Hong Kong faced a third wave of the coronavirus disease 2019 (COVID-19) pandemic, from July to September 2020. Whereas the first two waves mainly consisted of imported cases and generally affected younger patients, the third wave mainly consisted of local cases and their respective epidemiological associations. There were multiple outbreaks in residential care homes for older adults. The overall mortality rate increased from 0.69% in late June 2020 to 2% in late October 2020.1

Multiple studies have shown that advanced age and co-morbidities are risk factors for mortality in patients with COVID-19.2 3 4 Observational studies focused on older patients have reported in-hospital mortality rates of 19.2% to 35.9%.5 6 However, findings in other countries might not be generalisable to Hong Kong because of considerable variations in disease surveillance, hospitalisation thresholds, and treatment guidelines worldwide. Therefore, an in-depth study of older adults with COVID-19 in Hong Kong is needed.

In 2020, Hong Kong had one of the highest rates of COVID-19–related hospitalisation worldwide. The local healthcare policy required hospitalisation of all patients aged ≥65 years who had COVID-19; those patients were then admitted to isolation wards, regardless of disease severity. This unique situation enabled us to perform a comprehensive review of the clinical course and outcomes of older patients with COVID-19 in Hong Kong. We compared mortality rates among age-groups and frailty levels to determine whether such factors had predictive value for survival.

This retrospective observational study included patients aged ≥65 years who were admitted to Tuen Mun Hospital, Hong Kong, for management of polymerase chain reaction–confirmed COVID-19 between 1 July 2020 and 31 August 2020. Cases were identified from the hospital’s Infectious Disease Team database. We excluded patients who had previously been discharged for COVID-19 and readmitted for other causes, as well as patients who had not been discharged by 31 October 2020 (ie, the date of study commencement).

Hospitalised cases were managed in accordance with standardised practices; routine nursing and medical care were provided under the supervision of infectious disease specialists. Each patient’s clinical data (ie, baseline characteristics, co-morbidities, clinical presentation, laboratory findings, treatment, clinical outcomes, and complications) were retrieved from electronic medical records. The 2007 version of the Clinical Frailty Scale (CFS) was used to assess frailty with scores from 1 (very fit) to 9 (terminally ill).7 The CFS scores were retrospectively derived on the basis of patient co-morbidities, premorbid mobility, and levels of function; these factors were determined using clinical notes, medical and nursing admission assessments, and allied health records. Presenting symptoms and onset dates were reported by patients or their caregivers. Chronic heart disease was defined as any ischaemic or valvular heart disease, arrhythmia, and/or heart failure. Chronic respiratory disease was defined as asthma, chronic obstructive pulmonary disease, bronchiectasis, and/or obstructive sleep apnoea. Chronic kidney disease was defined as chronic kidney disease stage ≥3a. Viral load was determined by the cycle threshold (CT) value in polymerase chain reaction analysis of specimens from the respiratory tract; this value reflected the number of amplification cycles required to produce a detectable amount of viral RNA and was inversely proportional to the viral load. Laboratory results were recorded at baseline unless otherwise specified.

Primary outcomes were the clinical course and outcomes of patients, including their clinical presentation, laboratory findings, treatment, clinical deterioration (defined as hypoxia onset, mechanical ventilation requirement, or intensive care unit [ICU] admission), complications (eg, acute kidney injury, liver impairment, superinfection, thromboembolic, and acute ischaemic events), and in-patient mortality. We compared these findings between survivors and non-survivors. Secondary outcomes were the mortality rates according to age-group and frailty level.

Hypoxia was defined as oxygen desaturation that resulted in a need for supplemental oxygen. In accordance with the KDIGO (Kidney Disease: Improving Global Outcomes) 2012 acute kidney injury guideline,8 acute kidney injury was defined as an increase in serum creatinine by >26.5 mmol/L within 48 hours or an increase to ≥1.5-fold above baseline, where baseline presumably occurred within the previous 7 days. Liver impairment was defined as an increase of >3-fold above the upper normal limit of serum alanine aminotransferase. Superinfection was defined as secondary bacterial, viral, or fungal infection that occurred ≥48 hours after admission.

Statistical analyses were performed using SPSS (Window version 22.0; IBM Corp, Armonk [NY], Unite States). All continuous variables in this study had skewed distributions using the Kolmogorov–Smirnov test and were expressed as medians with interquartile ranges (IQRs), while categorical variables were expressed as numbers with percentages (%). The Mann-Whitney U test was used to compare non-parametric continuous data between groups. As appropriate, the Chi squared test or Fisher’s exact test was used to compare categorical variables. The Cochran–Armitage trend test was used to assess mortality trends. All statistical tests were two-sided and P<0.05 was considered indicative of statistical significance.

During the study period, 427 patients were admitted to Tuen Mun Hospital for management of COVID-19. After the exclusion of paediatric patients and adults aged <65 years (n=323), as well as older adults who had not yet been discharged by the study date (n=3), 101 patients were included in the study.

Baseline patient characteristics are shown in Table 1. The median age was 73 years (range, 65-96); 99% of patients were Chinese, 52.5% were men, and 28.7% were old age home residents. Furthermore, 30.7% had at least mild frailty (CFS score ≥5). Overall, 85% of the older patients had at least one co-morbid chronic disease, including hypertension (73.3%); diabetes mellitus (37.6%); hyperlipidaemia (50.5%); chronic heart (14.9%), lung (6.9%), or kidney (5.9%) diseases; stroke (15.8%); dementia (9.9%); obesity (3%); and active malignancy (3%).

Patients were generally admitted 3 days (IQR, 1-6) after symptom onset (Table 1). Only 4% of patients were asymptomatic on admission, while only 2% of patients remained completely asymptomatic throughout the course of disease. Common presenting symptoms included fever (80.2%), cough (63.4%), sputum (37.6%), dyspnoea (17.8%), diarrhoea (11.9%), and anosmia (5%). Overall, 11.9% of patients required oxygen support on admission.

Laboratory findings are shown in Table 2. The median trough CT value was 16.6. Lymphopenia and hyponatraemia were common; the median trough lymphocyte count and sodium level were 0.6 × 10⁹/L and 133 mmol/L, respectively. Elevated levels of lactate dehydrogenase, C-reactive protein, D-dimer, and ferritin were also common.

Antiviral drugs were administered to 86.1% of patients, while antibiotics were administered to 83.2% of patients. During the study period, combined administration of lopinavir-ritonavir and interferon beta-1b was the most commonly used COVID-19-specific antiviral treatment approach. Other COVID-19 treatments (eg, systemic steroid, remdesivir, tocilizumab, convalescent plasma, and extracorporeal blood purification) were administered in accordance with each patient’s clinical indications. Systemic steroid treatment was administered to 48.5% of patients; it was mostly administered to patients who developed hypoxia. Overall, 4% of patients received convalescent plasma, 8% required renal replacement therapy, and 1% required extracorporeal membrane oxygenation.

Clinical deterioration occurred in more than half of the older patients. Fifty-two patients (51.5%) developed hypoxia, generally on day 8 (IQR, 5-11) after symptom onset. The outcomes of the 52 patients who developed hypoxia are shown in Figure 1; among the 16 patients who received ICU support, 13 required mechanical ventilation and six died. Three patients did not require mechanical ventilation after ICU admission; all three survived. Thirty-six patients with hypoxia were admitted to general wards because they were not candidates for ICU admission or did not require intensive care; of these 36 patients, 25 survived and 11 died. All 11 patients who died without ICU support had a do-not-resuscitate order and thus did not receive cardiopulmonary resuscitation. Among the 49 patients who did not develop hypoxia, all survived. The overall mortality rate was 16.8% (n=17); the mortality rate among patients who developed hypoxia was 32.7%. Among all ICU patients and among ICU patients who required mechanical ventilation, the mortality rates were 37.5% and 46.2%, respectively.

Acute kidney injury and liver impairment each occurred in 25.7% of patients (Table 3). Superinfection occurred in 17.8% of patients, while delirium occurred in 5.9% of patients. Three patients (3%) experienced thromboembolic or ischaemic events: deep vein thrombosis, acute ischaemic stroke, and acute myocardial infarction (n=1 each). The median time from admission to discharge was 18.5 days (IQR, 12-26), while the median time from admission to death was 15 days (IQR, 10-30).

Patients who died during the index admission were older (median age, 72 vs 82 years, P=0.028) and had greater frailty (median CFS score 3 vs 5, P=0.009) [Table 1]. A higher viral load was observed in non-survivors (trough CT value 17.2 vs 15.4, P=0.005). Non-survivors also had a lower trough lymphocyte count (0.7 vs 0.4 × 10⁹/L, P<0.001); a higher international normalised ratio (1 vs 1.1, P=0.032); and higher peak levels of creatinine kinase (117 vs 225.5 U/L, P=0.014), lactate dehydrogenase (326 vs 522 U/L, P=0.014), C-reactive protein (90.1 vs 148 mg/L, P=0.008), and procalcitonin (0.25 vs 0.28 ng/mL, P=0.004) [Table 2]. More non-survivors had acute kidney injury (15.5% vs 76.5%, P<0.001) and superinfection (13.1% vs 41.2%, P=0.006) [Table 3].

The mortality rates in patients aged 65-69, 70-79, 80-89, and ≥90 years were 9.1% (3/33), 10% (3/30), 30% (9/30), and 25% (2/8), respectively (Fig 2). Patients who were very fit and well (CFS score 1-2) had a mortality rate of 5.7% (2/35); patients who were managing well or vulnerable (CFS score 3-4) had a mortality rate of 14.7% (5/34); patients with mild to moderate frailty (CFS score 5-6) had a mortality rate of 23.5% (4/17); and patients with at least severe frailty (CFS score ≥7) had a mortality rate of 40% (6/15) [Fig 3]. The Cochran–Armitage trend test showed that mortality linearly increased with both age (P=0.031) and CFS score (P=0.003).

As of 31 October 2020, there were >5300 COVID-19 cases in Hong Kong; the median age was 43 and the overall case fatality rate was 2%.1 Previous studies have shown that mortality is much higher among older patients. A large prospective cohort study of 20 000 hospitalised patients with COVID-19 in the United Kingdom (median age, 74 years) revealed a mortality rate of 26%.3 Another cohort study of 5700 hospitalised patients with COVID-19 in New York revealed a mortality rate of 32.7% among the 1425 patients aged >60 years.9 Because hospitalisation is required for older adults (aged ≥65 years) with COVID-19 in Hong Kong, our in-patient mortality of 16.8% can be regarded as a close approximation of the case fatality rate for this age-group; this was significantly higher than the case fatality rate in the general population. The broad hospitalisation requirement for older adults in Hong Kong may also explain the substantially lower mortality rate in this study, compared with studies in countries where only patients with severe disease were hospitalised.

Our findings suggest that older patients tend to have symptomatic COVID-19. Fever occurred in >80% of patients; only 2% of patients remained completely asymptomatic throughout the course of disease. A meta-analysis of 41 studies by He et al,10 which involved >50 000 patients from all age-groups, revealed that the pooled percentage of asymptomatic COVID-19 was 15.6%—this was much higher than the rate in the present study. In addition to the possible effects of age differences, the high rate of symptoms reported in this study could also be related to the early identification and active screening of high-risk patients (eg, patients who had contact with positive cases and were placed under close medical surveillance in quarantine centres).

