The World Health Organization aims to eradicate hepatitis B virus (HBV) by 2030 and prevention of vertical transmission is a key element of its eradication efforts.1 The risk of chronic infection depends on the timing of infection acquisition and is highest during the perinatal period, such that chronic infection occurs in approximately 90% of newborns from HBV-infected mothers.2 The risk is dramatically reduced by administration of hepatitis B immunoglobulin to newborns at birth, in combination with a complete course of hepatitis B vaccination.3 Despite a 75% to 90% reduction in the carrier rate with these measures, they have not resulted in complete eradication of HBV infections. Among the maternal and obstetric factors examined, a high maternal HBV DNA level during pregnancy is the strongest risk factor leading to immunoprophylaxis failure.4 5 6 7

The immunoprophylaxis failure rate in Hong Kong is reportedly 1.1%, according to the results of a local prospective multicentre observational study.5 Immunoprophylaxis failure occurs only in those women with high viral load (ie, ≥6 log₁₀ copies/mL [≥171 821 IU/mL]; immunoprophylaxis failure rate 4.2%) or hepatitis B e-antigen (HBeAg)–positive status (immunoprophylaxis failure rate 4.5%). The use of antiviral treatment during the third trimester in highly viraemic mothers to suppress viral load has been advocated to reduce the risk of chronic HBV infection in newborns.8 9 To achieve this, it is essential to establish a management strategy that includes HBV DNA assessment for identification of high-risk patients, as well as initiation of prompt antiviral treatment in the antenatal period.

An enhanced service model for pregnant women who had positive screening results for hepatitis B surface antigen (HBsAg) was established on 15 May 2017 at Queen Mary Hospital in Hong Kong (Fig 1). All women were offered blood tests for HBV DNA, performed by the Department of Medicine, The University of Hong Kong, during their first antenatal visits at Tsan Yuk Hospital or Queen Mary Hospital. The cost of HK$400 per test was borne by the patients; the laboratory results were reviewed by hepatologists.

Pregnant women with HBV DNA levels of ≥200 000 IU/mL were triaged by hepatologists for an early clinic appointment, generally before 33 weeks of gestation, to receive counselling regarding potential antiviral treatment. Tenofovir disoproxil fumarate (TDF) 300 mg daily was chosen for its potent efficacy and risk of pre-existing or emergent resistant mutants from previous lamivudine and telbivudine treatments.10 11 12 Drug compliance and HBV DNA level were monitored regularly. All other pregnant women with viral loads of <200 000 IU/mL were also scheduled for an elective long-term follow-up appointment. Irrespective of viral load, all neonates born from pregnant women with hepatitis B were administered HBV vaccine and hepatitis B immunoglobulin within 12 hours of birth. The present study aimed to evaluate the patients’ acceptance and outcome of this enhanced service model for management of pregnant women carrying hepatitis B.

This retrospective review included all women who attended the antenatal clinic from 15 May 2017 to 31 December 2019. Information regarding hepatitis B carrier status, HBV DNA blood test acceptance, viral load, patient triage, and TDF acceptance were retrieved from the antenatal record system and clinical management system under the Hong Kong Hospital Authority. The HBV DNA assays were performed in Department of Medicine, The University of Hong Kong.

Each patient’s HBV carrier status was determined by an HBsAg test performed during pregnancy. Hepatitis B virus DNA level was considered high for viral loads of ≥200 000 IU/mL and low for viral loads of <200 000 IU/mL. The rate of antenatal acceptance of TDF was defined as the proportion of women taking TDF in the group with high viral loads who had been counselled by hepatologists. Descriptive statistics are reported.

Of 13 082 women who attended the antenatal clinic from 15 May 2017 to 31 December 2019, 375 pregnant women had positive HBsAg screening results; the carrier rate was 2.9%. In total, 102 (27.2%) women had undergone HBV DNA testing or received regular hepatological follow-up before pregnancy. Blood tests for HBV DNA and hepatological reviews were offered to 273 pregnant women. Two women refused further assessment and four women did not attend the blood test visit. Reasons for refusal or non-attendance were not documented. Of the four women who did not attend the blood test visit, two were reminded of the need for a blood test at subsequent antenatal visits, but did not complete the tests. Overall, the acceptance rate for hepatological review was 97.8% (267/273). Among the 267 women who accepted hepatological reviews, blood tests were not performed because of pregnancy termination due to trisomy 21 (n=1) and miscarriage (n=1). Thus, the final cohort comprised 265 pregnant women who had HBV viral load results available for triage assessment. The median gestational age at the time of HBV testing was 17 weeks.

Sixty (22.6%) pregnant women were HBV carriers with viral loads of ≥200 000 IU/mL; highest level was 688 000 000 IU/mL. The median age of women with high viral loads was not substantially lower than that of women with low viral loads (33 years vs 35 years; Wilcoxon rank sum test; not significant).

Fifty eight of the 60 patients with high viral loads were scheduled for hepatological review before the expected date of delivery. First hepatological review appointments were scheduled for 55 (91.7%) women and 44 (73.3%) women at or before 32 and 28 weeks of gestation, respectively. Among the three women who scheduled their first hepatological review appointment after 32 weeks of gestation, two delayed the referral submission and one had attended the antenatal clinic at an advanced stage of gestation (Fig 2).

One patient did not attend a hepatological review appointment before 28 weeks of gestation. The remaining 57 women with high viral loads received antenatal counselling regarding TDF and 56 women agreed to take the drug, thereby constituting an antenatal acceptance rate of 96.6% (56/58). The acceptance rates of TDF among women with high viral loads are shown in the Table.

Treatment with TDF commenced at a median gestational age of 26 weeks (range, 20-38 weeks). Overall, 44 (78.6%) women received 300 mg daily TDF at or before 28 weeks of gestation. Among the 12 women who began TDF treatment after 28 weeks of gestation, four had deferred blood tests for assessment of viral load, six had late antenatal clinic appointments, one did not attend the initial appointment at 28 weeks, and one attended the clinic at 33 weeks of gestation. Overall, 52 (92.9%) women commenced TDF treatment at or before 32 weeks of gestation.

Screening for HBV carrier status is a universal antenatal test in Hong Kong. Women who have positive screening results are counselled regarding the risk of vertical transmission. In 1983, a neonatal HBV vaccination programme was introduced in Hong Kong to cover vaccination for first newborns of carrier mothers. This became universal in November 1988; hepatitis B immunoglobulin and hepatitis B vaccine have since been administered to all babies born to mothers carrying HBV. These measures focus mainly on postnatal neonatal immunoprophylaxis; however, they lack a robust system for actively reducing the antenatal risk of vertical transmission, as well as a referral system that ensures long-term hepatological follow-up for carrier mothers.

The present study demonstrated an effective and acceptable approach involving HBV DNA testing during triage of obstetric patients for prevention of perinatal HBV transmission. Data from the Centre of Health Protection have shown that the HBsAg prevalence in pregnant women is decreasing, from >10% in the early 1990s to 5.0% in 2017.13 The HBV carrier rate in the present study (2.9%) was lower than that previously reported in Hong Kong. Our cohort included women with HBsAg who were tested from May 2017 to December 2019; the low carrier rate in the present study might reflect a continuous reduction in overall HBsAg prevalence, due to universal neonatal vaccination.14 However, more than 70% of the pregnant women in our cohort did not have HBV viral load testing or regular hepatological surveillance before pregnancy. This is an important public health concern, because HBV carriers with high viral loads are at higher risk of mother-to-child transmission of HBV, as well as development of liver cirrhosis and hepatocellular carcinoma. With proper antenatal education and general awareness, nearly 98% of the obstetric patients in our population were willing to undergo self-financed HBV DNA testing.

Viral load is a key factor that influences immunoprophylaxis failure4; a higher risk of immunoprophylaxis failure has been demonstrated in women with viral loads of ≥200 000 IU/mL. Positive HBeAg screening results, maternal age <35 years, and body mass index ≤21 kg/m² have been associated with a higher mean viral load.15 Our study showed that 22.6% of women had viral loads of ≥200 000 IU/mL, which was comparable to previous findings. Although age was not a statistically significant factor in the present study, a previous study showed that women with high viral loads were younger than women with low viral loads.5 The prevention of perinatal transmission is of considerable importance in achieving complete eradication of HBV. Incorporation of HBV DNA testing during pregnancy is a key element that can facilitate identification of at-risk pregnant women who may benefit from antenatal antiviral prophylaxis. Ideally, both liver function test and HBeAg should be assessed in pregnant women to determine their HBV disease status; antiviral treatment may be initiated for maternal indications. Although the presence of HBeAg suggests a high risk of immunoprophylaxis failure, HBeAg was not routinely assessed during triage in the present cohort because it was not regarded as an indicator of the need for antiviral treatment to prevent vertical transmission.9 16 17 Additionally, HBV DNA quantification provides a continuous assessment of risk according to viral load, compared to the dichotomous result of HBeAg screening. Therefore, HBV DNA level should be used to identify women who should receive antiviral treatment.18

Tenofovir disoproxil fumarate is the drug of choice for antenatal prophylaxis because of its potent effect and the possibility of mutants resistant to lamivudine and telbivudine, due to prior treatment with those drugs.11 12 19 Breastfeeding is not contra-indicated for women who are taking TDF. A highly promising rate of antenatal acceptance of TDF (96.6%) was observed among women who had undergone antenatal hepatological review. This indicates the need for surveillance and the usefulness of patient education during the antenatal period.

Although the optimal timing of antiviral treatment remains controversial, randomised controlled trials show that initiation of TDF during the period between 28 and 32 weeks of gestation is effective in reduction of immunoprophylaxis failure. Earlier initiation of antiviral treatment is unnecessary, because the immunoprophylaxis failure rate is not appreciably reduced. Postponement of treatment to a point later than 32 weeks of gestation may result in an insufficient duration of treatment and suboptimal viral load reduction at delivery.10 20 Guidelines from the American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver recommend initiation of treatment at 28 to 32 weeks of gestation.9 21 The present study demonstrated a feasible framework for triage of nearly all pregnant women with high viral loads before their dates of delivery. Nearly 93% were able to initiate antiviral prophylaxis at or before 32 weeks of gestation; this could only be attained with an appropriate hepatological review appointment during pregnancy. The arrangement could be further improved if women could attend antenatal visits earlier during pregnancy, blood test logistics could be simplified, and resources could be allocated more effectively.

