Introduction

Advances in the primary care of thalassaemia major (TM) including optimal blood transfusion and chelation therapy have improved patient survival into adulthood. At the same time, patients’ quality of life has also significantly increased and the expectation of having a family – a key aspect of quality of life – is consequently an important aspiration for many of them. Although spontaneous fertility can occur in well-transfused and well-chelated patients with spontaneous puberty and normal menstrual function, the majority are subfertile mainly due to hypogonadotropic hypogonadism (HH) as a consequence of transfusional haemosiderosis (Skordis et al., 1998). Those who fail to achieve pregnancy spontaneously require assisted reproductive techniques (ART).

Planned pregnancy is essential both in spontaneous and ART conceptions, since pregnancies in patients with TM are high risk for both the mother and the baby. However, these risks can be minimized through pre-pregnancy counselling involving the various members of the multidisciplinary team: the haematologist, the reproductive medicine specialist, the cardiologist and the obstetrician, in conjunction with the endocrinologist and the specialist nurse.

The management of patients with thalassaemia intermedia (TI) is similar to that of TM, with minor adjustments. Older patients with TM usually have HH and are unlikely to conceive spontaneously, whereas patients with TI are potentially fertile with an intact hypothalamic-pituitary-gonadal (HPG) axis (Chatterjee & Katz, 2000). Furthermore their management during pregnancy is different in that TI patients have an increased thrombotic risk, compared to regularly transfused patients and may need transfusion during pregnancy to decrease this risk (Nassar et al., 2006). In addition to complications specific to iron overload, TM patients also face the risk of thromboembolism; this is particularly so after splenectomy and in those with auto-antibodies.

Women with TM appear to have premature ovarian ageing compared with non-thalassaemic women, raising a concern around the maximum age at which ovarian reserve is sufficient for hormonal stimulation to be successful. Ovarian reserve reflects the capacity of the ovary to provide eggs that are capable of fertilization resulting in a healthy and successful pregnancy. It also determines the risk of miscarriage (Singer et al., 2011). In ovarian reserve testing, ultrasound techniques are used to indirectly measure of the size of the residual ovarian follicle pool. Reproductive aging is directly related to the decline in the number of antral follicles. Low gonadotropin secretion in women with TM results in reduced ovarian antral follicle count and ovarian volume, though levels of anti-Müllerian hormone (AMH), a sensitive marker for ovarian reserve independent of gonadotropin effect, are mostly normal. AMH, which prevents recruitment of non-dominant follicles and reduces the responsiveness of ovarian follicles to FSH during cyclic recruitment, is produced by the pre-antral and early antral follicles. Low ovarian reserve is considered predictive of low chances of spontaneous pregnancy and for poor ovarian response to hormonal stimulation. AMH is the earliest marker of change with age and has very little intercycle and intracycle variability and therefore emerges as an important biomarker for assessment of reproductive capacity in TM, demonstrating that fertility is preserved in the majority of those younger than 30 to 35 years. AMH can be useful in future studies aiming at improved chelation for fertility preservation (Leung & Lao, 2012).

Spontaneous pregnancies in women with a preserved hypothalamic-pituitary-gonadal axis, who have normal menstrual cycles, are common. On the other hand women with primary or secondary amenorrhea are able to conceive following ovulation induction therapy. However, most of the other potential complications in TM must be seriously considered before and during pregnancy.

Management of Subfertility in Females

Although 80-90% of patients have HH, gonadal function is intact in the majority of patients, indicating that fertility is usually salvageable, i.e. ovulation in females and spermatogenesis in males can be induced by exogenous gonadotropin therapy, ‘bypassing’ the HPG axis (De Sanctis et al., 1988a, 1988b). However, other endocrine disorders, namely diabetes mellitus and hypothyroidism, may also influence the outcome of fertility treatment and need to be corrected by standard care. Successful spontaneous pregnancies, as well as those resulting from the induction of gametogenesis, have been documented in TM females and males (Aessopos et al., 1999; Skordis et al., 2004).

