Haemoglobin Bart’s hydrops fetalis syndrome (BHFS), also known as homozygous α⁰-thalassaemia major or homozygous α-thalassaemia 1, was first described in 1960.1 2 It was considered fatal in the 1960s to 1970s,3 and fetuses often died in utero, were stillborn or died during the early neonatal period.4 When prenatal screening and diagnosis for thalassaemia first started in Hong Kong in 1983, BHFS was advocated as an indication for termination of pregnancy.5 Nonetheless, the availability of intrauterine transfusions (IUTs)6 7 and intrauterine exchange transfusions (IUETs) enabled affected fetuses to survive the perinatal period.

Since the world’s first reported case of survival in 1985 in Canada,8 increasing numbers of BHFS survivors have been reported worldwide, including in Hong Kong.9 The traditional view of its fatality has been challenged,10 11 and in the 1990s there was lively debate about the ethical concerns surrounding active resuscitation and treatment of BHFS babies. Regular transfusions and iron chelation allow BHFS patients to survive even beyond adulthood, and haematopoietic stem cell transplantation12 13 14 offers a cure for this disease, albeit at the expense of possible significant morbidities and compromised quality of life. Long-term morbidities for this cohort of patients thus become an important issue to address. Information gathered by this territory-wide retrospective study will assist physicians in contemplating perinatal management and counselling of parents.

The setting for this study was all eight public hospital paediatric haematology units in Hong Kong that care for patients with transfusion-dependent thalassaemia. Records of patients diagnosed with BHFS (either antenatally or postnatally) who survived beyond the neonatal period and who were subsequently managed long-term at those units from 1 January 1996 to 31 December 2015 were retrieved from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System using the International Classification of Diseases diagnostic code 282.7, searching only for Haemoglobin-Bart’s disease. Data cross-checking was performed with the help of the Hong Kong Paediatric Haematology and Oncology Study Group and paediatric haematologists from the eight hospitals.

Information about patient and parent characteristics, availability of antenatal care and diagnosis, antenatal ultrasonographic findings, reasons for continuation of pregnancy, use of intrauterine transfusions, perinatal course, presence of congenital malformations, subsequent neonatal and long-term neurodevelopmental outcome, and availability of stem-cell transplantation and subsequent outcomes were collected and studied. Patients with BHFS who were not born in Hong Kong were excluded from this study. No missing cases were identified during the 20-year study period, as confirmed from personal communications with both paediatric and adult haematologists from all public hospitals in Hong Kong. As BHFS pregnancies are considered high risk owing to possible maternal-fetal complications, it was presumed that no cases would have been managed by private doctors without support from a neonatal intensive care unit.

This study was primarily descriptive in nature. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM Corp., Armonk [NY], United States). Continuous variables are expressed as median and range.

This study complied with the Declaration of Helsinki and approval was obtained from the Institutional Review Board of The University of Hong Kong / Hong Kong Hospital Authority West Cluster and all other clusters of participating hospitals. Verbal (parental) consent was obtained but formal written consent was not required by the institutional review board, as this retrospective study did not involve direct patient care (Ref No. HKUCTR-2148).

Surviving patients with BHFS were identified in five of the eight local paediatric haematology units. A total of nine infants were found, of whom five were female and four male. All patients were Chinese, and all were confirmed to be homozygous for the Southeast Asian α-thalassaemia deletion. Six pairs of parents were heterozygous for the Southeast Asian deletion, and three pairs refused genetic testing, one of which was suspected to be a case of non-paternity (case 7). For case 6, the mother was heterozygous for the Southeast Asian deletion (α-thalassaemia 1), whereas the father had an α3.7 single deletion (α-thalassaemia 2). The child demonstrated maternal uniparental disomy and isodisomy (Tables 1 and 2).6 13 14 15 16 17 18 19 20

Among the nine mothers, one received no antenatal care, two received antenatal care in a local private centre, and one received antenatal care in mainland China. All were considered normal and received no IUT. For the remaining five mothers who received antenatal care in a public hospital, all had BHFS diagnosed antenatally in their neonates (two by cordocentesis, one by chorionic villus sampling, one by amniocentesis, and one by both cordocentesis and chorionic villus sampling). All five couples decided to continue the pregnancy after counselling: two for religious reasons and three out of personal preference. All five patients had IUT/IUET performed two to four times. Antenatal ultrasonography of seven fetuses revealed cardiomegaly in four and hydropic changes in two, one of which subsequently resolved after IUT. Placentomegaly was detected in three mothers and polyhydramnios in one. Pre-eclampsia was reported in two mothers and was controlled with antihypertensive drugs (Tables 2 and 3).6 13 14 15 16 17 18 19 20