To the best of our knowledge, the multidisciplinary efforts of obstetricians and hepatologists have enabled Queen Mary Hospital to become the first public hospital in Hong Kong with enhanced antenatal management for pregnant women carrying hepatitis B. The proportion of women with high viral loads was comparable to the proportions in previous studies. Our results indicated the usefulness of HBV DNA blood tests in pregnant women and high acceptance of antenatal antiviral treatment. Triage according to HBV DNA level allowed early hepatological review and commencement of antiviral medication, thereby reducing the viral load at the time of delivery and minimising the risk of vertical transmission. This service model was adopted as a framework for implementation of a fully funded enhanced antenatal service to prevent mother-to-child transmission of HBV in public maternity units, commencing 1 January 2020.

Concept or design: PW Hui.
Acquisition of data: C Ng, PW Hui.
Analysis or interpretation of data: C Ng, PW Hui.
Drafting of the manuscript: PW Hui.
Critical revision of the manuscript for important intellectual content: KW Cheung, CL Lai.

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

All authors have disclosed no conflicts of interest.

The authors thank Mr John Yuen for performing HBV DNA analysis.

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

This research was approved by the Institutional Review Board of the University of Hong Kong / Hospital Authority West Cluster (Ref UW 20-092).

1. World Health Organization. Global Health Sector Strategy on viral hepatitis 2016-2021, towards ending viral hepatitis. 2016. Available from: http://apps.who.int/iris/bitstream/handle/10665/246177/WHO-HIV-2016.06-eng.pdf?sequence=1. Accessed 2 Feb 2020.

2. Edmunds WJ, Medley GF, Nokes DJ, Hall AJ, Whittle HC. The influence of age on the development of the hepatitis B carrier state. Proc Biol Sci 1993;253:197-201. Crossref

3. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. BMJ 2006;332:328-36. Crossref

4. Cheung KW, Seto MT, Wong SF. Towards complete eradication of hepatitis B infection from perinatal transmission: review of the mechanisms of in utero infection and the use of antiviral treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2013;169:17-23. Crossref

5. Cheung KW, Seto MT, Kan AS, et al. Immunoprophylaxis failure of infants born to hepatitis B carrier mothers following routine vaccination. Clin Gastroenterol Hepatol 2018;16:144-5. Crossref

6. Wen WH, Chang MH, Zhao LL, et al. Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention. J Hepatol 2013;59:24-30. Crossref

7. Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepat 2012;19:e18-25. Crossref

8. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98.

9. Terrault NA, Lok AS, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99. Crossref

10. Pan CQ, Duan Z, Dai E, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med 2016;374:2324-34. Crossref

11. Hyun MH, Lee YS, Kim JH, et al. Systematic review with meta-analysis: the efficacy and safety of tenofovir to prevent mother-to-child transmission of hepatitis B virus. Aliment Pharmacol Ther 2017;45:1493-505. Crossref

12. Hu YH, Liu M, Yi W, Cao YJ, Cai HD. Tenofovir rescue therapy in pregnant females with chronic hepatitis B. World J Gastroenterol 2015;21:2504-9. Crossref

13. Viral Hepatitis Control Office, Special Preventive Programme, Centre for Health Protection, Department of Health, Hong Kong SAR Government. Surveillance of Viral Hepatitis in Hong Kong—2017 Update Report. Available from: https://www.chp.gov.hk/files/pdf/viral_hepatitis_report.pdf. Accessed 2 Feb 2020.

14. Lao TT, Sahota DS, Chan PK. Three decades of neonatal vaccination has greatly reduced antenatal prevalence of hepatitis B virus infection among gravidae covered by the program. J Infect 2018;76:543-9. Crossref

15. Cheung KW, Seto MTY, So PL, et al. Optimal timing of hepatitis B virus DNA quantification and clinical predictors for higher viral load during pregnancy. Acta Obstet Gynecol Scand 2019;98:1301-6. Crossref

16. Hu Y, Xu C, Xu B, et al. Safety and efficacy of telbivudine in late pregnancy to prevent mother-to-child transmission of hepatitis B virus: a multicenter prospective cohort study. J Viral Hepat 2018;25:429-37. Crossref

17. Jourdain G, Ngo-Giang-Huong N, Harrison L, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med 2018;378:911-23. Crossref

18. Cheung KW, Lao TT. Hepatitis B—Vertical transmission and the prevention of mother-to-child transmission [in press]. Best Pract Res Clin Obstet Gynaecol. In press.

19. Cheung KW, Seto MT, Lao TT. Prevention of perinatal hepatitis B virus transmission. Arch Gynecol Obstet 2019;300:251-9. Crossref

20. Yang X, Zhong X, Liao H, Lai Y. Efficacy of antiviral therapy during the second or the third trimester for preventing mother-to-child hepatitis B virus transmission: a systematic review and meta-analysis. Rev Inst Med Trop Sao Paulo 2020;62:e13. Crossref

21. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1-98. Crossref

Total knee arthroplasty (TKA) is the most effective and efficacious surgical method to improve pain and function for patients with end-stage osteoarthritis; however, TKA has been associated with substantial blood loss. In addition to visible blood loss from the surgical field and wound drainage, hidden blood loss occurred in patients undergoing TKA, which resulted in mean blood loss of 1.5 L.1 Therefore, perioperative blood transfusion was needed in up to 38% of patients undergoing TKA.2

Blood transfusion is not risk-free. Often, no adverse effects are encountered by patients who undergo blood transfusion. However, adverse effects occasionally occur, ranging from minor allergic reactions to blood-borne infection and potentially fatal acute immune haemolytic reaction. With the implementation of best international practices to warrant blood transfusion safety by the Blood Transfusion Service in Hong Kong, the transfusion risk has significantly decreased in the past two decades.3 However, absolute safety in transfusion cannot be achieved because of the window period for detecting infections, possibility of emerging infections, and potential human errors related to the process of transferring collected blood from donors to transfusion recipients. Notably, researchers in Hong Kong reported the first two cases (worldwide) of transmission of Japanese encephalitis virus, via blood transfusion to immunocompromised hosts, in 2018.4 In addition to the general risks associated with transfusion, blood transfusion has been independently associated with poor surgical outcome. Specifically, patients who underwent transfusion exhibited an eight-fold to 10-fold excess risk of adverse outcomes, defined as postoperative complications in the American College of Surgeons National Surgical Quality Improvement Project.5 With respect to total hip or knee arthroplasty, a dose-dependent relationship between transfusion and risk of surgical site infection was observed.6

With increasing understanding regarding the benefits and risks of blood transfusion, as well as alternative approaches for patients who experience blood loss, the concept of patient blood management (PBM) was developed. The World Health Organization defines PBM as ‘a patient-focused, evidence-based and systematic approach to optimise the management of patients and transfusion of blood products for quality and effective patient care. It is designed to improve patient outcomes through the safe and rational use of blood and blood products and by minimising unnecessary exposure to blood products…’.7 The three major components of PBM are as follows: (1) optimisation of the patient’s own blood mass; (2) minimisation of blood loss; and (3) optimisation of physiological tolerance to anaemia.8 This new standard of care is now well-established in some centres in the US, Austria, and Western Australia, as well as nationally in the Netherlands. However, PBM remains an uncommon practice in Asia.

We introduced the PBM programme for patients undergoing TKA in our institution, beginning in 2014. Various components were introduced gradually (in phases) from 2014 to 2018. The key measures of PBM in preoperative, intra-operative, and postoperative periods were fully implemented in 2018. To the best of our knowledge, our PBM programme is a pioneer PBM programme in Hong Kong. The aim of the present study was to assess the effectiveness of the multimodal PBM approach in our university-based centre.

This single-centre retrospective study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref UW 19-600). The requirement for patient consent was waived by the review board. We retrospectively collected blood transfusion data regarding patients who underwent unilateral primary TKA in our centre from 1 January 2013 to 31 December 2018. Patients who underwent one-stage bilateral primary TKA or revision TKA were excluded from our study. Patients with acquired or congenital coagulopathy, as well as those currently taking anticoagulants, were included in our study; notably, these patients were at greater risk of perioperative blood loss and transfusion.

The primary outcome measure was the mean yearly transfusion rate, which was defined as the number of patients who received transfusion after TKA (during the same hospitalisation episode) divided by the number of patients who underwent TKA during the period from 1 January to 31 December; this result was multiplied by 100. The mean units of blood given per transfusion episode in 1 year was defined as the cumulative total number of blood units transfused to patients after TKA in 1 year divided by the number of transfusion episodes in that year. Transfusion data were retrieved from the Clinical Data Analysis and Reporting System, a database developed by the Hong Kong Hospital Authority for research purposes; this database contains medical information recorded by the Hong Kong Hospital Authority since 1993.

Secondary outcome measures were mean length of hospital stay after surgery, the rate of unexpected readmission through the Emergency Department after discharge from the hospital, the proportion of patients who had early prosthetic joint infection requiring revision surgery within 90 days after index surgery, and the 90-day mortality rate. These data and other patient demographic data (eg, age and sex), perioperative data (eg, American Society of Anesthesiologists [ASA] physical status), and preoperative haemoglobin level were retrieved from our patient records, as well as a local joint replacement registry.

Patient blood management was a relatively new concept in Hong Kong when it was first implemented in our institution in 2014. Initially, this programme was a standalone surgeon-initiated programme without external support; it was implemented in sequential stages based on PBM guidelines provided by the National Blood Authority in Australia.9 The sequential stages of PBM implementation in our centre are described in Table 1. The PBM strategies included modern surgical, anaesthetic, and perioperative care. In 2014, PBM was initiated with instructions regarding proper indications for transfusion, single-unit transfusion policy,10 and restrictive transfusion policy with transfusion triggered at haemoglobin ≤8 g/dL in healthy individuals.11 In 2015, the traditional practice of routine placement of a surgical drain during TKA (associated with a higher transfusion rate12) was stopped; the use of topical tranexamic acid (injection of 1 g tranexamic acid into knee joint at the end of the surgical procedure, shown to reduce postoperative blood loss and transfusion rate13) was implemented to reduce perioperative blood loss. In 2016, preoperative anaemia screening and optimisation were initiated via collaboration with haematologists. Patients with preoperative haemoglobin <11 g/dL were examined for causes of anaemia, in accordance with Network for Advancement of Transfusion Alternatives guidelines14; their erythropoiesis and preoperative haemoglobin characteristics were optimised before TKA was performed. For example, patients with iron-deficiency anaemia were checked for gastrointestinal blood loss and prescribed iron supplementation; their haemoglobin levels were rechecked after supplementation to confirm achievement of ≥11 g/dL before TKA. To further reduce intra-operative blood loss, combined intravenous tranexamic acid (15 mg/kg administered intravenously at the induction of anaesthesia) and topical tranexamic acid were implemented; these are reportedly effective for reduction of blood loss.15 In 2017, a more stringent restrictive transfusion policy was adopted with transfusion triggered at haemoglobin ≤7 g/dL in healthy individuals. Moreover, active warming (a modern anaesthetic technique used during intra-operative care) was implemented to avoid intra-operative hypothermia16; this hypothermia has been associated with greater volume of blood loss and the need for transfusion.17 18 By the beginning of 2018, all above PBM strategies were fully implemented.

