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Genetic counsellors operate as a part of the multi-disciplinary team in the care of patients in reproductive and family planning [1]. They serve as a critical resource for the identification and education of individuals and their families that are at (more...)

The genetic counsellor will facilitate genetic evaluation for confirmation of carrier status, and/or diagnostic testing in a pregnancy for identification of affected foetuses. Genetic counsellors may also serve as a resource to identify regional experts including haematologists to enrich family understanding regarding the diagnosis of α-thalassaemia including the long-term outcomes and how the needs of the diagnosis would impact the family based on their regional resources.

The care of patients with clinically severe forms of α-thalassaemia (haemoglobin Bart’s hydrops foetalis, HbH hydrops foetalis, and some severe forms of HbH disease) is complex, depending on both Obstetric/Maternal Fetal Medicine expertise for the prenatal management, as well as haematology, and access to safe blood for chronic transfusion needs. The resources to support this care vary globally, and consultation with local providers is essential for families to understand the implications of the diagnosis and long-term care based on their locality. In addition, given the development of newer therapies in the setting of thalassaemia, the genetic counsellor may also identify and make patients aware of opportunities to participate in clinical trials.

In the event of a pregnancy diagnosis, supporting the family through understanding their immediate management options and pregnancy decision-making is essential [4]. This involves both the logistical care coordination as well as the psychosocial aspects in adjusting to a diagnosis in their foetus. This support will include the acute needs to manage the family’s feelings of potential grief and loss of the anticipated healthy or unaffected child, as well as the long-term needs of navigating the future, which could include identifying a path forward to mitigate those risks in a future pregnancy. Identification of resources, including individual therapy and regional support groups related to pregnancy loss, pregnancy termination, and/or families and individuals with clinically significant forms of α-thalassaemia, may be essential to offer these families for on-going needs.

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A genetic consultation will include a review of known family history by obtaining a 3-generation pedigree (family tree). This information is valuable to understand family history that may be related to thalassaemia in the family, including a history of (more...)

Ideally, screening for thalassaemia occurs during the preconception period, although most couples begin a pregnancy unaware of their risk. Identification of potential carriers can be ascertained through the complete blood count (CBC) assessment. This is often recognized with the initial pregnancy evaluation, though evidence of a decreased mean corpuscle volume (MCV) or mean corpuscle haemoglobin (MCH) can be misdiagnosed as iron deficiency anaemia. While screening for iron deficiency or iron deficiency anaemia is a routine component of prenatal care, specific evaluation for genetic etiologies remains essential in patients at increased risk due to geographic ancestry. Importantly, iron deficiency and α-thalassaemia are not mutually exclusive and may co-occur in a patient. Geographic ancestry of the patient is key, and screening through molecular testing of the α-globin locus should be considered in an individual with haematologic values suggestive of microcytic, hypochromic anaemia and reporting origins in Southeast Asia, China, South Asia, the Pacific Islands, the Middle East, Mediterranean, Latin America or Africa. Evaluation of α-thalassaemia status should include complete blood count and peripheral blood smear as well as haemoglobin electrophoresis or high-performance liquid chromatography (HPLC) to rule out other haemoglobinopathies. Simultaneous α-globin gene testing to detect common α-thalassaemia deletions and point mutations is critical. This is because normal haemoglobin electrophoresis or HPLC results do not exclude most common forms of α-thalassaemias, and it is important to distinguish between α⁺-thalassaemia trait from α⁰-thalassaemia trait, which determines the risk of clinically severe disease (e.g., haemoglobin Bart’s hydrops foetalis) in the foetus. When a patient is identified to be a carrier for α-thalassaemia, emphasizing the implications for other family members is also important and a discussion including identifying those that could be at risk and support for educating these relatives should be a part of the genetic counselling purview (see Chapter 1 and Chapter 14).

Depending on the pregnant person and the partner’s carrier status there is a spectrum of clinically meaningful outcomes for a pregnancy and child. Haemoglobin Bart’s hydrops foetalis is the result when both parents have α⁰-thalassaemia trait, which deletes both α-globin genes on the same chromosome (--/αα), the affected foetus inherits the deleted chromosomes from each parent (--/--) [5]. In pregnancies at risk for haemoglobin Bart’s hydrops foetalis, due to the known eventual development of anaemia and hydrops, early confirmation of a diagnosis is critical for optimal management in those patients that elect to pursue foetal therapy. Foetal hydrops due to other forms of α-thalassaemia include non-deletion or unstable mutations in the α-gene even in the presence of one or two normal α-globin genes (--/α^Tα or - α^T/-α^T). This condition, known as haemoglobin H hydrops foetalis, is more severe in the intrauterine period and foetal rescue by active in utero management may also be considered [6–8]. The postnatal course is highly variable depending upon the type of α-globin gene mutation, ranging from a non-transfusion dependent moderate anaemia to transfusion dependency. Therefore, knowledge of the parental genotypes is critical for counseling regarding prenatal risks, management options and prognosis.

