest.

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

This research was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref No.: 2020.176) and was performed in accordance with the tenets of the Declaration of Helsinki. A waiver of obtaining patient consent has been approved by the Research Ethics Committee for this retrospective study.

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16. Dogra MR, Katoch D, Dogra M. An update on retinopathy of prematurity (ROP). Indian J Pediatr 2017;84:930-6. Crossref

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26. Chow PP, Yip WW, Ho M, Lok JY, Lau HH, Young AL. Trends in the incidence of retinopathy of prematurity over a 10-year period. Int Ophthalmol 2019;39:903-9. Crossref

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28. Binkhathlan AA, Almahmoud LA, Saleh MJ, Srungeri S. Retinopathy of prematurity in Saudi Arabia: incidence, risk factors, and the applicability of current screening criteria. Br J Ophthalmol 2008;92:167-9. Crossref

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34. Kelkar J, Kelkar A, Sharma S, Dewani J. A mobile team for screening of retinopathy of prematurity in India: cost-effectiveness, outcomes, and impact assessment. Taiwan J Ophthalmol 2017;7:155-9. Crossref

35. Zupancic JA, Ying GS, de Alba Campomanes A, Tomlinson LA, Binenbaum G; G-ROP Study Group. Evaluation of the economic impact of modified screening criteria for retinopathy of prematurity from the Postnatal Growth and ROP (G-ROP) study. J Perinatol 2020;40:1100-8. Crossref

36. Xie W, Liang C, Xiang D, Chen F, Wang J. Resilience, anxiety and depression, coping style, social support and their correlation in parents of premature infants undergoing outpatient fundus examination for retinopathy of prematurity. Psychol Health Med 2021;26:1091-9. Crossref

37. Löfqvist C, Andersson E, Sigurdsson J, et al. Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol 2006;124:1711-8. Crossref

38. Löfqvist C, Hansen-Pupp I, Andersson E, et al. Validation of a new retinopathy of prematurity screening method monitoring longitudinal postnatal weight and insulinlike growth factor I. Arch Ophthalmol 2009;127:622-7. Crossref

39. Eckert GU, Fortes Filho JB, Maia M, Procianoy RS. A predictive score for retinopathy of prematurity in very low birth weight preterm infants. Eye (Lond) 2012;26:400-6. Crossref

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A recent population survey in Hong Kong showed that 68% of men and 67% of women aged >40 years seeking medical advice for lower urinary tract symptoms (LUTS) had ≥2 nocturia episodes/night1; these prevalences are greater than that among individuals of similar age reported in other global studies.2 Across urology clinics in Southeast Asian countries, nocturia has emerged as the most common presenting symptom (up to 88%) among men with LUTS requiring treatment3; however, at least half of these patients were dissatisfied with the results of treatment.4

Nocturia is no longer considered a distinct urologic disease.5 Indeed, it is related to disorders within and outside the lower urinary tract, which are associated with diminished bladder capacity, increased rate and volume of nocturnal urine production, sleep disturbance, or a combination of these symptoms.6 Thus, initial treatment is difficult and there is a need for a tool that captures relevant aetiological information earlier in the diagnostic pathway.

The short form of the Targeting the individual’s Aetiology of Nocturia to Guide Outcomes (TANGO) is a recently developed, 22-item, dichotomous-choice, multi-dimensional, self-administered questionnaire in English with robust psychometric properties.7 8 This questionnaire covers four thematic areas regarding aetiologies and co-morbidities related to nocturia: cardiovascular or metabolic disorders, sleep/nocturnal pain/apnoea variables, urinary tract symptoms, and mental health and well-being (including falls). This study was performed to translate and cross-culturally adapt the TANGO into Chinese, ie, to produce a Chinese version of the TANGO [TANGO (CV)], then evaluate its reliability and validity for use in Hong Kong.

We adopted the cross-cultural translation methodology described by Sperber9 and recommended by the original authors of the TANGO.7 Six independent bilingual translators were asked to produce six forward translations (in Chinese) of each item of the TANGO, with the goal of conceptual translation; all six forward translations were back-translated to English, yielding six back-translations.

The six back-translations (in English) were reviewed by a panel of urologists (n=4), urology nurse specialists (n=2), and staff without a medical background (n=2) who were not involved in conducting this study, to produce a preliminary draft of each item in the translated tool. Each item in the English back-translations was compared with the original English version by ranking in terms of language comparability and the interpretation similarity using a Likert scale from 1 (extremely comparable/similar) to 7 (not at all comparable/similar). Items from the back-translations with a mean score <2.50 were retained. The forward translations (Chinese) of the retained back-translated English items were reviewed and compared in a panel consensus meeting comprising four urologists, two urology nurse specialists, and two bilingual translators. These items were used to draft the final version of the translated tool, the TANGO (CV).

After linguistic translation, a prospective psychometric evaluation study was conducted. From December 2019 to March 2020, we recruited male and female patients aged 45 to 90 years who presented to the urology clinic for management of LUTS problems and with self-reported nocturia episodes of ≥2 per night as patient group. Exclusion criteria were a history of prostatic surgery and/or prostate cancer, as well as the presence of active urinary tract infection, active cancer receiving treatment, bladder stone, neuropathic bladder, dependent daily activities (including feeding, bathing, and walking with assistance), diabetes insipidus, renal failure, pregnancy, and/or illiteracy. Healthy individuals of similar age with self-reported nocturia episode of ≤1 per night were recruited as controls.

After recruitment, participants completed the TANGO (CV), the Chinese version of the International Prostate Symptom Score (IPSS),10 the International Consultation on Incontinence Questionnaire Nocturia module (ICIQ-N),11 the Nocturia-Specific Quality-of-Life Questionnaire (NQoL),12 the Hong Kong Chinese version of the Overactive Bladder Symptom Score (OABSS-HKC) questionnaire,13 the Epworth Sleepiness Scale (ESS),14 and the Chinese version of the STOP-Bang questionnaire.15 Participants underwent assessment of their histories of hypertension, diabetes mellitus, hyperlipidaemia, cerebrovascular accident, ischaemic heart disease, peripheral oedema, and obstructive sleep apnoea; their responses were cross-checked with the diagnostic codes of the central registry and their previous medical records. Blood glucose, glycated haemoglobin (HbA1c), and estimated glomerular filtration rate were measured. Participants were also given bladder/sleep diaries to record the time and volume of each voiding event, along with their sleep information (times of going to bed, falling asleep, awakening from sleep, and rising from bed), for 4 consecutive days at home within 2 weeks after recruitment. Participants then returned the bladder/sleep diaries to the clinic and repeated the TANGO (CV).

Reliability (inter-item correlation) was determined by internal consistency based on the Kuder–Richardson Formula 20 (KR-20) coefficient, which is specifically designed for dichotomous-choice questionnaires.16 Test-retest reliability was determined using Cohen’s kappa value (κ) and the intra-class correlation coefficient (ICC) by comparing the agreement of repeat responses for each item and the congruency of the number of positive responses to the tool between recruitment and follow-up (2 weeks later). κ≥0.4 and ICC ≥0.7 were considered acceptable reliability.17

We examined content validity by assessing the level of missing data, which indicated acceptability and difficulty in terms of participant understanding of items within the tool. Construct validity, which reflects the theory underlying nocturia, was evaluated by comparing the number of the positive responses to each of the four domains and all four domains of the TANGO (CV) with data regarding bladder/sleep diary–based parameters, as follows:

1. Cardiovascular/metabolic domain (Questions 1-7) was compared with the bladder diary (nocturia episodes, rate and volume of nocturnal urine output between falling asleep and awakening, and nocturnal polyuria index);
2. Sleep-related domain (Questions 8-13) was compared with the bladder diary [sleeping time, sleep latency, sleep quality, and degree of vitality after sleep, using a scale from 0 (the worst) to 10 (the best)];
3. LUTS domain (Questions 14-18) was compared with the bladder diary as in (1);
4. General well-being domain (Questions 19-22) was compared with the bladder diary as in (2);
5. The whole tool (all four domains, Questions 1-22) was compared with the abovementioned parameters.