In addition to PBM strategies, other changes in patient selection and perioperative management were implemented between 2013 and 2018. First, the degree of medical co-morbidities may have differed because of the establishment of another joint replacement centre in July 2016; this new centre provided joint replacement surgeries for patients with improved medical fitness, among patients with end-stage osteoarthritis in our hospital. Therefore, the medical co-morbidities of the patients in 2013 and 2018 were compared on the basis of ASA status. Second, because of technological advances in the design of TKA prostheses over time, there were differences in the numbers of modern-design TKA prostheses between 2013 and 2018; these modern-design TKA prostheses aimed to improve knee kinematics, rather than reduce transfusion rate. However, these prostheses were unlikely to bias our transfusion rate results, according to a prior assessment of factors predictive of transfusion rate in patients undergoing TKA.19

In 2013, no PBM strategies had been implemented in our institution, whereas all strategies had been fully implemented by 2018. The Chi squared test was used to compare the transfusion rate between patients who underwent TKA in 2013 and those who underwent TKA in 2018; differences with P<0.05 were considered statistically significant. As mentioned above, medical co-morbidities of the patients in 2013 and 2018 were compared on the basis of ASA status.

In total, 262 and 215 patients underwent primary TKA in our centre in 2013 and 2018, respectively (Table 2). There were no significant differences in mean age (2013: 72.17±9.76 years; 2018: 72.49±9.27 years, P=0.71) or sex (male:female) ratio (2013, 61:201; 2018, 63:152, P=0.14) between the groups. The preoperative haemoglobin level was also similar between the groups (2013: 12.77±1.42 g/dL; 2018: 12.89±1.42 g/dL, P=0.35). However, there was a significant difference in ASA distribution between the groups (P=0.03). There was a comparatively greater proportion of patients with ASA Grade II status in 2018 (2013: 57.6%; 2018: 68.8%).

The primary outcome was the mean transfusion rate in 1 year. There was a significant difference in the mean transfusion rate after primary TKA between 2013 and 2018 (2013: 31.3%; 2018: 1.9%, P<0.001); however, there was no significant difference in the mean units of blood transfused per transfusion episode (2013: 1.62±0.78; 2018: 1.00±0.00, P=0.12). Moreover, the mean annual transfusion rate after primary TKA exhibited stepwise reduction as PBM strategies were implemented during the period from 2014 to 2018 (Fig).

Regarding secondary outcomes, the mean length of hospitalisation was significantly lower in 2018 (2013: 14.49±8.10 days; 2018: 8.77±10.14 days, P<0.001). However, there was no difference in the unexpected readmission rate through the Emergency Department (2013: 3.8%; 2018: 3.7%, P=0.96), the proportion of patients who exhibited early prosthetic joint infection within 90 days after index surgery (2013: 0.4%; 2018: 0%, P=0.36), or the proportion of patients with 90-day mortality (2013: 0%; 2018: 0.5%, P=0.27).

Blood transfusion is a life-saving therapy, but is a limited resource. In recent years, there have been recurrent blood shortages in Hong Kong, and the Hong Kong Red Cross has issued an urgent appeal for blood donors on several occasions.20 21 22 23 The amount of blood stored in blood banks is determined by supply and demand. To increase blood supply, additional blood donors are needed. The Annual Report of Hong Kong Red Cross in 2018/2019 revealed that 4% of blood donors were aged >60 years, and the largest group of blood donors were aged 41-50 years (23.7% of donors).24 With the increasing number of older people in Hong Kong, more blood donors are needed from older age-groups. In addition, healthcare professionals should be judicious in prescribing transfusion, and should consider methods to minimise transfusion. Our study demonstrated the effectiveness of implementing PBM in our centre. In addition to comparing the mean transfusion rate in 2013 and 2018, this study included an audit of the mean annual transfusion rate after primary TKA from 2014 to 2018 (Fig).

Globally, PBM is not a new concept. In May 2010, the World Health Organization formally recognised the importance of PBM and recommended its use to the 193 member states.25 Subsequently, PBM has been successfully implemented in Western countries, especially Australia26 and the US.27 The Asia-Pacific PBM Expert Consensus Meeting Working Group assessed the status of PBM in Asia.28 In Singapore, PBM was implemented nationally, beginning in 2013. The Ministry of Health and Blood Services Group actively promoted PBM at public hospitals in the first few years; regular national audits of PBM-related efforts have been performed since 2017 to promote appropriate use of red blood cell transfusion and implementation of preoperative anaemia screening for elective surgeries. Patient blood management programmes were successfully implemented in National University Hospital and Singapore General Hospital.28 29 In Korea, PBM was implemented through a professional initiative by the Korean Research Society of Transfusion Alternatives of the Republic of Korea in 2006; the Korean Patient Blood Management Research Group was formed to promote greater PBM use in 2016. The efforts of the Korean Patient Blood Management Research Group resulted in achievement of several PBM milestones in 2016.28 Notably, PBM was included in the Korean Transfusion Guidelines; a new steering committee was also formed, comprising leading physicians from various specialties. Patient blood management was successfully implemented in a number of Korean hospitals, which led to a reduction in transfusion rate.30 31 32 In Malaysia, PBM has been promoted at the local hospital level.28 In the Department of Maternal and Fetal Medicine at the Sultan Haji Ahmad Shah Hospital, women at high risk of anaemia are screened for iron deficiency anaemia in early pregnancy; iron-deficient women are provided oral or intravenous iron supplementation.

At our institution, PBM was first implemented in 2014 as a surgeons’ initiative in the Division of Joint Replacement Surgery. In addition to good surgical techniques, good perioperative care is an important determinant of surgical outcomes. Patient blood management is a component of our overall perioperative management protocol in the modern enhanced recovery after surgery programme. With implementation of PBM strategies and measures in the enhanced recovery after surgery programme, the length of hospitalisation was shortened in 2018, compared with 2013. Despite the shorter length of stay, there were no differences in the unexpected readmission rate through the Emergency Department, the proportion of patients who had early prosthetic joint infection within 90 days after index surgery, or the proportion of patients who had 90-day mortality.

To the best of our knowledge, there have been few studies regarding PBM in patients undergoing TKA in Hong Kong. In 2015, Lee et al33 reported their pioneering experience with implementation of PBM in patients undergoing TKA; their PBM protocols included typing and screening only for patients with preoperative haemoglobin of <11 g/dL, and restrictive transfusion triggered at haemoglobin 8 g/dL. When they compared outcomes before and after introduction of the PBM programme, the transfusion rate (before: 10.3%; after: 3.1%, P=0.046) and cross-match rate (before: 100%; after: 3.1%, P<0.001) both decreased. We implemented PBM in our institution, beginning in 2014. Modern surgical, anaesthetic, and perioperative techniques in PBM were gradually introduced from 2014 to 2018. Our PBM protocols are more comprehensive than those of Lee et al, because our protocols were designed in accordance with the PBM guidelines provided by the National Blood Authority in Australia.9 Therefore, our transfusion rate in TKA in 2018 decreased to 1.9%.

Prosthetic joint infection is a severe complication in arthroplasty; affected patients often require revision surgery. Notably, patients who underwent treatment for prosthetic joint infection exhibited a significant, independent risk of increased mortality, due to the direct adverse effect of infection and the indirect effect of poor underlying health condition.34 In a recent meta-analysis involving 21 770 patients who underwent total hip and knee arthroplasty, patients who received allogeneic blood transfusion had a significantly greater risk of surgical-site infection (pooled odds ratio: 1.71, P=0.02).35 Recently, a dose-dependent relationship was observed between allogeneic transfusion and surgical site infection after total hip or knee arthroplasty.6 Therefore, PBM was expected to reduce the incidence of surgical site infection in our centre. However, because of the relatively small sample size in our study and the relatively low incidence of prosthetic joint infection (approximately 1%), a difference in the incidence of prosthetic joint infection between 2013 and 2018 could not be identified. When PBM was fully implemented in our centre (2018), the transfusion rate after primary TKA was 1.9%; this was comparable to international reported values. Specifically, when PBM strategies were implemented in the US, the transfusion rates were approximately 4.5%.36 When PBM is implemented by high-volume surgeons with an eight-step checklist to reduce bleeding, the transfusion rate after TKA could be as low as 0.0044%.37 Therefore, a transfusion rate of 0% is achievable.

As the transfusion rate decreased in patients undergoing TKA, there were also benefits to the healthcare system. Blood transfusion involves many costs associated with blood transfer from donors to recipients (eg, collection, screening, storage, transportation, and prescription of donated blood). We do not have data regarding the cost of packed red blood cells in Hong Kong; however, the cost was estimated to be approximately 1130 USD/unit in a study conducted in the US.36 Therefore, reduced transfusions through implementation of PBM can result in lower healthcare expenditures, which are of considerable importance because of the increasing demand for TKA among the aging population in Hong Kong.

There were some limitations in this study. First, it was a retrospective study; thus, compliance with PBM strategies could not be fully verified. However, as each strategy was introduced throughout the course of the study, there was gradual reduction in the transfusion rate. Therefore, compliance with the strategies was presumably optimal. Second, because different strategies were implemented successively, the strategies with the greatest contribution to the reduced transfusion rate could not be identified. Third, because this was not a prospective randomised placebo-controlled interventional trial, a causal relationship between PBM strategies and reduction in transfusion rate could not be established. However, our study provided an assessment of real-world implementation of PBM strategies within a large hospital; thus, it comprises pioneering research in Hong Kong. Fourth, some potential cofounding factors may not have been identified or controlled in the present analysis. For example, the type of prosthesis used was not analysed as a separate factor. However, preoperative haemoglobin levels (the most significant predictor of blood transfusion19) were compared between both groups. To the best of our knowledge, there remains minimal relevant literature regarding the effect of TKA prosthesis on the transfusion rate.