Preterm delivery occurred in seven of the nine cases, with a median gestational age at delivery of 33 weeks. All infants had respiratory depression at birth and required resuscitation, neonatal intensive care unit admission, and intubation. Surfactant for respiratory distress syndrome was required by five infants, and five demonstrated persistent pulmonary hypertension of the newborn, which required high-frequency oscillation ventilation and inhaled nitric oxide administration. Inotropic support with or without hydrocortisone was required by four infants with haemodynamic instability (poor cardiac contractility, heart failure, and/or hypotension). In case 6, the infant required cardiopulmonary resuscitation for more than 20 minutes after cardiac arrest. Postnatally, exchange transfusion was performed in five babies: two received a double-volume transfusion and three received a single-volume transfusion. Three infants received a transfusion within the first 24 hours of life. The median pre- and post-transfusion haemoglobin level was 90 and 170 g/L, respectively. All infants showed improved haemodynamic stability after transfusion. Congenital malformations were noted in all cases in this cohort (Tables 3 and 4).6 13 14 15 16 17 18 19

All four male babies had hypospadias that required urethroplasty, and two had concomitant undescended testes that required orchidopexy. Dental (case 1) and skeletal (case 3) anomalies were noted in two patients. Regarding the cardiovascular system, patent ductus arteriosus was noted in five cases and a secundum atrial septal defect in three. Regarding the digestive system, one infant (case 3) had type 3 jejunal atresia, for which end-to-end anastomosis was performed on day 4 of life. Two patients had neonatal hepatitis: one case resolved with time and the other still requires regular follow-up for elevated transaminase levels. No cases of cerebrovascular malformations were identified in this local cohort.

Both survivors who have reached adulthood are of short stature and have failed to achieve their final adult height, that is, to reach their predicted mid-parental height. Nonetheless, both had a normal puberty. Among the nine survivors, two have long-term neurological deficits, both manifested as mild spastic diplegia, although not affecting mobility. Five infants had delayed development, one of whom continues to have borderline low intellect (IQ, 80-89) after reaching adulthood (case 1). Two have normal intellect (cases 2 and 4) despite the need for multidisciplinary training during infancy, and the remaining two (cases 6 and 7) are attending mainsteam schools that provide extra training and support. The two cases diagnosed most recently (cases 8 and 9) have had normal development to date (Tables 3 and 4).6 13 14 15 16 17 18 19

Two patients received a stem-cell transplant: one an human leukocyte antigen DR 1 antigen–mismatch sibling-donor cord-blood transplant, and the other a 10/10 peripheral-blood stem-cell transplant from a matched unrelated donor. Both patients underwent transplantation at 20 to 21 months of age. Both achieved 100% donor chimerism 1 month after transplantation and remain transfusion-independent. Of the remaining seven patients who require regular transfusion every 3 to 6 weeks, only one shows moderate hepatic iron overload (case 2), and none have demonstrated infective complications. All five survivors older than 2 years received iron chelation therapy: three with deferasirox and two with deferiprone (one of whom has changed to deferoxamine owing to neutropenia). The median serum ferritin level was 1961 pmol/L (range, 411-5312 pmol/L). Endocrinopathies were noted in three patients: one had primary gonadal failure but did not require hormonal replacement therapy (case 1), one had hypogonadism requiring testosterone (case 5), and one (case 2) had partial adrenal insufficiency requiring stress-dose steroid but not regular hydrocortisone replacement (Tables 4 and 5).6 13 14 15 16 17 18 19

In Southeast Asia, BHFS is the most common cause of fetal hydrops.5 21 Because it is an autosomal recessive disorder, when both parents have two α-globin gene deletions in cis on chromosome 16 (each parent, --/αα), any offspring will have a 25% chance of having BHFS. In BHFS, haemoglobin tetramers of only gamma chains (γ₄) is ineffective in erythropoiesis and oxygen delivery to tissues. The ensuing anaemia and tissue hypoxia interfere with organogenesis and development and also lead to fetal heart failure, extramedullary erythropoiesis, and maternal complications. In contrast to --^FIL and --^THAI gene deletions reported in the Philippines and Thailand, respectively, the --^SEA or Southeast Asian deletion (the most common mutation in Hong Kong and demonstrated in all nine BHFS cases in this study) affects only the α-globin gene while sparing the embryonic ζ-globin gene, thus permitting production of Portland 1 (ζ₂γ₂) and Portland 2 (ζ₂β₂) haemoglobins. Hence, the affected fetus can survive through the antenatal and early neonatal period.