Management of subfertility requires careful planning and preparation (a thorough work-up), including pre-pregnancy counselling of the couple (see below). Fertility assessment of patients with thalassaemia should also include evaluation of the partner according to standard criteria (see https://www.rcog.org.uk/, 2021). The fertility options are dependent on two factors: (a) her partner’s carrier status and (b) the site of damage to the HPG axis. If both partners are homozygous for thalassaemia the use of donor gametes, preferably donor sperm, is the ideal option as sperm can be more easily available from sperm banks, whereas the use of donor eggs is technically more complicated with an unpredictable success rate (Deech, 1998). If the partner is heterozygous, then pre-implantation genetic diagnosis (PGD) is another option, where diagnosis can be made prior to conception. This method may be more acceptable to certain communities with religious beliefs against termination of affected pregnancies. Lastly, in patients with severe organ damage or where both partners have TM, an alternative option may be adoption. When considering adoption, the family environment and competencies need to be taken into consideration.

Methods for induction of ovulation

Induction of ovulation with pulsatile gonadotropin-releasing hormone (GnRH) infusion is only possible at the early stage of HPG damage, when gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH) are pulsatile. But most of patients with HH are a pulsatile but with functional gonads, and are therefore likely to benefit from gonadotropin therapy (80% success rate) (Skordis et al., 2004). The drugs used, however, are powerful and can often induce growth of two or more follicles, with the risk of twin or triplet pregnancy and often result in ovarian hyperstimulation syndrome. In this condition the ovarian blood vessels become more permeable and leak fluid into the abdomen causing ascites and dehydration. About 1-2% of women undergoing induction of ovulation develop severe hyperstimulation syndrome causing abdominal pain, dyspnoea, vomiting and rapid weight gain. Severe cases are admitted to hospital to manage serious complications such as electrolyte imbalance, hypovolaemic shock, renal and respiratory insufficiencies and arterial thromboembolism, which can be life threatening. Induction of ovulation should therefore only be undertaken by a specialist reproductive team, according to Human Fertilization and Embryology Authority (HFEA) guidelines (Deech, 1998). Patients should be counselled regarding the risk of hyperstimulation syndrome, multiple pregnancy, ectopic pregnancy and miscarriage. The risk of hyperstimulation and multiple births can be minimized by vigilant monitoring of the induced cycle by endovaginal ultrasound scans. For such procedures, it is important to obtain informed consent.

Carefully documented notes should be kept throughout. Induction of ovulation may be indicated in women with primary amenorrhea, secondary amenorrhea, or those with normal menstrual function who fail to conceive, and also in planned pregnancy where both partners are thalassaemics. Stimulation of follicular development to retrieve mature oocytes is essential in these cases, because of the greater chance of pregnancy occurring following the transfer of more than one embryo. The induction of the growth of follicles necessitates the administration of the ovulation induction drugs and different induction protocols. The regime to be followed will be dependent on the team’s local protocol (see Figure 1 for an established protocol).

Most ovulation induction protocols for thalassaemia patients use standard medications. Agents include gonadotropins (FSH and LH) and clomiphene citrate, which are used to stimulate development of follicles, and human chorionic gonadotropin (HCG), that mimics LH to trigger ovulation at the end of follicular development. Adjuvant medications, such as GnRH analogues for ovarian suppression are not used in thalassaemia as the hypothalamic–pituitary axis is not intact. The dose and frequency of gonadotropin injections depend on the woman’s response, which is evaluated by the number and size of the growing follicles and levels of oestradiol. hCG is administered when at least two follicles reach 17 mm in size and 36 hours after the administration of hCG egg collection is performed.

It should be remembered to counsel the patient for egg collection and storage if haemopoietic transplant or gene therapy are contemplated. This of course, usually is done at an earlier age, in adolescent patients.