In conclusion, our results demonstrated the effectiveness of PBM implementation on transfusion rate in patients undergoing TKA. From 2014 to 2018, there was a stepwise reduction in transfusion rate after TKA; this was similar to findings in previously published research. This is one of the few studies in Hong Kong to review PBM in surgical practice. Although we focused on patients undergoing TKA, the principles of PBM could be useful for other medical or surgical specialties.

All authors contributed to the concept or design of the study, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

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 thank Dr CK Lee, Chief Executive and Medical Director, Hong Kong Red Cross Blood Transfusion Service, Hong Kong, for providing advice on the patient blood management programme. We also acknowledge and express our gratitude to the following departments of our hospital for the support in this multidisciplinary project: Nursing Division, Department of Orthopaedics and Traumatology; Operation Theatre Services; and Blood Transfusion Committee.

This research has been presented in part as an oral presentation at the Hong Kong Hospital Authority Convention 2018.

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 Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref UW 19-600). The requirement for patient consent was waived by the review board.

1. Sehat KR, Evans R, Newman JH. How much blood is really lost in total knee arthroplasty? Correct blood loss management should take hidden loss into account. Knee 2000;7:151-5. Crossref

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6. Everhart JS, Sojka JH, Mayerson JL, Glassman AH, Scharschmidt TJ. Perioperative allogeneic red blood-cell transfusion associated with surgical site infection after total hip and knee arthroplasty. J Bone Joint Surg Am 2018;100:288-94. Crossref

7. World Health Organization. WHO Global Forum for Blood Safety: patient blood management. Available from: https://www.who.int/bloodsafety/events/gfbs_01_pbm/en/ Accessed 5 Jan 2020.

8. Isbister JP. The three-pillar matrix of patient blood management-an overview. Best Pract Res Clin Anaesthesiol 2013;27:69-84. Crossref

9. National Blood Authority Australia. Patient Blood Management Guidelines. Available from: https://www.blood.gov.au/pbm-guidelines. Accessed 9 Jan 2020.

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11. Hardy JF. Current status of transfusion triggers for red blood cell concentrates. Transfus Apher Sci 2004;31:55-66. Crossref

12. Zhang Q, Liu L, Sun W, et al. Are closed suction drains necessary for primary total knee arthroplasty? A systematic review and meta-analysis. Medicine (Baltimore) 2018;97:e11290. Crossref

13. Panteli M, Papakostidis C, Dahabreh Z, Giannoudis PV. Topical tranexamic acid in total knee replacement: a systematic review and meta-analysis. Knee 2013;20:300-9. Crossref

14. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines. Br J Anaesth 2011;106:13-22. Crossref

15. Shang J, Wang H, Zheng B, Rui M, Wang Y. Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty: A meta-analysis of randomized controlled trials. Int J Surg 2016;36:324-9. Crossref

16. Benson EE, McMillan DE, Ong B. The effects of active warming on patient temperature and pain after total knee arthroplasty. Am J Nurs 2012;112:26-33. Crossref

17. Rajagopalan S, Mascha E, Na J, Sessler DI. The effects of mild perioperative hypothermia on blood loss and transfusion requirement. Anesthesiology 2008;108:71-7. Crossref

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19. Boutsiadis A, Reynolds RJ, Saffarini M, Panisset JC. Factors that influence blood loss and need for transfusion following total knee arthroplasty. Ann Transl Med 2017;5:418. Crossref

20. Ernest K. Hong Kong Red Cross issues urgent appeal for blood donors as supplies dwindle. South China Morning Post [newspaper on the internet]. 2017 May 4: Health & Environment. Available from: https://www.scmp.com/news/hong-kong/health-environment/article/2092982/hong-kong-red-cross-issues-urgent-appeal-blood. Accessed 10 Mar 2020.

21. City urged to donate blood amid severe shortage. The Standard [newspaper on the internet]. 2017 Aug 11: Local. Available from: https://www.thestandard.com.hk/breaking-news/section/3/94995/City-urged-to-donate-blood-amid-severe-shortage. Accessed 10 Mar 2020.

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23. Coronavirus fears drain Hong Kong's blood banks. Radio Television Hong Kong [newspaper on the internet]. 2020 Feb 12. Available from: https://news.rthk.hk/rthk/en/component/k2/1508174-20200212.htm. Accessed 10 Mar 2020.

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Chemotherapy, radiotherapy, certain medications for cancer, and some rheumatological and haematological diseases are gonadotoxic, which can jeopardise patients’ fertility, particularly that of young cancer survivors.1 With advancements in treatment, the 5-year survival rate of patients with cancer in childhood and adolescence has increased to over 80%.2 Thus, improving their quality of life and reducing their risk of infertility is an important aspect of their management plan.

International clinical guidelines, including the American Society of Clinical Oncology (ASCO),3 European Society for Medical Oncology (ESMO),4 and Royal College of Radiologists guidelines,5 suggest discussion of fertility preservation (FP) with patients of childhood and reproductive age during the course of cancer therapy. However, a study showed that fewer than half of oncologists routinely refer their patients to reproductive endocrinologists, and even fewer oncologists follow the guidelines, despite their willingness to discuss infertility in relation to cancer therapy.6 Moreover, a lack of awareness and related training about FP among clinicians may cause underutilisation of FP services worldwide, including in Canada, the US, and Hong Kong.7 8 9 In Hong Kong, clinicians and patients alike may consider FP as an expensive, privatised option without subsidisation.

In a previous cross-sectional study that evaluated the awareness, attitudes, and knowledge of FP among clinicians across different specialties in Hong Kong, only 45.6% of clinicians were familiar with FP.10 As current medical students will become our future clinicians, it is important to assess their level of understanding and awareness of fertility and FP, as this may greatly influence their future practice and consideration of appropriate interventions to improve affected patients’ outcomes. Cross-sectional studies have been conducted to assess college students’ awareness and knowledge of fertility in Canada,11 Serbia,12 and the US.13 These studies in Western populations showed knowledge inadequacy about age-related fertility decline and FP. However, to the best of our knowledge, there are no studies in a Chinese population that have aimed to investigate the awareness, knowledge gaps, and attitudes of medical students regarding fertility and FP. Therefore, the aims of this study were to evaluate the awareness of, attitudes towards, and knowledge regarding FP among Chinese medical students in Hong Kong.

This was a cross-sectional survey conducted from November 2018 to June 2019. The study population consisted of Chinese medical students from The Chinese University of Hong Kong. Chinese undergraduate students aged ≥18 years studying in the Medicine programme and capable of communicating in English were included. Those who were non-Chinese, under age 18 years, incapable of communicating in English, and those who refused to join the study were excluded.

Eligible participants were invited to complete a self-administered online survey. The online survey was sent to participants by internal mass email and social networking applications. Snowball sampling was done by encouraging medical students to send the online survey to their classmates to boost the response rate.

The online survey was developed on an electronic form (MyCUform). The self-administered survey included a brief explanation and was comprised of four parts: (1) baseline demographic data (Table 1); (2) awareness of FP; (3) knowledge about FP (Table 2); multiple choice questions consisting of five or six options on knowledge about fertility and FP; and (4) attitudes towards FP (Tables 3 and Table 4). It consisted of 38 questions and took approximately 15 minutes to finish. The survey was developed after reviewing the literature.14 15 16 It was assessed for logical validity by three physicians in the Department of Obstetrics and Gynaecology, who reviewed the accuracy of the contents. The survey was also piloted on a small number of doctors and medical students for content clarity and modified accordingly to incorporate the pilot participants’ feedback. The final version was then administered to the full study’s participants.

Statistical analysis was performed using SPSS (Windows version 24.0; IBM Corp, Armonk [NY], US). Continuous data were described as means, standard deviations, and percentiles. Categorical data were summarised as frequencies and percentiles. Subgroup analyses were performed between gender and year groups, with the medical students split into junior (year 1-4) and senior (year 5-6) year groups. Junior medical students had not completed the clinical attachments of the obstetrics and gynaecology module rotation (OB-GYN), whereas senior medical students had finished the OB-GYN module in year 5. The categorical data were tested by Pearson’s Chi squared test or Fisher’s exact test to check for significant differences between groups. Results with P values of <0.05 were considered statistically significant.

Approximately 700 Chinese medical students were approached through social networking applications and email, and 243 completed the online survey (response rate: 34.7%). Table 1 summarises the participants’ demographic data. In terms of age distribution, there was no significant difference (P=0.597) between the two groups.

Overall, 71.2% (n=173) of respondents were aware of FP strategies. Despite this, 77.8% (n=189) of respondents were not familiar with any clinics or specialists who provide FP services. Senior students showed better awareness than junior students of the above items (P<0.001). The majority (86.8%, n=211) had not heard of any regulations related to FP. Gamete and embryo freezing were the most well-known FP methods, with female students being significantly more aware than male students of those methods (P<0.003).

The majority (71.2%, n=173) responded that they would discuss the option of FP with their patients as future doctors, even if the treatment had a <30% chance of causing infertility. If a treatment had a ≥70% chance of causing infertility, nearly all (95.5%, n=232) students would discuss FP.

Table 2 shows the results of the questions that address knowledge about fertility and FP. Overall, there were no gender differences besides the response regarding the age range of a woman’s significant fertility decline: proportionally more female students answered that item correctly (45.7% vs 38.8%; P<0.05).

Knowledge regarding FP was mainly acquired from electronic media (58.4%, n=142), medical school (57.6%, n=140), and medical professionals (38.7%, n=94). More senior students than junior students acquired fertility knowledge through medical school education (81.4% vs 30.7%; P<0.0001) and medical professionals (54.3% vs 21.1%; P<0.0001).

Most of the responding students (86.4%, n=210) wished to know more about FP, with 80.7% (n=196) of the students agreeing that there is a need to incorporate FP material into the medical curriculum.

Regarding attitudes, 94.2% (n=229) of medical students agreed that establishing one or two dedicated clinics or centres for FP counselling is necessary. Subgroup analysis indicated that more male medical students would like to have two dedicated centres (75.0% vs 68.2%, P=0.021). More senior than junior students agreed that FP should be available solely as a public service (89.1% vs 71.9%; P=0.001). Overall, 97.9% (n=238) of participants thought that practice guidelines for FP should be required. More than half of respondents (59.7%, n=145) agreed that there should be an age limit for FP. More female than male students agreed to set an age limit for FP (65.7% vs 51.5%, P=0.025).

Among various factors considered by medical students to determine whether to recommend FP to patients, the desire to have children (51.0%, n=124), the prognosis of cancer or a medical condition (23.5%, n=57), and time available before gonadotoxic treatment (7.4%, n=18) were the most likely considerations.