In Hong Kong, prenatal screening using a cut-off for maternal mean corpuscular volume of ≤80 fL and prenatal diagnosis using chorionic villus sampling, amniocentesis, and cordocentesis have been practised since 1983,22 23 24 25 thereby contributing to a decline in BHFS incidence for two decades. Despite public health endeavours in prenatal screening, however, BHFS babies continue to be born without prior prenatal diagnosis or parental counselling, resulting in adverse maternal and fetal outcomes.26 Causes of this phenomenon are principally two-fold: lack of proper antenatal screening and diagnosis, as well as improper implementation of screening or diagnostic procedures (Table 1). Better public education in both mainland China and Hong Kong would rectify the situation. Such education should stress the importance of early accurate prenatal diagnosis and the possible serious sequelae of late presentation or delayed diagnosis. Obstetricians should also note that normal paternal mean corpuscular volume does not exclude fetal BHFS because of the rare occurrence of maternal uniparental disomy (case 6)27 and non-paternity (possible in case 7).27 Routine mid-trimester scanning is imperative and diagnosis of BHFS should be considered if ultrasonography or clinical features are suggestive of BHFS (cardiomegaly, placentomegaly,18 28 and hydrops), regardless of the parents’ mean corpuscular volume.27 Placental thickness measurement allows early detection of BHFS in the first trimester, even before the appearance of hydropic features.18 28 If hydropic changes are detected, confirmation by cordocentesis and haemoglobin electrophoresis is warranted.

Suggested salient points of counselling for parents who opt for continuation of pregnancy are shown in the online supplementary Appendix. Once considered fatal, BHFS can now be detected and diagnosed antenatally, with survival being possible albeit not without complications. Detailed antenatal counselling for parents who are contemplating continuation of an affected pregnancy is crucial. Possible maternal-fetal complications, such as gestational hypertensive disorder and intrauterine growth restriction or death, should be addressed. On the basis of local experience, IUT is advised because there is a risk of miscarriage or intrauterine infection (case 9). Multiple IUTs may be indicated if fetal anaemia is suggested by serial Doppler ultrasonography (peak systolic velocity of the middle cerebral artery of >1.5 multiples of the median). Premature delivery and perinatal respiratory depression are often encountered. Neonatal intensive care unit admission and intubation are anticipated from local experience. Inotropic support may be required in the early neonatal period, as well as cardiopulmonary support, such as mechanical ventilation, surfactant treatment, high frequency oscillation ventilation, and nitric oxide inhalation for persistent pulmonary hypertension of the newborn. Exchange transfusion is often performed postnatally, in most cases within the first 24 hours of life.

Congenital malformations are often encountered, the most common being genitourinary and musculoskeletal defects, but are usually amenable to surgical correction. It is worth noting that all male babies in our local cohort displayed hypospadias. Two-thirds of our patient cohort showed growth retardation, global developmental delay, and/or long-term residual neurological deficits. These findings are comparable to those from an international case series29 and an overseas case report.11 Lifelong hypertransfusions every 4 to 6 weeks and iron chelation are expected for BHFS survivors. Haematopoietic stem-cell transplantation is a possible cure and has been successful in some local cases (Table 3). Nevertheless, transplant-related mortality and morbidity should not be overlooked. The proposal that parents produce a subsequent sibling to serve as a ‘saviour baby’ and potential donor is feasible but raises ethical concerns. Careful consideration and proper parental counselling are necessary.

