Background. Hydroxyurea reduces pain crises, acute chest syndrome and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes are an impediment to its use. Patient data on the effects of hydroxyurea when taken during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium (SCDIC) is a cooperative research program of eight clinical centers, a data coordinating center, and the National Heart, Lung, and Blood Institute (NHLBI). One of the SCDIC programs is an SCD patient registry including at least 300 participants from each center.
Methods. The SCDIC Registry retrospectively questioned participants regarding pregnancy history, hydroxyurea use and pregnancy outcomes. Of 2436 subjects 15-45 years of age, 2375 answered at least one pregnancy-related question, including hydroxyurea use during conception, the month and year the pregnancy ended, the outcome (live birth, stillbirth, miscarriage, abortion, currently pregnant), hydroxyurea use during pregnancy and what trimester (females only), and for live births - prematurity, birth weight < 5.5 lbs, and medical complications in the baby. The primary outcome was miscarriage or stillbirth, with separate analyses for males and females. Univariate logistic regression was used to identify significant covariates and predictors, and multivariate logistic regression was used to select the best fitting models. All models included severe sickle cell genotype, pregnancy order (1-3, 4-6, >6) and history of miscarriage or stillbirth at each pregnancy
WResults. Among 1,357 women, 1797 pregnancies were reported for a crude rate of 1.32 pregnancies per woman; among 1018 men, 620 pregnancy conceptions were reported for a rate of 0.61 per man. Overall, in 221 (12.3%) of reported pregnancies in women and in 122 (19.7%) of reported pregnancies conceived by men, conception occurred while on hydroxyurea (P<0.001). We further analyzed 2062 pregnancies that did not end in elective abortion as reported by 920 individuals. Pregnancy order, severe sickling genotype of the parent and prior history of still birth or miscarriage were significantly associated with stillbirth or miscarriage in univariate analyses. After adjustment for these covariates, hydroxyurea use at conception was associated with a 2.1-fold increase in the odds of miscarriage or stillbirth in pregnancies conceived by males (P = 0.046) and hydroxyurea use at conception and during the first trimester was associated with a 3.3-fold increase in the odds of miscarriage or stillbirth in pregnancies conceived by women (P<0.001). Hydroxyurea use at conception and during the first trimester was also independently associated with birth weight <5.5 lbs (OR 2.4, P=0.01), but not prematurity or medical problems in the newborn.
Discussion. There are important limitations to our study. The pregnancy history is self-reported and therefore complicated by recall bias. The completion of the reproductive history form varied by age. The dates of pregnancies ending in miscarriage were more often missing than other outcomes, so we could not use age at pregnancy in statistical analyses. Males may not have known or remembered all of the pregnancies they conceived that did not end in live birth, and we did not collect information about the female partners of males with SCD. Furthermore, the availability and use of hydroxyurea has increased over time. Nevertheless, our results suggest that the use of hydroxyurea at conception in males and at conception and the first trimester in females may be associated with adverse pregnancy outcomes. Our findings support advising patients who plan a pregnancy to temporarily discontinue hydroxyurea before attempting to conceive and during the first trimester in females, and to provide alternative approaches to prevent SCD complications during this time.
Gordeuk:Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Hankins:Novartis: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; LINKS Incorporate Foundation: Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; Global Blood Therapeutics: Consultancy, Research Funding; UptoDate: Consultancy. Kutlar:Novartis Pharmaceuticals: Consultancy, Research Funding; Global Blood Therapeutics: Research Funding, Speakers Bureau; Micelle Biopharma: Consultancy; NIH/NHLBI (SCDIC): Research Funding; Novo Nordisk: Research Funding; Forma Therapeutics: Research Funding; REACH: Other: DSMB Member; NOHARM: Other: DSMB Member; Bluebird Bio: Other: DSMB Member. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Shah:Alexion: Speakers Bureau; Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy. Kanter:BEAM: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy.
Asterisk with author names denotes non-ASH members.