We observed some differences between survivors and non-survivors in terms of baseline patient characteristics, laboratory findings, and complications. Non-survivors were significantly older and had greater frailty; they also had a higher viral load, lower lymphocyte count, higher inflammatory marker levels, and higher incidences of acute kidney injury and superinfection. Because of sample size limitations, we did not perform multivariate analyses of each factor potentially associated with mortality; however, we observed some trends. For example, death occurred in 29% of patients with at least mild frailty (CFS score ≥5) and 33.3% of patients who required supplemental oxygen on admission; these features might be early indicators of poor prognosis. Furthermore, death occurred in 50% of patients with acute kidney injury and 38.9% of patients with superinfection. Such complications could also be indicators of poor prognosis because the associated mortality rates were not negligible.

In this study, patients generally showed clinical deterioration on day 8 after symptom onset. This is consistent with the findings by Zhou et al2 in Wuhan, where the times from illness onset to dyspnoea and sepsis were 7 and 9 days, respectively. Additionally, the overall rate of deterioration was high among older patients, such that 51.5% developed hypoxia during the course of disease. This was comparable to the results of a study by Mostaza et al,6 in which exacerbation of dyspnoea occurred in 43% of 400 older patients. These high rates are a cause for concern because older patients with COVID-19 are reportedly more susceptible to silent hypoxia,11 12 which may be missed without close monitoring; thus, subsequent treatment may be delayed.

In this study, a do-not-resuscitate order had been issued for each of the 11 hypoxic patients who died after a lack of ICU support. These patients constituted 10.9% of all older patients in the study; they were substantially older and had greater frailty, both of which were contra-indications for ICU admission. The care team was able to promptly identify these patients and involve them (and/or their families) in advanced care planning. Because resources are limited during the COVID-19 pandemic, it is important to identify patients at risk of deterioration, as well as patients with poor reserve who are unlikely to survive the disease. In the early stages of the global pandemic, some countries proposed age limits for access to intensive care because of crises in their healthcare systems; such proposals created ethical dilemmas and allegations of ageism.13 14 Frailty screening was proposed to replace the age criterion for resource allocation13; accordingly, we compared its association with in-patient mortality to the association of age with in-patient mortality.

Frailty has been defined as an ageing-related decline in physiological reserve, which leads to increased vulnerability to stress. It has been associated with poor clinical outcomes in older adults7 15 16 and has been used to predict chest infection–related mortality.17 The CFS is a simple nine-point tool for assessing frailty. Compared with non-frail patients (CFS score 1-4), at least mild frailty (CFS score ≥5) has been independently associated with all-cause mortality in hospitalised patients.18

A few studies have shown a relationship between frailty and COVID-19–related mortality. In a European multicentre cohort study of in-patients with COVID-19, Hewitt et al19 found that the hazard ratio for mortality increased with increasing CFS score; compared with CFS score 1-2, the adjusted hazard ratios were 1.55 for CFS score 3-4, 1.83 for CFS score 5-6, and 2.39 for CFS score 7-9. Disease outcome was more accurately predicted by frailty than by age or co-morbidity. Moreover, mortality rates in patients with CFS scores 5-6 and ≥7 were 30.9% and 41.5%, respectively; these were broadly similar to our findings. In the United Kingdom, Brill et al20 conducted a study of very old patients with COVID-19; they found a significantly higher CFS score (but not significantly older age) among patients who died than among patients who survived. The results of both above studies are consistent with our findings.

In this study, we observed a substantial increase in mortality, from approximately 10% in patients aged 65-79 years to approximately 30% in patients aged 80-89 years. However, the mortality rate reached a plateau and did not increase with further increases in age. In contrast, mortality progressively increased with increasing frailty, from 5.7% in patients who were fit and well (CFS score 1-2) to 40% in patients with at least severe frailty (CFS score ≥7). Although both age and frailty had linear statistical relationships with mortality, the linearity was more pronounced for frailty. Our findings support the use of frailty screening at admission for all older patients with COVID-19; this early assessment can predict adverse outcomes, regardless of initial symptoms and disease severity. Rather than age alone, frailty and age should be considered together when making decisions about resuscitation and advanced care planning.

A notable strength of this study was that it provided a comprehensive overview of the clinical course and outcomes in all older patients with COVID-19, over a wide range of disease severity, because of the non-selective hospitalisation policy in Hong Kong. Because all admitted older adults were included in the study, there was no selection bias. Furthermore, because patients who had not been discharged by the study date were excluded from the study, data were available for all clinical outcomes among the included patients.

There were some limitations in this study. First, it had a small sample size. Tuen Mun Hospital was the only designated centre in the New Territories West Cluster in Hong Kong that provided acute care during the index admission for patients with COVID-19; it covered a population of >1 million. Although this was a cluster-based study, the sample size was small and certain statistical tests could not be performed because they were underpowered. Future multicentre or multi-cluster studies may yield more comprehensive results. Second, the CFS score was determined in a retrospective manner; it might have been limited by the availability of functional assessment data from electronic records. While assessments of patients under geriatric care are usually comprehensive, evaluations might have been incomplete for patients who were new to the Hospital Authority. To minimise potential errors, the scores were separately determined by two geriatric specialists, then stratified into four categories of CFS score. Although dedicated prospective assessments are preferable, previous studies have shown that retrospectively determined CFS scores have high precision and reliability, compared with prospectively determined scores.21 Third, some data were missing. For example, effective reporting of disease symptoms and onset might be difficult for dependent older adults; moreover, some blood tests (eg, procalcitonin, ferritin, and D-dimer) were not performed for some patients. Finally, the results of this study might not be generalisable to other countries or centres because the management of patients with COVID-19 largely depends on local practices. Hospitalisation rates, treatment thresholds, and therapeutic regimens may considerably vary around the world. Thus, our findings should be carefully interpreted and compared with the results of other studies.

Clinical deterioration was common in older patients with COVID-19. Mortality was high with respect to the overall case fatality rate. Linear relationships with mortality were observed for both age and frailty.

Concept or design: EMYY Tam, YK Kwan.
Acquisition of data: EMYY Tam, YK Kwan, YY Ng.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: EMYY Tam.
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.

All authors have disclosed no conflicts of interest.

An abstract of this study was submitted to the Hospital Authority Convention 2021.

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

This study was approved by the New Territories West Cluster Research Ethics Committee (Ref No: NTWC/REC/20135).

1. Centre for Health and Protection, Department of Health, Hong Kong SAR Government. Latest situation on cases on COVID-19 (as of 31 October 2020). Available from: https://www.chp.gov.hk/files/pdf/local_situation_covid19_en_20201031.pdf Accessed 31 Oct 2020.

2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62. Crossref

3. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985. Crossref

4. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239-42. Crossref

5. Wang L, He W, Yu X, et al. Coronavirus disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up. J Infect 2020;80:639-45. Crossref

6. Mostaza JM, García-Iglesias F, González-Alegre T, et al. Clinical course and prognostic factors of COVID-19 infection in an elderly hospitalized population. Arch Gerontol Geriatr 2020;91:104204. Crossref

7. Dalhousie University. Clinical Frailty Scale. Available from: https://www.dal.ca/sites/gmr/our-tools/clinical-frailtyscale. html. Accessed 31 Oct 2020.

8. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:179-84. Crossref

9. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052-9. Crossref

10. He J, Guo Y, Mao R, Zhang J. Proportion of asymptomatic coronavirus disease 2019: a systematic review and metaanalysis. J Med Virol 2021;93:820-30. Crossref

11. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med 2020;202:356-60. Crossref

12. Dhont S, Derom E, Van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res 2020;21:198. Crossref

13. Cesari M, Proietti M. COVID-19 in Italy: ageism and decision making in a pandemic. J Am Med Dir Assoc 2020;21:576-7. Crossref

14. Ayalon L, Chasteen A, Diehl M, et al. Aging in times of the COVID-19 pandemic: avoiding ageism and fostering intergenerational solidarity. J Gerontol B Psychol Sci Soc Sci 2021;76:e49-52. Crossref

15. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146-56. Crossref

16. Kundi H, Wadhera RK, Strom JB, et al. Association of frailty with 30-day outcomes for acute myocardial infarction, heart failure, and pneumonia among elderly adults. JAMA Cardiol 2019;4:1084-91. Crossref

17. Luo J, Tang W, Sun Y, et al. Impact of frailty on 30-day and 1-year mortality in hospitalised elderly patients with community-acquired pneumonia: a prospective observational study. BMJ Open 2020;10:e038370. Crossref

18. Bagshaw SM, Stelfox HT, McDermid RC, et al. Association between frailty and short- and long-term outcomes among critically ill patients: a multicentre prospective cohort study. CMAJ 2014;186:E95-102. Crossref

19. Hewitt J, Carter B, Vilches-Morgara A, et al. The effect of frailty on survival in patients with COVID-19 (COPE): a multicentre, European, observational cohort study. Lancet Public Health 2020;5:e444-51.

20. Brill SE, Jarvis HC, Ozcan E et al. COVID-19: a retrospective cohort study with focus on the over-80s and hospital-onset disease. BMC Med 2020;18:194. Crossref

21. Stille K, Temmel N, Hepp J, Herget-Rosenthal S. Validation of the clinical frailty scale for retrospective use in acute care. Eur Geriatr Med 2020;11:1009-15. Crossref

Uncorrected refractive error is the leading cause of visual impairment among children worldwide; it affects nearly 13 million children under the age of 16 years, half of whom live in China.1 Uncorrected refractive error can lead to various broader issues if not treated in a timely manner.2 Uncorrected refractive error in school-aged children reportedly has negative effects on academic performance,3 physical and mental health, and quality of life.4 Fortunately, over 80% of refractive error can be easily and safely corrected by accurately prescribed spectacles.5 However, the correction rate in rural areas in China is very low.6 A study in 2014 revealed that in rural China, as few as one in six children needing spectacles actually wears them.7

The lack of vision problem awareness at the family level is an important contributing factor in the low rate of refractive correction in rural areas.8 There are two main ways for parents to learn about vision problems in their children: from the children themselves and from their teachers. Information conveyed by a teacher is more likely to receive parental attention and cause parents to take action.9 Teacher-to-parent communication (TPC) allows parents and teachers to exchange information, strengthen feelings of mutual obligation and trust, and coordinate efforts to help students thrive in terms of mental health, school engagement, and school performance.10 11

However, the relationship between TPC and vision care–seeking behaviour among students is not well-investigated, particularly in more realistic settings. Researchers have indicated that teachers have an important role in vision care for students. Chinese rural teachers can perform vision screening accurately for students with only moderate training.12 Teachers can help to improve the uptake of spectacles and the use of spectacles among students who participate in free spectacles distribution programmes.13 Considering the potentially important role of teachers in vision care for students, further analyses are needed regarding the interactions between TPC and vision care–seeking behaviour among students.

In this study, our overall goal was to identify the associations between TPC and vision care–seeking behaviour among students. Specifically, when teachers informed students’ parents that their children could not see the blackboard clearly, we assessed whether the information sharing interacted with vision care–seeking behaviour among students, including refraction examinations and spectacles ownership. To meet this goal, we had three specific objectives. First, we documented the rates of vision care–seeking behaviour in four groups, according to whether and how the parents were informed about vision problems in their children. Second, we explored the relationship between TPC and refraction examination history. Third, we investigated the association between spectacles ownership and TPC.

The data analysed in this study were collected in two adjacent provinces (Gansu and Shaanxi) of western China in September 2012. In each of the provinces, one prefecture that is of the province was chosen for this study: Tianshui prefecture in Gansu and Yulin prefecture in Shaanxi. For sample selection, we obtained a list of all rural primary schools in each prefecture. We randomly selected 252 townships, then randomly selected one school per township for inclusion in the study. Within each school, one class was randomly chosen in each of the fourth and fifth grades. This cross-sectional study was approved by Stanford University (No. ISRCTN03252665, registration site: http://isrctn.org).