Table 1

Key points in induction of ovulation include:

Male Fertility and Induction of Spermatogenesis

The induction of spermatogenesis in male patients with thalassaemia is more challenging than the induction of ovulation in their female counterparts, with a success rate of only 10-15% in moderate to severely iron loaded patients and advanced aged patients (Skordis et al., 2004). The induction process must be undertaken according to HFEA guidelines, with an emphasis on consent and counselling (Deech, 1998). An established protocol for induction of spermatogenesis is described below:

Table 2

induction of spermatogenesis.

Hormonal treatment of pubertal disorders in thalassaemia is a complex issue due to the many associated complications. Therefore, each patient has to be assessed individually. Collaboration between endocrinologists and other doctors is crucial. Male patients with onset of HH before completion of pubertal development generally have testes smaller than 5 ml in volume and usually require therapy with both hCG and HMG or recombinant FSH to induce spermatogenesis.

The treatment process is demanding and may take up to 2 years. The initial regimen of hCG is usually 2,000 – 3,000 IU administered intramuscularly twice a week. The clinical response is monitored, and testosterone levels are measured every 2 to 3 months. Dosage adjustments of hCG may be needed to determine an optimal response. If the patient is fully virilised and 8-12 months of HCG therapy has not resulted in the production of sperm, then FSH therapy should be initiated. Sperm banking procedures, even in subjects with reduced sperm count and motility, are recommended. Once pregnancy has occurred FSH therapy can be stopped and spermatogenesis can be maintained with HCG alone (Sanctis, Soliman & Yassin, 2012). If this treatment regimen does not result in adequate sperm production after a maximum of 2 years, there is no indication to continue.

The recent advent of micromanipulation techniques such as intra-cytoplasmic sperm injection (ICSI) has improved conception rates, even in oligo-asthenospermic patients. Therefore, sperm cryopreservation should be considered in all subjects with a stated wish to have children in future unless already azoospermic, to better preserved fertility and so the chance of conception. However, recent literature on sperm DNA damage in males with thalassaemia (De Sanctis et al., 2008) raises anxiety about mutagenic risks in these individuals, especially after ICSI, where natural protective barrier against gamete selection during fertilization is lost however no birth defects were reported in children of thalassaemics fathers.

Pre-Pregnancy Counselling

Before embarking on fertility treatment, it is important that patients and their partners attend pre-pregnancy counselling, which has a three-fold purpose: (a) evaluation of eligibility, (b) an opportunity for physicians to review the medications involved and (c) time for a discussion between physician/s, patient and partner regarding the risks associated with induced fertility and pregnancy.

Evaluation of eligibility

Each patient should be assessed regarding suitability to embark on pregnancy with optimum outcome both for the mother and the fetus. There are at least three important factors that must be cautiously taken into consideration before encouraging women with TM to embark on pregnancy: degree of cardiac impairment, liver dysfunction and the risk of vertical transmission of viruses.

