An important part of care for TM women is providing them with information about their reproductive state and initiating an overall plan for a prepregnancy care (see below). FSH and estradiol levels in the follicular phase in TDT women are not reliable markers for gonadal function evaluation, and hormone stimulation tests to assess gonadal function did not yield consistent results [62, 73, 74]. More advanced methods such as hormonal profile along with ovarian reserve testing (ORT) in TM women of reproductive age are scarce. A more recent study utilized antral follicle count (AFC), a strong predictor of ovarian reserve, and found it to be lower in TM compared to normal controls, in particular in TDT women 30 years and older [8].

Anti-Mullerian hormone (AMH), another sensitive marker of ovarian reserve, is applied often in fertility clinics. It represents the early primordial follicle pool in the ovary, and is therefore independent of gonadotropin effect [75–77]. It may therefore emerge as a more reliable marker for reproductive potential and predictor of success of assisted reproductive technology in thalassemia women. Two studies assessed AMH levels in TDT women, both describe low to a low-normal range compare to normal controls. However, a clear downward trend of AMH levels in older women, in the mid-30s and older, was noted [8, 77]. The two studies showed a reverse correlation between AMH and iron overload measures, NTBI or ferritin, that was independent of the patients’ age. It appears that fertility declines in older TDT women who may have a faster drop in their ovarian reserve pool than age-matched normal women (Figs. 14.1 and 14.2). This suggests that duration of exposure to iron may increase the deleterious effects and exhaust the ovarian reserve, possibly through direct ovarian tissue effect (as discussed in earlier sections of this chapter). Therefore, it is important to initiate assessment, discussion, and consultation regarding patients’ wishes and efforts to preserve fertility at a young age. Attempts to reduce iron overload through intensified chelation therapy may be helpful to restore some reproductive function in some cases. Notably, improvement in gonadal function was observed in one female who gave birth to two healthy children without hormonal stimulation after intense iron chelation treatment [3]. In addition, elective cryopreservation of oocytes or ovarian tissue should be considered, while the oocytes and tissue are still attainable.

Over the past decade, there has been increasing interest in methods to expand the reproductive options of patients facing gonadotoxic therapies for various types of malignancies [78, 79]. There is, however, very limited such information for thalassemia patients. A recent successful ovarian tissue cryopreservation was demonstrated both in an adolescent thalassemia patient [80] and in a TDT woman prior to receiving gonadotoxic preconditioning treatment for hematopoietic stem cell transplantation (HSCT). Reimplantation of ovarian tissue resulted in IVF pregnancy and delivery of a healthy baby [81].

Prepregnancy counseling and planning are essential in order to minimize risk to the pregnant thalassemia woman and to the fetus. Apart from subfertility, other systemic and endocrine disorders, primarily cardiac disease, liver dysfunction, diabetes mellitus, and chronic viral infections, hamper fertility ability and pregnancy. Ideally, a multidisciplinary team comprised of a hematologist, reproductive medicine specialist, obstetrician, and cardiologist should be involved. In many cases, a psychologist is helpful also. Partner screening for carrier status of a thalassemia syndrome is essential and genetic counseling may be needed. The safety of pregnancy for mothers with TDT has been discussed in several reports [68, 73, 82–84]. A number of systems require prepregnancy evaluation and consideration during pregnancy:

Based on the above, it seems that, irrespective of spontaneous or induced ovulation, the current outcome of attempted pregnancies in TDT women, with proper multidisciplinary guidance and care, is optimistic. More than 500 pregnancies in TDT women have been reported; the majority delivered healthy term babies, while preterm babies were reported in 13–35 %, some related to multiple pregnancies [94]. Complications included a higher frequency of miscarriage, intrauterine growth retardation (IUGR), and low birth weight. Cesarean section is most often the chosen delivery method due to concerns of cephalopelvic disproportion resulting from maternal short stature and skeletal deformities and normal fetal growth [68, 70, 84, 88, 95–97]. Reports show a variable increase in iron load, which ranged from 10 to 100 % greater ferritin levels than preconception, likely related to the differences in the increase in blood transfusion during pregnancy. Some have noted a higher incidence of complications during pregnancy; these include: cardiac issues (compromised LV function, arrhythmias, and hypertension), gestational diabetes, impaired glucose tolerance, and renal colic (Table 14.1). There were no reports of increase in incidence of thrombosis or preeclampsia.

While ovulation induction in TM women can result in successful pregnancies and births, successful paternity seems to occur less often in TM men, a discrepancy that is not well understood. It is estimated that more than one half of men with TM are affected by oligospermia, asthenospermia, and possibly compromised sperm quality [7, 17, 48, 62, 67]. However, great variability in TDT phenotypes in these studies likely affects these estimates. Additionally, emerging iron chelation treatments may positively impact this high prevalence. Infertility in TM men appears to have multiple causes, including HH, late-onset hypogonadism, abnormal spermatogenesis, and possibly nutrient deficiencies combined with an increase in oxidative stress that affects sperm qualities, as discussed above.