The data collected in this study included three parts: a standardised maths test, questionnaires, and a vision screening. The standardised maths test was timed (25 min) and proctored by two study enumerators at each school. Mathematics testing was conducted to reduce the effect of home learning on performance; this facilitated greater focus on classroom learning.7 We standardised the baseline maths score, such that the mean score was 0 and the standard deviation was 1.

Questionnaires were used to collect data from students, including grade, gender, boarding status, the main caregivers, parental education, and siblings. A parental questionnaire asked whether any family members wore spectacles and whether the parents thought spectacles were useful. Family wealth was calculated by summing the values, as reported in the China Rural Household Survey Yearbook,14 of the items on the list of 13 durable consumer goods owned by the family. A parental questionnaire asked about ownership of 13 selected items as an index of family wealth. The distance from the school to the county seat was approximated using Google Maps (Google LLC, Mountain View [CA], United States).

Vision care–seeking behaviour was measured via self-reporting on the questionnaires administered to students; it included refraction examination history (defined as undergoing a refraction examination in a professional institution before the day of questionnaire administration) and spectacle ownership (defined as the possession of spectacles before the day of questionnaire administration). To reduce the measurement error, we also asked these two questions to each student’s parents. Individuals with inconsistent answers were excluded from the study.

Teacher-to-parent communication was measured by asking parents whether they had been informed by teachers that their children could not see the blackboard clearly. Students were also asked whether they had informed their parents about their vision problems. Based on the responses to these two questions, we allocated all students with vision problems into four groups: neither teachers nor students informed parents (uninformed group), only students informed parents, only teachers informed parents, and both teachers and students informed parents (Fig).

After completion of the maths test and questionnaires, a two-part eye examination was administered to students by a team of qualified optometrists who followed a prescribed protocol to ensure standardisation and quality.

First, visual acuity screenings were administered using Early Treatment Diabetic Retinopathy Study eye charts, which are regarded as the worldwide standard for accurate visual acuity measurement.15 Visual acuity values, measured by the Early Treatment Diabetic Retinopathy Study eye charts, were transformed into logarithm of the minimum angle of resolution (logMAR) units; logMAR is one of the most commonly used continuous scales in the field of ophthalmology/optometry.3 15 Students who failed the visual acuity screening test (using a visual acuity cut-off of ≤6/12 in either eye) were enrolled in a second vision test.

The second vision test was conducted by a team of one optometrist, one nurse, and one staff assistant. Children with uncorrected visual acuity ≤6/12 in either eye underwent cycloplegia with up to 3 drops each of cyclopentolate 1% and proparacaine hydrochloride 0.5%. To ensure that vision problems among the students could be treated using spectacles, the students were examined via automated refraction (Topcon KR 8900; Topcon, Tokyo, Japan) and subjective refinement by a local optometrist who had previously been trained by experienced optometrists from Zhongshan Ophthalmic Center.

Vision problems in the students could be corrected using spectacles if they met the following criteria: first, an uncorrected (ie, without spectacles) visual acuity of ≤6/12 in either eye and refractive error within the limits associated with significantly greater improvement in visual acuity upon correction (myopia ≤-0.75 dioptres, hyperopia >=2.00 dioptres, or astigmatism [non-spherical refractive error] >=1.00 dioptres)7; second, visual acuity improvement to >6/12 in both eyes was possible with spectacles.

Descriptive statistical analyses were performed to summarise the demographics of the students and to compare the proportions of students who had undergone refraction examination and owned spectacles among four groups by using the Chi squared test and one-way analysis of variance. Refraction examination and spectacle ownership were both regarded as dummy variables that equalled one if the corresponding behaviour had occurred before the study.

Multiple logistic regression was conducted to ascertain the relationship between TPC and vision care–seeking behaviour, including refraction examination history and spectacle ownership. In all regression analyses, the same covariates were controlled. Variables included standardised maths score, grade (grade 5=1), sex (male=1), boarding status (boarding at school=1), logMAR (continuous scale of visual acuity), whether parents are the main caregivers (yes=1), parental education for both mother and father (completed >=12 years of education=1), siblings (at least one sibling=1), whether any family members wear spectacles (yes=1), whether parents think spectacles are useful (yes=1), family wealth, and distance from school to the county seat. A P value of <0.05 was regarded as a statistically significant difference. All analyses were performed using Stata 14.1 (Stata Corp, College Station [TX], United States).

Among 19 934 students in 252 schools, 4839 (24.3%) students failed the vision screening. In total, 3177 (65.7%) students in 250 schools were eligible for spectacles to improve visual acuity (two schools were excluded because no students at either school met the inclusion criteria). After the exclusion of students with missing information, the remaining 2922 students were divided into four subgroups. In our study, 42.3% (n=1235) of parents were not informed by either their children or their children’s teachers. Teacher-to-parent communication enabled 35.9% (n=1050) of parents to learn about vision problems in their children. In total, 20.2% (n=590) parents were informed only by teachers and 15.7% (n=460) were informed by both teachers and students, respectively (Fig).

The mean (± standard deviation) age of all students with vision problems was 10.51 ± 1.10 years (range, 8-15). Among all respondents, 1418 (48.5%) were boys and 1504 (51.5%) were girls. Most students’ main caregivers were their parents (86.4%). Other participants’ characteristics are shown in Table 1, including the comparison of characteristics among the four groups.

The rate of vision care–seeking behaviour among all students was very low. The number of students who received vision care services decreased gradually at each step. In all, 57.7% (n=1687) of parents were informed about vision problems in their children; only 32.7% (n=954) of all parents took their children for refraction examinations. Finally, only 19.2% (n=560) of students owned spectacles before the study (Table 2). The rates of vision care–seeking behaviour significantly differed among the four groups. When comparing the rates of refraction examination history and spectacle ownership among three types of informed groups with the uninformed group, we found significant differences (P<0.001) in all comparisons (Table 2). In the uninformed group, comparatively few parents took their children to receive a refraction examination and/or obtained spectacles for their children. In the group where parents were informed only by students, more children had undergone refraction examinations and/or owned spectacles than in the group where parents were informed only by teachers. When both teachers and students informed parents, the rates of refraction examinations and spectacles ownership were highest among the four groups.

In the multiple logistic regression analyses of potential predictors of refraction examination, we found that information sharing (including TPC) was significantly associated with refraction examination history (Table 3). Compared with the uninformed group, the odds of students having a refraction examination was higher in each of the other three groups. When only teachers informed parents, the odds ratio (OR) was 1.499, which was lower than in the group where only students informed parents (OR=2.839). When both students and teachers informed parents, the odds of students having a refraction examination was highest (OR=5.565). Additionally, the following characteristics were significantly positively associated with refraction examination history: receiving a better maths score (P=0.031), being male (P=0.015), having a worse visual ability (P<0.001), having at least one other family member who wears spectacles (P<0.001), being in the top wealth tercile (P<0.018), and having parents who think that spectacles are useful (P<0.001) [Table 3].

Multiple logistic regression analyses were used to estimate the relationship between TPC and spectacles ownership (Table 4). Teacher-to-parent communication was significantly positively associated with spectacles ownership, regardless of whether students informed parents about their vision problems. The odds of students having spectacles ownership in the group where parents were informed by both teachers and students (OR=7.935) was almost 1.8 times that in the group where parents were informed only by students (OR=4.413). The odds of students having spectacles ownership in the group where parents were informed by students only was twice that in the group where parents were informed only by teachers (OR=1.755). Furthermore, the following characteristics were significantly positively associated with spectacles ownership: having worse visual acuity (P<0.001), having parents as the main caregivers (P<0.017), having at least one other family member who wears spectacles (P<0.001), and having parents who think spectacles are useful (P<0.001). Notably, students with at least one sibling (P=0.003) were more unlikely to purchase spectacles (Table 4).

In this study, we found that the rate of vision care–seeking behaviour was very low in our sample area, similar to previous results.16 17 There are two possible reasons for the low vision care–seeking behaviour rate. First, parents may not know that their children cannot see the blackboard clearly; thus, they will not actively seek vision care services. Second, the number of students receiving vision care services has been decreasing throughout the process of three stages: parental knowledge that their children have vision problems, parental action to ensure their children undergo refraction examinations, and parental acquisition of spectacles for their children. Furthermore, despite sufficient information, many parents do not seek vision care services because of misinformation or misunderstanding.18 19

Knowledge of vision problems is the initial aspect of the vision care–seeking process for students. The rates of refraction examination history (18.1%) and spectacles ownership (6.6%) were the lowest in the uninformed group, which comprised more than 40% of parents in this study. When parents were informed by students and/or teachers, the rate of vision care–seeking behaviour was much higher. Teacher-to-parent communication provides an important method for parents to learn about vision problems in their children. In this study, 20.2% of parents learned about their children’s vision problems only from teachers.

Although a considerable proportion of students did not receive vision care in the care-seeking process, TPC can reduce this to some extent. When both teachers and students informed parents, the rate of spectacles ownership was the highest. In the group that parents were informed by both teachers and students, 46% of students finally received spectacles, which is 7-times more students than in the group in which parents were not informed. Furthermore, the odds of students having refraction examination and spectacles ownership were higher in the group where parents were informed only by students than in the group where parents were informed only by teachers. These additional opportunities may increase the likelihood that parents act to correct those vision problems.

There are two possible explanations for the positive association between TPC and vision care–seeking behaviours among students in this study. Teacher-to-parent communication provides an important channel for parents to learn about the vision problems in their children, which is a starting point and key aspect of vision care for students. Second, TPC reinforces the effects of students informing their parents. Compared with the group where parents were informed only by students, the rates of refraction examinations and spectacles ownership were nearly twofold greater in the group where parents were informed by both students and teachers. This was presumably because parents learned about vision problems in their children from two sources; the information from the students was reinforced by the information from the teacher.20

Small efforts by teachers may have great benefits in terms of vision care for students. Compared with intervention programmes to increase the correction rate,7 21 the results of present study indicate that TPC is both easy and cost-effective. Teachers should inform parents that their children cannot see the blackboard clearly. Studies of free spectacles distribution programmes have also shown that teachers can improve spectacles usage rates among students who have received spectacles.13 22 Moreover, wearing spectacles can improve academic performance,7 21 implying that TPC may both increase the correction rate and have a positive role in academic performance. Therefore, policymakers should carefully consider the role of teachers in protecting vision among students. Indeed, the Chinese Government has noted that multilateral cooperation (involving teachers, schools, parents, and society in general) should be encouraged to protect vision among students, in an effort to improve health status among young people by 2020.23

Unfortunately, the TPC ratio is very low. A recent study in China noted that approximately half of the parents and teachers communicate, in any form, during the course of an entire school year.24 In our study, the proportion of parents who were informed by teachers was only approximately 36%, including parents informed only by teachers (20%) and parents informed by both teachers and students (16%). This is presumably because teachers do not know a particular student’s vision status because it is not a vital consideration for most education work. Vision screening is the best method to detect vision problems.25 The education bureau and the health bureau should conduct routine vision screenings and encourage teachers to engage in vision protection (eg, communicate with parents about vision problems in students).5 25 If those stakeholders began to take action, more parents will learn about vision problems in their children and seek vision care services.