1. The most important issue is that of cardiac function because cardiac complications remain the leading cause of death in transfused patients. The cardiac load is increased during pregnancy by at least 25-30% due to increased heart rate and stroke volume. This, along with iron load, has a real potential for premature death from cardiac failure. Therefore it is prudent that all patients with TM have cardiac assessment by echocardiography (left ventricular ejection fraction >65%; fractional shortening >30%), by electrocardiogram (ECG), both at rest and with exercise, and by 24 hour tape recording to check for rhythm disorders (Aessopos et al., 1999). If left ventricular dysfunction can be demonstrated in patients under stressful conditions or if significant arrhythmias have occurred, then women should be strongly advised against planning pregnancy (Hui et al., 2002). Most of the non-invasive cardiac investigations are relatively insensitive for detecting early cardiac iron loading. Modified magnetic resonance imaging (MRI) using gradient T2* measurements, can quantify iron levels, and can accurately relate these to left ventricular dimensions assessed using the same technique (Anderson et al., 2001). If the facility exists, cardiac MRI should be performed with the aim of identifying a T2* of less than 20 ms. If cardiac iron load is detected and especially if complications are detected, it strongly advised to intensify iron chelation therapy before embarking on a pregnancy so that the cardiac T2* > 20 ms wherever possible. There is evidence that cardiac function can be restored to a great extent (refer to chapter 3) by aggressive chelation, which however, may require several months and up to 2 years.
2. Liver function should be evaluated by biochemical tests, with the possibility of iron overload status being assessed by MRI. With respect to hepatitis C-positive cases, these women should be given a course of antiviral agents to attain hepatitis C RNA-negative status. Iron overload in the liver should be treated before pregnancy and optimisation of the iron burden is advisable as much as possible in the pre-conception period for liver iron of < 7 mg/g (dry weight) (dw). Liver and gall bladder (and spleen if present) ultrasound should be used to detect the presence of gallstones.
3. Before embarking on pregnancy, it is also important to establish bone heath by plain radiography of the spine and dual-energy X-ray absorptiometry scanning of the hip and spine (bone mineral density scoring) and correction of osteoporosis/osteopenia by institution of appropriate therapy (see Chapter 10, Osteoporosis). In addition all women should have vitamin D levels optimised before pregnancy and thereafter maintained in the normal range.
4. All patients should be screened for the human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV) and rubella. The opportunity should not be missed to ensure rubella immunity prior to pregnancy. If the patient is HIV positive and wishes to have a family, she should be advised of the usual recommendations for care which include appropriate antiviral agents, delivery by Caesarean section and the avoidance of breast feeding to reduce the risk of vertical transmission.
5. Patients should also be screened for diabetes, thyroid hypofunction and acquired red cell antibodies.
6. Both partners should be screened for haemoglobinopathies (Galanello & Origa, 2010).

Table 3

Eligibility evaluation includes the following examinations:

Table 4

Feasibility evaluation includes the following elements:

Review of medications

This is a good opportunity to review medications and to advise patients about their dietary habits, smoking and alcohol, and to commence supplements of folic acid, calcium and vitamin D. Patients on oral chelators (DFX or DFP) should be advised to switch to DFO, prior to induction of ovulation/spermatogenesis (Singer & Vichinsky, 1999). Hormone replacement therapy should also be terminated at least 4-6 weeks prior to induction of gametogenesis. Bisphosphonates are contraindicated during pregnancy and breast-feeding is not advised because of the considerable negative calcium balance associated with these states. Given the long biological half-life of bisphosphonates, ideally they should be stopped at least 6 months prior to conception, although there are no consensus guidelines. It is of paramount importance to ensure adequate calcium and vitamin D intake before and throughout pregnancy. Other medications that should be discontinued for at least six months prior to fertility treatment include interferon, ribavirin and hydroxycarbamide (hydroxyurea).

Hypothyroid patients receiving thyroid replacement therapy should receive increased doses, as needed to ensure they are euthyroid. Hyperthyroidism is rare in patients with thalassaemia. However, if a patient is receiving anti-thyroid medication such as carbimazole, they should be switched to propyl thiouracil.

Table 5

Medication review for pregnancy focus points:

Risks Associated with Pregnancy

All patients should be made aware that pregnancy per se does not alter the natural history of thalassaemia. If pregnancy is managed in a multidisciplinary setting, the fetal outcome is usually improved with a slight reduction in incidence of growth restriction (Aessopos et al., 1999; Ansari et al., 2006; Tuck, 2005). It has been shown that the risks of pregnancy-specific complications such as antepartum haemorrhage and pre-eclampsia in thalassaemia are similar to that in the background population. It has also been shown that DFO is not required during pregnancy in patients who are not iron overloaded and have adequate cardiac function prior to pregnancy. Serum ferritin is likely to increase by 10%, despite increases in frequency of blood transfusion (Aessopos et al., 1999; Butwick, Findley & Wonke, 2005; Daskalakis et al., 1998; Tuck, 2005). The aim during pregnancy is to maintain pre-transfusion haemoglobin concentration above 100 g/l. Once pregnancy is confirmed, the patient should be managed in a multidisciplinary setting with a team consisting of an obstetrician, midwife, physician, haematologist, cardiologist and endocrinologist. The patient should be made aware that although pregnancy is high risk, the outcome is usually favourable.