Criterion validity was estimated by comparing the number of the positive responses to each of the four domains and all four domains with the responses to items on other questionnaires evaluating similar constructs, as follows:

1. Cardiovascular/metabolic domain was compared with ESS, STOP-Bang questionnaire, ICIQ-N-4(b) and NQoL sleep/energy domain, NQoL bother/concern domain, NQoL global QoL domain, and total score of NQoL;
2. Sleep-related domain was compared with ESS, STOP-Bang questionnaire, ICIQ-N-4(b), and NQoL;
3. LUTS domain was compared with IPSS voiding (sum of scores of Questions 1, 3, 5, and 6), IPSS storage (sum of scores of Questions 2, 4, and 7), ICIQ-N-4(b), OABSS (total), and NQoL;
4. General well-being domain was compared with IPSS QoL, NQoL sleep/energy domain, NQoL bother/concern domain, NQoL global QoL domain, and total score of NQoL.

We assumed that a correlation coefficient ρ≥0.4 was moderate and acceptable18 as evidence of construct/criterion validity.

For discriminant validity, receiver operating characteristic analysis, in combination with Youden’s J statistic [ie, sensitivity–(1-specificity)], was performed to explore whether the sum of positive responses to the whole tool could be used to distinguish: (1) patients from controls; and (2) patients with significant nocturia distress from patients with mild nocturia distress (Question 12 of NQoL).

Assuming a type I error (α) of 0.05 and type II error (1-β) of 0.8, we calculated that:

1. a Spearman’s correlation coefficient (ρ) of 0.4 (with ρ=0.0 for the null hypothesis) required a sample size of 46 participants19;
2. κ=0.4 for each item (with κ=0 for the null hypothesis) for the test-retest reliability of the TANGO (CV) required a minimum sample of 47 respondents.17

Assuming an attrition rate of 20%, approximately 60 participants (patients and controls) were needed.

Continuous data were reported as mean and standard deviation or median and range. Categorical data were described using frequencies and percentages. For comparisons of continuous data, Student’s t test or the Mann-Whitney U test was used, depending on the data distribution; for comparisons of categorical data, the Pearson Chi squared test or Fisher’s exact test was used. The Spearman’s correlation coefficient was used to assess associations between parametric or ordinal data and continuous data with a skewed distribution; the Pearson correlation coefficient was used to assess associations between normally distributed continuous data. SPSS Statistics (Windows version 26.0; IBM Corp, Armonk [NY], United States) was used for data analysis. P values <0.05 were considered statistically significant.

Comparability scores for each item in the TANGO (CV) ranged from 1.38 (0.52) to 2.25 (1.28), with an overall mean score of 1.70 (0.88). Similarity scores for each item ranged from 1.00 (0.52) to 2.13 (1.36), with an overall mean score of 1.63 (0.88). The TANGO (CV) is shown in the online supplementary Table.

This study included 65 participants, which include 51 (78.5%) patients (mean age: 67 years; 35 men, 16 women) with mean self-reported nocturia episodes of 3.39 per night (standard deviation=0.98; range, 2-5) and 14 (21.5%) controls (mean age: 67 years; 11 men, three women) with mean self-reported nocturia episodes of 0.79 per night (standard deviation=0.43, range, 0-1). The demographic and baseline clinical characteristics are shown in Table 1; the bladder/sleep diary–based parameter data are shown in Table 2. The control group had fewer positive responses (median=2.33) to items in the TANGO (CV), less nocturia distress, higher functional bladder capacity during daytime and night-time, and a lower nocturnal urine excretion rate; however, control participants reported similar prevalences of medical conditions that could cause nocturia, compared with patients who experienced ≥2 nocturia episodes/night.

All 65 participants reported that the questions in the tool were clearly presented, and they answered 99.6% of the items in the tool (total items=22 × 65=1430). Two (3%) participants required assistance with comprehension to complete the TANGO (CV). Missing responses were noted for items related to the use of antihypertensives (n=1), the diagnosis of diabetes mellitus/impaired glucose level (n=1), and unstable glucose level (n=1); three men were unable to respond to the question concerning prostate enlargement [Table 3]. In total, 41 (63%) participants reported at least one positive response (total responses=72) in the cardiovascular/metabolic domain, 48 (74%) participants reported at least one positive response (total responses=154) in the sleep-related domain, 54 (83%) participants reported at least one positive response (total responses=119) in the LUTS domain, and 21 (32%) participants reported at least one positive response (total responses=32) in the general well-being domain. The item with most positive responses was nocturia within 3 hours after going to bed (80% of participants) and the item with the fewest positive responses was the use of diuretics (0 responses) [Table 3]. Among the four thematic areas, 90% of participants had positive responses to ≥1 domain. Only three (6%) of the 51 patients with ≥2 nocturia episodes/night exhibited nocturia-related problems that were limited to a single domain.

The KR-20 coefficients of the four domains of the TANGO (CV) were 0.354-0.615 (best in sleep-related and general well-being domains; worst in cardiovascular/metabolic domain), suggestive of fair to moderate subscale internal consistency. For the whole tool, the KR-20 coefficient was 0.711 (ie, >0.700), indicating satisfactory overall internal consistency. Kappa values were between 0.817 and 0.871 for items in each of the four domains and 0.866 for the whole tool, whereas ICCs were between 0.878 and 1.000 for the subtotal positive responses in each of the four domains and 0.972 for the whole tool; these findings indicated near-perfect test-retest reliability.

Table 4 shows the construct (convergent) validity of the TANGO (CV). The sleep-related domain was positively correlated with sleep latency [ρ=0.471 (P<0.001)], whereas it was negatively correlated with sleep quality [ρ=-0.407 (P=0.002)] and vitality after sleep [ρ=-0.467 (P<0.001)], as reported in the bladder/sleep diary. The LUTS domain was positively correlated with the number of nocturia episodes, rate of nocturnal urine production, and volume of nocturnal urine production [ρ=0.513 (P<0.001), ρ=0.333 (P=0.016), and ρ=0.309 (P=0.026), respectively]. However, the LUTS domain was not correlated with sleep/vitality parameters. In contrast, the general well-being domain was significantly positively correlated with the rate and volume of nocturnal urine production [ρ=0.319 (P=0.018) and ρ=0.312 (P=0.021), respectively]; it was significantly negatively correlated with vitality after sleep [ρ=-0.403 (P=0.002)]. The cardiovascular/metabolic domain did not display significant correlations with the bladder/sleep diary parameters. Nonetheless, the whole tool was significantly positively correlated with the number of nocturia episodes [ρ=0.378 (P=0.006)], the rate and volume of nocturnal urine production [ρ=0.394 (P=0.004) and ρ=0.380 (P=0.006), respectively], and sleep latency very closely [ρ=0.275 (P=0.051)]; it was significantly negatively correlated with sleep quality and vitality after sleep [ρ=-0.392 (P=0.004) and ρ=-0.483 (P<0.001), respectively].

Criterion validity was confirmed for each domain and the whole tool (ρ=0.287-0.687). Regarding criterion validity, the cardiovascular/metabolic domain was only significantly correlated with the STOP-Bang questionnaire. The sleep-related domain was not correlated with questionnaires specifically designed to assess obstructive sleep apnoea. However, this domain was strongly correlated with the IPSS, IPSS QoL, and the sleep/energy, bother/concern, and total domains of NQoL (Table 5). The LUTS domain was significantly correlated with the STOP-Bang questionnaire, IPSS, OABSS questionnaire, and NQoL; the strongest correlations involved IPSS total [ρ=0.651 (P<0.001)], OABSS [ρ=0.642 (P<0.001)], and NQoL bother/concern [ρ=0.551 (P<0.001)]. In contrast to the LUTS domain, the general well-being domain was significantly correlated with the ESS; it was also correlated with the IPSS, OABSS questionnaire, ICIQ-N-4(b) and NQoL, but these correlations were weaker than the correlations of the LUTS domain (Table 5).

