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.

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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.

1. Eriksson AW, Fellman J. Temporal trends in the rates of multiple maternities in England and Wales. Twin Res Hum Genet 2007;10:626-32. Crossref

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.

1. Webster K, Eadon H, Fishburn S, Kumar G; Guideline Committee. Ectopic pregnancy and miscarriage: diagnosis and initial management: summary of updated NICE guidance. BMJ 2019;367:l6283. Crossref

2. Karman H, Potts M. Very early abortion using syringe as vacuum source. Lancet 1972;1:1051-2. Crossref

3. Sharma M. Manual vacuum aspiration: an outpatient alternative for surgical management of miscarriage. Obstet Gynaecol 2015;17:157-61. Crossref

4. Elsedeek MS. Comparison between the traditional non-guided and a novel ultrasound-guided technique for office fitting of intrauterine contraceptive devices. Int J Gynecol Obstet 2016;133:338-41. Crossref

5. Ali MK, Ramadan AK, Abu-Elhassan AM, Sobh AM. Ultrasound-guided versus uterine sound-sparing approach during copper intrauterine device insertion: a randomised clinical trial. Eur J Contracept Reprod Health Care 2022;27:3-8. Crossref

6. Chung JP, Law TS, Mak JS, Liu RC, Sahota DS, Li TC. Hyoscine butylbromide in pain reduction associated with ultrasound-guided manual vacuum aspiration: a randomized placebo-controlled trial. Reprod Biomed Online 2022;44:295-303. Crossref

7. Doubilet PM, Benson CB, Bourne T, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med 2013;369:1443-51. Crossref

8. Wie JH, Choe S, Kim SJ, Shin JC, Kwon JY, Park IY. Sonographic parameters for prediction of miscarriage: role of 3-dimensional volume measurement. J Ultrasound Med 2015;34:1777-84. Crossref

9. Bar-Hava I, Aschkenazi S, Orvieto R, et al. Spectrum of normal intrauterine cavity sonographic findings after first-trimester abortion. J Ultrasound Med 2001;20:1277-81. Crossref

10. Kong GW, Lok IH, Yiu AK, Hui AS, Lai BP, Chung TK. Clinical and psychological impact after surgical, medical or expectant management of first-trimester miscarriage—a randomised controlled trial. Aust N Z J Obstet Gynaecol 2013;53:170-7. Crossref

11. Chung JP, Chung CH, Mak JS, Li TC, Kong GW. Efficacy, feasibility and patient acceptability of ultrasound-guided manual vacuum aspiration for treating early pregnancy loss. Aust N Z J Obstet Gynaecol 2019;59:71-6. Crossref

12. Milingos DS, Mathur M, Smith NC, Ashok PW. Manual vacuum aspiration: a safe alternative for the surgical management of early pregnancy loss. BJOG 2009;116:1268-71.Crossref

13. Macisaac L, Darney P. Early surgical abortion: an alternative to and backup for medical abortion. Am J Obstet Gynecol 2000;183 (2 Suppl):S76-83. Crossref

14. Morrison J. The care of women requesting induced abortion. Guideline No. 7. J Obstet Gynaecol 2003;23:521-4. Crossref

15. Tasnim N, Mahmud G, Fatima S, Sultana M. Manual vacuum aspiration: a safe and cost-effective substitute of electric vacuum aspiration for the surgical management of early pregnancy loss. J Pak Med Assoc 2011;61:149-53.

16. Sajan R, Pulikkathodi M, Vahab A, Kunjitty VM, Imrana HS. Expectant versus surgical management of early pregnancy miscarriages—a prospective study. J Clin Diagn Res 2015;9:QC06-9. Crossref

17. Wen J, Cai QY, Deng F, Li YP. Manual versus electric vacuum aspiration for first-trimester abortion: a systematic review. BJOG 2008;115:5-13. Crossref

18. Zhang J, Gilles JM, Barnhart K, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353:761-9. Crossref

19. Shelley JM, Healy D, Grover S. A randomised trial of surgical, medical and expectant management of first trimester spontaneous miscarriage. Aust N Z J Obstet Gynaecol 2005;45:122-7. Crossref

20. Jurkovic D, Ross JA, Nicolaides KH. Expectant management of missed miscarriage. Br J Obstet Gynaecol 1998;105:670-1.Crossref

21. Goldberg AB, Dean G, Kang MS, Youssof S, Darney PD. Manual versus electric vacuum aspiration for early first-trimester abortion: a controlled study of complication rates. Obstet Gynecol 2004;103:101-7. Crossref

22. Hornstein MD, Osathanondh R, Birnholz JC, et al. Ultrasound guidance for selected dilatation and evacuation procedures. J Reprod Med 1986;31:947-50.

