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Amid A, Lal A, Coates TD, et al., editors. Guidelines for the Management of α-Thalassaemia [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2023.
Introduction
Haemoglobin Bart’s hydrops foetalis is the most severe form of α-thalassaemia. It results from homozygosity for deletion of both α-globin genes (--/--) on chromosome 16.
Following the completion of primitive erythropoiesis in the first 8–10 weeks of embryonal life, embryonic ζ-genes (HBZ) are silenced and α-globin replaces the ζ-globin for the production of foetal haemoglobin (HbF, α2γ2). With the deletion of all four α-globin genes in a foetus with haemoglobin Bart’s hydrops foetalis, α-globin chains are not being produced. In the absences of α-globins, HbF is not formed and, instead, the excess γ-globins form a tetramer haemoglobin (γ4), referred to as haemoglobin (Hb) Bart’s. The Hb Bart’s has extremely high oxygen affinity, impeding the release of oxygen to the developing foetal tissues and is essentially non-functional. The profound anaemia and tissue hypoxia leads to development of foetal hydrops in the second or third trimester, as well as other complications like neurodevelopmental compromise and congenital birth defects. Consequently, most pregnancies that are not treated with foetal transfusions are nonviable and will result in foetal demise or neonatal death shortly after delivery [1–4]. Rare survivors who have not received intrauterine transfusion have been reported after a medically unstable neonatal period. It is thought that continued low-level expression of embryonic ζ-gene and persistence of Hb Portland (ζ2γ2) throughout pregnancy may provide some degree of tissue oxygenation in these patients. As such, homozygosity for deletions that also encompass HBZ (e.g. --FIL or --THAI deletions) are incompatible with life, and affected mothers may present with recurrent early pregnancy loss [5].
In addition to severe clinical consequences of haemoglobin Bart’s hydrops foetalis on the foetus, this condition also affects mothers. Maternal mirror syndrome is a known complication in pregnancies affected with hydrops foetalis, regardless of etiology. This complication is characterized by the development of maternal oedema, proteinuria, and hypertension [6]. Dystocia and postpartum hemorrhage due to placental enlargement are among other maternal complications. In addition, the significance of the psychological burden of pregnancies affected by this condition cannot be understated.
Diagnosis
Affected pregnancies that have not been diagnosed through screening process (see Chapter 14: Prevention and control of alpha-thalassaemia diseases) may present with pregnancy loss, or features of hydrops in the second or third trimester. The diagnosis of hydrops can be reflected by ultrasound findings through increased cardiothoracic ratio (≥0.5), enlarged placenta (>18mm before 15 weeks and >30mm after 18 weeks), other signs of hydrops (fluid collection in any one compartment including pericardial effusion, pleural effusion, ascites, or skin edema), elevated middle cerebral artery peak systolic velocity (MCA-PSV), amniotic fluid abnormalities (oligohydramnios and polyhydramnios), fetal growth restriction and echogenic bowel. MCA-PSV >1.5 multiples of the median (MoM) for gestational age is suggestive of moderate to severe anaemia. Of note, MCA-PSV is less reliable for assessing anaemia in haemoglobin Bart’s hydrops foetalis compared with other anaemias, especially in early stages of hydrops [7–9].
A diagnosis of haemoglobin Bart’s hydrops foetalis is confirmed by molecular testing by chorionic villus sampling, amniocentesis or foetal blood demonstrating the deletion of all four α-globin genes or presence of >80% of Hb Bart’s, < 20% Hb Portland, and complete absence of HbF on haemoglobin electrophoresis performed on foetal cord blood obtained from the percutaneous umbilical blood sampling (PUBS) [11, 12]. In the absence of prenatal diagnosis, observation of hydrops with or without elevated MCA-PSV on foetal ultrasound during the second or third trimester and microcytosis or hypochromia in both parents are highly suggestive of this diagnosis. Haemoglobin Bart’s hydrops foetalis is the most common cause of foetal hydrops in Southeast Asia, accounting for 60% to 90% of the cases [2].