In the present study, the effects of students informing parents were greater than the effects of teachers informing parents when only one party informs the parents of vision problems. This finding implies that parents were more likely to act when they received information from students. However, students are often unaware of vision problems. Thus, teachers have an important effect; a previous survey reported that teachers were most likely to perceive visual impairment in children (70.6%), followed by the children’s parents (18.9%) and by the children themselves (7.9%).26 Therefore, careful attention is needed concerning the role of teachers in identifying vision problems, encouraging communication between students and their parents about such problems.

There were three important limitations in this study. First, the study could not investigate any causal link between TPC and vision care–seeking behaviour because of the cross-sectional design. However, the findings provide a foundation for follow-up analyses of causality. Second, this study only focused on whether teachers informed parents about vision problems in their children; it did not collect information concerning how parents were informed. Teacher-to-parent communication may happen in many ways, particularly in the internet era (eg, teachers communicate with parents via instant messenger). Additional research is needed to determine the types of TPC that are most effective in vision care for students. Third, the participants in this study were recruited from two provinces in rural north-western China, which limits the external validity of the findings. Despite this limitation, in the context of widespread uncorrected vision impairment among students,27 our study still has important implications for improving the uptake rate of vision care services.

Teacher-to-parent communication can significantly enhance the rates of refractive examinations and spectacles uptake through direct and indirect ways. Not only teacher informing provides a new channel for parents to learn about their students’ vision problems, but also reinforce the information told by students. Teacher-to-parent communication is an easy and cost-effective way to improve the rate of vision care–seeking behaviour. Policymakers should encourage teachers to be more involved in students’ vision protection, such as motivating teachers to communicate timely with parents about the students’ vision status.

Concept or design: K Du, J Huang.
Acquisition of data: H Guan, Y Shi.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: K Du.
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.

All authors have no conflicts of interest to disclose.

This research was supported by the 111 Project (Ref: B16031). H Guan has received funding from the National Natural Science Foundation of China (Ref: 71803107). The funders had no role in the design of the study, the acquisition or interpretation of results, or the decision to submit the manuscript for publication.

This study was approved by Stanford University (No. ISRCTN03252665). Permission was received from local boards of education in each region and the principals of all schools. The presented data are anonymised, and the risk of identification is low. The principles of the Declaration of Helsinki were followed throughout.

1. Jonas JB, Xu L, Wei WB, et al. Myopia in China: a population-based cross-sectional, histological, and experimental study. The Lancet 2016;388:S20. Crossref

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4. Chadha RK, Subramanian A. The effect of visual impairment on quality of life of children aged 3-16 years. Br J Ophthalmol 2011;95:642-5. Crossref

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6. He M, Xu J, Yin Q, Ellwein LB. Need and challenges of refractive correction in urban Chinese school children. Optom Vis Sci 2005;82:229-34. Crossref

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8. Resnikoff S, Pasolini D, Mariotti SP, Pokharel GP. Global magnitude of visual impairment caused by uncorrected refractive errors in 2004. Bull World Health Organ 2008;86:63-70. Crossref

9. Adams KS, Christenson SL. Trust and the family–school relationship examination of parent–teacher differences in elementary and secondary grades. J Sch Psychol 2000;38:477-97. Crossref

10. Franklin CG, Kim JS, Ryan TN, Kelly MS, Montgomery KL. Teacher involvement in school mental health interventions: A systematic review. Child Youth Serv Rev 2012;34:973-82. Crossref

11. Kraft M, Dougherty SM. The effect of teacher-family communication on student engagement: evidence from a randomized field experiment. J Res Educ Eff 2013;6:199-222. Crossref

12. Sharma A, Li L, Song Y, et al. Strategies to improve the accuracy of vision measurement by teachers in rural Chinese secondary schoolchildren: Xichang pediatric refractive error study (X-PRES) report no. 6. Arch Ophthalmol 2008;126:1434-40. Crossref

13. Yi H, Zhang H, Ma X, et al. Impact of free glasses and a teacher incentive on children’s use of eyeglasses: a cluster-randomized controlled trial. Am J Ophthalmol 2015;160:889-96.e1. Crossref

14. China National Bureau of Statistics. China Statistical Yearbook. Beijing, China: China State Statistical Press; 2013.

15. Camparini M, Cassinari P, Ferrigno L, Macaluso C. ETDRS-Fast: implementing psychophysical adaptive methods to standardized visual acuity measurement with ETDRS charts. Invest Ophthalmol Vis Sci 2001;42:1226-31.

16. Qian DJ, Zhong H, Nie Q, Li J, Yuan Y, Pan CW. Spectacles need and ownership among multiethnic students in rural China. Public Health 2018;157:86-93. Crossref

17. Zhao J, Guan H, Du K, et al. Visual impairment and spectacles ownership among upper secondary school students in northwestern China. Hong Kong Med J 2020;26:35-43. Crossref

18. Dudovitz RN, Izadpanah N, Chung PJ, Slusser W. Parent, teacher, and student perspectives on how corrective lenses improve child wellbeing and school function. Matern Child Health J 2016;20:974-83. Crossref

19. Senthilkumar D, Balasubramaniam SM, Kumaran SE, Ramani KK. Parents’ awareness and perception of children’s eye diseases in Chennai, India. Optom Vis Sci 2013;90:1462-6. Crossref

20. Verhulst FC, Dekker MC, van der Ende J. Parent, teacher and self-reports as predictors of signs of disturbance in adolescents: whose information carries the most weight? Acta Psychiatr Scand 1997;96:75-81. Crossref

21. Ma Y, Congdon N, Shi Y, et al. Effect of a local vision care center on eyeglasses use and school performance in rural China: a cluster randomized clinical trial. JAMA Ophthalmol 2018;136:731-7. Crossref

22. Wang X, Ma Y, Hu M, et al. Teachers’ influence on purchase and wear of children’s glasses in rural China: The PRICE study. Clin Exp Ophthalmol 2019;47:179-86. Crossref

23. Ministry of Education, PRC Government. Ministry of education on implement plan for comprehensive prevention and control of myopia among children and adolescents. Available from: http://www.moe.gov.cn/srcsite/A17/moe_943/s3285/201808/t20180830_346672.html. Accessed 9 Jan 2020.

24. Li G, Lin M, Liu C, Johnson A, Li Y, Loyalka P. The prevalence of parent-teacher interaction in developing countries and its effect on student outcomes. Teach Teach Educ 2019;86:102878. Crossref

25. Glewwe P, Park A, Meng Z. A better vision for development: eyeglasses and academic performance in rural primary schools in China. J Dev Econ 2016;122:170-82. Crossref

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27. Ma Y, Zhang X, He F, et al. Visual impairment in rural and migrant Chinese school-going children: prevalence, severity, correction and associations. Br J Ophthal 2022;106:275-80. Crossref

Endometrial cancer is among the most common gynaecological malignancies worldwide. Among women with endometrial cancer, 90% initially report postmenopausal bleeding (PMB).1 2 3 4 5 Approximately 10% of postmenopausal women are estimated to experience PMB.1 Generally, there is no harmful underlying cause of PMB; however, women with recurrent PMB require medical assessment to distinguish between benign aetiology (eg, vaginal atrophy, uterine fibroids, and polyps) and endometrial cancer. Endometrial assessment is needed to exclude underlying malignancy.2 6 7 8 9 10

The endometrium can be examined non-invasively, using transvaginal sonography (TVS) to measure endometrial thickness (TVS-ET); alternatively, it can be examined invasively via blinded undirected endometrial sampling, saline infusion sonography, or diagnostic hysteroscopy.11 12 13 Although both TVS-ET and blinded endometrial sampling are recommended as first-line investigations,2 6 7 14 15 16 17 18 the gold standard approach for PMB investigation remains diagnostic hysteroscopy with visually guided endometrial sampling; this allows direct visualisation of the uterine cavity and histological investigation.19

Importantly, hysteroscopy is invasive and carries risks of complications such as infection, bleeding, uterine perforation, and visceral injury to the cervix or nearby organs (eg, bladder and bowel); it cannot be performed in women with cervical stenosis.20 Additionally, some women report that hysteroscopy is uncomfortable and painful within an out-patient or office setting; thus, hysteroscopy, cervical dilation, and uterine curettage have been performed under general anaesthesia in such cases. Although TVS-ET has become an established investigational tool, there remains a lack of consensus concerning the endometrial thickness (3, 4, or 5 mm) that constitutes ‘abnormal’. Our previous study of 4300 women with PMB demonstrated that 3% of women with PMB and endometrial thickness ≤3 mm had endometrial cancer.21

Patient preference regarding investigation approach is an important component of the decision care pathway. Individual women must balance the risks associated with an invasive procedure (eg, diagnostic hysteroscopy) with the risk of missing an endometrial cancer diagnosis if they select a non-invasive assessment (eg, TVS-ET). To our knowledge, the nature of this balance has not been assessed. The aim of the present study was to determine the extent to which women with PMB would accept the risk of missing endometrial cancer if they were to undergo TVS-ET as the first investigation of PMB.

This cross-sectional study was conducted in a tertiary centre in Hong Kong from June 2016 to June 2017. Women referred by either primary or secondary healthcare providers to the One-stop PMB Clinic for assessment and management were invited to participate in the study. Patient assessments included history taking, physical examination, pelvic ultrasound to measure endometrial thickness and screen for other pelvic pathologies, Pap smear (for women without recent Pap smear records), endometrial sampling with or without hysteroscopy. Women were excluded if they had <1 year of amenorrhea; had a prior TVS finding of endometrium thickness ≥5 mm; were aged ≥70 years; had dementia or mental retardation; and/or were unable to read or understand Chinese.

Prior to their clinic consultation, study participants completed a structured interview that was administered by an independent interviewer. Women were asked to first read an information leaflet regarding PMB, which described the risk of endometrial cancer, possible investigation options, and the risks associated with each option. The leaflet and interviewer explained that hysteroscopy and endometrial biopsy were expected to achieve a 100% detection rate, but these methods involved risks of pain, bleeding, infection, and uterine perforation related to uterine cavity exploration. The leaflet and interviewer also explained that TVS-ET did not require entry into uterine cavity but would potentially miss some cases of endometrial cancer. The leaflet and interviewer did not disclose the percentage of endometrial cancers that would fail to be detected by TVS-ET. After they had read the leaflet, women were asked to complete a study questionnaire regarding their sociodemographic characteristics and their personal and family histories of gynaecological cancer; they also completed the Chinese version of the 20-item State-Trait Anxiety Inventory to measure their trait and state anxiety levels. The women’s state and trait scores were categorised as above or below the scale midpoint. Women then underwent assessment of utilities regarding examination by either hysteroscopy or TVS-ET and the possibility of a missed cancer diagnosis, using the standard gamble technique.22

The standard gamble technique is the gold standard method used to determine utility towards a particular health state when a risk is involved. Individuals are asked to choose whether they prefer to have a certain guaranteed option or health state with a guaranteed outcome and no risk, or whether they would prefer an alternative option which entails some risk. The risks for the two health states are varied until the individual becomes indifferent to either option. At the point of indifference, the ‘utility’ for the health state under consideration is considered equal to ‘p’, while the utility of the alternative health state is considered equal to ‘1–p’.