23. Chaikof M, Lazer T, Gat I, et al. Lower complication rates with office-based D&C under ultrasound guidance for missed abortion. Minerva Ginecol 2017;69:23-8. Crossref

24. Acharya G, Morgan H, Paramanantham L, Fernando R. A randomized controlled trial comparing surgical termination of pregnancy with and without continuous ultrasound guidance. Eur J Obstet Gynecol Reprod Biol 2004;114:69-74. Crossref

25. Shah MS, Cinnioglu C, Maisenbacher M, Comstock I, Kort J, Lathi RB. Comparison of cytogenetics and molecular karyotyping for chromosome testing of miscarriage specimens. Fertil Steril 2017;107:1028-33. Crossref

26. Soler A, Morales C, Mademont-Soler I, et al. Overview of chromosome abnormalities in first trimester miscarriages: a series of 1,011 consecutive chorionic villi sample karyotypes. Cytogenet Genome Res 2017;152:81-9. Crossref

27. Yu FN, Leung KY. Diagnosis and prediction of miscarriage: can we do better? Hong Kong Med J 2020;26:90-2. Crossref

28. Asherman JG. Traumatic intra-uterine adhesions. J Obstet Gynaecol Br Emp 1950;57:892-6. Crossref

29. Hooker AB, Lemmers M, Thurkow AL, et al. Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update 2014;20:262-78. Crossref

Neoadjuvant chemotherapy (NAC)—chemotherapy delivered before definitive breast cancer surgery—was first described in the late 1970s as treatment for locally advanced (often inoperable) breast cancers; it was intended to reduce tumour size and facilitate surgery.1 Subsequently, the use of NAC has been extended to early operable breast cancers.2 3 4 5 This approach offers the advantages of down-staging the disease, potentially reducing the extent of surgery, and allowing breast-conserving surgery (BCS); in the current era of individualised treatment, it supports evaluations of therapeutic efficacy.2 6

There is evidence that NAC is equivalent to adjuvant chemotherapy in terms of preventing breast cancer recurrence.6 It demonstrated equal effectiveness in terms of disease-free survival and overall survival in the National Surgical Adjuvant Breast and Bowel Project B-18 trial.7 Furthermore, a recent meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group showed no significant differences between NAC and adjuvant chemotherapy for distant recurrence, breast cancer mortality, or death from any cause.8

Here, we hypothesised that the use of NAC would change over time among patients with breast cancer in Hong Kong, considering its increasing acceptance as a treatment approach. Thus, the objectives of this study were to investigate the use of NAC over time in patients registered with the Hong Kong Breast Cancer Registry (HKBCR), and to assess the effectiveness of NAC among patients with breast cancer in Hong Kong according to rates of pathological complete response (pCR) and BCS. This study also evaluated alterations in breast cancer biomarkers, including oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 proliferation index.

Records were retrieved from the HKBCR regarding Hong Kong Chinese female patients who were diagnosed with invasive breast cancer in the period of 2006 to 2017. Patients were excluded for the following reasons: stage 0 or stage IV disease, missing or unknown information regarding surgery, and concurrent neoadjuvant endocrine treatment or NAC received outside Hong Kong (which may involve different clinical considerations).

Breast cancer was categorised into four biological subtypes based on clinicopathological criteria, in accordance with recommendations by the St Gallen 2013 Consensus Guideline.9 A cut-off of <14% reportedly has the strongest correlation with the gene-expression definition of the luminal A-like subtype; a cut-off of ≥14% is generally regarded as the threshold for a high Ki-67 proliferation index. Histological grade 3 was used as a surrogate indicator of the luminal B-like subtype if Ki-67 information was unavailable.10 Pathological complete response was defined as no histological evidence of malignancies (ypT0) or the presence of only in-situ residuals in breast tissue (ypTis) and complete disappearance of lymph node metastasis (ypN0) after surgery.11 The same definitions have been adopted by the MD Anderson Cancer Center,12 as well as the Austrian Breast & Colorectal Cancer Study Group.13

Ethics approval for this study has been obtained from six relevant approving bodies. Written informed consent for data collection was obtained during patient recruitment into the HKBCR, who were from 20 hospitals and 37 clinics (online supplementary Appendix). Patient demographics, pre-chemotherapy and post-chemotherapy disease staging, tumour characteristics, and prescribed chemotherapeutic agents were evaluated. The effectiveness of neoadjuvant chemotherapy was assessed in terms of the rates of pCR and BCS. Baseline tumour characteristics were analysed, including size, nodal stage, histological grade, Ki-67 level, hormone receptor status, and HER2 status.

Descriptive statistics were used to summarise demographic and clinical characteristics of patients. Continuous variables are shown as mean, standard deviation, and range; categorical variables are reported as frequency and percentage. Means were compared between groups using independent samples t tests. The Pearson Chi squared test was used to evaluate differences in pCR according to biological subtype and surgical approach. Data were analysed using SPSS (Windows version 22.0; IBM Corp, Armonk [NY], United States). All P values were derived from two-sided statistical tests, and P values <0.05 were considered statistically significant.