Most participants (80.2%, n=195) responded that the government should subsidise FP in patients undergoing gonadotoxic treatment, with senior students expressing stronger support for subsidisation than junior students (86.0% vs 73.7%; P<0.02). More than half of the responding students agreed that the government should subsidise 30% to 50% of the cost of FP procedures including sperm (79.8%, n=194) and egg freezing (80.2%, n=195), and in vitro fertilisation (IVF) [67.9%, n=165]. More senior than junior students thought that the government should subsidise >70% of the cost of IVF (34.1% vs 20.1%; P<0.02).

Table 3 shows the respondents’ attitudes towards elective and medical gamete and embryo freezing. More male students than female students expressed agreement with FP provision to men because of having no suitable partner (34.0% vs 22.1%; P<0.05). Table 4 illustrates attitudes towards family planning among the responding medical students. More male than female students were determined not to delay their family planning (16.5% vs 7.9%, P=0.037).

With the advancement of technology, FP has become increasingly effective at enabling patients who have undergone gonadotoxic treatment to raise families. However, as shown by many previous studies on medical students’ understanding of FP, this study reflects an overall worldwide tendency towards a lack of awareness and knowledge about fertility and FP.11 12 13 To the best of our knowledge, this is the first study that has aimed to investigate the awareness, knowledge, and attitudes of Chinese medical students regarding fertility and FP, as well as identifying their knowledge gaps in the subject.

The majority of Chinese medical students in Hong Kong have heard of at least one FP strategy. Senior students had significantly greater awareness than junior students of FP, reproductive techniques, and the availability of specialty clinics, likely reflecting the knowledge and exposure gained during the clinical OB-GYN module in the fifth year of study. This suggests that appropriate and timely education can improve medical students’ awareness of FP.

Previous studies have shown that even brief educational interventions about FP to medical students and house staff have potential benefits.13 To provide quality service, ASCO and ESMO guidelines suggest that patients with cancer be informed of their potential fertility decline and referred to FP services after treatment.3 4 Most students responded that they would refer patients to FP services even if treatment had only a low risk of infertility, but they were not familiar with the actual practice of FP, including relevant regulations and referral methods. Downloadable fact sheets on the effects of cancer treatment on fertility, available options for FP, and a list of service providers with reference costs stated should be available and accessible for proper patient education and counselling.

There are several misconceptions among medical students regarding knowledge about fertility and FP. The responding medical students tended to overestimate the age of the female fertility peak and the success rate of IVF and underestimate the risk of infertility in women at age 45 years (Table 2). Overestimation of female fertility has also been observed in overseas studies.11 12 13 17 18 Medical students have better knowledge about female fertility than male fertility. This could be explained by the fact that there have been many more studies about the concern of female fertility decline with age. As sex education programmes at the secondary and university levels mainly emphasise pregnancy prevention education rather than infertility awareness, there may be a lack of knowledge about the impact of ageing on fertility among women.11 Fertility-related knowledge should be included in the undergraduate medical curriculum and ideally be integrated in high school education as well to enhance public education on this topic. Beyond patient care, medical students’ inadequate knowledge about this topic also has great implications for their future careers and personal lives. They may delay their own family planning for career reasons without sufficient consideration of their impending fertility decline or may have a false sense of security regarding the success rate of IVF. Therefore, more education about fertility is required, which was also supported by the respondents of our study.

Electronic media play a significant role in the promotion of FP, especially among junior students. In contrast, medical school was the main source of FP knowledge for senior students, followed by medical professionals and electronic media. This is consistent with findings in American medical students and house staff.13 Media reports of female celebrities undergoing FP procedures, particularly egg freezing, could explain the high prevalence of student familiarity with this procedure and their lack of knowledge about other, less popular options.19 Knowledge acquisition through both the medical curriculum and electronic media have proven to be significant, particularly in people who have not received formal education about FP. This can be applied to the general public, although it poses a risk of promoting misinformation: people could be misled into having a false sense of security regarding successful childbearing late in one’s reproductive life through the use of FP methods.11 Therefore, caution should be used to ensure that materials released through the media are accurate.

Most of the responding medical students would first consider the patient’s desire when referring patients for FP, while 41.3% of physicians would consider the patient’s prognosis first.10 This finding could be explained by the medical students’ lack of medical practice experience and doctors’ awareness of resource limitations, as it has been shown that junior doctors make judgements mostly based on their own assumptions, compared with the experience-based judgements made by senior doctors.20

The private sector is the only current provider of FP services in Hong Kong. More male than female medical students who responded to our survey had positive attitudes towards the establishment of related facilities. The cost of freezing gametes is at least US$7800 (US$1 to HK$7.8),21 and the median monthly household income of a 1-person family in Hong Kong is US$1282.22 There are currently no gamete freezing subsidy programmes available. Such high costs are unaffordable to many patients, and especially patients with cancer are already financially burdened by their current treatment. In this regard, most medical students agreed that the government should subsidise FP services to patients undergoing gonadotoxic treatment, with more than half agreeing that 30% to 50% is a reasonable subsidy proportion.

There has been an increasing trend towards elective FP in recent years, which has opened up a debate about the ethicality of FP for non-medical indications and whether FP should only be provided for medical reasons. Our study reflected overwhelming support for FP for medical reasons. However, the responding medical students’ opinions were mixed regarding elective freezing for non-medical indications. Only approximately half of the respondents agreed that FP should be provided to people because they have not found a suitable partner, or because they delay family planning for the sake of career development. Despite the mixed responses regarding elective freezing, Chinese medical students from Hong Kong were more supportive of elective freezing than undergraduates and medical students from the US.23 This finding may be driven by the higher cost of FP in the US compared with that in Hong Kong.23 Indeed, elective freezing has gained popularity in recent years. Still, the greater acceptance of FP for medical reasons echoes the healthcare-related perceptions and expectations of patients in Hong Kong: fertility is not a necessity, and FP healthcare is considered a luxury as opposed to a necessity for immediate physical well-being.

This study’s participants were more supportive of elective freezing for women than men. This is likely because of their awareness that women’s fertility declines relatively earlier than that of men. Moreover, women in Hong Kong are expected to have a predominantly domestic and childrearing role within their families,16 largely because of deeply rooted traditional Chinese familial constructs in which women tend to take on homemaking roles. However, the male medical students who responded were also concerned about their own family planning. This study’s results show that more male than female medical students were determined not to delay their family planning or stated their intent to have gametes frozen because they had no suitable partner.

Most medical students agree that their future fertility is important to them. Over half of the responding medical students stated their intent to delay family planning for career development, and the majority plan to have their first child between age 30 and 34 years (the average age of residency completion is 29 years). However, few responded that they would consider undergoing FP treatments. This paradoxical response is consistent with the results of another study on Hong Kong university students that showed low inclination to seek help in the event of fertility problems compared with Western counterparts.16 The taboo of childlessness in Chinese culture may be another reason why planning and conversation are discouraged in the event of infertility.16 Thus, students may view FP techniques as drastic and unconventional, preferring natural conception. As discussed earlier, the lack of correct knowledge about age-related female fertility decline could also lead to such results. Medical training is long, potentially delaying doctors from starting families during their most fertile years. Education is beneficial not only to future patients, but also to current and future physicians’ quality of life.

As a form of convenience sampling, the online survey method was chosen to efficiently distribute the survey throughout the large population of medical students. However, this inherently came with limitations, including low response rate, small sample size, selection bias, and the inability to characterise non-respondents. Ideally, students of other medical schools in Hong Kong should be included to make our study more comprehensive; however, this would be logistically difficult. Because of constraints on advertising, the study consisted of slightly more senior than junior students and more female than male respondents. Moreover, our study did not specifically ask about the educational background of students that may have influenced their knowledge. However, there was no significant difference in the age distribution between the junior and senior student groups. Information bias may have also affected the responses from students who had not completed the OB-GYN module.

In conclusion, this study revealed important aspects of FP from the perspective of Chinese medical students in Hong Kong. In particular, we highlighted that awareness and knowledge of FP are limited among medical students. There is a strong worldwide need to increase education about and exposure of FP in the curriculum to improve medical students’ knowledge. More involvement from the public sector and enhancement of facilities in terms of service provision and financial support for FP services are also needed. Given the variety of perspectives on childbearing among different cultures, this should be taken into account when doctors consider FP options for their patients and themselves. Only by increasing awareness and knowledge can more accepting attitudes towards FP arise among our doctors, allowing for better clinical outcomes and quality of life for future patients.

Concept or design: JPW Chung, EYL Ng.
Acquisition of data: All authors.
Analysis or interpretation of data: EYL Ng.
Drafting of the article: All authors.
Critical revision for important intellectual content: JPW Chung.

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

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

The authors would like to thank the medical students at The Chinese University of Hong Kong for their kind participation in the study.

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

Ethical approval for the study was obtained from the Survey and Behavioural Research Ethics Committee (Ref SBRE-18-168).

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7. Chung JP, Haines CJ, Kong GW. Sperm cryopreservation for Chinese male cancer patients: a 17-year retrospective analysis in an assisted reproductive unit in Hong Kong. Hong Kong Med J 2013;19:525-30. Crossref

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Despite advances in paediatric critical care medicine, death remains inevitable in some instances, due to various aetiologies.1 2 In paediatric critical care medicine settings, patients who would have otherwise died may be kept ‘alive’ by advanced cardiovascular and ventilatory support. Some patients on cardiopulmonary support may experience irreversible cessation of all brain function, which is regarded as brain death (BD).3 4 5 6 Because BD or cardiopulmonary death is equivalent to death, there is no obligation for the physician to provide further futile treatment.1 2 3 4 7 Nevertheless, miraculous survivals have been reported in lay media involving patients who were previously declared BD or dead, which has created a mis-informed understanding of BD.8 In this retrospective study, all patients who underwent BD assessment over a 16-year period were evaluated to determine whether survival occurred following BD assessment; the demographics of patients diagnosed with BD were compared with those of all other patients diagnosed with cardiopulmonary death at a paediatric intensive care unit (PICU). The null hypothesis was that there would be no demographic or clinical differences between patients diagnosed with BD and those diagnosed with cardiopulmonary death.

All children admitted to the PICU of a university-affiliated teaching hospital and trauma centre (Prince of Wales Hospital) between October 2002 and October 2018 were included in the study. The Prince of Wales Hospital provides tertiary PICU service for children, from birth to age 16 years, in the Eastern New Territories of Hong Kong. The institutional ethics committee approved this review and waived the requirement for patient consent.