Receiver operating characteristic analysis (Fig) showed that a cut-off of four positive responses on the TANGO (CV) could distinguish patients from controls (Youden’s J statistic=0.453; area under the curve=0.818, 95% confidence interval [CI]=0.683-0.953; odds ratio=7.81, 95% CI=2.02-30.30; sensitivity: 83%, specificity: 62%), whereas a cut-off of five positive responses could distinguish patients with significant nocturia distress from patients with mild nocturia distress (Youden’s J statistic=0.398; area under the curve=0.729, 95% CI=0.581-0.878; odds ratio=4.07, 95% CI=1.17-14.15; sensitivity: 70%, specificity: 63%).

The International Continence Society (ICS) defines nocturia as the need to wake at least once during the night to void. Each instance of voiding is preceded and followed by sleep.20 A recent Delphi panel convened by the ICS5 recommended using disease-specific questionnaires in the diagnostic pathway for nocturia. In English, there are a few psychometrically validated disease-specific measurement tools for nocturia: the NQoL, developed and validated by Abraham et al12; the ICIQ-N, a form of the NQoL modified from the ICIQ (https://iciq.net/iciq-nqol); and the Nocturia, Nocturnal Enuresis and Sleep-Interruption Questionnaire (NNES-Q) developed by Bing et al.21 The ICIQ-N11 is a combined questionnaire that incorporates a bladder diary–Nocturia Impact Diary.22 However, all of these tools mainly focus on the impact of nocturia on distress and quality of life in affected patients; none of them explore the aetiologies of nocturia.

The TANGO has emerged as a questionnaire that can capture information concerning the multifaceted nature of nocturia and identify nocturia-related co-morbidities.7 23 This tool is expected to be useful across various medical specialties to facilitate, improve, and accelerate the process of nocturia management. Thus far, the TANGO has been translated into Dutch,24 Arabic,25 and Turkish.26 However, none of these translated versions have been subjected to validity assessment using a bladder/sleep diary. To our knowledge, the present study is the first to perform such an assessment.

The ages of our study participants were similar to that of individuals in whom nocturia is commonly observed (>60 years). We found that the TANGO (CV) could be easily comprehended by patients visiting urology clinics, as indicated by the small percentage of missing responses (0.4%) and minimal need for assistance from medical staff (97%); these results suggested good content validity. The low rate of missing responses might be related to the dichotomous-choice nature of responses to items, which facilitated answers by participants.

In all, 94% of our participants with ≥2 nocturia episodes/night were affected by multiple domains of aetiological factors/nocturia-related co-morbidities; approximately 8% of patients reported experiencing falls, which is a higher percentage than in a previous study that used a nocturia-specific questionnaire (<3%).27 The distribution of aetiologies/co-morbidities of nocturia in our study was similar to the distribution reported by a Turkish group26: the LUTS domain was most commonly observed, followed by the sleep-related domain, and then the cardiovascular/metabolic domain. However, the rate of poor general well-being was lower in the present study than in the Turkish study. The simple TANGO (CV) can easily capture information concerning the multifactorial nature of nocturia that could be not elucidated by other nocturia-specific questionnaires.11 12 21 22 Thus, it will facilitate the provision of more individualised treatment for nocturia.

The KR-20 coefficient for the whole tool was 0.711 (>0.700), confirming the internal consistency of the whole TANGO (CV) tool. The highest domain-specific positive response correlation coefficient was observed in the sleep-related domain, implying that nocturia is closely related to impaired sleep quality and disrupted sleep architecture.

The high ICC value (>0.8) for each domain of nocturia-related problems confirmed the excellent test-retest reliability of the tool, in combination with the convergent validity identified in the sleep-related, LUTS, and general well-being domains of the TANGO (CV). With the exception of the cardiovascular/metabolic domain, criterion validity was also established for other domains and the whole TANGO (CV) tool; the criterion validity was the greatest in the LUTS domain, followed by the sleep-related domain and then the general well-being domain. Importantly, the original version of the TANGO7 does not provide a symptom score, although such a score is strongly recommended in European Association of Urology guidelines as a means of quantifying symptoms and distinguishing patients with mild problems from patients with severe problems.28 In this regard, a scoring system involving the various domains of the TANGO has recently been proposed to distinguish the relative contributions of nocturia aetiologies to treatment outcomes.8 In the present study, we showed that by using cut-offs of four and five positive responses, respectively, the sum of the positive responses could distinguish individuals with more nocturia episodes (≥2/night) from individuals with fewer nocturia episodes (≤1/night), and patients with significant nocturia distress (Question 12 of NQoL) from patients with mild nocturia distress (Fig). These findings confirmed the discriminatory validity of the TANGO (CV).

The cardiovascular/metabolic domain demonstrated suboptimal performance in terms of internal consistency, convergent, criterion, and discriminant validity. These findings might be related to selection bias in that patients with higher cardiovascular risk were not recruited [ie, there was a low positive response rate (72 of 455 potential responses, 16%)].

The TANGO (CV) can be used to investigate common aetiologies and nocturia-related outcomes across multiple medical specialties, providing guidance for subsequent treatment. For example, positive responses to Questions 1, 2, and 3 in the cardiovascular/metabolic domain and Question 13 in the sleep-related domain may indicate that desmopressin is less appropriate or even contraindicated for the treatment of nocturia, in accordance with the recent consensus report by the ICS.5 The questionnaire can also be used as a screening tool for epidemiological studies and routine clinical work-up for nocturia. It is a simple, rapid, easily understood, and clinically meaningful tool that can help clinicians to thoroughly evaluate nocturia aetiology and related problems earlier in the clinical pathway of nocturia treatment. Moreover, it may be useful in categorising or predicting the prognosis of nocturia in adults.

The limitations of the current study included the fact that about 70% of the participants were men, which may limit its utility in assessment of female patients with nocturia. Additionally, the sample size was insufficient to clarify correlations among domain variables, number of positive responses, and subtotal and total symptom scores across the various questionnaires used for validation. The inclusion of patients with more pronounced illnesses within the studied domains should be considered to clearly identify relationships among nocturia, aetiologies, lower urinary tract function, and co-morbidities, as measured by bladder/sleep diaries and validated questionnaires.

The TANGO (CV) is a multi-dimensional, self-administered, formally translated, psychometrically validated Chinese version of the TANGO. It can be used to screen for aetiologies and measure the impacts of nocturia-related problems on affected individuals, including their quality of life. The sum of positive responses to the whole tool was significantly correlated with the degree of nocturia-related distress.

Concept or design: SKK Yuen, W Bower, CF Ng.
Acquisition of data: SKK Yuen, CSY Li, HSW Kwok.
Analysis or interpretation of data: SKK Yuen, PKF Chiu, JYC Teoh.
Drafting of the manuscript: SKK Yuen, CF Ng.
Critical revision of the manuscript for important intellectual content: SKK Yuen, CF Ng, SSM Hou.

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.

As editors of the journal, CF Ng and JYC Teoh were not involved in the peer review process. Other authors have disclosed no conflicts of interest.

We thank all staff from Lithotripsy and Uro-investigation Centre of Prince of Wales Hospital and research staff from Department of Urology of The Chinese University of Hong Kong for facilitating the data collection.

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

The study protocol was approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee (Ref No.: 2019.400), in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Informed consent to take part in the research was obtained from all participants.

1. Yee CH, Chan CK, Teoh JY, et al. Survey on prevalence of lower urinary tract symptoms in an Asian population. Hong Kong Med J 2019;25:13-20. Crossref

2. Bosch JL, Weiss JP. The prevalence and causes of nocturia. J Urol 2013;189(1 Suppl):S86-92. Crossref

3. Ho LY, Chu PS, Consigliere DT, et al. Symptom prevalence, bother, and treatment satisfaction in men with lower urinary tract symptoms in Southeast Asia: a multinational, cross-sectional survey. World J Urol 2018;36:79-86. Crossref

4. Ho LY, Chan CK, Chu PS. Patient opinion of lower urinary tract symptoms and their treatment: a cross-sectional survey in Hong Kong public urology clinics. Hong Kong Med J 2017;23:562-9. Crossref

5. Everaert K, Hervé F, Bosch R, et al. International Continence Society consensus on the diagnosis and treatment of nocturia. Neurourol Urodyn 2019;38:478-98. Crossref

6. Weiss JP, Blaivis JG, Blanker MH, et al. The New England Research Institutes, Inc. (NERI) Nocturia Advisory Conference 2012: focus on outcomes of therapy. BJU Int 2013;111:700-16. Crossref

7. Bower WF, Rose GE, Ervin CF, Goldin J, Whishaw DM, Khan F. TANGO—a screening tool to identify comorbidities on the causal pathway of nocturia. BJU Int 2017;119:933-41. Crossref

8. Rose GE, Bower WF. Development of a scoring process for the nocturia causality screening tool TANGO: a rationale and methodology. Aust N Z Continence J 2020;26:32-8. Crossref

9. Sperber AD. Translation and validation of study instruments for cross-cultural research. Gastroenterology 2004;126(1 Suppl 1):S124-8. Crossref

10. Chan HC. The psychometric evaluation of the Chinese version of the International Prostate Symptom Score (IPSS) [thesis]. Hong Kong: The University of Hong Kong; 2004: 174.