In total, 13 990 patients with invasive breast cancer were initially screened for inclusion. After the exclusion of 555 patients, 13 435 patients (13 625 breast cancer cases) were included in this study (Fig 1). The NAC group comprised 1084 patients (1097 breast cancer cases) and the non-NAC group comprised 12 351 patients (12 528 breast cancer cases).

In the NAC group, the median age was 49.7 years (interquartile range, 43.5-56.7; range, 21.9-81.6), and half of the patients (53.8%) were premenopausal. The median invasive clinical tumour size was 4.0 cm (range, 0.55-20.0). The patients’ clinical characteristics (eg, age, biological subtype, clinical tumour stage, nodal stage, and cancer stage) are shown in Table 1.

Among the 13 625 breast cancer cases, 13.6% of affected patients aged <40 years were treated with NAC, compared with 8.0% and 1.9% of affected patients aged 40-69 years and ≥70 years, respectively (Table 1). The administration of NAC was positively associated with cancer stage at diagnosis: the proportion increased from 0.3% in patients with stage I disease to 26.9% among patients with stage III disease (Table 1). Furthermore, greater proportions of patients with luminal B (HER2-positive), HER2-positive (non-luminal), or triple-negative subtypes of breast cancer received NAC.

For the assessment of changes in NAC adoption, the 13 435 patients were divided into two groups according to the year of diagnosis: periods of 2006-2011 and 2012-2017. The proportion of patients treated with NAC nearly doubled from 5.6% in 2006-2011 to 10.3% in 2012-2017 (Table 1).

Further analysis indicated that the use of NAC was significantly increased in patients with stages II and III breast cancers, but not in patients with stage I breast cancer. It was most pronounced among patients with stages IIB (7.8% in 2006-2011 vs. 13.3% in 2012-2017) and III (20.7% vs. 32.6%) disease. An increase in the use of NAC was also observed in patients with all biological subtypes of breast cancer. In particular, substantial increases were observed among patients with triple-negative (6.4% vs. 14.3%), HER2-positive (non-luminal) [8.9% vs. 13.9%], and luminal B (HER2-positive) [8.0% vs. 18.9%] tumours (Table 1).

Among the 1084 patients who received NAC, 353 were diagnosed with HER2-positive (non-luminal) cancer. Anti-HER2 agents were added to chemotherapy in 73.7% of these patients, and the proportions increased from 57.6% in 2006-2011 to 82.5% in 2012-2017; taxane-carboplatin-trastuzumab was the most frequently used regimen. In contrast, for patients with HER2-negative tumours or unknown HER2 status, NAC regimens most commonly consisted of anthracyclines (doxorubicin or epirubicin), administered in combination or sequentially with taxanes (paclitaxel or docetaxel).

Two hundred and twenty-one (20.1%) of 1097 breast cancer cases treated with NAC achieved pCR in the breast and axillary lymph nodes. Subsequent analysis according to biological subtype revealed that outcomes were optimal in patients with HER2-positive (ER-negative and PR-negative) tumours, among which nearly half (46.0%) achieved pCR. Pathological complete response rates in luminal B (HER2-positive) and triple-negative subtypes were 29.4% and 29.3%, respectively; these were significantly higher than the rates in other hormone-positive subtypes (all P<0.05; Fig 2).

Factors significantly associated with pCR included ER/PR negativity and HER2 positivity. Within the HER2-positive population, pCR was more common for hormone receptor–negative tumours than for hormone receptor–positive tumours; it was also more common in patients who received trastuzumab. Other factors (eg, age, menopausal status, clinical tumour and nodal stages, ER status, and Ki-67 proliferation index) did not appear to influence the achievement of pCR.

Figure 3 shows the proportions of patients treated with NAC who subsequently underwent different types of breast surgery, categorised according to clinical cancer stages. Patients with clinical stage IIA disease were most likely to switch from mastectomy to BCS after NAC; 53.9% underwent BCS after NAC, compared with 38.2% of patients with stage IIA disease who did not receive NAC. The second highest proportion was observed among patients with clinical stage IIB disease, 38.3% of whom underwent BCS after NAC. Even among patients with clinical stage III disease, 14.1% underwent BCS after NAC. Significant differences in the rate of BCS were also observed between the NAC and non-NAC groups in patients with stages IIA (P=0.02) and IIB (P=0.031) disease.

Biomarkers were compared between diagnostic core biopsies and final surgical specimens. Excluding the 221 patients who achieved pCR after NAC, 844 breast specimens with residual tumours were evaluated after final surgery. Patients without data regarding biomarkers in either pre-chemotherapy or post-chemotherapy or both were excluded from this analysis. Alterations in ER, PR, and HER2 statuses after NAC are shown in Table 2. Most patients had no change in their ER status, but 7.6% switched from positive to negative or from negative to positive. With respect to PR status, a shift occurred in 17.4% of patients, and a shift in HER2 status was detected in 10.9% of patients. More than one-fifth (21.3%) of patients with residual tumours had a change in at least one receptor status after NAC. Ki-67 proliferation index was also evaluated; among the 297 cases assessed, 131 (44.1%) showed alterations after NAC.