The demographics and clinical characteristics of deceased children were collected from the principal author’s database (KLH), in which every PICU admission was registered; data were also collected retrospectively from the Clinical Management System of the hospital. All deaths were reviewed, including those of patients with clinical evidence of BD who underwent BD assessment. Brain death was defined as irreversible loss of all functions of the brain, including the brainstem. The presence of coma, absence of brainstem reflexes, and positive apnoea test were essential findings for diagnosis of BD. The diagnosis of BD was mainly clinical and was made in accordance with the hospital’s standard protocol for paediatric patients.4 9 Patients were classified either as BD or cardiopulmonary death.

The demographics and clinical characteristics of these two groups of patients were summarised as median (interquartile range [IQR]) or as number (percentage), and were compared using the Chi squared test, Fisher’s exact test, or Mann-Whitney U test, as appropriate. Patient characteristics included age, sex, length of PICU stay (time from PICU admission to withdrawal of ventilator support), and diagnoses associated with PICU admissions. The GraphPad Prism 6 software (GraphPad Software, La Jolla [CA], US) and SPSS (Windows version 19.0; IBM Corp, Armonk [NY], US) were used for statistical analysis. All comparisons were two-tailed, and P values <0.05 were considered statistically significant.

Of the 2784 children admitted to the PICU, 127 (4.6%) died in the PICU (Table 1). All but seven children were of Chinese ethnicity. There were 73 boys (57.5%) and 54 girls (42.5%); the median age was 3.2 years (IQR: 0.94-7.34 years). Most patients had not previously been admitted to the PICU (n=103, 81%), and most patients were aged >1 year (74.8%). Of the 127 patients who died, BD assessments were performed for 22 (17.3%) patients who had clinical evidence of BD; all 22 patients were diagnosed with BD. The remaining 105 (82.7%) patients were diagnosed with cardiopulmonary death.

Comparison of the two groups showed that length of PICU stay was significantly longer for patients with BD (8.5 days; IQR: 4.75-14 days) than for patients with cardiopulmonary death (2 days; IQR: 1-10 days; P=0.004). The two groups shared similar demographics. The most common diagnoses associated with death in the PICU were infections (29.1% of patients), oncological diagnoses (13.0%), and cardiovascular diagnoses (13.8%) [Table 1]. Comparison of the two groups showed that trauma (P=0.003) and intracranial events (P=0.041) were more common in patients with BD, whereas respiratory diagnoses (P=0.033) were more common in patients with cardiopulmonary death. With respect to the cause of injury, the combined proportion of accident and trauma-related injury was greater in patients with BD than in patients with cardiopulmonary death (27.3% vs 3.8%, P<0.001). Among patients with BD, the most common mechanisms of brain injury were hypoxic-ischaemic injury (eg, cardiac arrest, shock, and/or respiratory failure), central nervous system infection, and traumatic brain injury (Table 2). Organ donation was approved by the families of four of the 22 patients with BD (18.2%) and was performed successfully in three of these four patients.

Our local guideline for BD determination does not include patients aged <2 years. Nevertheless, we found no difference in the proportion of patients aged <2 years between the BD (n=7) and cardiopulmonary death groups (n=42) [31.8% and 40%, P=0.47]. There was a non-significant trend towards greater use of ancillary tests (eg, radionuclide cerebral perfusion scan or electroencephalography) for BD determination in patients aged <2 years, compared with patients aged >2 years (85.7% and 53.3%, P=0.19). The United Kingdom guidelines recommend that ancillary tests are not required in infants from gestational age of 37 weeks to 2 months after birth.10 None of the patients were within this age range in our study.

Family acceptance of the diagnosis of BD may have influenced the length of PICU stay in our study. Among patients with documented family acceptance of the diagnosis of BD, the time interval from BD to withdrawal of ventilator support was 0.5 days (range, 0-1.5 days; n=10). This interval was prolonged among patients with documented family resistance of the diagnosis of BD (median, 8 days; range, 5-16 days; n=5, P=0.005); three of the five patients’ families eventually accepted withdrawal of ventilator support, whereas the remaining two patients remained on ventilator support and lapsed into cardiac arrest after 16 days and 66 days.

Over this 16-year period, BD assessment was only performed in 22 (17.3%) patients who had clinical signs of BD; all 22 patients were confirmed to have BD. Notably, patients with BD had longer length of PICU stay and a greater combined proportion of accident and trauma-related injury, while patients with cardiopulmonary death had a greater frequency of respiratory diagnoses. In the present study, the percentage of patients with BD in the PICU was comparable to the numbers of patients with BD in two large reports (one from the US and the other from Canada; Table 3).5 6 Accident and trauma-related injury led to one in four diagnoses of BD in our study, whereas the proportions of accident and trauma-related injury, as well as traumatic brain injury, were higher in the US and Canada.

Guidelines for BD assessment vary in terms of the numbers of examinations, numbers and types of physicians, time intervals between examinations, and use of ancillary tests.11 12 In general, if BD is suspected, two physicians (neither of whom would be involved in organ harvesting from the patient) should perform two sets of brainstem examinations, at least 6 hours apart to ensure sufficient observation time. A single apnoea test should also be performed. If the results of these tests are positive, the patient can then be declared legally and clinically BD.1 2 3 4 Before these examinations, conditions that may confound the clinical diagnosis of BD should be excluded.1 2 3 4 11 12 Absence of the pupillary reflex to direct and consensual light, as well as the absence of corneal, cough, and gag reflexes, support the clinical diagnosis of BD. The calorie test can aid in determining the integrity of the oculovestibular reflex. A positive result consists of the absence of eye deviation when ice water is irrigated into an external auditory canal. The apnoea test is performed after the second examination of brainstem reflexes; only a single apnoea test is needed. Before the apnoea test is performed, the physician must confirm that the patient is not hypothermic, is euvolemic, and has normal arterial pressure of carbon dioxide and pressure of oxygen levels. The patient should then be connected to a pulse oximeter and the ventilator should be disconnected. Concurrently, 100% O₂ is delivered into the trachea at 6 L/min. A patient with BD may exhibit systolic blood pressure <90 mm Hg, significant oxygen desaturation, or cardiac arrhythmia. If respiratory movements are absent and the arterial pressure of carbon dioxide is ≥60 mm Hg, the apnoea test result is considered positive. If the patient is very unstable and an apnoea test might not be tolerated, or if the results of the apnoea test are inconclusive, physicians may opt for other neuro-diagnostic options (eg, four-vessel cerebral angiography, radionuclide cerebral perfusion scan, and/or electroencephalography). A lack of blood perfusion to the brain and lack of electrical activity would support a diagnosis of BD.

The length of PICU stay was longer for patients with BD than for patients with cardiopulmonary death; this differed from the trends observed in the US and Canada (Table 3).5 6 As noted in the Results, family acceptance of the diagnosis of BD may have influenced the length of PICU stay in our study. Unfortunately, not all stakeholders understand or accept the implications of a diagnosis of BD. In our experience, the reasons for the family’s resistance might be two-fold. First, it might be emotionally difficult to accept the death of a loved one, when the child is apparently ‘breathing’ and appears physically ‘well’ when ventilatory support is provided. Second, the family might have confused persistent vegetative state with BD3 4; notably, patients with persistent vegetative state have intact brainstem function, while patients with BD have an irreversible loss of brainstem function. In such instances of confusion, families may wish to wait for the patient’s ‘miraculous revival’.1 13 14 15 16 While the acknowledgement of BD as biological death may be counterintuitive to the public, there is a need to emphasise and accept that BD is legal death.17 Thus, public education is necessary to resolve common misconceptions regarding the biological and legal statuses of patients with BD.18 Notably, among university students in Hong Kong, improved knowledge has been shown to promote acceptance of the withdrawal of ventilator support following BD.19 From a physician’s perspective, withdrawal of ventilator support for patients with BD should not be regarded as withdrawal of life support; in addition, continued use of ventilator support that allows a patient to lapse into cardiac arrest is not a suitable option. Prolonged and unnecessary treatment in the PICU prevents other critically ill patients from using the PICU service; it also constitutes ineffective use of scarce medical resources. Abuse of PICU beds is undesirable because medical resources in the public sector are extremely competitive and limited.20 Further studies regarding physician counselling skills and family acceptance of the diagnosis of BD may improve resource utilisation.

Medical professionals should closely monitor aetiologies that can lead to BD and consider discussions with affected patients’ families at an early stage of medical treatment. These early discussions would allow more time for families to comprehend the implications of a BD assessment and potential positive test results. In a previous study, we found that prolonged length of PICU stay was associated with a Do-Not-Attempt-Resuscitation order, which was placed in nearly half of our PICU deaths; this finding implied that patients’ families often need considerable time to accept the end-of-life decision when futility of medical treatment becomes evident.1 Family acceptance of the diagnosis of BD is critical for successful management of such situations. If family acceptance is not achieved, physicians may become involved in a conflict with the family, which results in an ethical dilemma regarding the need to continue treatment for a patient with BD. For example, one patient in the present study remained in the PICU for 66 days due to this difficult situation. Communication to identify common values and establish options based on objective criteria may resolve potential disputes and allow physicians and families to reach agreements before, during, and after BD assessment.21

A practical aspect of BD assessment involves its implications for the organ donation process. Four of 22 patients’ families opted for organ donation; notably, all four families also accepted the diagnosis of BD. Successful donations of liver or kidneys were made from three patients. Acceptance of the diagnosis of BD may be associated with acceptance of organ donation and withdrawal of ventilator support.19 Support for organ donation, which was initiated by the organ transplant coordinator, had avoided potential instances of conflict. Acceptance of the diagnosis of BD could be a factor, in combination with other cultural and religious beliefs, for the lower organ donation rate than that observed in Western countries.12

In this study, one in five PICU deaths were BD. Acute hypoxic-ischaemic injury was the most common mechanism of brain injury; moreover, accident and trauma-related injuries were the cause of injury in one quarter of patients with BD. Diagnosis of BD was associated with significantly longer PICU stay. Notably, the organ donation rate was suboptimal. These findings emphasise the importance of injury prevention in childhood, as well as the need for education of the public regarding acceptance of BD and support for organ donation.

Concept or design: KL Hon.
Acquisition of data: KL Hon, CC Au, TT Tse, WS Lin, TC Leung, TC Chow.
Analysis or interpretation of data: KL Hon, CC Au, TT Tse, WS Lin, TC Leung, TC Chow, AKC Leung.
Drafting of manuscript: KL Hon, CC Au, TT Tse, WS Lin, TC Leung, TC Chow.
Critical revision of the manuscript for important intellectual content: KL Hon, CC Au, CK Li, HM Cheung, SY Qian, AKC Leung.