Globally, 69 survivors are reported in the international BHFS registry29 with our local cohort (n = 9) contributing about one-seventh of cases. Approximately two-thirds of all cases used IUT29 (41/69; 59%), which is similar to the proportion of local cases (5/9; 56%). Globally29 and locally, most infants were delivered prematurely (respectively, 47/66; 71% and 7/9; 78%). Approximately one-fifth (14/69) of all BHFS survivors underwent stem-cell transplantation,29 again similar to our local situation (2/9). Congenital anomalies were present in all of the local patients, compared with two-thirds (37/55; 64%) worldwide,29 although urogenital and limb defects remained the most common. Nearly half (26/55; 47%) of global BHFS survivors demonstrated various degrees of transient or permanent neurodevelopmental impairment,29 in contrast to two-thirds of our cohort. Sohan et al (2002)30 described the first BHFS survivor in the United Kingdom: a 38-week-old baby girl of Hong Kong parents, who was referred at 21 weeks of gestation for hydrops fetalis, received serial IUT and had BHFS antenatally diagnosed. Two exchange transfusions were performed postnatally and the baby was discharged on day 6 of life followed by transfusions every 4 to 5 weeks. At the time of that publication, she was 18 months old and had normal growth and development apart from bilateral transverse palmar creases and a mild lobster-claw deformity of the right foot.30

This is the first territory-wide multicentre retrospective study to describe in depth the basic demographic characteristics and perinatal and long-term outcomes of BHFS survivors in Hong Kong over the past two decades or so. It also explores the reasons and cultural circumstances for which parents opted to continue the pregnancy despite public health endeavours to promote antenatal screening. Furthermore, it adds two more local cases to those submitted and recently published by the BHFS International Consortium.29 However, the small sample size precludes statistical analyses, and the data covers only the eight local public hospitals with haematology units and a period of 20 years (as the cut-off age in Hong Kong for paediatric care is 20 years and the Clinical Data Analysis and Reporting System began only in 1996). Survivors beyond 20 years of age and patients who defaulted follow-up to receive long-term medical care in the private sector or overseas were excluded from this study. In addition, the numbers of abortions and stillbirths, as well as BHFS babies with early neonatal death were not studied. Multidisciplinary collaboration between obstetricians, paediatric haematologists, and adult-care physicians at all local hospitals and concerted efforts in data collection and analysis are recommended. With the establishment of the Hong Kong Children’s Hospital in 2018, it is hoped that a standardised protocol of management and counselling can be compiled, data collection streamlined, and analysis facilitated for future research.

To conclude, survival of patients with BHFS is possible but not without short- and long-term complications. Local epidemiology of BHFS survivors is similar to that reported for an international registry. Detailed antenatal counselling of parents with a non-judgemental attitude and cautious optimism are imperative.

Online supplementary information (Appendix) is available for this article at www.hkmj.org.

We thank the Hong Kong Paediatric Haematology and Oncology Study Group and the paediatric haematologists from the eight participating hospitals for patient management, case contribution, and data cross-checking.

The authors have no conflicts of interest to disclose.

1. Lie-Injo LE, Hie JB. Hydrops foetalis with a fast-moving haemoglobin. Br Med J 1960;2:1649-50. Crossref

2. Lie-Injo LE. Alpha-chain thalassemia and hydrops fetalis in Malaya: report of five cases. Blood 1962;20:581-90.

3. Weatherall DJ, Clegg JB, Boon WH. The haemoglobin constitution of infants with the haemoglobin Bart’s hydrops foetalis syndrome. Br J Haematol 1970;18:357-67. Crossref

4. Boon WH. Further studies in Bart’s hydrops foetalis in Singapore. J Singapore Paediatr Soc 1970;12:79-84.

5. Liang ST, Wong VC, So WW, Ma HK, Chan V, Todd D. Homozygous alpha-thalassaemia: clinical presentation, diagnosis and management. A review of 46 cases. Br J Obstet Gynaecol 1985;92:680-4. Crossref

6. Fung TY, Lau TK, Tam WH, Li CK. In utero exchange transfusion in homozygous alpha-thalassaemia: a case report. Prenat Diagn 1998;18:838-41.

7. Lee SY, Chow CB, Li CK, Chiu MC. Outcome of intensive care of homozygous alpha-thalassaemia without prior intra-uterine therapy. J Paediatr Child Health 2007;43:546-50. Crossref

8. Beaudry MA, Ferguson DJ, Pearse K, Yanofsky RA, Rubin EM, Kan YW. Survival of a hydropic infant with homozygous alpha-thalassemia-1. J Pediatr 1986;108(5 Pt 1):713-6. Crossref

9. Lam TK, Chanh V, Fok TF, Li CK, Feng CS. Long-term survival of a baby with homozygous alpha-thalassemia-1. Acta Haematol 1992;88:198-200. Crossref