During the early phase of the study period, a multidisciplinary approach was not widely used for breast cancer management; thus, most treatment decisions were based on the discretion of the attending surgeon or oncologist. Nevertheless, locally advanced diseases and hormonal receptor–negative tumours were generally the targets of NAC. Over time, NAC has been increasingly accepted, as shown in updates of various national and international guidelines (eg, National Comprehensive Cancer Network guidelines14 and European Society of Medical Oncology guidelines15). This inclination clearly contributed to the substantial increase in NAC use during the periods analysed in this study: from 5.6% in 2006-2011 to 10.3% in 2012-2017.

The increased use of NAC was mainly attributed to advancements in translational research, along with new evidence from clinical trials that have led to a better understanding of breast cancer biology and the establishment of tumour biology–based targeted treatments.16 After the expansion of its use in adjuvant therapy, trastuzumab was first registered for use as neoadjuvant therapy for breast cancer in 2006 under the Department of Health in Hong Kong. Its entry into the Hospital Authority Drug Formulary soon followed, and it was included in the safety net enlistment by 2009. This timeframe suggests that the drug has become accessible to a much broader spectrum of patients under the care of public sector hospitals in Hong Kong; it is also compatible with the considerable increase in use of trastuzumab over time. In our dataset, among patients with HER2-positive (non-luminal) tumours, the proportion of patients using anti-HER2 regimens in neoadjuvant therapy increased from 57.6% in 2006-2011 to 82.5% in 2012-2017.

Neoadjuvant trials allow rapid assessment of drug efficacy; they can accelerate the development and approval of treatments for early breast cancer. Pathological complete response has been proposed as a surrogate endpoint for predictions of long-term clinical benefit.17 Although it is difficult to compare outcomes among trials and individual series because of heterogeneity in terms of study design and patient populations, the results of some meta-analyses have suggested that the achievement of pCR after NAC is a predictor of overall survival, disease-free survival, and relapse-free survival.18

Our results are consistent with findings by von Minckwitz et al11 and the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) meta-analysis,17 which concluded that frequency of pCR was low in patients with low-grade, hormone receptor–positive tumours, whereas it was much higher among patients with more aggressive subtypes (ie, triple-negative and HER2-positive [non-luminal] tumours). Overall, these data suggest that the underlying molecular subtypes influence the rates of pathological responses. Further improvements in the rate of pCR have been observed in cases of HER2-positive (non-luminal) tumours treated with dual anti-HER2 targeted agents, as well as cases of triple-negative breast cancer treated with platinum and immunotherapy. Moreover, trials have also been done or in progress to evaluate the need for additional chemotherapy in selected patients with residual disease after NAC; the results of those trials are expected to provide further insights regarding treatments for further improving survival outcomes in neoadjuvant setting.18 19 20

Standard prognostic indicators, such as tumour size at the time of surgical resection or the number of involved lymph nodes, are no longer applicable in the neoadjuvant setting; systemic therapy often down-stages the disease and may lead to eradication. There is increasing evidence that the tumour response to NAC can facilitate prognostic predictions. In the multidisciplinary management of breast cancer, the identification of prognostic variables for patients receiving NAC can help to determine whether additional therapy is warranted. Given the strong support for an association between prognosis and clinicopathological features in the neoadjuvant setting, clinicians may be able to avoid additional interventions after surgery (e.g., additional chemotherapy) in patients who are otherwise considered high risk at initial presentation since pCR has been achieved. This is because although HER2-positive and triple negative breast cancers carry poor prognosis, these tumours have higher pCR rates after NAC, and pCR in HER2-positive (non-luminal) and triple-negative tumours was associated with excellent prognosis.11 17 21

Quality of life–focused research has shown that body image scores are significantly better among patients who undergo BCS than among patients who undergo mastectomy. Patients who undergo BCS are less worried about their appearance, have more freedom in their choice of clothing, feel less upset about changes in their bodies, and feel more accepted by their partners.22 These findings reinforce the benefits of NAC for breast cancer in terms of down-staging the disease, increasing resectability, and enhancing BCS eligibility among patients who would otherwise require mastectomy. Furthermore, a systematic review of NAC for operable breast cancer revealed that the mastectomy rate was lower among patients who received NAC than among patients who underwent surgery prior to adjuvant chemotherapy (relative risk=0.71; 95% confidence interval [CI]=0.67-0.75); the use of NAC did not hinder local control (hazard ratio=1.12; 95% CI=0.92-1.37).23 Long-term follow-up analyses also showed that preoperative chemotherapy increased rates of BCS without increasing the rates of locoregional recurrence.24 25 In a previous study in Hong Kong, univariate analysis revealed that patients who achieved pCR after NAC had a higher likelihood of successful BCS (P=0.028). Pre-chemotherapy disease staging (P=0.001) and tumour size (P=0.005) were also important factors that influenced successful conversion to BCS.5

However, a recent meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group showed that, compared with adjuvant chemotherapy, NAC was associated with more frequent local recurrence; the 15-year rates of local recurrence were 21.4% for NAC and 15.9% for adjuvant chemotherapy (rate ratio=1.37; 95% CI=1.17-1.61; P=0.0001).8 Thus, continued follow-up of patients registered in the HKBCR and updates will provide important insights with respect to NAC on long-term outcomes.