Partner testing is critical in the determination of reproductive risks. Couples should be made aware of the spectrum of outcomes with this diagnosis. Haematology management after birth may be essential with varying transfusion needs. A less-severe form of thalassaemia remains possible depending on the parental genotypes.

If the father does not have α⁰-thalassaemia trait and paternity is assured, then the foetus will not have haemoglobin Bart’s hydrops foetalis, but may still be at risk for severe prenatal presentation with anaemia and hydrops or an attenuated form where presentation may occur in childhood or later in life.

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All reproductive planning options should be reviewed with couples at risk for α-thalassaemia disease spectrum including the risks, benefits, and limitations of in vitro fertilization (IVF) with preimplantation genetic testing (PGT-M) to mitigate (more...)

Procedures for foetal testing include chorionic villus sampling (CVS), amniocentesis, and percutaneous umbilical cord blood sampling (PUBS; cordocentesis) [9–11]. The CVS procedure is performed between 10 and 13 weeks gestation by the sampling of placental tissue. This procedure is performed by ultrasound guidance either transcervically or transabdominally depending on placental positioning. The amniocentesis procedure removes a sample of the amniotic fluid surrounding the foetus and is performed ideally between 15 to 20 weeks gestation. This procedure will be performed under ultrasound guidance using a needle into the amniotic cavity.

After either the CVS or amniocentesis procedure the cells will require culturing which can take two weeks or more depending on the sample. Setting clear patient expectations is critical in the decisions regarding choosing the prenatal diagnosis procedure, this includes discussion regarding turn-around time for results in the context of gestational age. These details will be regionally specific but turn-around time for foetal diagnostic results will often exceed four weeks.

For a pregnancy demonstrating evidence of foetal anaemia, where initiation of foetal therapy sooner would benefit the foetal course, foetal blood sampling should be considered. This procedure, referred to as either PUBS (percutaneous umbilical blood sampling) or cordocentesis is performed under direct ultrasound guidance using a needle in the umbilical vein to obtain foetal blood. This procedure may be used to simultaneously confirm foetal anaemia and initiate treatment by infusion of red blood cells. The earliest this is usually performed is the 18th week of gestation. Molecular testing can be performed on any of the above specimens, including foetal DNA extracted from the foetal cord blood sample. Evaluation of Hb Bart’s (>80%) from the cordocentesis sample may also be used in the diagnosis of an affected foetus (Please see Chapter 14).

Finally, for those patients at risk for having a foetus with haemoglobin Bart’s hydrops foetalis who do not proceed with prenatal diagnosis, ultrasound may be used as a tool to detect features consistent with a diagnosis of haemoglobin Bart’s hydrops foetalis [12]. These findings include developments of foetal effusions consistent with hydrops spectrum, increased cardio-thoracic diameter ratio, and elevated middle cerebral artery (MCA) peak systolic velocity on Doppler (see Chapter 14).

Options in the setting of a foetal diagnosis include continuation with foetal therapy, pregnancy surveillance alone or pregnancy termination. For those patients that choose to continue in pregnancy, counselling by a MFM provider is necessary to ensure clear understanding of the implications of initiating foetal transfusions versus electing to carrying a foetus with haemoglobin Bart’s hydrops foetalis without foetal therapy. Both maternal and foetal risks should be weighed and a defined treatment and/or surveillance plan should be determined [4].

For those patients that elect to proceed with foetal transfusions the expectations regarding outcomes including the delivery of a child with chronic transfusion needs should be discussed. Ultimately, the option for a curative treatment by bone marrow transplantation could be considered with multiple variables impacting the likelihood of success including identification of a donor. Referral to paediatric haematology for extensive counselling regarding long-term prognosis and management is crucial to set the appropriate expectations and understanding for these families [4].

Summary and recommendations

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Comprehensive family history is essential to understand what, if any, reproductive risks may be present and should be addressed. This may include a family or personal history of anaemia, recurrent pregnancy loss or hydrops foetalis. Preconception/Early (more...)