10. Thornley I, Lehmann L, Ferguson WS, Davis I, Forman EN, Guinan EC. Homozygous alpha-thalassemia treated with intrauterine transfusions and postnatal hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;32:341-2. Crossref

11. Lücke T, Pfister S, Dürken M. Neurodevelopmental outcome and haematological course of a long-time survivor with homozygous alpha-thalassaemia: case report and review of the literature. Acta Paediatr 2005;94:1330-3. Crossref

12. Chik KW, Shing MM, Li CK, et al. Treatment of hemoglobin Bart’s hydrops with bone marrow transplantation. J Pediatr 1998;132:1039-42. Crossref

13. Ng PC, Fok TF, Lee CH, et al. Is homozygous alpha-thalassaemia a lethal condition in the 1990s? Acta Paediatr 1998;87:1197-9. Crossref

14. Zhou X, Ha SY, Chan GC, et al. Successful mismatched sibling cord blood transplant in Hb Bart’s disease. Bone Marrow Transplant 2001;28:105-7. Crossref

15. Fung TY, Kin LT, Kong LC, Keung LC. Homozygous alpha-thalassemia associated with hypospadias in three survivors. Am J Med Genet 1999;82:225-7. Crossref

16. Kwan WY, So CH, Chan WP, Leung WC, Chow KM. Re-emergence of late presentations of fetal haemoglobin Bart’s disease in Hong Kong. Hong Kong Med J 2011;17:434-40.

17. Lee SY, Li CK, Ling SC, Shiu YK. Survival of homozygous alpha-thalassemia with aplasia/hypoplasia of phalanges and jejunal atresia. J Matern Fetal Neonatal Med 2009;22:711-3. Crossref

18. Kou KO, Lee H, Lau B, et al. Two unusual cases of haemoglobin Bart’s hydrops fetalis due to uniparental disomy or non-paternity. Fetal Diagn Ther 2014;35:306-8. Crossref

19. Au PK, Kan AS, Tang MH, et al. A fetus with Hb Bart’s disease due to maternal uniparental disomy for chromosome 16. Hemoglobin 2016;40:66-9. Crossref

20. Tongsong T, Wanapirak C, Sirichotiyakul S, Chanprapaph P. Sonographic markers of hemoglobin Bart disease at midpregnancy. J Ultrasound Med 2004;23:49-55. Crossref

21. Wasi P, Na-Nakorn S, Pootrakul S. The alpha-thalassaemias. Clin Haematol 1974;3:383-410.

22. Chan TK, Chan V, Todd D, Chosh A, Wong LC, Ma HK. Prenatal diagnosis of alpha-and beta-thalassemias: experience in Hong Kong. Hemoglobin 1988;12:787-94. Crossref

23. Rubin EM, Kan YW. A simple sensitive prenatal test for hydrops fetalis caused by alpha-thalassaemia. Lancet 1985;325(8420):75-7. Crossref

24. Kan YW, Bellevue R, Rieder RF, Valenti C, Dozy AM. Prenatal diagnosis of a-thalassemia. Clin Res 1974;22:374A.

25. Kan YW, Golbus MS, Dozy AM. Prenatal diagnosis of alpha-thalassemia. Clinical application of molecular hybridization. N Engl J Med 1976;295:1165-7. Crossref

26. Lee AC, Wong KW, So KT, Cheng MY. Why are thalassaemia patients born when prenatal screening is available? Hong Kong Med J 1998;4:121-4.

27. Dame C, Albers N, Hasan C, et al. Homozygous alpha-thalassaemia and hypospadias—common aetiology or incidental association? Long-term survival of Hb Bart’s hydrops syndrome leads to new aspects for counselling of alpha-thalassaemic traits. Eur J Pediatr 1999;158:217-20. Crossref

28. Ghosh A, Tang MH, Lam YH, Fung E, Chan V. Ultrasound measurement of placental thickness to detect pregnancies affected by homozygous alpha-thalassaemia-1. Lancet 1994;344:988-9. Crossref

29. Songdej D, Babbs C, Higgs DR, BHFS International Consortium. An international registry of survivors with Hb Bart’s hydrops fetalis syndrome. Blood 2017;129:1251-9. Crossref

30. Sohan K, Billington M, Pamphilon D, Goulden N, Kyle P. Normal growth and development following in utero diagnosis and treatment of homozygous alpha-thalassaemia. BJOG 2002;109:1308-10. Crossref