Neoadjuvant chemotherapy can cause changes in ER, PR, and HER2 statuses, as well as the Ki-67 level, in patients with invasive breast cancer.26 27 A possible explanation for this phenomenon is that chemosensitive cancer cells are destroyed by chemotherapy, whereas chemoresistant cells survive; such a change could alter the receptor status. Furthermore, because ER, PR, and HER2 are highly interdependent, a change in one receptor could lead to changes in the other receptors.28 A systematic review showed that the rates of ER and/or PR discordance range from 2.5% to 51.7%; among patients who received NAC combined with trastuzumab, up to 43% exhibited a switch to HER2 negativity.29

Thus far, there are only limited data regarding the prognostic value of changes in biomarkers after NAC among patients with breast cancer.28 Several groups have reported that a switch from negative to positive status (for ER, PR, or HER2) is associated with better overall survival.30 31 Additionally, outcomes are better among patients with stable hormone receptor status profiles than among patients with altered profiles.32 Notably, Guarneri et al33 reported that patients with loss of HER2 overexpression tended to have a greater risk of relapse, compared with patients who remained HER2-positive; in contrast, a decrease in Ki-67 expression after NAC was reportedly associated with better outcomes.34

Because of the above observations, biomarkers and Ki-67 levels should be retested after NAC. Such retesting is particularly important for tumours that were ER/PR-negative and/or HER2-negative before treatment because a shift to a positive status would indicate a need for endocrine therapy and/or trastuzumab. The results of these changes may influence clinical decisions regarding subsequent treatment and help to identify patients with better outcomes after NAC.28 35

This study had several limitations. First, it was a retrospective analysis and the earliest records in the database were incomplete; the missing information particularly affected breast cancer biomarkers, and Ki-67 was not routinely tested in Hong Kong public hospitals. Second, selection bias may have been present because the receipt of NAC was largely dependent on surgeon assessment and patient preference. In recent years, the potential for such bias has decreased because multidisciplinary management of breast cancer is gradually becoming the preferred approach. Considering the complexities of treatment planning, monitoring, and evaluation, decisions regarding preoperative systemic therapy require input from surgeons, oncologists, radiologists, and pathologists. Of note, the comparison of rates of surgery types between NAC and non-NAC groups can only be regarded as approximation, as assignment of patients into these two groups is not randomised; furthermore, clinical stages may differ from pathological stages, thus they may not be comparable.

Changes in the clinical management of breast cancer led to increased use of NAC in Hong Kong during the period of 2006 to 2017. Neoadjuvant chemotherapy was effective in tumour down-staging; one-fifth of patients subsequently achieved pCR in the breast and axillary lymph nodes. In particular, higher rates of pCR were detected in HER2-positive (non-luminal) and triple-negative subtypes. After NAC, greater proportions of patients with clinical stage IIA or IIB disease underwent BCS. Currently, post-NAC adjustments to treatment are based on whether pCR has been achieved. In the future, alterations in breast cancer biomarkers after NAC may provide useful guidance regarding further adjuvant therapy. The indications for NAC have expanded from the treatment of locally advanced breast cancers (to facilitate surgery) to the down-staging of early disease, thereby facilitating BCS. Under the care of a multidisciplinary team, patients with early breast cancer who have an appropriate indication should consider receiving NAC before surgery. Further studies are warranted to evaluate the benefits of individual NAC regimens.

Concept or design: PSY Cheung.
Acquisition of data: DMS Tse, HM Lee, PY Tam.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: YHY Chan.
Critical revision of the manuscript for important intellectual content: PSY Cheung, CCH Kwok.

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.

The authors thank all patients who have joined the Hong Kong Breast Cancer Registry (HKBCR), as well as the research staff who have participated in data collection from 20 hospitals and 37 clinics throughout the territory (online supplementary Appendix). The authors also acknowledge the following steering committee members who provided guidance for the development of the HKBCR: Dr Sharon Wing-wai Chan (United Christian Hospital), Dr Wai-ka Hung (Pedder Clinic), Dr Lawrence Pui-ki Li (Alpha Oncology Centre), and Dr Chun-chung Yau (Hong Kong Sanatorium & Hospital).