Women were first asked to complete a standard gamble related to blindness, thereby ensuring that they understood the process. Subsequently, they were asked to complete a standard gamble to test their preferences towards the investigations of PMB. Each woman was asked to choose between the following tests: (1) TVS-ET, which is less invasive but involves some risk of missing endometrial cancer (probability of 1–p), or (2) an invasive test with hysteroscopy and endometrial biopsy, which detects 100% of all cancers but carries the risks described during the structured interview. To determine the level of acceptance of missing endometrial cancer during TVS-ET, the women were initially informed that the assumed detection rate of the TVS-ET was 75%; this detection rate was then increased in 5% intervals to 90%, then in 1% intervals to 98%, and finally in 0.1% intervals to 99.9%. We recorded the stated detection rate at which the woman was indifferent to either option. The missed endometrial cancer rate that women would accept to avoid an invasive procedure was defined as 1–detection rate.

Sociodemographic characteristics, past and current gynaecological history findings, and anxiety levels are presented as mean ± standard deviation or median and interquartile range; qualitative variables are presented as absolute frequency and percentage. The acceptable rate of endometrial cancer detection by TVS-ET alone, as an alternative to invasive hysteroscopy/biopsy, is presented as median and interquartile range. Differences in scores among sociodemographic groups were compared using the Mann-Whitney U test. SPSS software (Windows version 20; IBM Corp, Armonk [NY], United States) was used for all statistical analyses. A P value of <0.05 was considered statistically significant.

During the study period, 202 women agreed to participate in the study; 200 of these women completed the questionnaires and the standard gamble assessments. Table 1 summarises the sociodemographic, obstetric and gynaecological histories, and anxiety levels of these 200 women. Overall, 11 (5.5%) of the 200 women were subsequently diagnosed with cancer or an atypical endometrium: nine had endometrial cancer, one had cervical cancer, and one had atypical hyperplasia. Among 42 patients who underwent Pap smears in our clinic, smear results showed atypical glandular cells in two patients with endometrial cancer, while four patients with endometrial cancer had a shift in vaginal flora suggestive of bacterial vaginosis; the remaining smear results were normal.

The median endometrial cancer detection rate or utility that women would require for selection of TVS-ET to avoid invasive hysteroscopy examination was 95% (interquartile range=80%-99.9%). Overall, 77 (38.5%) women required TVS-ET to have a 99.9% detection rate for endometrial cancer. Thus, 38.5% of the women in our cohort would require TVS-ET to be comparable with diagnostic hysteroscopy before they would accept TVS-ET as the sole method for examination of the endometrium and uterine cavity.

Table 2 summarises the results of univariate analysis of the relationships between patient characteristics and the TVS-ET endometrial cancer detection rate. Women with previous hysteroscopy experience required the endometrial detection rate by TVS-ET to be significantly higher than did women without previous hysteroscopy experience (P=0.047). There were no significant differences in required endometrial cancer detection rates by TVS-ET among other sociodemographic characteristics, past and current obstetric and gynaecological histories, and state or trait anxiety (Table 2).

To our knowledge, this study is the first to utilise the standard gamble technique to evaluate patient preference with regard to approaches used for the investigation of PMB. Specifically, we assessed the extent to which women would prefer to avoid an invasive investigation (eg, hysteroscopy and biopsy) if a non-invasive alternative were available. Our findings suggested that TVS-ET would need to detect approximately 95% of endometrial cancers (or miss approximately 5% of endometrial cancers) for women to select TVS-ET with the intention of avoiding an invasive investigation. However, our analysis also suggested that nearly 40% of the participants required TVS-ET to detect nearly all endometrial cancers before they would select TVS-ET as the sole investigational approach.

There are sparse published data concerning patient preferences for the investigation of PMB. Our literature review revealed a single study by Timmermans et al.23 However, that study was limited to 39 participants and the results were obtained via telephone survey. In contrast to our protocol, Timmermans et al23 only assessed patient preferences after the women’s investigations had been completed; thus, their reported clinical experiences and preferences might have been biased. In the present study, we adopted the standard gambling approach which enabled a more quantitative analysis of patient willingness to select a different investigational approach. The standard gamble method is the gold standard approach for assessment of preferences in an uncertain situation24; it can be used to express the outcomes of different choices. It has been used previously to explore the acceptable risk of miscarriage after a high-risk Down syndrome screening test25 26 27 28; it has also been used to explore patient preferences concerning the risks of other medical treatments.

Currently, endometrial thickness cut-off values in endometrial pathology or cancer screening differ among hospitals.2 6 19 The most commonly used cut-off endometrial thickness value is 4 mm². Our study population of postmenopausal women accepted an endometrial cancer detection rate of 95% when using TVS-ET alone, with the intention of avoiding the more invasive procedure of hysteroscopy/endometrial biopsy. In our previous study, TVS-ET offered endometrial cancer detection rates of 97%, 94.1%, and 93.5% using 3 mm, 4 mm, and 5 mm as respective cut-off values.21 Thus, a TVS-ET cut-off of 3 mm would generally be consistent with the endometrial cancer detection accuracy that women in our study required for TVS-ET to be used as the sole investigational approach. In our study population, women with previous hysteroscopy experience required TVS-ET to have higher detection rates; hence, they preferred hysteroscopic assessment.

There were some limitations in our study. First, women aged ≥70 years were excluded because we presumed that they would have difficulty understanding the standard gamble technique and/or completing the study questionnaires without assistance. Second, although our sample size was sufficient to assess our primary goal, it was inadequate for subgroup analysis. Larger studies are needed to explore the relationships of specific patient characteristics with the acceptable rate of endometrial cancer detection by TVS-ET alone, particularly in relation to factors such as personal history of cancer or precancerous conditions. Finally, our findings concerning the acceptable rate of endometrial cancer detection by TVS-ET reflect the preferences of women who participated in our study; they may not be generalisable to populations with different sociodemographic characteristics or clinical management pathways.

Clinicians should incorporate patient preferences concerning the investigation of PMB to enable an informed choice about invasive testing to exclude endometrial cancer. Our study population accepted an endometrial cancer detection rate of 95% by TVS-ET alone; this rate could be used to guide the design of future PMB investigation strategies.

Concept or design: LWY Fung, ECW Cheung, ASW Wong, DS Sahota.
Acquisition of data: LWY Fung, ECW Cheung, ASW Wong, DS Sahota.
Analysis or interpretation of data: LWY Fung, DS Sahota.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.

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

All authors have disclosed no conflicts of interest.

The authors acknowledge the clinical care provided by gynaecologists and nursing staff at the One-stop Postmenopausal Bleeding Clinic, Prince of Wales Hospital. We thank Miss Jennifer SF Tsang for her help with database management.

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

Ethics approval was obtained in August 2015 from The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (CREC Ref 2015.437).

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27. Chan YM, Leung TY, Chan OK, Cheng YK, Sahota DS. Patient’s choice between a non-invasive prenatal test and invasive prenatal diagnosis based on test accuracy. Fetal Diagn Ther 2014;35:193-8. Crossref

28. Chan YM, Chan OK, Cheng YK, Leung TY, Lao TT, Sahota DS. Acceptance towards giving birth to a child with beta-thalassemia major—a prospective study. Taiwan J Obstet Gynecol 2017;56:618-21. Crossref

The fetal gallbladder can be observed by antenatal ultrasound scan at 14 weeks of gestation.1 During the morphology scan at approximately 20 weeks of gestation, >99% of fetal gallbladders can be observed; in 75% of cases of non-visualisation of fetal gallbladder (NVFGB), a gallbladder is clearly present during subsequent scans.2 However, the visualisation rate drops to 75% to 85% after 32 weeks of gestation when the gallbladder becomes contractile.3 4

Although sonographic examination of the fetal gallbladder is not technically difficult, the International Society of Ultrasound in Obstetrics and Gynecology and other professional bodies have not yet included the gallbladder as a routine component of the mid-trimester anatomical survey.5 6 7 8 The problem with routine examination of the fetal gallbladder is that non-visualisation of the gallbladder can lead to challenging counselling and antenatal diagnosis because NVFGB is related to a wide spectrum of fetal conditions. While NVFGB may be a transient phenomenon in a normal fetus or the result of gallbladder agenesis (a benign congenital anomaly), it can also be associated with more serious underlying conditions such as biliary atresia, cystic fibrosis, or chromosomal abnormalities. While it is generally simple to identify chromosomal abnormalities and cystic fibrosis by amniocentesis, the antenatal diagnosis of biliary atresia is challenging because no diagnostic antenatal test is currently available. Because biliary atresia can be fatal without early postnatal intervention and may eventually require liver transplantation, uncertainty regarding the antenatal diagnosis of such a condition may cause significant parental anxiety; some parents may even consider termination of pregnancy to avoid the risk of a severe abnormality in their child.9 10

A systematic review of isolated NVFGB in Western populations revealed that the incidences of transient non-visualisation, gallbladder agenesis, biliary atresia, cystic fibrosis, and chromosomal abnormalities were 69.4%, 24.7%, 3.5%, 2.4%, and 1.4%, respectively. The incidences of biliary atresia, cystic fibrosis, and chromosomal abnormalities were higher in cases of non-isolated NVFGB with additional sonographic abnormalities: 18.2%, 23.1%, and 20.4%, respectively.11 However, the incidences may differ considerably among Chinese women with NVFGB, as cystic fibrosis is uncommon in Asian populations, while biliary atresia is more prevalent in Chinese individuals.12 13 14 15 16 The aim of this study was to investigate the outcomes of fetuses with NVFGB in a cohort of Chinese women; the findings may provide guidance for the management of NVFGB.

This retrospective review included cases of NVFGB among Chinese pregnant women at five public fetal medicine clinics in Hong Kong from 2012 to 2019. In these clinics, fetal morphology scans were limited to high-risk cases and fetal gallbladder assessment was not routinely performed, in accordance with guidelines from the International Society of Ultrasound in Obstetrics and Gynecology.5 17 When cases of NVFGB were detected incidentally or referred from private clinics, the pregnant women were provided counselling regarding possible differential diagnoses and offered amniocentesis for chromosomal analysis. In cases of serious fetal abnormalities where parents decided for legal termination of pregnancy before 24 weeks of gestation, post-mortem examinations were arranged with parental consent. After birth, babies with NVFGB were referred to paediatricians for further evaluation.

The following data were reviewed: demographic information, gestational age at detection of NVFGB, findings during the morphology scan and subsequent scans, results of all amniotic fluid investigations if amniocentesis had been performed, pregnancy outcome, all neonatal imaging reports, operations performed on the baby and intra-operative findings, and autopsy findings in case of termination of pregnancy. The cases were segregated into isolated and non-isolated groups according to the absence or presence of additional sonographic findings. The incidences of subsequent visualisation of gallbladder, gallbladder agenesis, biliary atresia, cystic fibrosis, and chromosomal abnormalities were compared between the two groups.

The study protocol was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee on 3 March 2020 (CREC Ref. No.: 2020.060). This manuscript was written in accordance with STROBE reporting guidelines.

Fisher’s exact test was used for comparisons between the isolated and non-isolated groups. All statistical analyses were performed using SPSS software (Windows version 22.0; IBM Corp., Armonk [NY], United States). P values <0.05 were considered statistically significant.

Among 19 cases of NVFGB detected at a median gestational age of 21.3 weeks (interquartile range, 20.0-22.3 weeks), 10 (52.6%) were isolated and nine (47.4%) were non-isolated. Eleven (58.0%) cases had transient non-visualisation, four (21.0%) had gallbladder agenesis, three (15.8%) had chromosomal abnormalities (trisomy 18, trisomy 21, and 22q11.2 de novo microduplication), and one (5.2%) had biliary atresia. There were no cases with features suggestive of cystic fibrosis (Tables 1 and 2).