All authors have full access to the data, contribute to the study, approve the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, KL Hon was not involved in the peer review process. Other authors have no conflicts of interest to disclose.

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

The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee approved this review (CREC Ref. No. 2016.116).

1. Hon KL, Poon TC, Wong W, et al. Prolonged non-survival in PICU: does a do-not-attempt-resuscitation order matter. BMC Anesthesiol 2013;13:43. Crossref

2. Hon KL, Luk MP, Fung WM, et al. Mortality, length of stay, bloodstream and respiratory viral infections in a pediatric intensive care unit. J Crit Care 2017;38:57-61. Crossref

3. Goila AK, Pawar M. The diagnosis of brain death. Indian J Crit Care Med 2009;13:7-11. Crossref

4. Sarbey B. Definitions of death: brain death and what matters in a person. J Law Biosci 2016;3:743-52. Crossref

5. Kirschen MP, Francoeur C, Murphy M, et al. Epidemiology of brain death in pediatric intensive care units in the United States. JAMA Pediatr 2019;173:469-76. Crossref

6. Joffe AR, Shemie SD, Farrell C, Hutchison J, McCarthy-Tamblyn L. Brain death in Canadian PICUs: demographics, timing, and irreversibility. Pediatr Crit Care Med 2013;14:1-9. Crossref

7. Citerio G, Murphy PG. Brain death: the European perspective. Semin Neurol 2015;35:139-44. Crossref

8. Daoust A, Racine E. Depictions of “brain death” in the media: medical and ethical implications. J Med Ethics 2014;40:253-9. Crossref

9. Verheijde JL, Rady MY, Potts M. Neuroscience and brain death controversies: the elephant in the room. J Relig Health 2018;57:1745-63. Crossref

10. Marikar D. The diagnosis of death by neurological criteria in infants less than 2 months old: RCPCH guideline 2015. Arch Dis Child Educ Pract Ed 2016;101:186. Crossref

11. Greer DM, Varelas PN, Haque S, Wijdicks EF. Variability of brain death determination guidelines in leading US neurologic institutions. Neurology 2008;70:284-9. Crossref

12. Chua HC, Kwek TK, Morihara H, Gao D. Brain death: the Asian perspective. Semin Neurol 2015;35:152-61. Crossref

13. Al-Shammri S, Nelson RF, Madavan R, Subramaniam TA, Swaminathan TR. Survival of cardiac function after brain death in patients in Kuwait. Eur Neurol 2003;49:90-3. Crossref

14. Burkle CM, Sharp RR, Wijdicks EF. Why brain death is considered death and why there should be no confusion. Neurology 2014;83:1464-9. Crossref

15. Shewmon DA. Chronic “brain death” meta-analysis and conceptual consequences. Neurology 1998;51:1538-45. Crossref

16. López-Navidad A. Chronic “brain death”: meta-analysis and conceptual consequences. Neurology 1999;53:1369-70. Crossref

17. Truog RD, Miller FG. Changing the conversation about brain death. Am J Bioeth 2014;14:9-14. Crossref

18. Shah SK, Kasper K, Miller FG. A narrative review of the empirical evidence on public attitudes on brain death and vital organ transplantation: the need for better data to inform policy. J Med Ethics 2015;41:291-6. Crossref

19. Leung KK, Fung CO, Au CC, Chan DM, Leung GK. Knowledge and attitudes toward brain stem death among university undergraduates. Transplant Proc 2009;41:1469-72. Crossref

20. Truog RD. Brain death-too flawed to endure, too ingrained to abandon. J Law Med Ethics 2007;35:273-81. Crossref

21. Burns JP, Truog RD. Futility: a concept in evolution. Chest 2007;132:1987-93. Crossref

Miscarriage is the most common early pregnancy complication, which constitutes a large burden for patients and the overall healthcare system. Approximately one in four women experiences early pregnancy loss during her lifetime; such losses have significant negative psychological and social impacts on affected women.1 2 3 4 Miscarriage has been ranked the second most common diagnosis for admissions in the past 10 years in Hong Kong.5 In-patient hospital admissions for miscarriage were considerably reduced following establishment of out-patient early pregnancy assessment clinics (EPACs) in various hospitals. Women visit EPACs to seek reassurance that their pregnancy remains viable, which may be difficult because gestational sac size and embryonic growth are not uniform6; moreover, estimates of gestational age are misleading in women with irregular menstrual periods.7 8 A score that signifies the likelihood of a viable pregnancy may be helpful for clinicians working in EPACs.9 10 This score would enable clinicians to target appropriate early psychological or clinical support, thereby minimising psychological morbidity, especially for patients with finite resources.

Probability models to predict pregnancy viability have been reported; these combine clinical history, sonographic assessment of gestational sac and heart pulsation, and biochemical measurements.3 9 11 12 13 However, some models cannot be utilised in initial counselling, because they require calculators or biochemical measurements which may not yet be available.9 12 13 In a recent systematic review regarding prediction of miscarriage in women with viable intrauterine pregnancy, it was found that many combinations of markers have been tested with varying diagnostic accuracy; however, no meta-analysis could be performed on combination models.14 Furthermore, the meta-analysis did not involve assessment of the proportions of women with intrauterine pregnancy of uncertain viability, and no scoring system or cut-off value could be derived for counselling.

The Bottomley score11 is a scoring system independent of biochemical measurements, which utilises clinical and ultrasound parameters, including maternal age, severity of bleeding, and ultrasound features (eg, mean sizes of gestational sac and yolk sac, as well as presence of fetal heart pulsation). It has been validated in comparison with more complicated probability-based models in women with intrauterine pregnancy of uncertain viability; however, the validation study was limited by small sample size and the exclusion of one third of the eligible women due to missing variables and absence of data regarding pregnancy outcomes.12 The scoring system was also limited by the absence of data regarding body mass index (BMI) and smoking status, which might affect the likelihood of viable pregnancy.11 Furthermore, ethnicity influences miscarriage risk—black women are reportedly more likely to miscarry than white women,15 whereas rates among South and East Asian women are reportedly similar to those of white women after adjustment for confounders.16 The objective of the present study was to assess and validate the Bottomley score for prediction pregnancy viability until 16 weeks of gestation in a cohort of Chinese pregnant women who presented to our hospital with threatened miscarriage or abdominal pain before 12 weeks of gestation.

This non-interventional prospective observational study was performed at the Prince of Wales Hospital, Hong Kong, between July 2013 and June 2015. An out-patient EPAC is available in this hospital to receive referrals of first trimester pregnant women with vaginal bleeding, abdominal pain, or both, and suspected threatened miscarriage, threatened miscarriage with uncertain viability, and/or abdominal pain complicating intrauterine pregnancy; referrals were made by general practitioners or accident and emergency medical officers. All gynaecologists at the EPAC had ≥3 years of experience in ultrasound scans, as well as in diagnosis and treatment of miscarriage.

For this study, Chinese women aged ≥18 years with a singleton intrauterine pregnancy, referred before 12 weeks of gestation based on last menstrual period, were invited to participate. Participants provided demographic data for both standard clinical treatment and determination of the pregnancy viability score. Women were excluded if they underwent pregnancy termination, had an ectopic or multiple pregnancy, had pregnancy at an unknown location, or were diagnosed with miscarriage at the time of initial presentation. Women with intrauterine pregnancy of uncertain viability underwent a second ultrasound examination after 7 to 14 days to determine fetal viability, in accordance with published guidelines.17 18 19

Detailed information regarding obstetrics history and history of the current pregnancy were obtained, including abdominal pain (graded by pain score) and vaginal bleeding (assessed using a pictorial blood loss chart with number of pads used; no bleeding was regarded as a score of 0, while clots or flooding was regarded as a score of 4). Information regarding smoking status (smoker or non-smoker), alcohol intake, and BMI were collected. Smokers included women who continued to smoke, as well as those who had discontinued smoking ≤2 weeks before presentation to our hospital.20 Alcohol users included women who consumed >2 units per day, once or twice per week, in the month before and during their pregnancy.21 Body mass index was classified in accordance with international classification as underweight, normal, overweight, or obese.22

All women underwent a structured ultrasound assessment. All transvaginal ultrasound scans were performed using a GE Voluson 730 ultrasound machine (GE Healthcare, Zipf, Austria) to ascertain the location and viability of the pregnancy. Mean gestational sac diameter, mean yolk sac diameter, size of fetal pole, and presence of fetal heart pulsation were documented. The Royal College of Obstetricians and Gynaecologists guidelines17 18 and National Institute for Health and Care Excellence guidelines19 were used for diagnosis of miscarriage, intrauterine pregnancy of uncertain viability, viable pregnancy, ectopic pregnancy, or pregnancy of unknown location. In women with a history of vaginal bleeding, a hypoechoic or anechoic crescent-shaped area on ultrasound images was regarded as a subchorionic haematoma; its three-dimensional size was classified as small, medium, or large when its size ratio (relative to gestational sac size) was <0.2, 0.2-0.5, or >0.5, respectively.

Each pregnancy was assigned a Bottomley score based on clinical history and ultrasound parameters.11 All clinicians were blinded to the score and all women in this study were treated in accordance with our established standard clinical protocols. Pregnancies were categorised as viable or miscarriage at the repeat ultrasound scan conducted between 13 and 16 weeks of gestation, according to the presence or absence of fetal heart pulsation. Women with miscarriage were treated in accordance with current guidelines.17 19 Watchful waiting, or medical or surgical evacuation of the uterus, were offered according to each patient’s clinical condition. For medical evacuation, misoprostol 800 μg vaginally was used as first-line treatment, with follow-up assessment to check for complete evacuation. Patient treatment was not affected by participation in the study.

Ethics approval was obtained from the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref CREC-2013.348). Written informed consent was obtained from all participants.

Bottomley and colleagues11 reported that the areas under the receiver operating characteristic (ROC) curves of their score were 0.90 and 0.72 using a combination of history and ultrasound parameters and history alone, respectively. To determine whether the Bottomley score in our local population exceeded the discriminatory power of the history-alone model and achieved discriminatory power similar to that of the combined model, sample size analysis, using MedCalc Statistical Software version 18.5 (MedCalc Software bv, Ostend, Belgium), showed that a minimum sample size of 750 was required for a type 1 error of 1% and power of 90%, with the assumption that miscarriage occurred in one of every 10 pregnancies. The planned sample size was increased to 1500 to allow for the worst-case scenario of 50% non-participation rate and 50% loss to follow-up rate.