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

Ethics approval for this study has been obtained from the following six approving bodies:
1. The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee, Hong Kong (Ref No.: CRE-2009.037)
2. Kowloon West Cluster Research Ethics Committee, Hospital Authority, Hong Kong (Ref No.: KW/EX/08-090)
3. Research Ethics Committee (Kowloon Central/ Kowloon East), Hospital Authority, Hong Kong (Ref No.: KC/KE-09-0013/ER-3)
4. Hong Kong East Cluster Research Ethics Committee, Hospital Authority, Hong Kong (Ref No.: HKEC-2010-004)
5. New Territories West Cluster Clinical & Research Ethics Committee, Hospital Authority, Hong Kong (Ref No.: (8) in NTWC/CREC/866/10)
6. Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster, Hong Kong (Ref No.: UW 09-378)

Written consent was also obtained from all patients in the study who were recruited from the participating hospitals and clinics.

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The coronavirus disease 2019 pandemic dramatically changed modern life. Traditional didactic lecture methods suddenly became impossible,1 and there was a need to maintain social distancing. A shift to online didactic lectures was the most common solution. However, there is evidence that information acquisition becomes inefficient beyond the first 10 to 15 minutes of a lecture.2 It may be even more difficult to concentrate in online lectures that lack interaction between the speaker and audience. Notably, videos longer than 10 minutes are less likely to be viewed.3 4 Short online video lectures (ie, micromodules), with or without interactive elements, offer an attractive alternative. Such micromodules can be incorporated into the flipped classroom (FC) model, which is a pedagogical paradigm shift that rearranges how time is spent in and out of the classroom.5

The FC model is becoming increasingly popular in medical education. It is attractive to the current generation of students who are accustomed to utilising digital media; on average, 70% of students prefer this learning model.6 Students can learn pre-class materials at their own pace; they can also enjoy more in-class active learning and interaction. Moreover, they can negotiate the FC platform at their preferred time and in their preferred place. Instead of passively delivering information in class, educators can devote valuable contact time to interactions with students, exploration of their needs, and discussions of more nuanced and challenging topics.6 The acquisition of foundational information becomes an active self-directed process, outside of the classroom.

Considering the continuous growth of medical literature, today’s medical students must acquire an expanded field of knowledge before graduation. A modern urology clerkship should alleviate the intense time pressures placed on students by helping them to effectively and efficiently develop diagnostic and procedural core competencies. Where possible, students should be allowed to learn by active participation, rather than listening and reading, during the limited available contact time. The FC model holds great promise in achieving this goal.7

The success of the FC model requires an efficacious online platform that facilitates self-directed learning; stringent evaluation of the online platform is necessary. However, methodologically rigorous qualitative and quantitative studies and evidence-based recommendations are scarce.8 Most published works quote practical wisdom, anecdotes, and principles of educational theory as the basis for their recommendations.9

This pilot study was conducted to compare our institution’s online micromodule platform with traditional didactic lectures in facilitating the acquisition of foundational urological knowledge by medical students.

This prospective, single-centre, single-blind randomised controlled trial, performed at a tertiary academic hospital, investigated whether online micromodules are non-inferior to traditional didactic lectures as an instructional medium; this trial is a component of a larger movement towards the FC approach in clinical training.

The urology clerkship is a surgical subspecialty in our faculty curriculum. All medical students have 1 week of clinical attachment in their final year of medical clerkship training (Year 6). The standard curriculum consists of lectures, bedside tutorials, and clinical shadowing. Traditionally, lectures are delivered to the whole class at the beginning of the academic year. Students then shadow our team in small groups on the wards, in clinics, and in the operating theatre. Teaching is opportunistic, based on symptoms, signs, investigations, diseases, and procedures encountered in the clinical setting. Formal knowledge assessment is conducted during end-of-year examinations in the form of written examinations (multiple-choice questions [MCQs] and short-answer questions), objective structured clinical examinations (OSCEs), and clinical short case examinations.

In this study, we selectively assessed knowledge transfer with regard to two urology topics: approaches to lower urinary tract symptoms (LUTS) and haematuria. First, a didactic lecture on the management of LUTS and haematuria, along with other topics, was recorded during its delivery in our routine lecture series for final-year students. Subsequently, two micromodules were prepared concerning the management of LUTS and haematuria; the micromodule content was similar to the didactic lecture content. The study participants continued with their scheduled urology training in Year 6; therefore, the study intervention was regarded as supplemental curriculum. Because the participants’ overall learning opportunities were not affected, we decided to obtain only verbal consent for inclusion in the study.

Medical students in Years 4 to 6 with no exposure to the urology subspecialty rotation were voluntarily recruited for the study. Participants were randomly allocated to either traditional didactic lectures or online micromodules; rigorous proctored tests were administered in accordance with the schedule shown in the Figure. Permuted block randomisation was conducted using a computer program. Random allocation sequences were placed into identical sealed and numbered envelopes. Designated research staff members were responsible for allocating consecutively numbered envelopes to the participants.