Amniocentesis was performed in eight of the nine non-isolated cases; three chromosomal abnormalities (33.3%) were found, including trisomy 18 (case 1), trisomy 21 (case 2), and 22q11.2 de novo microduplication (case 3). Case 1 ended in neonatal death and the parents declined post-mortem investigation. Case 2 was a dichorionic twin pregnancy; selective feticide was performed on the fetus with trisomy 21, but post-mortem investigation could not be performed because of the long interval between selective feticide and delivery of the normal co-twin. Termination of pregnancy was performed in case 3 and gallbladder agenesis was confirmed at autopsy. Termination of pregnancy was also performed in case 4 because of multiple structural abnormalities; chromosomal microarray (CMA) findings were normal and post-mortem investigation revealed normal gallbladder. Live birth occurred in the remaining five cases; in one case, the gallbladder was observed during a subsequent antenatal scan and the postnatal outcome was normal, while NVFGB persisted in the other four cases. Among the four cases with persistent NVFGB, one (11.1%) had biliary atresia that required liver transplantation (case 6); antenatal scans had shown a hepatic hilar cyst (Fig 1), which was highly suggestive of cystic biliary atresia.18 Postnatal examination showed a normal gallbladder in the other three cases. None of the five live births had features suggestive of cystic fibrosis (Table 1 and Fig 2).

Among the 10 cases of isolated NVFGB, amniocentesis was performed in one, while chorionic villi sampling was performed in the first trimester because of positive Down syndrome screening result in another; CMA findings were normal in both cases. In four cases, gallbladders were observed during subsequent antenatal scans at a mean follow-up interval of 1.0 week (range, 0.3-2.0); NVFGB persisted in the other six cases. Among the six cases with persistent NVFGB, gallbladder agenesis was confirmed in four (66.7%) and gallbladders were observed after birth in two (33.3%). None of the 10 cases had features suggestive of cystic fibrosis after birth (Table 1 and Fig 2).

The characteristics of isolated and non-isolated groups are compared in Table 2. The incidence of serious abnormalities (chromosomal abnormalities, biliary atresia) was significantly higher in the non-isolated group than in the isolated group (44.4% vs 0%; P=0.029). Notably, all serious conditions in the cohort (all three cases of chromosomal abnormalities and the only case of biliary atresia) were observed in the non-isolated group, while all benign conditions (all four cases of isolated gallbladder agenesis) were observed in the isolated group. The incidences of transient non-visualisation did not significantly differ between the isolated and non-isolated groups (60.0% vs 55.6%; P=1.000).

In our cohort, cases of isolated NVFGB had a good overall prognosis, with a 60% probability that the gallbladder would be observed in a subsequent scan and a 40% probability of gallbladder agenesis. This incidence of transient non-visualisation (60%) is consistent with findings by Yayla and Bayik2 (75%) and Di Pasquo et al11 (69.4%). In our cases of transient NVFGB, the gallbladder was observed during a subsequent antenatal scan in 40%, and during the postnatal period in the remaining 20%. The mean interval between NVFGB and subsequent antenatal detection of the gallbladder was 1 week. Therefore, a second sonographic examination within 1 week after NVFGB would help to alleviate parental anxiety and avoid the need for further investigations in nearly half of such cases. Even in cases with persistent isolated NVFGB, the prognosis remains good, because the gallbladder is likely to be observed after birth in one-third of cases; while gallbladder agenesis is likely in the remaining cases. Our findings are similar to the results of a recent systematic review of seven studies in Western populations, including 217 cases of isolated NVFGB; most cases had transient non-visualisation (69.4%) and gallbladder agenesis (24.7%), but some cases had serious conditions (biliary atresia [3.5%], cystic fibrosis [2.4%], and chromosomal abnormalities [1.4%]).11 Therefore, further investigations to rule out such serious abnormalities remain important in cases of isolated NVFGB.

In the aforementioned review, the incidences of biliary atresia, cystic fibrosis, and chromosomal abnormalities were much higher when NVFGB occurred in combination with other ultrasound abnormalities (18.2%, 23.1%, and 20.4%, respectively).11 Copy number variants were observed in one of three cases with chromosomal abnormalities in our study and two of 11 such cases in the study by Di Pasquo et al11; these findings support the recommendation for the use of CMA, rather than karyotyping.19 20 21 However, our results differ from the findings reported by Di Pasquo et al11 in that none of our cases had cystic fibrosis, which is unsurprising because cystic fibrosis is rare in Chinese individuals; moreover, our incidence of biliary atresia (11.1%) was much lower than expected, considering that biliary atresia is reportedly threefold more common in Chinese individuals than in Caucasian individuals.12 13 14 15 16

Based on the data described above, in cases of non-isolated NVFGB or persistent isolated NVFGB, amniocentesis may help to rule out chromosomal abnormalities; this approach is generally simple with current CMA technology.19 20 However, the antenatal diagnosis of biliary atresia is challenging because fetal bile duct patency cannot be determined by sonographic examination; NVFGB may be the only suggestive sign of biliary atresia. When NVFGB is associated with a hepatic hilar cyst or heterotaxy, a diagnosis of biliary atresia is likely.18 However, it is difficult to differentiate biliary atresia from gallbladder agenesis in cases of isolated NVFGB. Thus, a low amniotic fluid gamma-glutamyl transpeptidase (AFGGT) level has been proposed as an indicator of biliary atresia.22 23 24 Gamma-glutamyl transpeptidase (GGT) is initially derived from the fetal biliary tract, passed into the gastrointestinal tract, and finally excreted into the amniotic fluid. The AFGGT level decreases with increasing gestational age because progressive maturation of the anal sphincter impairs the passage of GGT from the gastrointestinal tract into the amniotic fluid.22 25 26 The anal sphincter muscles become fully mature by 20 weeks of gestation, and the AFGGT level becomes very low after 22 weeks of gestation. Therefore, it may be difficult to distinguish between a low level related to biliary atresia and a low level related to normal development after 22 weeks of gestation.25 26 Using an AFGGT level below the 5th centile, Bardin et al23 reported 100% sensitivity in the detection of biliary atresia, with a false positive rate of 4%, between 17 and 22 weeks of gestation (Table 3). Using AFGGT level and/or intestinal alkaline phosphatase <0.5 multiples of the median, Dreux et al24 also reported 100% sensitivity before 22 weeks of gestation; however, their false positive rate was 20%. Notably, when the test was performed after 22 weeks of gestation, the sensitivity decreased to 20%. Therefore, gestational age at amniocentesis is a critical consideration during the assessment of biliary atresia; if NVFGB is first detected near 22 weeks of gestation, amniocentesis should be performed immediately, rather than waiting for sonographic examination to be repeated. Another limitation of using the AFGGT level to identify biliary atresia is that it has a moderately low positive predictive value: 43% to 75% before 22 weeks of gestation, and 17% thereafter.23 24 Accordingly, a positive AFGGT test result is not diagnostic of biliary atresia, particularly in cases of isolated NVFGB where the incidence of biliary atresia is presumably low. Conversely, the negative predictive value of AFGGT is near 100%; a negative test result is very reassuring, which can help to alleviate parental anxiety and avoid unwarranted termination of pregnancy.23 24 When NVFGB is detected after 22 weeks of gestation, the fetal blood GGT level may be useful for identification of biliary atresia.27 28 However, cordocentesis may be unwarranted, as the procedure-related risk outweighs the possible diagnostic benefit, particularly in cases of isolated NVFGB where the risk of biliary atresia is presumably low.

In Caucasian populations, the incidence of cystic fibrosis is 1:2500-3500 live births and the carrier rate is 1:50; in contrast, this hereditary disease is extremely rare among East Asian individuals (1:350000 people in Japan and 1:300000 live births in Hong Kong).15 16 29 Unsurprisingly, we did not observe cystic fibrosis in either group of NVFGB cases. Therefore, in the absence of significant family history, consanguinity, or concurrent ultrasound features suggestive of cystic fibrosis (eg, echogenic or dilated bowel), amniocentesis for genetic testing for cystic fibrosis is not recommended in cases of NVFGB in Hong Kong. Assessment of the parental CFTR gene mutation status may be a useful alternative.

Based on our findings and the results of previous studies, we propose the following approach for the management of NVFGB. When NVFGB is detected, a detailed morphology scan should be performed to identify associated abnormalities, such as hepatic hilar cyst and heterotaxy (indicative of biliary atresia) or echogenic and dilated bowel (suggestive of cystic fibrosis). A sonographic examination of the gallbladder should be repeated within 1 week. Considering the potential for chromosomal abnormalities (even in cases of isolated NVFGB), amniocentesis is recommended for CMA analysis in cases of persistent NVFGB. The AFGGT assay can also be performed before 22 weeks of gestation; counselling prior to the test should involve an explanation of the moderately low positive predictive value for identification of biliary atresia. Beyond 22 weeks of gestation, the AFGGT level is not useful for identifying biliary atresia, but cordocentesis for GGT level may be useful. However, cordocentesis is generally not recommended because the procedure-related risk outweighs the possible diagnostic benefit, particularly in cases of isolated NVFGB where the risk of biliary atresia is presumably low. Further testing for cystic fibrosis may be unnecessary in Chinese fetuses unless the NVFGB is associated with other ultrasound features suggestive of cystic fibrosis, significant family history, or consanguinity. Further research is needed concerning AFGGT reference values and the ability of the AFGGT level to identify biliary atresia in Chinese fetuses with NVFGB.

Similar to other reports regarding NVFGB, our study was limited by its retrospective design and small cohort size. Because fetal gallbladder examination has not been a routine practice in Hong Kong, we cannot calculate the prevalence of NVFGB. To our knowledge, this is the first report of NVFGB in a Chinese cohort. Moreover, our results differed from findings in Caucasian populations in that we did not observe cystic fibrosis in our cohort; such information may be useful during antenatal counselling in cases of NVFGB.

The prognosis of isolated NVFGB is generally good because the non-visualisation is either transient or related to gallbladder agenesis. While investigations of chromosomal abnormalities and biliary atresia are reasonable in cases of NVFGB, testing for cystic fibrosis may be unnecessary in Chinese fetuses unless the NVFGB is associated with consistent ultrasound features, significant family history, or consanguinity.

Concept or design: YH Ting, TY Leung.
Acquisition of data: YH Ting, PL So, KW Cheung, TK Lo, TWL Ma.
Analysis or interpretation of data: YH Ting.
Drafting of the manuscript: YH Ting, TY Leung.
Critical revision of the manuscript for important intellectual content: All authors.

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

All authors have disclosed no conflicts of interest.

The research was presented as poster in the 30th World Congress on Ultrasound in Obstetrics and Gynecology, 16-18 October 2020, and was published as an abstract in Ultrasound in Obstetrics & Gynecology (Ting Y, Leung T, Law K, Lo T, Cheung K, So P. VP09.12: Non-visualisation of fetal gall bladder in a Chinese cohort. Ultrasound Obstet Gynecol 2020;56(S1):84).

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 on 3 March 2020 (CREC Ref. No.: 2020.060).

1. Goldstein I, Tamir A, Weisman A, Jakobi P, Copel JA. Growth of the fetal gall bladder in normal pregnancies. Ultrasound Obstet Gynecol 1994;4:289-93. Crossref

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5. Salomon LJ, Alfirevic Z, Berghella V, et al. Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2011;37:116-26. Crossref

6. Australasian Society for Ultrasound in Medicine. Guidelines for the performance of second (mid) trimester ultrasound. 2018. Available from: https://www.asum.com. au/files/public/SoP/curver/Obs-Gynae/Guidelines-for-the-Performance-of-Second-Mid-Trimester-Ultrasound.pdf. Accessed 24 Aug 2020.