Decision making process
Active management of affected pregnancies with early prenatal diagnosis and intrauterine transfusions (IUT) can produce viable offspring. Outcomes in the foetus and neonate correlate with the adequacy of prenatal transfusion management. Active management with IUT may resolve the complication of foetal hydrops, improve the delivery outcomes, and should in turn reduce the overall risk for maternal complications due to foetal hydrops [3, 5, 14–18]. Intrauterine transfusions have not been demonstrated to affect the incidence of structural findings, which suggests that hypoxia during organogenesis may be a factor. Furthermore, concerns regarding neurodevelopmental compromise due to sustained in utero hypoxia persist [5]. There is an emerging body of evidence that supports the impact of IUT to preserve neurodevelopment [17]. A review of outcomes following IUT in 14 pregnancies with hydrops foetalis demonstrated generally favourable outcomes, with mild delays in four (29%) and normal neurodevelopmental assessment in 10 (71%) [15].
Given risks for severe maternal complications in the setting of untreated hydrops foetalis, expectant management should be discouraged, however for patients electing for expectant management, maternal risks due to mirror syndrome should be emphasized. Close surveillance to mitigate these risks are essential [13].
Regardless of the decision, extensive psychosocial support should be offered. Education about options for future pregnancy should also be provided, including the use of in vitro fertilization (IVF) with preimplantation genetic testing (PGT-M).
Prenatal management
If the family elects to pursue IUTs, they should be referred to a centre with expertise in this technique if it is not available locally [13].
If patients elect to proceed with foetal therapy, IUT should be initiated as soon as technically possible (18 weeks at most foetal treatment centers) to minimize the long-term impacts of foetal hypoxia [13]. The aim of IUT regimen should be to prevent or reverse foetal hydrops, allow for normal growth and development of the foetus, and eliminate maternal complications that are associated with hydrops. While the protocol for IUTs is similar to standard protocols used for haemolytic disease of the foetus and newborn (HDFN) [19], there is one important difference: in haemoglobin Bart’s hydrops foetalis, the foetal haemoglobin concentration does not represent the amount of functional haemoglobin in foetal red blood cells. This is because the predominant haemoglobin (Hb Bart’s), which accounts for > 80% of haemoglobin in the faetus, is functionally useless in oxygen delivery due to its extremely high oxygen affinity [2, 5]. Thus, in addition to the need to correct anaemia, one should also consider the amount of non-functional Hb Bart’s and, ideally, this should be kept at <20% of total haemoglobin. Nevertheless, the optimal protocol establishing the transfusion volume or their frequency for the treatment of foetuses affected with haemoglobin Bart’s hydrops foetalis remains an area of continued research. It is likely that more frequent transfusions are needed shortly after the diagnosis of hydrops while less frequent transfusions may be needed with next transfusions. We do not administer phenobarbital, as is done by some experts for foetuses with HDFN because severe hyperbilirubinemia does not occur in those who have received sufficient transfusions.
Delivery considerations
Postnatal care
The neonatal course and outcome in the setting of haemoglobin Bart’s hydrops foetalis is greatly affected by the timing and effect of the IUT approach [15, 17]. Early delivery may be indicated when the foetus remains hydropic, with limited or no foetal transfusions accomplished. Alternatively, it may occur at or near-term gestation following resolution of hydrops foetalis.
Overall, the neonatal course is frequently complicated by varying degrees of respiratory distress, pulmonary hypertension, and hyperbilirubinemia. Newborns are also often small for gestational age due to early foetal hypoxia, and they may have associated birth defects, as noted above. The primary approach to treatment of the newborn with haemoglobin Bart’s hydrops foetalis is serial red cell transfusions, but the specific transfusion approach will be highly dependent on the timing of delivery in relationship to the last IUT and the degree of illness. Acute cardiopulmonary illness is often responsive to increasing oxygen delivery through decreasing ineffective Hb Bart’s fraction and increasing effective haemoglobin with transfused red blood cells, which may require exchange transfusion in some cases. For these reasons, planned delivery at a centre with expertise in neonatal resuscitation and paediatric haematology, and with a blood bank and clinical laboratories that can support urgent neonatal transfusions and the indicated laboratory evaluations is important.
Neonatal resuscitation and early management
Infants born with hydrops are likely to also be affected by prematurity, with critical illness due to cardiopulmonary failure. If urgent delivery is indicated at this point in pregnancy, every effort should be made for delivery to occur in an experienced neonatal centre with ready access to blood products appropriate for neonatal transfusion as emergent transfusion may be required. If time allows, emergency packed (high haematocrit) red blood cells should be prepared and available prior to delivery, to allow for urgent administration during neonatal resuscitation if needed.
