Assisted Reproductive Technology Required to Achieve High Conception Rates, Despite a Low Incidence of Hypogonadotrophic Hypogonadism in Thalassemia and Sickle Cell Disease Patients
Authors: Perram Jacinta , Anderson Stephanie , Matthews Stephen , Gou Melly , Ho P. Joy 
Published: November 2021

Abstract
Background
Early and effective iron chelation has improved life expectancy and decreased disease complications for people with transfusion dependent thalassemia (TDT) and Sickle Cell Disease (SCD). Fertility challenges and pregnancy complications have historically limited reproductive options in this group, however improved disease management has made subfertility a chronic disease complication requiring attention. Despite this, there are very few reports on rates of conception and pregnancy outcomes in this population.
Methods
A 20 year retrospective analysis (1997 - 2017) was performed to evaluate fertility outcomes in women with TDT and SCD at an Australian referral centre. Patients with TDT and SCD who tried to conceive during the study period were included. Use of assisted reproductive technologies (ART), as well as pregnancy outcomes and neonatal and maternal complications were assessed.
Results
Eleven women with TDT and 3 with SCD tried to conceive during the study period. Median age at conception was 28 years (range 21-35). A total of 28 pregnancies and 25 live births were reported, including 2 spontaneous early pregnancy losses, a termination for anencephaly and a reduction of triplets. There was 1 multiple gestation in the cohort. At least 1 live birth occurred in 13 of the 14 women (93%). Spontaneous conception was reported in 9 women, of whom 8 had at least one resulting live birth, with a total of 15 live births from spontaneous conception. Of 5 women who were unable to conceive spontaneously, four had a diagnosis of hypogonadotrophic hypogonadism (HH) - two conceived following ovarian stimulation (OS), one required in vitro fertilization (IVF), and one did not pursue IVF following unsuccessful OS. The cause of subfertility was unknown in one patient, who conceived with IVF following failed OS. Three women who had an initial spontaneous conception required assisted reproductive technology (ART) for subsequent pregnancies, with no cause for subfertility identified.
Mean ferritin at conception was 2911 mmol/L (range 164 to 8697mmol/L), and there was no association between ferritin at conception and need for ART. A trend was observed between increasing age and use of ART. Nine of the thirteen (69%) women who achieved pregnancy underwent Cesarean section for their first delivery. Prematurity (birth prior to 37 weeks' gestation) occurred in 5 (20%) of live births. Intrauterine growth restriction (IUGR) evidenced by birth weight &lt;10 th centile for gestational age at birth was observed in 7 of 25 births (28%). This included one very low birth weight neonate delivered following induction for suspected IUGR. Respiratory distress syndrome occurred in two neonates in the setting of prematurity (delivered at 31 and 33 weeks gestation), both from women with TDT. Post partum hemorrhage (PPH) occurred after four deliveries in three women with TDT. There were no neonatal or maternal deaths.
Conclusions
Our data is the first analysis of fertility and pregnancy outcomes in Australian patients with TDT or SCD. Publications in this area are limited, and primarily report on pregnancy outcomes without capturing failure to conceive. Our findings are encouraging, with high conception rates achieved, with the use of ART where needed. Ferritin level did not predict difficulty with spontaneous conception and few of the women (29%) had HH, despite many having significant hyperferritinemia. Overall, 48% of live births resulted from ART, despite 58% of these patients not having a diagnosis of HH. This indicates that pituitary iron deposition with resultant HH alone does not adequately explain subfertility in this population. Our data also highlight the importance of affordable ART access for this patient population despite the clinical gains achieved with effective chelation therapy.
Pregnancies were largely uncomplicated with excellent maternal and foetal outcomes. A high rate of IUGR was observed, supporting classification of pregnancy in this population as high risk. Rates of Cesarean section for first delivery were more than double the Australian average, likely in part due to high IUGR rates. Neonatal complications and PPH occurred at general population rates. Guidelines around pregnancy management in this population abound, however large prospective studies are needed to identify those at risk of sub- and infertility, even in the era of effective chelation.

Disclosures
No relevant conflicts of interest to declare.