11. Avery K, Hashim H, Gardener N, Abrams P, Donovan J, Abraham L. Development and psychometric evaluation of the ICIQ nocturia module: the ICIQ-N. (Abstract 595), in ICS/IUGA 2004. Paris; 2004.

12. Abraham L, Hareendran A, Mills IW, et al. Development and validation of a quality-of-life measure for men with nocturia. Urology 2004;63:481-6. Crossref

13. Yiu MK, Li CM, Hou SM, Wong CW, Tam S, Chu SK. Reliability and validity of the overactive bladder symptom score in Hong Kong Chinese. Hong Kong Med J 2013;19:504-10. Crossref

14. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-5. Crossref

15. Ha SC, Lee DL, Abdullah VJ, van Hasselt CA. Evaluation and validation of four translated Chinese questionnaires for obstructive sleep apnea patients in Hong Kong. Sleep Breath 2014;18:715-21. Crossref

16. Kuder GF, Richardson MW. The theory of the estimation of test reliability. Psychometrika 1937;2:151-60. Crossref

17. Bujang MA, Baharum N. Guidelines of the minimum sample size requirements for Cohen’s kappa. Epidemiol Biostat Public Health 2017;14:e12267. Crossref

18. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Philadelphia (PA): Lawrence Erlbaum Associates; 1988.

19. Bujang MA, Baharum N. Sample size guideline for correlation analysis. World J Soc Sci Res 2016;3:37-46. Crossref

20. Hashim H, Blanker MH, Drake MJ, et al. International Continence Society (ICS) report on the terminology for nocturia and nocturnal lower urinary tract function. Neurourol Urodyn 2019;38:499-508. Crossref

21. Bing MH, Moller LA, Jennum P, Mortensen S, Lose G. Validity and reliability of a questionnaire for evaluating nocturia, nocturnal enuresis and sleep-interruptions in an elderly population. Eur Urol 2006;49:710-9. Crossref

22. Holm-Larsen T, Andersson F, van der Meulen E, Yankov V, Rosen RC, Nørgaard JP. The Nocturia Impact Diary: a self-reported impact measure to complement the voiding diary. Value Health 2014;17:696-706. Crossref

23. Bower WF, Everaert K, Ong TJ, Ervin CF, Norgaard JP, Whishaw M. Questions to ask a patient with nocturia. Aust J Gen Pract 2018;47:465-9. Crossref

24. Decalf V, Everaert K, De Witte N, Petrovic M, Bower W. Dutch version of the TANGO nocturia screening tool: cross-culturally translation and reliability study in community-dwelling people and nursing home residents. Acta Clin Belg 2020;75:397-404. Crossref

25. Altaweel W, Alrumayyan M, Seyam R. Arabic language validation of TANGO questionnaire for nocturia: a translation into the Arabian Peninsula dialect. Neurourol Urodyn 2020;39:2146-52. Crossref

26. Culha MG, Culha Y, Buyukyilmaz F, Turan N, Bower W. “TANGO” nocturia scanning tool: Turkish validity and reliability study. Low Urin Tract Symptoms 2021;13:88-92. Crossref

27. Yamanishi T, Fuse M, Yamaguchi C, et al. Nocturia Quality-of-Life questionnaire is a useful tool to predict nocturia and a risk of falling in Japanese outpatients: a cross-sectional survey. Int J Urol 2014;21:289-93. Crossref

28. Gravas S, Cornu JN, Gacci C, et al. EAU Guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO). European Association of Urology Guidelines Office: Arnhem, The Netherlands; 2020. Available from: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Non-Neurogenic-Male-LUTS-2023.pdf. Accessed 26 Jul 2023.

In many developed countries, the incidence of twin pregnancies is rising because of the increase in maternal age and increasing use of assisted reproductive procedures.1 2 Postpartum haemorrhage (PPH) is more common in twin pregnancies than in singleton pregnancies; this is usually attributed to substantial distension of the uterus in twin pregnancies, which leads to uterine atony after delivery.3 4 Risk factors for severe PPH in singleton pregnancies include hypertensive disorders, failure to progress during the second stage of labour, oxytocin augmentation, instrumental delivery, and fetal macrosomia.5 However, there have been few studies concerning specific risk factors for PPH in twin pregnancies because twin pregnancy itself is considered a risk factor for PPH. This study evaluated risk factors for PPH in twin pregnancies, particularly factors associated with major PPH, to facilitate identification of high-risk twin pregnancies. Better preparation for peripartum management of these high-risk twin pregnancies should allow a multidisciplinary approach involving experienced obstetricians, anaesthetists, haematologists, and radiologists to reduce maternal morbidity and mortality associated with massive haemorrhage.

This retrospective study included all women with twin pregnancies who delivered at >24 weeks of gestation in a single tertiary obstetric training unit from 2009 to 2018 (10-year period) and experienced PPH (blood loss of ≥500 mL). Obstetric data for these women were identified using a comprehensive obstetric database; their electronic and paper records were then carefully reviewed. Various maternal demographic and clinical characteristics (eg, maternal age, parity, method of conception, body mass index, mode of delivery, cause of PPH, and antenatal complications such as gestational diabetes and pre-eclampsia) were compared between women with and without PPH to identify possible risk factors. Postpartum haemorrhage was classified using three thresholds for blood loss volume: ≥500 mL (all PPH), >1000 mL (major PPH), and >1500 mL (severe PPH). Risk factors for each threshold of PPH were analysed. Women with intrauterine fetal death of one or both twins were excluded from analysis.

In our unit, PPH was managed using a standard protocol, which began with various oxytocic agents including oxytocin/ergometrine, oxytocin bolus and infusion, and carboprost injections. If medical treatment was unable to control haemorrhage, second-line conservative procedures involving either intrauterine balloon tamponade or compression sutures were used depending on the clinical situation, as well as the attending obstetrician’s clinical judgement.

Data entry and analysis were performed using SPSS (Windows version 24.0; IBM Corp, Armonk [NY], United States). Possible risk factors were analysed by the Chi squared test or Fisher’s exact test, as appropriate. P values <0.05 were considered statistically significant. Logistic regression analysis was conducted to identify significant risk factors for PPH in twin pregnancies. Statistically significant risk factors identified in univariate analysis were entered into a stepwise logistic regression model. Odds ratios and corresponding 95% confidence intervals were calculated.

In total, there were 47 076 deliveries during the study period, including 686 deliveries of multiple pregnancies (680 twin pregnancies and six triplet pregnancies); only twin pregnancies were included in the final analysis. Concerning the mode of delivery, 99 women (14.6%) had normal vaginal delivery of both twins, 67 women (9.9%) had instrumental or vaginal breech delivery of one or both twins, and 514 women (75.6%) had caesarean delivery of one or both twins, of which 17 women had combined deliveries (the first twin was delivered vaginally and the second twin was delivered by caesarean section). The overall incidence of all PPH (≥500 mL) in this cohort of twin pregnancies was 27.8% (189/680), including minor PPH (500-1000 mL, 137/680 [20.1%]), major but not severe PPH (1001-1500 mL, 30/680 [4.4%]), and severe PPH (>1500 mL, 22/680 [3.2%]). In our database, the overall incidence of all PPH (27.8% vs 5.7% [2649/46 390]), as well as the incidences of major PPH [>1000 mL; including severe PPH] (7.6% vs 0.86% [397/46 390]) and severe PPH [>1500 mL] (3.2% vs. 0.44% [204/46 390]), were all significantly higher in twin pregnancies than in singleton pregnancies during the study period (P<0.001). Most instances of PPH in twin pregnancies (147/189, 77.8%) were caused by uterine atony; other causes were placenta praevia or accreta (34/189, 18.0%) and genital tract trauma (8/189, 4.2%). Although most instances of PPH in twin pregnancies were caused by uterine atony, 86.4% of women with uterine atony had only minor PPH (500-1000 mL); in contrast, 82.4% of women with placenta praevia had major PPH >1000 mL (Table 1).