Initial management of the newborn with hydrops includes early/immediate intubation, evacuation of pleural effusions, if present, and surfactant administration, given the effect of hydrops on delayed lung maturation. If ascites has been documented and the abdomen is taut or thought to be impeding diaphragmatic excursion, paracentesis can be performed. Pulmonary hypertension may complicate respiratory disease. Rapid placement of umbilical arterial and venous lines facilitates resuscitation and provides access for transfusion. Initial transfusion consists of packed red blood cells ~10 mL/kg (using estimated dry weight, and potentially divided into 5 mL/kg aliquots) after sampling of blood to document baseline haemoglobin and haematocrit, complete blood count (CBC) with manual differential for assessment of nucleated red blood cell (NRBC) count and haemoglobin electrophoresis for haemoglobin Bart’s fraction. Blood sample can be sent directly from cord blood at the time of delivery.
As noted, the approach to transfusion should be based on the history and timing of in utero red cell transfusions, while also considering the level of acute illness. By increasing oxygen carrying capacity, red cell transfusion often results in decreased severity of cardiopulmonary illness in newborns with haemoglobin Bart’s hydrops foetalis, with improved markers of oxygenation and decreased metabolic acidosis, if present. Those newborns with only a single in utero transfusion and more severe critical illness should be considered for urgent transfusion (as above), and a more aggressive postnatal transfusion approach utilizing direct or exchange transfusion, even if Hb Bart’s fraction result is not yet available. Those newborns with two or more in utero transfusions may be able to be managed more judiciously, even if hydrops has not fully resolved. Additional transfusions may await laboratory results with respect to Hb Bart’s fraction. Alternatively, given that haemoglobin electrophoresis is not necessarily available every day from the clinical laboratory, even at quaternary paediatric centres, the kinetics of response to in utero transfusions (i.e., haemoglobin Bart’s fraction from baseline PUBS results and its change with subsequent transfusions) can be used to inform additional empiric transfusions by estimating the baseline haemoglobin Bart’s fraction until laboratory results are available.
As noted, newborns with haemoglobin Bart’s hydrops foetalis are at risk for pulmonary hypertension. Newborns with respiratory distress or cyanosis should have pre- and post-ductal oxygen saturations monitored to assess for physiology consistent with persistent pulmonary hypertension of the newborn (PPHN). A pre-ductal (usually right upper extremity) oxygen saturation > 5% higher than a post-ductal (lower extremity) saturation raises concern for PPHN, which can be further investigated by echocardiography. Increase in effective haemoglobin via direct or exchange transfusion improves severity of pulmonary hypertension. Although extracorporeal life support (ECLS) is not necessarily contraindicated in term and near-term newborns, transfusion may result in clinical improvement to a level that averts the need for ECLS and should be strongly considered prior to ECLS cannulation unless the clinical course is complicated by other factors that exacerbate the level of cardiopulmonary illness (e.g., sepsis, meconium aspiration syndrome). Lung hypoplasia has been reported, which could preclude recovery despite ECLS support.
Transfusion
Hyperbilirubinemia
Hyperbilirubinemia requiring phototherapy is common due to haemolysis of haemoglobin Barts-containing endogenous RBC and repeated red cell transfusions. Elevated risk for kernicterus may also be present due to prematurity, low birth weight and acute illness, prompting use of “high-risk” thresholds for initiation of phototherapy from published nomograms. Serum bilirubin levels should be followed closely.
Echocardiography
Echocardiography should be performed during the neonatal hospitalization. It can support the diagnosis of PPHN or identify less severe pulmonary hypertension, and it can be used to monitor resolution of high cardiac output and increased chamber size with increasing effective haemoglobin. Regardless of level of illness, echocardiography is important for identifying and monitoring of any structural heart disease (particularly patent ductus arteriosus or secundum atrial septal defect, which cannot be diagnosed by foetal echocardiogram).
Neurologic evaluation and brain imaging
Brain injury due to foetal hypoxia, perturbed circulation with hydrops foetalis and postnatal illness, as well as other central nervous system findings, have been described. A neurological evaluation and brain MRI should be considered prior to hospital discharge to provide additional information for the family and to direct early developmental intervention, as infants and children with haemoglobin Bart’s hydrops foetalis are at risk for developmental delay.
