Introduction

Although patients with haemoglobin H (HbH) disease are mostly asymptomatic, during periods of stress, such as pregnancy, anaemia may be aggravated and patients may require transfusion [1, 2]. Therefore, regular prenatal care is recommended to improve pregnancy outcomes in women with HbH disease. Furthermore, patients with more severe forms of HbH disease (non-deletional HbH disease) have generally a more pronounced anaemia, require frequent, or rarely regular, transfusions. Chronic anaemia and iron overload may have adverse effect on endocrine function and, consequently, on an individual’s fertility. Finally, genetic counselling may be necessary in either pre-conception and prenatal periods for couples at risk of having an offspring with severe forms of α-thalassaemia and some couples seek preimplantation genetic diagnosis for selecting an unaffected offspring.

HbH disease and fertility

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Studies on the fertility outcomes of patients with α-thalassaemia are scarce. Individuals with HbH disease have a variable degree of anaemia and ineffective haematopoiesis, which can cause bone changes, and secondary iron overload [3]. In general, (more...)

Male fertility

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The hypothalamic-pituitary-gonadal axis also has an effect on male fertility. Spermatogenesis is a process that is hormonally driven by FSH and LH. Iron plays an important role in spermatogenesis, including the synthesis of DNA and germ cell growth. Same (more...)

As reviewed, infertility with iron-overload is mostly reported in patients with β-thalassaemia. In contrast, data on infertility in HbH disease are scarce. However, it is possible that anaemia, ineffective erythropoiesis, and iron overload, as well as other factors, affect the success of pregnancy. Therefore, managing HbH disease (especially those with non-deletional forms or those who require frequent or regular transfusions) and its potential impact on fertility and pregnancy requires a multidisciplinary approach that includes haematologists, fertility specialists, obstetricians, and mental health professionals. Adult patients with HbH disease who wish to start a family should have an early evaluation, especially when there is a prior history of iron overload. If a female with HbH disease with normal menstruation or a male with HbH has not been able to conceive within six months, they should be evaluated by a fertility specialist.

Typically, a fertility specialist will thoroughly assess all possible factors contributing to infertility, regardless of whether they are connected to thalassaemia. This evaluation usually involves an examination of both partners, including deficiency of hormone levels, ovulation process or spermatogenesis, irregularity of sperm movement, or genital tract abnormalities.

Pregnancy outcomes and transfusion during pregnancy in HbH disease

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Pregnancy with HbH diseases is often associated with an increased severity of anaemia and adverse maternal and foetal outcomes. Some patients with HbH disease may require blood transfusion during pregnancy [1]. The physiologic changes in pregnancy leading (more...)

Transfusion during pregnancy

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Individuals with HbH disease who get pregnant should be monitored for exacerbation of anaemia during pregnancy. Supplementation with folic acid is provided prior to and during pregnancy. Iron supplement does not have any benefit in improving maternal (more...)

Iron chelation during pregnancy

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Currently, three iron chelators are available for the treatment of iron overload: deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX), alone or in combination [27]. Indications and management of chelation during pregnancy are similar to those (more...)

Preimplantation genetic diagnosis

Preimplantation genetic diagnosis (PGD) involves a process to determine if an embryo is affected with the disease in question prior to implantation. It has the benefit that the woman can start her pregnancy knowing that the foetus would unlikely be affected [30, 31]. Currently, PGD or prenatal genetic testing (PGT) is of three types: (1) PGT-A for aneuploidies; (2) PGT-M for monogenic disorders (including thalassaemia); and (3) PGT-SR for structural chromosomal rearrangements [32]. The main steps of PGT include in vitro fertilization to produce embryos to be tested, sampling of the embryonic cells for the test (embryo biopsy), and laboratory tests. Finally, the embryos with an unaffected result are candidates to be transferred into the uterine cavity (which has been appropriately prepared) for implantation [33–35]. These steps are shortly discussed as follows:

1. In vitro fertilization. This needs an ovarian stimulation protocol to bring about adequate growth of several ova. These ova are then picked up. For the PGT purpose, each ovum is fertilized by only one sperm with the process of intracytoplasmic sperm injection (ICSI) using micromanipulator. The resulting embryos are cultured in special environment.
2. Embryo biopsy. Originally, embryo biopsy was performed at day 3 after fertilization, yielding 1–2 cells for analysis. These cells are blastomeres. More recently, with the improvement of culture technique, embryos can survive longer. At present, the majority of embryo biopsies are performed on day 4 or 5 at blastocyst stage, when embryos have developed further and have formed trophectoderm, providing 5–10 cells for the tests. This is called trophectoderm biopsy.
3. Laboratory testing. The obtained embryonic cells are subjected to genetic testing according to clinical risk. At its infancy, PGT was mainly used to screen or diagnose major chromosome aneuploidies using fluorescence in situ hybridization (FISH). Later on, with advances in molecular technologies, it became possible to analyse a greater number of chromosomes and single gene disorders.
4. Embryo transfer. Embryos with an unaffected result are candidates for transfer that can be performed in the same cycle or can be frozen for transferring later. Usually, the transfer cycle is planned and the uterine cavity, including endometrium, needs to be prepared for a suitable milieu for implantation.

In some institutes, polar body biopsy is used as another available technique for PGDT. However, this gives information of maternal derived genetic material only [36, 37]. It might be considered in cases where maternal alleles are the important factor for the disease to develop. The interpretation is that the ovum would contain the allele that is not found in the polar body. A drawback of this procedure is that it is somewhat complicated as polar bodies are tiny. In addition, if only the first polar body is analysed, meiotic recombination may invalidate the PGT diagnosis if it takes place at the gene of interest and it is not known which allele is with the ovum/zygote and which allele is with the second polar body after fertilization [37, 38].

That said, some obstacles still exist with PGT. With only a small number of cells (even with biopsy at the blastocyst stage), errors could easily arise. Molecular techniques that need amplification of genomic materials are vulnerable to failures, as the initial amount, or template, of DNA is small, especially if the biopsy is performed at the cleavage stage. The obtained cells may be lost during the transfer from one container to another. The cells may not be healthy and the nuclei may not be amplified properly. As a result, no diagnosis may not be obtained from the test [34, 35, 39].

Another problem with PGT is allele dropout. This occurs when one of the alleles at the locus of interest area fails to amplify. Consequently, the allele is not identified leading to a wrong result or diagnosis. Moreover, with the sensitivity of polymerase chain reaction (PCR) amplification, a small amount of DNA contamination can be amplified and can lead to misdiagnosis. Additional amplification of polymorphic markers that are linked to the genes of interest has been suggested to alleviate these problems [40, 41].

Preimplantation genetic diagnosis for HbH disease

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Severe forms of thalassaemia include β-thalassaemia major, β-thalassaemia/haemoglobin E disease and Hb Bart’s hydrops foetalis. The option of termination of pregnancy may be offered to couples who have a foetus affected by one (more...)

Pregnancy and fertility in α-thalassaemia major

The data on pregnancy and fertility patients on α-thalassaemia major are limited, but the management of transfusion-dependent β-thalassaemia can be applied. If individuals with α-thalassaemia major are concerned about their fertility or are planning to have children, it is recommended to consult with specialists in thalassaemia and reproductive medicine.

Pregnancy in individuals with α-thalassaemia trait

Alpha thalassaemia trait is not associated with significant fertility issues or reproductive problems [21, 49, 50]. However, it is essential to identify both partners carrying α-thalassaemia trait, as there is a risk of having a baby with haemoglobin Bart’s hydrops foetalis.

Summary and recommendations

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