Concerning the treatment of PPH in this cohort, 89.4% of women (169/189) had a successful outcome with medical treatment alone. In 20 patients, medical treatment was insufficient and second-line procedures were required: 12 patients received intrauterine balloon tamponade, four patients received compression sutures, and four patients underwent uterine artery embolisation. Three of the 20 patients subsequently required hysterectomy despite medical treatment and second-line procedures; the peripartum hysterectomy rate was 0.4% (3/680). There were no maternal deaths in this cohort.

Maternal characteristics and their associations with each type of PPH are shown in Table 2. Nulliparity and the use of oxytocin were significantly associated with all PPH ≥500 mL but not major PPH >1000 mL or severe PPH >1500 mL. Univariate analysis showed that in vitro fertilisation, maternal obesity, antepartum haemorrhage, placenta praevia, placental abruption, caesarean delivery, general anaesthesia, and intrapartum pyrexia were significantly associated with various types of PPH. Logistic regression analysis revealed that general anaesthesia and the use of oxytocin were significant risk factors for all PPH ≥500 mL; general anaesthesia, in vitro fertilisation, antepartum haemorrhage, placental abruption, and placenta praevia were significant risk factors for major PPH >1000 mL; in vitro fertilisation, placenta praevia, and obesity were significant risk factors for severe PPH >1500 mL (Table 3).

This cohort study showed that the incidence of PPH was significantly higher in twin pregnancies than in singleton pregnancies. More than one in four of all twin pregnancies (27.8%) had PPH, compared with only about one in 20 (5.7%) singleton pregnancies. Uterine atony caused most instances of PPH (77.8%) in our cohort of twin pregnancies. There has been speculation that because the uterus is more distended in twin pregnancies than in singleton pregnancies, uterine muscle contraction and retraction is weaker after delivery, leading to an increased incidence of uterine atony.6 However, we found that most cases of uterine atony–related PPH (86.4%) were mild, with blood loss of 500-1000 mL; morbidity from minor PPH is expected to be low. In contrast, the incidence of major PPH (>1000 mL; including severe PPH) was 7.6%; more than one-third (20/52) of the affected women required second-line procedures or hysterectomy. A previous study showed that blood loss of >1000 mL occurred in 24% of twin pregnancies6; another study revealed that the incidence of blood loss of >1500 mL was 3.9%.7 Although the incidence of major PPH varies among studies, it is clear that the potential for morbidity related to major or severe PPH requires specific attention to this high-risk group. Postpartum haemorrhage ≥500 mL remains a useful threshold for attention from frontline staff8; however, we suggest modifying the definition for PPH in twin pregnancies to >1000 mL regardless of the mode of delivery, rather than the threshold of ≥500 mL used for singleton pregnancies. Because many twin pregnancies involve only minor PPH that can be managed with basic measures, a blood loss threshold of >1000 mL would be a more effective criterion for identifying high-risk women who will require more advanced management such as blood product transfusions or second-line uterine-sparing procedures.

Efforts to identify risk factors for severe PPH in twin pregnancies may allow evaluation of available interventions to reduce such risks; they may also enable advance recognition of high-risk pregnancies, thereby facilitating staff and resource allocation during delivery to optimise peripartum management and reduce morbidity from maternal haemorrhage. In a retrospective cohort study of 1081 twin pregnancies in the United States, logistic regression analysis revealed that risk factors for PPH requiring blood transfusion were nulliparity, diabetes, intrapartum use of magnesium sulphate, low haematocrit level, low platelet count, and administration of general anaesthesia.7 A study of 171 twin pregnancies in Japan investigated risk factors for major PPH >1000 mL after vaginal delivery; gestational age ≥39 weeks, combined birth weight >5500 g, induction of labour, oxytocin administration during labour, and prolonged labour were identified as significant risk factors.6 Our study showed that the use of oxytocin and administration of anaesthesia were risk factors for PPH ≥500 mL in twin pregnancies. However, in contrast to the previous studies, diabetes and pre-eclampsia were not risk factors for PPH in our cohort. Although univariate analysis indicated that nulliparity was a significant risk factor for PPH ≥500 mL, it did not remain significant in logistic regression analysis.

In the present study, logistic regression analysis indicated that in vitro fertilisation was a significant risk factor for major PPH >1000 mL and severe PPH >1500 mL. To our knowledge, few studies have specifically investigated the relationship between assisted reproductive technology and PPH. Two retrospective cohort studies of singleton births after assisted reproductive technology revealed that in vitro fertilisation was significantly associated with a higher incidence of PPH, compared with spontaneous conception (odds ratios=1.3-1.46).9 10 However, published literature has shown inconsistent results regarding the relationship between assisted reproductive technology and PPH in twin pregnancies. A prospective cohort study of 400 dichorionic twin pregnancies did not identify differences in PPH incidence between women who conceived by in vitro fertilisation and women who conceived spontaneously.11 However, the authors did not report the definition for PPH used in their study. A retrospective cohort study of 1239 twin pregnancies by Bamberg et al12 revealed no difference in PPH incidence (defined as blood loss of ≥500 mL combined with haemoglobin level <10 mg/dL) between women who conceived by artificial reproductive technologies (eg, hormonal stimulation, intrauterine insemination, or in vitro fertilisation) and women who conceived spontaneously. A case-control study of >3000 women in Norway demonstrated an increased risk of severe PPH (>1500 mL) in singleton pregnancies conceived by in vitro fertilisation compared with controls; it also showed that the effect of in vitro fertilisation on severe PPH was more pronounced in multiple pregnancies. After controlling for maternal factors and pregnancy complications, the adjusted odds ratios for severe PPH after in vitro fertilisation were 1.6 in singleton pregnancies and 7.0 in multiple pregnancies.13 Direct inter-study comparisons of the effect of in vitro fertilisation on PPH in twin pregnancies are hindered by inconsistent PPH definitions and the involvement of various assisted reproductive techniques. In our study, we strictly defined in vitro fertilisation as assisted reproduction; we found that this risk factor was associated with major PPH and severe PPH but not minor PPH. Overall, in vitro fertilisation appears to be more frequently associated with severe PPH rather than minor PPH. There is speculation that in vitro fertilisation interferes with the formation of the maternal-fetal interface during the early stages of implantation, thereby causing early placental separation and uterine atony that result in PPH.10 14 Although the confounding effects of placenta praevia and in vitro fertilisation on severe PPH remain controversial,13 an increased incidence of placenta praevia has been associated with in vitro fertilisation; this use of in vitro fertilisation may contribute to the increased risk of PPH.15 In our study, logistic regression analysis indicated that placenta praevia and in vitro fertilisation were significant factors for major PPH >1000 mL and severe PPH >1500 mL. Therefore, we suspect that in vitro fertilisation increases the incidence of PPH by increasing the incidence of placenta praevia; however, in vitro fertilisation itself is also an independent risk factor for PPH. Considering the possible increased risk of major PPH in multiple pregnancies conceived by assisted reproductive technology, single embryo transfer should be recommended during in vitro fertilisation to reduce maternal morbidity from major haemorrhage.