Associated birth defects
For the most part, the anomalies associated with haemoglobin Bart’s hydrops foetalis do not require intervention during the neonatal hospitalization. While the exact underlying pathophysiology has not been fully elucidated, many of these structural defects are thought to be due to profound foetal hypoxia starting from the early foetal period. Limb anomalies, with nail hypoplasia, digital hypoplasia, or aplasia and distal limb amputation have been described in multiple reports, with more severe limb amputation described in cases of foetal demise. Genitourinary anomalies include hypospadias and cryptorchidism, but more severe forms including severe chordae and micropenis have been observed [10, 15]. These genitourinary anomalies are commonly described in male newborns with haemoglobin Bart’s hydrops foetalis. Jejunal atresia, atrial septal defect, and neuronal migration abnormalities have also been described.
Ongoing care and post-discharge follow-up
Once the newborn has stabilized from a cardiopulmonary and hematological standpoint, enteral feeds can be initiated and advanced consistent with gestational age and centreapproaches. Newborns are ready for discharge to home when they meet standard criteria and have established an appropriate growth trajectory.
In addition to a primary paediatrician, follow up should include referral to an experienced thalassaemia centre as infants undergo serial red cell transfusions with consideration for bone marrow transplant as definitive cure. Paediatric subspecialty follow-up for any anomalies should be arranged (e.g., urology, orthopedics). As infants and children with haemoglobin Bart’s hydrops foetalis (α-thalassaemia major) are at risk for developmental delay, close surveillance of the neurodevelopmental trajectory should occur by the child’s paediatrician, with consideration of referral to paediatric neurology, a high-risk infant follow-up clinic or other developmental screening centre, and physical and occupational therapy.
Hydrops foetalis due to rare forms of non-deletional haemoglobin H disease or homozygosity for mutational α+-thalasssaemia
While individuals with deletional haemoglobin H (HbH) disease and most patients with non-deletional forms of HbH disease do not require intensive foetal management, rarely, compound heterozygosity for a0-thalassaemia deletion and rare α+-thalassaemia mutations result in a very unstable haemoglobin. This can result in severe ineffective erythropoiesis and anaemia starting from the foetal period, leading to hydrops foetalis (HbH hydrops foetalis). Similarly, homozygosity for some non-deletional α+-thalassaemia mutations (e.g., Hb Constant Spring) can present with hydrops, although the majority of these patients will become non-transfusion dependent later in life [22, 23]. Prenatal screening and diagnosis of these patients are discussed in Chapter 14. Management of hydrops in these patients is similar to those with haemoglobin Bart’s hydrops foetalis, as discussed above.
Summary and recommendations
- Hydrops foetalis in the setting of a pregnancy in parents who are known carriers for α-thalassaemia is suggestive of foetal haemoglobin Bart’s hydrops foetalis in most cases. In this situation, the diagnosis should be confirmed as quickly as possible so that parents can be counselled in a timely manner.
- If the family wishes to pursue intervention, an initial IUT can be performed while awaiting the diagnosis.
- In a pregnancy with a confirmed diagnosis of haemoglobin Bart’s hydrops foetalis, nondirective counselling should include the option of expectant management, pregnancy termination, or foetal therapy with IUTs. Parents should be offered the opportunity to consult with a paediatric haematologist to understand the long-term outcomes, prognosis, and the requirements of postnatal and childhood management.
- If the family elects to pursue IUTs, they should be referred to a centre with expertise in this technique if it is not available locally.
- For patients electing to proceed with foetal therapy, IUTs should begin as soon as technically possible.
- Delivery should be planned at a tertiary care centre with availability of perinatology, paediatric haematology, and neonatology teams.
- While general principle of long-term management of patients with haemoglobin Bart’s hydrops foetalis is similar to those for transfusion dependent β-thalassaemia, the transfusion requirement for patients with haemoglobin Bart’s hydrops foetalis is different given the presence of non-functional Hb Bart’s. Table 1 summarizes the steps in management of newborn with diagnosis of haemoglobin Bart’s hydrops foetalis.
Table 1
Steps in management of newborn with diagnosis of haemoglobin Bart’s hydrops foetalis (α-thalassaemia major)
| Delivery at high-level paediatric centre Expertise in neonatal resuscitation Access to emergency blood products Ideally, clinical laboratories to support ongoing hematologic evaluation and therapy. If not available at delivery centre, transfer to appropriate centershould be arranged following initial resuscitation. |
| Stabiliazation and management of acute illness |
| Serial transfusion/exchange transfusion and monitoring haematology labs in consultation with paediatric haematologist |
| Monitoring and treatment of hyperbilirubinemia |
| Evaluation of associated anomalies and brain injury with paediatric subspecialty consultation if indicated |
| Referral to thalassaemia centre for follow up care after hospital discharge |
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