The risks of bone deformities may affect pregnancy and labour management, especially if cephalo-pelvic disproportion complicates delivery. Although most skeletal deformities are largely preventable by regular transfusion, spinal abnormalities associated with TM are related to regional blockade (Petrakos 2016). Osteoporosis and scoliosis are common in TM, despite transfusion therapy. Patients with osteoporosis usually have vertebral bodies with reduced height and the segmental position of the conus may be lower than predicted. It is therefore important to correct osteoporosis prenatally by hormone replacement and with bisphosphonates, when required, to increase bone density so that spinal anaesthesia becomes feasible. Bisphosphonates however have to be stopped at least 6 months prior to pregnancy due to their long biological half-life.

Table 6

Potential risks associated with pregnancy include:

It is important to note that the main risk to the mother are possible cardiac complications, which can be minimised by ensuring optimal cardiac function and good control of iron overload before the initiation of pregnancy.

Management of Pregnancy

Managing delivery

With respect to the management of labour, if the pregnancy is non-complicated one can wait for the spontaneous onset of labour. there is no current consensus on the mode and timing of delivery in this population. individual assessment should be made by the multidisciplinary team and according to the woman’s wishes. Similarly to the reported data, the author’s experience suggests that 80% of women with thalassaemia will require Caesarean section because of a higher frequency of cephalopelvic disproportion, largely due to short stature and skeletal deformity combined with normal fetal growth. It is desirable to use epidural anaesthesia wherever feasible, to avoid the risk of difficult intubation and trauma associated with general anaesthesia because of severe maxillofacial deformity in some TM patients.

If the mother has pre-pregnancy morbidities such as diabetes or cardiac disease then prolonged pregnancy should be avoided. Low dose deferoxamine may be used during prolonged labour in patients with cardiac disease.

If the haemoglobin is less than 100 g/l, cross-match 2 units on admission to the labour ward.

Postpartum care

After delivery, in principle deferoxamine can be recommenced because concentrations are very low in breast milk and because it is not absorbed by the oral route (Howard et al., 2012). Experience with breastfeeding in patients receiving deferoxamine is scant, however, and has not been examined in formal clinical trials. Breastfeeding should be encouraged in all cases except in those who are HIV and/or hepatitis C RNA-positive and/or HBV surface antigen (HbsAg) positive because of the risk of vertical transmission via breast milk.

Women with thalassaemia should be considered at high risk for venous thromboembolism and should receive low-molecular-weight heparin prophylaxis while in hospital. In addition this treatment should be administered for 7 days post discharge following vaginal delivery or for 6 weeks following caesarean section.

In case of miscarriage or termination of pregnancy the danger of thromboembolism is still present and low-molecular-weight heparin prophylaxis must be provided during and following the loss for at least 7 days.

All patients should be offered counselling regarding contraception. Intrauterine devices should be avoided because of the risk of infection. Taking oestrogen-containing birth control pills is also not advisable because of the risk of thromboembolism, in the author’s opinion. In most cases, the progesterone-only pill or barrier methods are appropriate. Male patients with HH are not spontaneously fertile and therefore contraception is not required.

Calcium and vitamin D supplements should be continued during breastfeeding, but bisphosphonate therapy for osteoporosis should only be resumed after cessation of breastfeeding (Howard et al., 2012).

Table 7

Key points for pregnancy care include:

Box

Summary and Recommendations.

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