Students randomised to the traditional didactic lecture were grouped into a class, which watched the pre-recorded 45-minute didactic lecture in the lecture theatre (as if the students were attending a standard lecture). Students randomised to the online micromodule group viewed the micromodules on separate computers at their own pace. The total runtime of these micromodules was 10 minutes each, and students were expected to explore the content in its entirety within 45 minutes. The breadth and depth of topics covered in both interventions were identical to each other and similar to past lectures; the only difference was the delivery medium. The students could not be blinded; however, all outcome assessors (including content creators) were blinded to intervention allocation because the didactic lecture was not delivered live or in person.

We used the Kirkpatrick’s four-level training evaluation model as the basis for evaluations of instructional effectiveness. In the context of online learning, Level 1 (reaction) refers to the student’s affective responses to training quality or relevance, usually measured by surveys; Level 2 (learning) refers to knowledge directly obtained from the online lecture, usually measured by knowledge tests such as MCQs and true-false questions; Level 3 (behaviour outcomes/transfer of learning) refers to improvements in the outcomes of tasks not directly taught in the instructional content, typically measured through practical or standardised examinations; and Level 4 (results) refers to the impact of training on organisational goals (ie, actual benefit to patients).

Prior to randomisation, a pre-intervention MCQ test was used to determine participant baseline knowledge. Immediately after randomisation and completion of training, participants repeated the MCQ test to determine the degree of knowledge acquisition (ie, Kirkpatrick Level 2). Their confidence in the subject matter was also measured using a 10-point scale (ie, Kirkpatrick Level 1).

After 3 weeks of teaching, each participant underwent individual assessments in outpatient clinics. The MCQ test was administered again to test knowledge retention. Then, an OSCE was administered to assess the participant’s approach to a real patient with either LUTS or haematuria. A nurse was present as a chaperone and third-party assessor, who gave a subjective assessment score, measured using a 10-point scale. The participant then presented the case to a urologist, who assessed the collected information using a structured marking scheme. Additionally, the urologist gave a subjective assessment score, similar to the nursing assessment. All student assessors were blinded to the allocated teaching approach. The scores from the nurses and urologists were used to assess student performance in the OSCE (ie, Kirkpatrick Level 3); they also were used to assess the overall effectiveness and safety of the micromodule teaching approach. Due to the study design, the impact of training on organisational goals (ie, Kirkpatrick Level 4) was not assessed.

Statistical analysis was performed using SPSS (Windows version 23.0; IBM Corp, Armonk [NY], United States). There was no crossover between treatment arms. Data were analysed using an intention-to-treat approach. Descriptive statistics (means, standard deviations, and ranges) were used for demographic data. Independent samples t tests or one-way multivariate analysis of variance were used for parametric continuous variables; the Mann–Whitney U test was used for non-parametric continuous variables; and the Chi squared test was used for categorical variables. P values <0.05 were considered statistically significant.

Between 4 December 2017 and 22 January 2018, 45 medical students voluntarily enrolled in this study at our hospital; 22 students were randomised to the didactic lecture group and 23 students were randomised to the online micromodule group. Most participants (77% and 74%, respectively) were in their final year of medical education. There were no significant differences in demographic composition between the two groups (Table 1). The difference in pre-intervention MCQ scores also was not statistically significant (P=0.471), indicating that the participants had similar baseline knowledge (Table 2).

In this study, the primary outcome was the difference in OSCE scores between the didactic lecture and online micromodule groups, as assessed by the urologists. This outcome corresponds to Level 3 of the Kirkpatrick model. Three-quarters of participants assessed real patients with LUTS; the remaining participants assessed patients with haematuria. There was no difference in OSCE score between the groups (13.09 ± 1.59 vs 12.98 ± 1.75, P=0.823) [Table 2].

The secondary outcome was the difference in knowledge acquisition and retention between interventions. Knowledge acquisition was defined as the difference between pre-intervention and post-intervention MCQ scores. Knowledge retention was defined as the difference between pre-intervention MCQ score and pre-OSCE MCQ score (taken 3 weeks after the intervention). Both of these outcomes correspond to Level 2 of the Kirkpatrick model. There were improvements in MCQ scores after teaching in both groups, although not statistically significant. However, there was no difference in the degree of improvement between the groups. Therefore, knowledge acquisition for the two groups were similar. For the assessment of knowledge retention, one-way multivariate analysis of variance with adjustment for pre-intervention MCQ scores revealed no statistically significant difference between post-intervention MCQ score and pre-OSCE MCQ score (Wilks’ Lambda=0.894, P=0.101, partial η²=0.106).

Finally, subjective assessment of confidence and competence was conducted; this assessment corresponds to Kirkpatrick Level 1. There was a significant improvement in post-intervention self-rated confidence, but there was no difference in the degree of improvement between the groups (Table 2). In terms of clinical performance (Kirkpatrick Level 3), there were no differences between the groups in terms of subjective assessment score by the urologists (7.89 ± 0.91 vs 7.70 ± 0.91, P=0.487) or nurses (8.05 ± 0.72 vs 8.04 ± 0.71, P=0.993).