Women were divided into viable or miscarriage groups according to pregnancy outcome. Comparisons of socio-demographic and pregnancy characteristics between the two outcome groups were performed using the Chi squared test or Fisher’s exact test, where appropriate, for categorical variables; the Mann-Whitney U test with post hoc Bonferroni correction was used for comparisons of continuous variables. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of significant predictors of miscarriage were determined by multivariate logistic regression analysis. Receiver operating characteristic curves were constructed to determine the discriminatory performance of the Bottomley score, as well as to determine the Bottomley score which predicted 90% viable pregnancies at the repeat ultrasound scan. Probit regression, with Bottomley score as the only independent predictor, was performed to estimate the probability of an ongoing viable pregnancy beyond the first trimester. Bottomley scores were truncated to a minimum value of -12 and a maximum value of 18, prior to Probit regression and ROC analyses. Patients lost to follow-up were excluded from the study. All analyses were performed using SPSS Statistics, version 20.0 (IBM Corp., Armonk [NY], United States) and MedCalc. P<0.05 was considered statistically significant.

Of the 1508 women invited to participate, 54 (3.6%) declined and two (0.1%) were lost to follow-up at 13 to 16 weeks of gestation (Fig 1). Table 1 summarises the socio-demographic characteristics, clinical signs and symptoms, and ultrasound measurements in the two outcome groups. The Bottomley score ranged from -41 to 24; 36 women (2.8%) had a score of ≤-12, and 64 (5.0%) had a score ≥18, while the score ranged from -12 to +1 in women with a pregnancy of uncertain viability at first assessment.

Unadjusted and adjusted ORs for risk of miscarriage after adjusting for covariates are summarised in Table 2. Subchorionic haematoma was noted in 167 pregnancies (13.1%), including 138 (82.6%) with bleeding. Haematoma size relative to gestational sac size was significantly associated with miscarriage (χ²=70.5, P<0.05) [Tables 1 and 2]. A pregnancy with a large haematoma was nearly two-fold more likely to miscarry, compared with other pregnancies (17/160 [10.6%] vs 66/1111 [5.9%]).

The area under the ROC curve of the discriminatory performance of the Bottomley score in all women was 0.91 (95% CI: 0.89-0.93, P<0.001). A score of ≥1 had a sensitivity of 91% (95% CI: 85.8-95.1%) and a false positive rate of 26.7% (95% CI: 24.1-29.4%). Figure 2 and Table 3 show the observed and estimated viability of a pregnancy after the first trimester, compared with the viability estimates by Bottomley et al11 at each viability score. The estimated probability of viability for a particular pregnancy, based on the Bottomley score, was determined: Probit(p) = 1.15109 + 0.17188 × score.

The estimated probability of viability reported by Bottomley and colleagues11 was within the 95% CI of the estimated probability determined by our Probit(p) function if the viability score was ≥0. The area under the ROC curve of the Bottomley score in women with a pregnancy of uncertain viability at initial presentation was only 0.74 (95% CI: 0.67-0.80).

To the best of our knowledge, this is the first report of independent external validation of the scoring system proposed by Bottomley et al.11 to predict early second trimester pregnancy viability in women with intrauterine pregnancy before 12 weeks of gestation. Moreover, it is the first study in a homogenous Chinese population. Our findings indicated that the Bottomley score could be used to predict the likely outcome of pregnancy, thus potentially alleviating maternal anxiety; this is particularly useful for women with symptoms of threatened miscarriage. The scoring system is simple to use and does not require a calculator (in contrast to previous models)8 11; moreover, it relies solely on information that can be readily obtained by any gynaecologist, without the need for blood tests.3 12 Women with a Bottomley score of ≥1 had a >90% probability of pregnancy viability beyond the first trimester. These women could be reassured, and further ultrasounds could be avoided. A low Bottomley score was associated with increased likelihood of miscarriage, such that half of the women with a score of -7 or -6 were expected to miscarry; this proportion reached 80% if the score was ≤-12. Proper counselling could be offered to prepare these women psychologically, thereby reducing the impact of pregnancy loss.

This scoring system incorporates several different variables that interact with each other. For example, a larger but empty gestational sac increases the likelihood of miscarriage, thus resulting in a lower (ie, more negative) score; however, this lower score would be counterbalanced by the presence of fetal heart pulsation and an appropriately sized yolk sac. In addition, although a negative score was unexpectedly determined for pregnancies with the presence of fetal heart pulsation, this negative score could be counterbalanced by a positive score for a larger gestational sac size.

Notable strengths in this study include its use of a priori determination of sample size to assess discriminatory performance. Moreover, the participation rate was high and few pregnancies were lost to follow-up. The resulting large sample size enabled assessment of discriminatory performance of the scoring system; it also allowed identification of predictors of miscarriage in our cohort of Chinese women and provided estimated sensitivities (±5%) at specific viability scores. Whereas only 10% of included patients were of Asian ethnicity in the study by Bottomley et al,11 our study was performed in a homogenous Chinese population; therefore, our findings suggest that the score is likely to be valid for various Asian populations, although further studies are necessary to validate its use in different Asian subgroups.

This scoring system was designed for use in all pregnant women with an intrauterine pregnancy before 12 weeks of gestation. Our analysis of the performance of this scoring system in pregnancies with uncertain viability alone also showed reasonable performance: pregnancy failure could be predicted in women with pregnancies of uncertain viability, with an area under the ROC curve of >0.5. However, this finding should be interpreted with caution, because there were only 223 women in this subgroup; our sample size was only sufficient to detect an area under the ROC curve of 0.65, assuming that the ratio of miscarriage to viability was 1:1. Of note, while the scoring system was reliable for estimation of pregnancy viability until 16 weeks of gestation, the implication of each score differed, compared with the previous study.11

Lastly, the miscarriage rate in this study was 13%, approximately 50% lower than the 20% to 30% rates reported by Kong et al1 and Bottomley et al.11 However, the observed rate of miscarriage among women with intrauterine pregnancy of uncertain viability at presentation was consistent with the rates observed in other studies.11 12 The relatively low overall miscarriage rate could have been due to differences in local referral practices, because some women attending our EPAC were asymptomatic, whereas women with heavy vaginal bleeding or severe abdominal pain might have been admitted directly for treatment; we were unable to ascertain how many women with early pregnancy loss were directly admitted without referral to the EPAC. We excluded women with ectopic pregnancy or pregnancy of unknown location because these women had empty uteri. By focusing on women with intrauterine pregnancy irrespective of viability, we presumed that our study would be more likely to generate useful clinical information for counselling if the model were validated. Notably, excluded women comprised only 0.9% of all women invited to participate in the study.

Other potential explanations for the low miscarriage rate could be differences in lifestyle factors, such as smoking and alcohol consumption, as well as incidence of obesity; in contrast to the findings in published literature,23 24 these factors were not associated with pregnancy outcome. Smoking during pregnancy is rare in Chinese women.25 Obesity is also uncommon; in the present study only 35 women (2.7%) had a BMI ≥30 kg/m², while the median weight of 53.3 kg and median BMI of approximately 21-21.5 kg/m² in this study were similar to the characteristics of women attending a first trimester Down syndrome screening clinic and of pregnant women enrolled in another prospective study (regarding the pelvic floor) in our centre.26 27 Lastly, the median duration of gestation at presentation to EPAC was 55 days in our study, whereas it was 50 days in the study by Bottomley et al.11 This could have contributed to our lower miscarriage rate, which decreases with gestational age.

Consistent with the findings of other studies, our multivariate analysis indicated that the following factors were associated with increased likelihood of miscarriage: increasing age, absence of fetal heart pulsation, heavier bleeding, and a large subchorionic haematoma. In addition to miscarriage, subchorionic haematoma increases the risk of placental abruption and preterm premature rupture of membranes.28 We previously proposed classification of the three sizes of the subchorionic haematoma, in relation to gestational sac size.29 We suggested assessment of the size of subchorionic haematoma relative to the gestational sac, rather than the mere presence or absolute size of subchorionic haematoma, in accordance with the approach used by clinicians in the United States.30 This parameter was expected to enhance prediction of miscarriage, but this hypothesis was not supported by multivariate analysis results; further studies are needed to more thoroughly investigate the usefulness of this parameter.

The results of our external validation study suggested that the scoring system would reliably predict probable pregnancy viability, despite slight differences in score implication. Application of this score could potentially enhance the treatment of women who initially present with early pregnancy complications. The cut-off value obtained in this study may be useful when counselling pregnant women. Further studies will be performed in our study centre to determine whether this externally validated scoring system could be utilised to reduce psychological morbidity by reassuring the women likely to maintain a viable pregnancy, while psychologically preparing other women for expected miscarriage.

Concept or design: OYK Wan, SSC Chan, JPW Chung.
Acquisition of data: OYK Wan, JWK Kwok
Analysis or interpretation of data: OYK Wan, JWK Kwok, DS Sahota.
Drafting of the manuscript: OYK Wan, DS Sahota, TTH Lao.
Critical revision of the manuscript for important intellectual content: OYK Wan, SSC Chan, JPW Chung, TTH Lao, DS Sahota.

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

As an editor of the journal, JPW Chung was not involved in the peer review process. The remaining authors have no conflicts of interest to disclose.

The results from this research have been presented, in part, at the following conferences:
1. Wan O, Chan SS, Kong G. A prospective observational study to validate the reliability of the early pregnancy viability scoring system. Ultrasound Obstet Gynecol 2015;46(Suppl 1):42. (Oral presentation)
2. Kwok J, Wan O, Chan SS. Subchorionic hematoma: its size and association with early pregnancy outcome. Ultrasound Obstet Gynecol 2015;46(Suppl 1):172. (Poster presentation)
3. Wan OY, Chan SS, Kong GW. A prospective observational study to validate the reliability of the early pregnancy viability scoring system. FOCUS in O&G 2015 Congress; 2015. May 30-31; Shatin, Hong Kong. The Chinese University of Hong Kong; 2015. (Oral presentation)
4. Wan OY, Chan SS, Kong GW. External validation of an early pregnancy viability prediction model via a prospective observational study. RCOG World Congress; 2016. Jun 20-22; Birmingham: United Kingdom; 2016. (Poster presentation)

This research was supported by a research grant from the Health and Medical Research Fund of Food and Health Bureau, Hong Kong SAR (HMRF Reference: 12131091). The study sponsor was not involved in the collection, analysis, or interpretation of data, or in the writing of the manuscript.

Ethics approval was obtained from the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref CREC-2013.348). Written informed consent was obtained from all the participants.

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