In our study, logistic regression analysis revealed that general anaesthesia was a significant risk factor for minor and major PPH, but not severe PPH. Although general anaesthesia may be an independent risk factor for all types of PPH, its relationship with severe PPH could be masked by confounding factors such as placenta praevia—in our centre, most women with placenta praevia deliver under general anaesthesia. There is conflicting evidence regarding the association of obesity with severe PPH. A recent study of risk factors for severe PPH demonstrated that obesity was significantly associated with severe PPH (>1500 mL) in pregnant women (both singleton and multiple pregnancies), but the finding was not supported by other epidemiological analyses.16 Another cohort study indicated that obesity only slightly increased the risk of PPH; the authors speculated that this result was related to the increasing rate of caesarean delivery among women with obesity.17 However, a large cohort study of 11 363 singleton pregnancies showed an approximate twofold increase in the risk of major PPH (>1000 mL) among women with obesity, independent of the mode of delivery.18 The authors found that the higher rates of PPH in women with obesity could not be attributed to either major perineal trauma or retained placenta; they suggested that the increased rate of PPH in women with obesity was related to uterine atony.18 However, our study was not sufficiently powered to analyse the relationship between obesity and uterine atony.

Limitations of this study include its retrospective design and the high rate of caesarean delivery in our cohort (75.6%). The high rate of caesarean delivery in twin pregnancies overall may have introduced sufficient bias that caesarean delivery itself was identified as a risk factor for PPH, as demonstrated in our univariate analyses for minor PPH and major PPH. Units with lower caesarean delivery rates in twin pregnancies may have findings that considerably differ from our results. Nevertheless, we believe that other risk factors for major and severe PPH remain valid regardless of the caesarean delivery rate.

Risk factors for severe PPH in twin pregnancies considerably differed from the risk factors identified in singleton pregnancies. In vitro fertilisation, placenta praevia, and maternal obesity were significant risk factors for severe PPH in twin pregnancies. Women with twin pregnancies who have obesity, conception by in vitro fertilisation, or placenta praevia should deliver in obstetric units with readily available blood product transfusions and the appropriate expertise for prompt management of severe PPH by a multidisciplinary team that includes experienced obstetricians, anaesthetists, interventional radiologists, and haematologists.

Concept or design: Both authors.
Acquisition of data: WWK To.
Analysis or interpretation of data: Both authors.
Drafting of the manuscript: CW Kong.
Critical revision of the manuscript for important intellectual content: WWK To.

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.

Both authors have disclosed no conflicts of interest.

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

Formal ethics approval for this research was granted by the Kowloon Central/Kowloon East Research Ethics Committee of Hospital Authority, Hong Kong (Ref No.: KC/KE-17-0065/ER-1). Because this was a retrospective study, the requirement for patient consent was waived by the Committee.

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

3. Kramer MS, Berg C, Abenhaim H, et al. Incidence, risk factors, and temporal trends in severe postpartum hemorrhage. Am J Obstet Gynecol 2013;209:449.e1-7. Crossref

4. Conde-Agudelo A, Belizán JM, Lindmark G. Maternal morbidity and mortality associated with multiple gestations. Obstet Gynecol 2000;95:899-904. Crossref

5. Sheiner E, Sarid L, Levy A, Seidman DS, Hallak M. Obstetric risk factors and outcome of pregnancies complicated with early postpartum hemorrhage: a population-based study. J Matern Fetal Neonatal Med 2005;18:149-54. Crossref

6. Suzuki S, Kikuchi F, Ouchi N, et al. Risk factors for postpartum hemorrhage after vaginal delivery of twins. J Nippon Med Sch 2007;74:414-7. Crossref

7. Blitz MJ, Yukhayev A, Pachtman SL, et al. Twin pregnancy and risk of postpartum hemorrhage. J Matern Fetal Neonatal Med 2020;33:3740-5. Crossref

8. Prevention and management of postpartum haemorrhage: Green-top Guideline No.52 [editorial]. BJOG 2017;124:e106-49. Crossref

9. Healy DL, Breheny S, Halliday J, et al. Prevalence and risk factors for obstetric haemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia. Hum Reprod 2010;25:265-74. Crossref

10. Hayashi M, Nakai A, Satoh S, Matsuda Y. Adverse obstetric and perinatal outcomes of singleton pregnancies may be related to maternal factors associated with infertility rather than the type of assisted reproductive technology procedure used. Fertil Steril 2012;98:922-8. Crossref

11. Moini A, Shiva M, Arabipoor A, Hosseini R, Chehrazi M, Sadeghi M. Obstetric and neonatal outcomes of twin pregnancies conceived by assisted reproductive technology compared with twin pregnancies conceived spontaneously: a prospective follow-up study. Eur J Obstet Gynecol Reprod Biol 2012;165:29-32. Crossref

12. Bamberg C, Fotopoulou C, Neissner P, et al. Maternal characteristics and twin gestation outcomes over 10 years: impact of conception methods. Fertil Steril 2012;98:95-101. Crossref

13. Nyfløt LT, Sandven I, Oldereid NB, Stray-Pedersen B, Vangen S. Assisted reproductive technology and severe postpartum haemorrhage: a case-control study. BJOG 2017;124:1198-205. Crossref

14. Sacha CR, Mortimer RM, James K, et al. Placental pathology of term singleton live births conceived with fresh embryo transfer compared with those conceived without assisted reproductive technology. Fertil Steril 2022;117:758-68. Crossref

15. Romundstad LB, Romundstad PR, Sunde A, von Düring V, Skjaerven R, Vatten LJ. Increased risk of placenta previa in pregnancies following IVF/ICSI; a comparison of ART and non-ART pregnancies in the same mother. Hum Reprod 2006;21:2353-8. Crossref

16. Siddiqui A, Azria E, Howell EA, Deneux-Tharaux C; EPIMOMS Study Group. Associations between maternal obesity and severe maternal morbidity: findings from the French EPIMOMS population-based study. Paediatr Perinat Epidemiol 2019;33:7-16. Crossref

17. Butwick AJ, Abreo A, Bateman BT, et al. Effect of maternal body mass index on postpartum hemorrhage. Anesthesiology 2018;128:774-83. Crossref

18. Fyfe EM, Thompson JM, Anderson NH, Groom KM, McCowan LM. Maternal obesity and postpartum haemorrhage after vaginal and caesarean delivery among nulliparous women at term: a retrospective cohort study. BMC Pregnancy Childbirth 2012;12:112. Crossref

Miscarriage occurs in 10% to 20% of pregnancies, and approximately one in four women will experience a miscarriage in their lifetime.1 It is managed using one of three approaches: expectant, medical, or surgical.

In 1972, manual vacuum aspiration (MVA) was introduced2 as an alternative method for the surgical management of miscarriage. It is performed using a handheld 60-mL syringe, which creates a suction force to aspirate the contents of the uterus through a cannula. This technique has various applications, including the management of first-trimester miscarriage, incomplete or missed miscarriage, endometrial biopsy, and first-trimester termination of pregnancy; it can also be used after failed medical evacuation of pregnancy. Because it only requires simple oral analgesics or conscious sedation, this procedure can be performed on an out-patient basis in a treatment (or procedure) room; thus, it avoids the use of a surgical theatre and the risks of general anaesthesia, resulting in a shorter hospital stay.3

Conventional MVA is performed without ultrasound guidance. However, because MVA is performed on an out-patient basis without general anaesthesia, ultrasound guidance may help to minimise discomfort and procedure duration by limiting the number of suction catheter passes and achieving a higher rate of complete evacuation. Studies by Elsedeek4 and Ali et al5 have shown that ultrasound guidance allows clinicians to avoid contact with the uterine fundus, leading to higher rates of procedure completion, significantly lower pain scores, and shorter procedure times. We previously demonstrated that ultrasound-guided manual vacuum aspiration (USG-MVA) is a feasible and effective alternative surgical approach for first-trimester miscarriage.6

Additionally, women with recurrent miscarriage may prefer surgical evacuation (rather than medical evacuation) because this approach facilitates the acquisition of products of conception for cytogenetic analysis. The use of USG-MVA causes less disruption of products of conception; it also can aid in the identification of chorionic villi for karyotyping. Therefore, USG-MVA may be particularly useful for women with recurrent miscarriage.

Ultrasound-guided manual vacuum aspiration is gaining acceptability, awareness, and recognition in Hong Kong, although it is not commonly used in clinical practice. To demonstrate the value of the procedure, this study aimed to assess the effectiveness of USG-MVA in the management of first-trimester miscarriage.

