Evaluating the Effect of Hydroxyurea on Fertility in Individuals Identifying As Women

Introduction: The effect of sickle cell disease (SCD) and hydroxyurea on fertility has recently been emphasized. Low anti-Mullerian hormone (AMH), suggestive of diminished ovarian reserve (DOR) has been identified at earlier ages in individuals with SCD. Recent studies have also suggested that hydroxyurea use by women with SCD leads to DOR. DOR, however, does not necessarily indicate infertility as many women who have SCD have pregnancies while using hydroxyurea prior to and during pregnancy. The effect of SCD and hydroxyurea on fertility must be determined to guide counselling particularly the need for fertility preservation if needed. The purpose of the study was to determine whether hydroxyurea affects fertility in women with SCD.

Methods: We conducted a cross-sectional study using a self-administered questionnaire. The questionnaire has been developed according to standard criteria using open ended and close ended questions and is web based. The questionnaire was piloted for validity, time to completion and clarity. This questionnaire is being distributed to individuals identifying themselves as women who have desired or had at least one pregnancy in the last 10 years and who provided informed consent. The participants are from the Blood Disorders Program at Toronto General Hospital and the Special Pregnancy Program at Mount Sinai Hospital in Toronto, Canada. The questionnaire includes questions about individual characteristics (e.g. SCD genotype), fertility issues, pregnancy and pregnancy loss history, hydroxyurea usage and compliance, as well as factors linked to DOR such as disease severity, obesity, iron overload, smoking, and past contraceptive use. The primary outcome is a composite of primary or secondary infertility defined as inability to conceive for > 1 year and/or the use of assisted reproductive techniques for infertility to achieve a pregnancy, and/or > 3, 1^st trimester losses. The secondary outcomes are the frequency of the individual components of the primary composite outcome. Statistical Analysis: Univariate analysis will determine the effect of hydroxyurea, SCD genotype, stroke prior to pregnancy, kidney disease, use of oral contraception, smoking, regular transfusion program, hospitalization, and pre-pregnancy use of iron chelators on the composite outcome. Linear regression will be used for continuous variables including years using hydroxyurea, age at pregnancy, and pre-pregnancy weight. A multivariable regression model will be developed to determine the effects of hydroxyurea on the composite outcome while adjusting for other characteristics that could affect the outcome such as age at pregnancy. The study is approved by the Research Ethics Board at each site. Recruitment is ongoing to achieve the required sample size.

Results: This is an interim analysis of 33 individuals with SCD who completed the questionnaire. Of these, 17 had attempted pregnancy, and 6 were using hydroxyurea during this time. The gestational age at which the 6 individuals discontinued hydroxyurea varied, with most stopping within the 1^st trimester. Birth control was used by 4, and 4 smoked before pregnancy. Pregnancy was reported by 15, and 5 experienced miscarriages, 20% of whom were using hydroxyurea. Parity varied: 40%, 20%, 26.7%, and 6.7 % had 1, 2, 3, and ≥4 pregnancies, respectively. First pregnancies mostly occurred between ages 18-30 years, with similar distribution for last pregnancies. Miscarriages occurred mostly once (n=4) or 3 times (n=1), with n=1 in later trimesters. Fertility treatments were needed by 9.1%. Of the 3 individuals tested, 2 had low AMH levels, suggesting DOR. Additionally, 2 had difficulty conceiving after previous pregnancies, and 5 reported prolonged efforts to conceive while using hydroxyurea.

Conclusion: The preliminary results describe the frequency of pregnancies and pregnancy loss in individuals with SCD. Further analysis of the completed cohort will attempt to delineate the effect of SCD and hydroxyurea on fertility. Addressing fertility issues is vital for individuals with SCD to ensure they receive the appropriate support and counselling for their reproductive health.