Our results show that both didactic lectures and online micromodules can help medical students achieve comparable outcomes in terms of acquiring, retaining, and applying foundational urological knowledge. Thus, online learning platforms may be viable substitutes for didactic lectures in the broader context of a move towards the FC approach.

In a systematic review of literature concerning the use of online lectures in undergraduate medical education,6 45 studies were identified; only 21 (47%) of those studies had clearly established control and intervention groups. Among the 21 studies, only six (29%) assessed learning using an OSCE or equivalent practical examinations; the remaining studies used MCQ tests. There was considerable heterogeneity in the manner by which online lectures were integrated into existing surgical curricula, which hindered meta-analysis. However, online lectures generally tended to be non-inferior to traditional lectures.

Online learning offers many benefits to educators and students. First, it ensures round-the-clock access to learning materials. Second, it allows students to revisit these materials throughout the curriculum. Third, online learning platforms can track and verify that students have accessed and completed specific materials. Fourth, electronic content can be updated in a convenient manner; distribution is instantaneous and universal. Fifth, students have autonomy over the sequence and pace of learning, as well as the allocation of time; these aspects allow them to tailor their learning experience to meet personal objectives. Sixth, although a higher initial investment may be required, online learning platforms can be reused, exchanged, and collaborated on; they offer new economies of scale.10 11 Finally, the coronavirus disease 2019 pandemic led to concerns about the spread of infection, such that online micromodules became an attractive option for medical student education that permitted social distancing. Notably, online micromodules represent easily accessible media that can be used for continuing medical education, and interactive teaching can be added to enhance learning experience.

An important limitation of online learning is that educators may utilise the scheduling freedom offered by online platforms to overburden students with learning materials; they may not consider the large amount of non-classroom time that may be allocated to other tasks. To avoid this phenomenon, we established ‘bite-sized’ modules (ie, micromodules) and ensured that all topics covered are highly relevant to future clinical practice. Such short modules also match the students’ attention spans.2 3 4 However, we acknowledge that educators may initially expend greater effort in the preparation of online modules.4

Although there were some improvements in MCQ scores after the lecture or micromodules, they were weaker than expected, potentially because the post-intervention MCQ test occurred immediately after the lecture and there was insufficient time for participants to process the lecture content. Another limitation of the study design was that there were no tutorials or in-class interactions after the lectures. Thus, the acquired knowledge may not have been consolidated, resulting in suboptimal knowledge retention. Nevertheless, this study was designed to demonstrate non-inferiority between pedagogical approaches. Educators should remember that online learning is one component of the overall FC model. An overhaul of the broader teaching mentality and existing curriculum is required to realise the paradigm shift offered by the FC model. Thus, simple conversion of existing lecture notes to an electronic format will not effectively facilitate learning. There is a need for full utilisation of software/technologies to prepare multimedia/truly interactive micromodules; this approach is more likely to enhance student learning experiences. It is also challenging to develop effective methods for assessment of student competencies. Educators should support and collaborate with clinicians in this regard, thereby complementing each other’s efforts.4 12 13 14 15

In addition to video lectures, online platforms can be used to deliver diverse educational content, including interactive multimedia learning modules, discussion forums, polling, and virtual patients. We deliberately excluded these materials for the duration of this study because they represent distinct instructional configurations in terms of content and interactivity. The combination of interactive elements and lecture into a single intervention group would have confounded and invalidated the results.6 8 Thus, the video lectures solely consisted of slide decks, narration, and video. More studies are needed to determine how to best incorporate these teaching approaches into the instructional design of future curricula.11

The present study focused on the transfer of clinical knowledge and management of common urological symptoms via micromodules. Future research should examine whether online lectures can also effectively transfer practical procedural skills. Because of time constraints and the curriculum system, exposure during the clerkship period is extremely limited. Therefore, the current instructional approach for physical examination and basic clinical procedures (eg, insertion of urethral and central venous catheters) is often informal, opportunistic, and unstructured. Further studies may clarify the role of online education in procedural training.

Online micromodules were non-inferior to a traditional didactic lecture in terms of knowledge transfer focused on urology topics. Further enhancement of the interactive elements of the instructional medium will improve learning experience. Micromodule utilisation can be optimised during the development of the FC model of teaching. In times such as the recent pandemic era, where social distancing must be maintained throughout the educational process, there is an urgent need for curriculum reform that maximises the use of technology to enhance medical student learning.

Concept or design: CF Ng.
Acquisition of data: CH Yee, PKF Chiu, JYC Teoh, FPT Lai.
Analysis or interpretation of data: K Lim.
Drafting of the manuscript: K Lim, CF Ng.
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 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.

This research received support from the Micro-Module Courseware Development Grant Scheme of The Chinese University of Hong Kong, Hong Kong (Ref No.: 3210817).

This research aimed to improve instruction through the use of educational tests administered to the participants. All participants provided informed consent without the collection of personal or sensitive data.

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