This retrospective observational study included all women who underwent USG-MVA in Hong Kong during the period from July 2015 to February 2021. Eligible patients were identified by hospital records in Prince of Wales Hospital and Union Hospital. The indications for USG-MVA included missed or incomplete miscarriage at <12 weeks of gestation, as well as the desire for cytogenetic examination of the products of conception to determine the underlying cause of miscarriage. For naturally conceived pregnancies, the date of the last menstrual period was used to determine gestational age. For artificially conceived pregnancies, gestational age was determined according to the date of ovulation, oocyte retrieval, or embryo transfer. All women were counselled about the management options: expectant, medical, conventional surgical (electrical vacuum aspiration with or without dilatation and curettage, under general anaesthesia), and USG-MVA.

Miscarriage was diagnosed by ultrasound examination. A diagnosis of missed miscarriage was made if a discrete embryo ≥7 mm without fetal heart pulsation, or an intrauterine gestational sac with a mean sac diameter of 25 mm excluding the fetal pole, was detected on transvaginal ultrasound. If only transabdominal ultrasound was performed, the crown-rump length was recorded; a second scan was performed 14 days later. A diagnosis of missed miscarriage also was made if the mean sac diameter was ≤25 mm without evidence of growth, or if there was a sustained absence of fetal heart pulsation, during a follow-up examination 7 to 14 days later.7 8

A diagnosis of incomplete miscarriage was made if the ultrasound examination showed residual products of conception after the initial passage, defined as consistent intra-uterine thickness of ≥11 cm in the sagittal and transverse planes, and/or if the patient experienced persistent symptoms such as pain or bleeding.9

Patients were excluded if they had a known history of uterine anomalies, cervical stenosis, and/or multiple fibroids with uterine distortion. Patients were also excluded if they had suspected infection, an abnormal coagulation profile, haemodynamic instability, and/or extreme anxiety that hindered their ability to tolerate a pelvic examination.

The primary outcome measure was the efficacy of USG-MVA in terms of complete evacuation of the uterus, without the need for further medical or surgical intervention. We also compared the complete evacuation rate with optimal outcomes in our unit from a previous randomised controlled trial (RCT) that involved other methods of miscarriage management.10 Secondary outcomes included whether patients could tolerate the entire procedure without discontinuation prior to completion; the success rate of karyotyping using chorionic villi obtained from USG-MVA–collected samples, compared with samples collected by conventional surgical evacuation in our unit during the same period; and procedural safety, defined as the occurrence of any clinically significant complications (eg, bleeding requiring blood transfusion, uterine perforation, infection, and vasovagal shock).

Ultrasound-guided manual vacuum aspiration was performed on an out-patient basis in a treatment room with a handheld syringe and flexible curette, as well as an ultrasound machine. Each patient was instructed to take misoprostol 400 μg orally 2 to 3 hours before the procedure for cervical priming; they were also instructed to take naproxen 500 mg 1 hour before the procedure for pre-emptive pain relief. Patients were instructed to take paracetamol or codeine, rather than naproxen, if they were allergic to non-steroidal anti-inflammatory drugs. Upon admission, patients were asked not to void because a full bladder enables better visualisation of the uterus on transabdominal ultrasound. Prophylactic antibiotics were not routinely administered prior to the procedure.

Ultrasound-guided manual vacuum aspiration was performed by an experienced clinician using a 60-mL handheld syringe with a self-locking plunge (MedGyn Aspiration Kit; MedGyn Products, Addison [IL], US) attached to a flexible curette (size 4-7 mm, according to clinician preference); a nurse assisted with ultrasound guidance. During USG-MVA, a speculum examination and swabbing were performed with aseptic technique. A paracervical block with 2% lidocaine was administered using a Terumo Dental Needle (Terumo, Tokyo, Japan). If necessary, the clinician performing the procedure could immobilise the cervix using a tenaculum. Local topical anaesthetic gel (xylocaine 2%) was applied to the cervix and suction catheter. To guide curette insertion into the uterine cavity, transabdominal ultrasound was performed using a Voluson E730 Expert USG system (GE Medical Systems, Kretztechnik, Zipf, Austria). Suction was applied with the handheld syringe to remove products of conception, which were then immersed in normal saline along with detached chorionic villi.

The USG-MVA procedure was completed when the ultrasound examination showed a thin endometrial lining, confirming that the uterine cavity was empty. Products of conception were sent to the laboratory for histological examination and cytogenetic analysis, in accordance with each patient’s preferences. All Rhesus-negative women were administered anti-D prophylaxis.

Patients were discharged 2 to 3 hours after the procedure if they were clinically healthy and haemodynamically stable. A postoperative telephone hotline was established; patients were advised to contact the ward at any time if they encountered excessive bleeding, abdominal pain, or fever. A follow-up appointment was scheduled 2 to 3 weeks after the procedure to ensure complete evacuation had been achieved.

Analyses were performed using SPSS (Windows version 23.0; IBM Corp, Armonk [NY], United States). Data were expressed as counts and percentages. Comparisons were conducted using the Chi squared test for categorical variables and Student’s t test for continuous variables. Two-tailed P values <0.05 were considered statistically significant.

In total, 331 patients were scheduled to undergo USG-MVA during the study period. Seventeen of these 331 patients did not undergo USG-MVA: 15 patients experienced passage of a tissue mass before the procedure, and two patients could not tolerate swabbing before the procedure. Thus, 314 patients successfully underwent USG-MVA (Fig).

The baseline characteristics of the 314 included patients are summarised in Table 1. All patients received oral misoprostol for cervical priming; all patients were able to tolerate and complete the procedure. There were no major complications such as uterine perforation or significant bleeding (ie, requiring blood transfusion or uterotonics). All patients were discharged within 3 hours after the procedure. The complete evacuation rate was 94.6% (297/314) [Table 2] and there were no unscheduled readmissions.

With respect to the results of other miscarriage management methods analysed in our previous RCT,10 we found that USG-MVA had a significantly higher complete evacuation rate compared with medical evacuation (94.6% vs 70%; P<0.001) or expectant management (94.6% vs 79.3%; P<0.001). Ultrasound-guided manual vacuum aspiration also had a complete evacuation rate that was comparable with the rate achieved by conventional surgical evacuation (94.6% vs 98.1%10; P=0.024). Furthermore, the rate of complete evacuation did not significantly differ between women with missed miscarriage and women with incomplete miscarriage (P=0.621).

Of the 17 patients (5.4%) who had incomplete evacuation during USG-MVA, eight (2.5%) subsequently underwent medical evacuation, whereas nine (2.9%) selected conventional surgical evacuation under general anaesthesia (Table 2).

In terms of histological examination, 66.2% of patients (208/314) requested karyotyping. Among samples from those patients, 95.2% (198/208) were suitable for karyotyping; the culture failure rate was 4.8% (10/208). During the same period, 82.9% (295/356) of samples obtained via conventional surgical evacuation10 were suitable for karyotyping, which is significantly lower than the 95.2% of samples obtained via USG-MVA (P<0.001).

Among the samples that were suitable for karyotyping, 65.7% (130/198) had an abnormal karyotype and 34.3% (68/198) had a normal karyotype. Of the 10 samples that were unsuitable for karyotyping, eight contained no chorionic villi, whereas two had a limited number of villi; these characteristics contributed to culture failure.

Since our unit introduced MVA as an alternative to conventional surgical evacuation of the uterus for first-trimester miscarriage, it has generally been well-received by eligible patients.11 Manual vacuum aspiration constitutes a safe and effective uterine evacuation procedure; it is widely used in other countries, including the United States and United Kingdom.11 12 13 14 Thus far, MVA is not commonly used in Hong Kong, possibly because there is a lack of familiarity with the procedure. This study was conducted to explore the utilisation and outcomes of USG-MVA, particularly with respect to the complete evacuation rate, safety, tolerability, and successful acquisition of chorionic villi for karyotyping.

In this study, the complete evacuation rate of USG-MVA was 94.6%, which is within the range of 89% to 98% reported in previous studies.12 15 The complication rate was low, tolerability was good, and the proportion of samples that were suitable for karyotyping was high.