7. NHS Mid and South Essex, University Hospitals Group. NHS Fetal Anomaly Screening Programme: National Standards and Guidance for England. Guidelines for performing the 18 weeks and 0 days to 20 weeks and 6 days gestation fetal anomaly scan. 2015. Available from: https://www.meht.nhs.uk/EasysiteWeb/getresource.axd?AssetID=17955&type=Full&servicetype=Attachment. Accessed 24 Aug 2020.

8. Cargill Y, Morin L. No. 223—Content of a complete routine second trimester obstetrical ultrasound examination and report. J Obstet Gynaecol Can 2017;39:e144-9. Crossref

9. Chan YM, Leung TN, Leung TY, Fung TY, Chan LW, Lau TK. The utility assessment of Chinese pregnant women towards the birth of a baby with Down syndrome compared to a procedure-related miscarriage. Prenat Diagn 2006;26:819-24. Crossref

10. Chan YM, Chan OK, Cheng YK, Leung TY, Lao TT, Sahota DS. Acceptance towards giving birth to a child with beta-thalassemia major—a prospective study. Taiwan J Obstet Gynecol 2017;56:618-21. Crossref

11. Di Pasquo E, Kuleva M, Rousseau A, et al. Outcome of non-visualization of fetal gallbladder on second-trimester ultrasound: cohort study and systematic review of literature. Ultrasound Obstet Gynecol 2019;54:582-8. Crossref

12. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009;374:1704-13. Crossref

13. Hsiao CH, Chang MH, Chen HL, et al. Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology 2008;47:1233-40. Crossref

14. Zhan J, Chen Y, Wong KK. How to evaluate diagnosis and management of biliary atresia in the era of liver transplantation in China. World Jnl Ped Surgery 2018;1:e000002. Crossref

15. Mirtajani SB, Farnia P, Hassanzad M, Ghanavi J, Farnia P, Velayati AA. Geographical distribution of cystic fibrosis; the past 70 years of data analysis. Biomed Biotechnol Res J 2017;1:105-12. Crossref

16. Leung GK, Ying D, Mak CC, et al. CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis. Mol Genet Genomic Med 2016;5:40-9. Crossref

17. Chen M, Leung TY, Sahota DS, et al. Ultrasound screening for fetal structural abnormalities performed by trained midwives in the second trimester in a low-risk population—237-an appraisal. Acta Obstet Gynecol Scand 2009;88:713-9. Crossref

18. Chalouhi GE, Muller F, Dreux S, Ville Y, Chardot C. Prenatal non-visualization of fetal gallbladder: beware of biliary atresia! Ultrasound Obstet Gynecol 2011;38:237-40. Crossref

19. Chau MH, Cao Y, Kwok YK, et al. Characteristics and mode of inheritance of pathogenic copy number variants in prenatal diagnosis. Am J Obstet Gynecol 2019;221:493. e1-11. Crossref

20. Zhu X, Chen M, Wang H, et al. Clinical utility of expanded noninvasive prenatal screening and chromosomal microarray analysis in high risk pregnancies. Ultrasound Obstet Gynecol 2021;57:459-465. Crossref

21. Grati FR, Molina Gomes D, Ferreira JC, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn 2015;35:801-9. Crossref

22. Muller F, Gauthier F, Laurent J, Schmitt M, Boué J. Amniotic fluid GGT and congenital extrahepatic biliary damage. Lancet 1991;337:232-3. Crossref

23. Bardin R, Ashwal E, Davidov B, Danon D, Shohat M, Meizner I. Nonvisualization of the fetal gallbladder: can levels of gamma-glutamyl transpeptidase in amniotic fluid predict fetal prognosis? Fetal Diagn Ther 2016;39:50-5. Crossref

24. Dreux S, Boughanim M, Lepinard C, et al. Relationship of non-visualization of the fetal gallbladder and amniotic fluid digestive enzymes analysis to outcome. Prenat Diagn 2012;32:423-6. Crossref

25. Burc L, Guibourdenche J, Luton D, et al. Establishment of reference values of five amniotic fluid enzymes. Analytical performances of the Hitachi 911. Application to complicated pregnancies. Clin Biochem 2001;34:317-22. Crossref

26. Bardin R, Danon D, Tor R, Mashiach R, Vardimon D, Meizner I. Reference values for gamma-glutamyl-transferase in amniotic fluid in normal pregnancies. Prenat Diagn 2009;29:703-6. Crossref

27. Muller F, Bernard P, Salomon LJ, et al. Role of fetal blood sampling in cases of non-visualization of fetal gallbladder. Ultrasound Obstet Gynecol 2015;46:743-4. Crossref

28. Ruiz A, Robles A, Salva F, et al. Prenatal nonvisualization of the gallbladder: a diagnostic and prognostic dilemma. Fetal Diagn Ther 2017;42:150-2. Crossref

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The incidence of pelvic organ prolapse (POP) is reportedly near 50% and the lifetime risk of POP requiring surgery is approximately 20%.1 2 With the increasing lifespan and emphasis on quality of life worldwide, older women increasingly prefer surgical treatment, instead of vaginal pessaries, as definitive treatment for POP.3 Surgical treatment options are either reconstructive or obliterative. Reconstructive surgery comprises native tissue repair (mainly vaginal hysterectomy [VH]), pelvic floor repair, and mesh-related repair; obliterative surgery comprises colpocleisis with or without concomitant VH.

Older women who undergo urogynaecological surgery have a higher surgical risk, regardless of fragility index; they have lower risks of prolapse recurrence and repeated surgery.4 Although the World Health Organization has defined old age as ≥65 years,5 a threshold of ≥75 years may be more appropriate for older women in terms of fragility and need for care. A previous Hospital Authority ageing projection6 indicated that the number of individuals aged 75 to 84 years will substantially increase in Hong Kong, while the numbers of individuals aged ≥85 years or ≤74 years will remain comparatively stable. A threshold of ≥75 years for geriatric medicine may be reasonable because most chronic, complex disabling disease occurs among individuals in this age-group.7

To our knowledge, despite the increasing number of women aged ≥75 years and the need for surgical treatment of POP among these individuals, there is limited evidence regarding the risks and benefits of the available surgical options. This multicentre, retrospective study was performed to review the surgical treatment of POP in women aged ≥75 years; we aimed to characterise its safety, effectiveness, and the type most often selected. We hope that the findings will help clinicians to counsel older women with POP who are considering surgical treatment.

This multicentre, retrospective cohort study was conducted at Kwong Wah Hospital, Pamela Youde Nethersole Eastern Hospital, Princess Margaret Hospital, and Prince of Wales Hospital. We included patients aged ≥75 years, all of whom underwent surgical treatment of POP in one of the above four gynaecological units between 2013 and 2018. We reviewed patient information from the Clinical Data Analysis and Reporting System and Clinical Medical System; for patients with incomplete data in the Clinical Medical System, we reviewed paper-based medical records. Ethical approvals were obtained from the Institutional Review Boards of all four Clusters including Hong Kong East Cluster, Kowloon Central Cluster, Kowloon West Cluster and New Territories East Cluster.

Demographic data and symptoms of prolapse were collected during each patient’s first visit to a participating gynaecology unit. Physical examinations were conducted to confirm POP, stage of prolapse, and the compartments involved; all examinations were performed using the International Continence Society Pelvic Organ Prolapse Quantification (POP-Q) staging system.7 Patients were offered vaginal pessary management or surgical treatment. Patients who opted for surgical treatment were scheduled for surgery with or without a trial period of vaginal pessary management. Preoperative urodynamics studies were performed if indicated. During the preoperative assessment, each patient underwent a comprehensive evaluation that included patient-reported symptoms of prolapse, as well as urinary, intestinal, and sexual statuses; they also underwent prolapse assessment using POP-Q staging. Thorough counselling was provided regarding reconstructive and obliterative treatment options, including a discussion of the potential benefits and risks of both procedures, as well as the need for concomitant VH or mid-urethral sling transobturator tape (TVT-O) for urodynamic stress incontinence.

Reconstructive procedures involved native tissue repair and mesh-related surgery. Native tissue repair mainly comprised vaginal hysterectomy followed by pelvic floor repair (VHPFR; eg, anterior and/or posterior colporrhaphy). In addition, sacrospinous ligament fixation was performed for stage ≥III uterine prolapse or vaginal vault prolapse. Patients with stage ≥III anterior compartment prolapse were offered anterior vaginal mesh repair. Obliterative surgery comprised colpocleisis with or without concomitant VH. Anterior vaginal mesh repair and colpocleisis were only offered to patients who were sexually inactive before surgery or agreed not to engage in sexual intercourse. Combinations of concomitant procedures were performed in the following order, using only the procedures selected by each patient and their surgeon: VH, mesh placement and sacrospinous fixation, native tissue repair, and TVT-O placement. All native tissue repair procedures were performed or supervised by a gynaecological specialist; all sacrospinous ligament fixation or anterior vaginal mesh repair procedures were performed or supervised by urogynaecologists. One dose of prophylactic intravenous antibiotic was administered during anaesthesia induction. In patients who underwent reconstructive surgery, one piece of vaginal gauze was placed to achieve haemostasis for 1 day. A Foley catheter was placed to ensure urinary drainage for 1 to 2 days according to the procedures used in each unit. Operative time, intra-operative blood loss, perioperative complications, and postoperative adverse events were recorded. Postoperative fever was defined as ≥2 readings of temperature ≥38°C with no positive culture or identifiable cause. A diagnosis of urinary tract infection was made on the basis of positive midstream urine culture results. A diagnosis of urinary retention was made when a patient could not void and required catheterisation. All instances of postoperative haematoma were diagnosed by imaging (ultrasound or computed tomography scan). When available, pathology reports were also reviewed.

All patients underwent the same postoperative assessment, which was structured using a standardised datasheet. Follow-up visits were scheduled at 6 to 12 weeks and 1 year after surgery, then annually until 5 years after surgery. Each follow-up visit evaluation included assessments of urinary and intestinal function; symptoms of prolapse, vaginal pain and dyspareunia; and symptoms of mesh erosion. Vaginal examinations and POP-Q assessments were performed to identify instances of POP recurrence or mesh-related complications, in accordance with the recommendations of the International Continence Society and the International Urogynecological Association.9 Prolapse recurrence was defined as the presence of subjective symptoms of prolapse or a POP-Q stage of ≥II in a clinical examination.

We compared patient demographic characteristics, POP severity, and surgical outcomes between two groups: reconstructive and obliterative surgeries. These comparisons were also made among four subgroups: VHPFR, transvaginal mesh surgery (TVM), VH plus colpocleisis, and colpocleisis alone. Statistical analyses were performed using SPSS (Windows version 26.0; IBM Corp, Armonk [NY], United States). Descriptive statistics were used to summarise demographic and clinical characteristics. Continuous variables were expressed as mean (standard deviation) or median (interquartile range); they were analysed by independent-samples t tests or the Mann-Whitney U test (comparison of two groups)/one-way analysis of variance or Kruskal–Wallis H test (comparison of ≥3 groups), depending on the normality of the data assessed by Shaprio–Wilk test. Categorical data were expressed as numbers and percentages; the Chi squared test and Fisher’s exact test were used for categorical data analysis. A P value of <0.05 was considered statistically significant.