The complete evacuation rate achieved using conventional dilatation and curettage reportedly ranges from 88% to 98%,16 17 which is consistent with previous data from our unit (98.1%).10 These rates are comparable with the rate achieved using USG-MVA in the present study. Moreover, complete evacuation rates achieved via medical management were 84% in an RCT by Zhang et al18 and 70% in our unit10; complete evacuation rates after expectant management reportedly ranged from 16% to 76%,19 20 similar to the rate of 79.3% observed in our unit.10 Overall, the complete evacuation rate achieved via medical or expectant management is substantially lower than the rate achieved using USG-MVA.

The rate of complications associated with conventional dilatation and curettage is reportedly similar21 to the rate of complications associated with MVA; neither approach has been linked to major complications. These low complication rates may be related to the use of ultrasound guidance, which lowers the risk of uterine perforation or false tract creation. There is evidence that ultrasound guidance for dilatation and curettage reduces the complication rate.22 23 In an RCT that investigated the use of ultrasound guidance during surgical termination of pregnancy, Acharya et al24 found significant reductions in infection rates, retained products of conception requiring repeat evacuation, and volume and duration of bleeding in patients who underwent the procedure with ultrasound guidance. Therefore, it is reasonable to expect that USG-MVA also has a lower complication rate, compared with conventional MVA lacking ultrasound guidance. However, ultrasound guidance requires additional equipment and staff with appropriate ultrasound probe training. Further research is needed to clearly determine whether the use of ultrasound during MVA provides a clinical benefit.

Because USG-MVA is an out-patient procedure performed with local anaesthesia in a procedure room, it does not require a surgical theatre or surgical staff. These modified requirements could reduce costs and allow the surgical theatre to be used for other procedures. Patients also would also not be required to fast for a prolonged period prior to general anaesthesia, which would reduce discomfort related to the miscarriage experience. Since a general anaesthesia is not required, it would facilitate a shorter hospital stay, allowing patients to return more rapidly to the comfort of their home after the procedure. Other benefits include the potential for reduced clinical costs and the availability of beds for other patients who require hospitalisation.

This study also demonstrated that a large proportion of samples obtained by USG-MVA are suitable for karyotyping, which is particularly important for women with recurrent miscarriage. The culture failure rates with products of conception obtained via conventional suction evacuation reportedly range from 10% to 40%25; these rates are higher than the culture failure rate using samples obtained by USG-MVA in the present study. Karyotyping requires relatively intact and fresh samples, which are often difficult to obtain by medical evacuation. The products of conception may be passed hours before a sample is sent to the laboratory; they may also be accidentally discarded by the patient.26 During conventional suction evacuation, the products of conception may be extensively damaged by the curette, leading to a higher rate of culture failure.

To our knowledge, this is the first large study in Hong Kong to assess USG-MVA over an extended period. It provides a clear picture of the utilisation of USG-MVA in Hong Kong, with important information regarding the complete evacuation rate, safety, and tolerability of the procedure.

A notable limitation in this study was its retrospective design. Although MVA is generally well-tolerated by patients, as demonstrated in previous studies,3 11 12 15 it causes greater discomfort than conventional dilatation and curettage under general anaesthesia.11 In the present study, tolerability was determined by review of patient medical records; it was solely based on whether a patient had been able to tolerate the entire procedure, and no measurement of pain was conducted. The use of a visual analogue scale score during the procedure may provide a better indication of the actual tolerability of the procedure. A previous trial of USG-MVA, conducted by our unit to investigate the efficacy of hyoscine butylbromide in reducing uterine contraction pain during the procedure, showed a slight reduction in pain score compared with placebo.6 Additional methods could be investigated to improve pain control during USG-MVA.

Furthermore, some patients may have experienced pain because misoprostol was administered for cervical priming prior to the procedure; this was intended to facilitate insertion of the suction catheter. The MedGyn Aspiration Kit provides suction catheters in sizes 4 to 7; if necessary, dilatation could thus be performed under ultrasound guidance using the suction catheters, thereby eliminating the need for misoprostol before the procedure and reducing the amount of pain involved in USG-MVA.

The clinicians who performed USG-MVA in this study ranged from supervised junior trainees to attending physicians with many years of experience. Although the procedures were performed by experienced clinicians who had completed at least 30 MVA procedures before independent practice, or by trainees who were directly supervised by an experienced clinician, differences in clinician experience have the potential to influence the rate of complete evacuation and the amount of pain involved. A standardised approach involving a few dedicated clinicians may reduce this variation.

In this study, data were available concerning the complete evacuation rate achieved by dilatation and curettage in our unit and also from the Union Hospital; however, no data were available from Union Hospital, where USG-MVA is also performed. Additionally, the present study was not designed to allow a comprehensive comparison of miscarriage management methods. In the future, a well-designed RCT should be conducted to compare outcomes among USG-MVA, surgical evacuation, and medical evacuation.

Importantly, no long-term follow-up was performed in this study; thus, we could not examine the long-term effects of USG-MVA.

Ultrasound-guided manual vacuum aspiration is regarded as a safe, simple, efficient, and cost-effective procedure. It allows patients to maintain greater autonomy, avoids the risks of general anaesthesia, and has a higher success rate in terms of collecting the products of conception for karyotyping. However, USG-MVA remains an invasive procedure, and some patients may not be able to endure the physical or (possible) emotional pain involved.27 The addition of ultrasound guidance to MVA may reduce the number of suctions required for complete evacuation and help clinicians avoid contacting the uterine fundus, thereby minimising the duration and severity of pain during the procedure. Further research is needed regarding approaches to minimise the physical and emotional pain that patients may experience during the procedure, such as the use of other pain-relieving agents to minimise discomfort during the procedure. Research is also needed to identify other potential advantages of USG-MVA with respect to other methods of miscarriage management. Moreover, prospective studies comparing pain scores with visual analogue scale scores and patient satisfaction are needed to determine whether the addition of ultrasound guidance to MVA has a meaningful effect on pain outcomes.

Because USG-MVA is an out-patient procedure that does not require a surgical theatre, an anaesthetist, and an overnight stay, it may be significantly less expensive than conventional surgical evacuation of the uterus. The cost of a USG-MVA procedure includes the MedGyn Aspiration Kit, which costs approximately US$18. A cost-effectiveness study is needed to fully explore the potential for reduced clinical costs.

Future research should also focus on the potential effects of USG-MVA on fertility. Asherman’s syndrome, caused by trauma to the basal layer of the uterus, is most commonly associated with dilatation and curettage28; it is detected in approximately 20% of patients after dilatation and curettage.29 We hypothesise that the use of USG-MVA without curettage may reduce endometrial trauma and the number of intrauterine adhesions, thereby lowering effects on future fertility. Currently, our unit is investigating this hypothesis via second-look out-patient hysteroscopy.

Ultrasound-guided manual vacuum aspiration is a safe and effective alternative to medical and conventional suction evacuation, with minimal complications (eg, uterine perforation, bleeding, and retained products of conception). Patients can avoid the risks of general anaesthesia and have a shorter hospital stay. Ultrasound-guided manual vacuum aspiration may be appropriate for patients with first-trimester miscarriage, particularly women who have experienced recurrent miscarriage and express a desire for karyotyping.

Concept or design: OSY Chau, TC Li, JPW Chung.
Acquisition of data: OSY Chau, TC Li, JPW Chung.
Analysis or interpretation of data: OSY Chau, JPW Chung.
Drafting of the manuscript: OSY Chau, JPW Chung.
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.

As an editor of the journal, JPW Chung was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

We thank all women who participated in this trial. We also express gratitude to Ms Margaret Hiu-tan Lee, Dr Ying Li, Ms Cheryl Lee, and Ms Yi-tso Kwan from the Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong for assistance in this study.

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

This study was performed in accordance with the Declaration of Helsinki. The human study protocol was approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee (Ref No.: CREC-2021-206) and the Union Hospital Ethics Committee (Ref No.: EC025), Hong Kong. All adult participants provided written informed consent for inclusion in this study. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines were followed when reporting this study.

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