In total, 343 patients underwent surgery for POP from 2013 to 2018 in the study hospitals. The types of surgical treatment at each hospital are shown in Table 1. Vaginal hysterectomy plus pelvic floor repair procedures were evenly distributed among all four hospitals. However, 93% of TVM procedures, 95% of VH plus colpocleisis procedures, and 50% of procedures comprising colpocleisis alone were performed in Prince of Wales Hospital, Princess Margaret Hospital, and Pamela Youde Nethersole Eastern Hospital, respectively.

Among the 343 patients, 216 (63%), 90 (26.2%), and 37 (10.8%) had stages II, III, and IV POP, respectively (Table 2). Furthermore, 289 (84.3%) patients underwent reconstructive surgery and 54 (15.7%) patients underwent obliterative surgery. Of the 289 reconstructive surgeries, 246 (71.7%) were native tissue repair procedures (mainly VHPFR), while 43 (12.5%) were TVM (36 had concomitant VH); among the 54 obliterative surgeries, 20 (5.8%) were colpocleisis plus VH, while the remaining 34 (9.9%) were colpocleisis alone (Table 3).

Table 2 compares demographic and clinical characteristics between the reconstructive and obliterative surgery groups. Patients with more advanced age chose obliterative surgery, rather than reconstructive surgery (81.9 vs 79.6 y; P=0.001). Other variables including parity, number of vaginal births, number of instrumental deliveries, body mass index, smoking, and coital activity were comparable between the two groups.

More patients with vaginal vault prolapse opted for obliterative surgery, rather than reconstructive surgery (38.9% vs 3.5%; P<0.001) [Table 2]. The difference was more striking when the colpocleisis alone group was compared with all patients who underwent reconstructive surgery (61.8%; P<0.001) [Table 3]. Moreover, the number of patients who had medical co-morbidities (eg, hypertension, diabetes mellitus, heart disease, or history of stroke) was greater in the obliterative surgery group than in the reconstructive surgery group (37% vs 4.8%, P<0.001) [Table 2].

Concerning patients with stage III/IV POP, more patients underwent TVM, rather than VHPFR, in the reconstructive surgery group (100% vs 16.7%; P<0.001); in the obliterative surgery group, more patients with stage III/IV POP underwent VH plus colpocleisis, rather than colpocleisis alone (100% vs 67.6%; P<0.004) [Table 3].

One case of carcinoma of the corpus uteri (Ca corpus) was confirmed from the pathology report of a patient who underwent VH. Thus, the incidence of Ca corpus was 0.3% (1/312). The affected woman was an asymptomatic patient in the TVM group; she had incidental findings of endometrial thickening during preoperative assessment. The results of endometrial aspiration could not exclude a diagnosis of hyperplasia. The patient underwent postoperative contrast-enhanced computed tomography of the abdomen and pelvis 2 months after surgery; there were no signs of distant metastasis. After detailed counselling, the patient refused further surgery or adjuvant therapy. For 25 months of follow-up, the patient’s cancer has remained in remission.

Table 4 shows surgical outcomes in both groups and all subgroups. Compared with obliterative surgeries, fewer reconstructive surgeries were performed under spinal anaesthesia (57.4% vs 38.1%; P=0.008). Notably, 76.5% of procedures comprising colpocleisis alone were performed under spinal anaesthesia (P<0.001). Obliterative surgeries had a shorter operative time (73.5 min vs 107 min; P<0.001) and fewer surgical complications (9.3% vs 28.0%; P=0.003) than did reconstructive surgeries. Among the four subgroups, colpocleisis alone had the shortest operative time (60 min; P<0.001) and least blood loss (50 mL; P<0.001).

Analysis of surgical complications (Table 4) showed that the VHPFR group had the highest intra- and peri-operative complication rate (30.1%; P=0.01), compared with the other subgroups. In the VHPFR group, four (1.6%) patients required conversion to laparoscopy/laparotomy (two had dense adhesion, one had large uterine size, and one had difficulty achieving haemostasis). There were three (1.2%) bladder injuries; all underwent primary repair with good recovery and did not experience long-term consequences. Four (1.6%) patients in the VHPFR group required intensive care unit (ICU) admission after surgery (one had fluid overload, one had respiratory acidosis, one had cardiac problems, and one had metabolic acidosis). In all, 29 (11.8%) patients had fever of unknown cause; 90% of them resolved by oral antibiotics. Ten (4.1%) patients had postoperative wound or pelvic haematoma, and 10 (4.1%) patients had urinary tract infection. In the TVM group, one (2.3%) patient required ICU admission because of fluid overload, while three (7%) patients had urinary retention after surgery. The VH plus colpocleisis and colpocleisis alone groups both included one patient with wound haematoma. In the TVM group, 32.6% of patients had concomitant TVT-O placement; 12.2%, 5%, and 2.9% of patients had concomitant TVT-O placement in the VHPFR, VH plus colpocleisis, and colpocleisis alone groups, respectively (P=0.001) [Table 4].

The median durations of follow-up were 13 and 17 months in the reconstructive and obliterative surgery groups, respectively (Table 4). The TVM group had a significantly longer median follow-up duration (25 months; P<0.001); this was consistent with the need to monitor any mesh complications. There was only one patient was lost to follow-up throughout the study period. Although there tended to be fewer instances of recurrence in the obliterative surgery group than in the reconstructive surgery group (7.4% vs 16.3%; P=0.092), the difference was not statistically significant. There also tended to be a higher rate of prolapse recurrence in the VHPFR group than in the TVM, VH plus colpocleisis, or colpocleisis alone groups (VHPFR 18%, TVM 7%, VH plus colpocleisis 5%, and colpocleisis alone 8.8%), but this trend was not statistically significant (P=0.091). Finally, few patients in each group underwent surgery for prolapse recurrence or stress urinary incontinence after surgery.

To our knowledge, this is the first multicentre retrospective study in Hong Kong concerning POP surgery for women aged ≥75 years. Overall analysis of demographic characteristics indicated that most patients underwent VHPFR because the largest proportion of patients had stage II POP. Most patients were sexually inactive (only four of 343 patients reported sexual activity), multiparous (median of four births overall), and had a history of exclusively vaginal delivery. The mean body mass index overall was 25.3 kg/m². Compared with reconstructive surgery, obliterative surgery was more frequently selected by patients who were older, had medical co-morbidities, had a history of pelvic floor repair surgery, and had vaginal vault prolapse.

In this study, we found that surgical treatment was a safe option for older women who sought to improve their quality of life. The postoperative mortality rate was zero, consistent with the low mortality rate 4.1% in a previous study.4 Notably, prior studies10 11 in Chinese populations suggested that poor quality of life and complications associated with vaginal pessary management lead to an increased likelihood of surgical treatment. In our study, over 80% of patients in the obliterative surgery group had an unsatisfactory vaginal pessary outcome; nearly half of the patients also had urinary retention. Therefore, it is reasonable that these patients chose POP surgery, despite their advanced age.

In studies from other countries, the reported rates of surgical complications associated with POP surgery in women aged ≥75 years were 30% to 40%.12 13 Although the VHPFR group had the highest rate of surgical complications among all subgroups in the present study, the rate of 30.1% was comparable to the rates in studies from other countries. However, 1.7% of patients in the reconstructive surgery group were admitted to the ICU after surgery; this was higher than the reported rate of 0.45% in a large cohort study with a mean patient age of 62.7 years.14 Because older women are more likely to experience fluid overload—it was present in 40% of the patients who required postoperative ICU care in our study—perioperative fluid replacement should be cautiously administered.

Patients in the obliterative surgery group had fewer surgical complications than did patients in the reconstructive surgery group. When the four types of surgeries were compared, the proportion of surgeries performed under spinal anaesthesia was greatest for procedures comprising colpocleisis alone; these procedures also had the least blood loss, shortest operative time, and fewest complications. Furthermore, the hospital stay in the colpocleisis alone group was comparable with the lengths in other groups, although significantly larger proportions of patients in the colpocleisis alone group had medical co-morbidities and were older.

Theoretically, colpocleisis with concomitant VH is superior to colpocleisis alone because it avoids the possibility of missing Ca corpus during surgery or later in the patient’s life15 16; however, it is associated with a longer operative time and increased blood loss.17 18 Our results were consistent with the findings in previous studies from other countries. Patients aged ≥75 years are beyond the peak incidence of Ca corpus: according to the Hong Kong Cancer Registry, the median age of patients with Ca corpus is 55 years.19 In the present study, one patient in the TVM group had Ca corpus; thus, the rate of incidental malignancy was 0.3%, which was comparable to the rate of 0.26% previously reported in Hong Kong.20 Currently, pelvic ultrasound is not a routine component of preoperative assessment. To reduce the risk of missing Ca corpus, preoperative transvaginal ultrasound (to assess endometrial thickness) and endometrial aspiration should be considered in women who have abnormal vaginal bleeding or plan to undergo uterine-preserving surgery.20

Although TVM is a more complex surgery than VHPFR, the rate of perioperative surgical complications was lower in the TVM group; hospital stays were comparable between the two groups. However, the operative time was longer and blood loss was greater in the TVM group. Compared with patients in the VHPFR group, patients in the TVM group had a lower rate of POP recurrence (all recurrences occurred in patients with stage III/IV POP) and a significantly longer follow-up duration. The mesh erosion rate in this study (2.3%) was lower than in another study in Hong Kong (8.9%), which had a longer follow-up duration of 40 months and included younger patients.21 When proper counselling is provided, TVM is a safe option for healthier patients with stage III/IV POP because stage III/IV POP is a risk factor for recurrence.22

Notable strengths of this study included its multicentre design and focus on POP surgery among older women in the Hong Kong Chinese population, which has not been previously explored. Patients in this study included all women aged ≥75 years who underwent POP surgery in a 6-year period at four hospitals; these hospitals are jointly accredited as a single urogynaecological training centre under the Hong Kong College of Obstetricians and Gynaecologists, and they have extensive experience performing all types of POP surgery (Table 1). Furthermore, the electronic medical record system of the Hospital Authority facilitated complete data collection and retrieval. However, there were a few limitations in this study. First, it was a retrospective study. Second, we did not perform quality of life assessment or investigate the presence of guilt concerning colpocleisis surgery. Because few patients reported sexual activity before surgery, we presume that most older women in Hong Kong would not regret the selection of colpocleisis because of its effects on sexual activity. Third, although the median follow-up period was <18 months, it may have been insufficient to fully characterise prolapse recurrence and gynaecological malignancy. Finally, the levels of independence and family support may be important factors for older women to consider before making any surgical decision; however, we did not have access to such data. These factors could be examined in future studies.

This multicentre retrospective study showed that multiple types of POP surgeries were safe and effective for women aged ≥75 years. Most surgical complications were self-limiting and the recurrence rate was low. The excellent results suggest that colpocleisis may be appropriate as primary surgery for fragile older women. These findings will facilitate preoperative counselling for older women with POP who are considering surgical treatment.

Concept or design: D Wong, SSC Chan
Acquisition of data: All authors.
Analysis or interpretation of data: D Wong, SSC Chan.
Drafting of the article: D Wong, SSC Chan.
Critical revision 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.

All authors have disclosed no conflicts of interest.

We would like to express our gratitude to Ms LL Lee, Dr TH Chan and Dr CW Chu for data collection and entry.

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

This study was approved by the Hong Kong East Cluster Ethics Committee (HKECREC-2020-069), the Kowloon Central Cluster Ethics Committee (KC/KE-20-0223/ER-2), the Kowloon West Cluster Ethics Committee (EX-20-108[150-02]), and the New Territories East Cluster Ethics Committee (NTEC-2020-138).

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