Impact of Clomiphene Citrate on Multiple Gestation Births and Perinatal Outcomes: A Nationwide Cohort Study.

OBJECTIVE To evaluate the occurrence of multiple gestation birth and perinatal adverse outcomes in pregnancies resulting from clomiphene citrate (CC) treatment compared to non-exposed pregnancies. DESIGN Nationwide cohort study in an university hospital-based research center. SUBJECTS Pregnancies lasting more than 22 weeks of gestation, in women aged between 18-43 years between 2013 to 2019, recorded in the French health data warehouse (SNDS). EXPOSURE(S) Pregnancies exposed to CC were assigned to a 1:5 unexposed control cohort based on maternal age, calendar year of childbirth, French social deprivation index, history of hypertension and diabetes. Exclusion criteria were IVF/ICSI treatment or gonadotrophins within 12 months before pregnancy and pregnancies occurring in women with the dispensing of CC between 12 to 2 months, and/or less 11days before the beginning of the pregnancy. MAIN OUTCOME MEASURE(S) Multiple gestation birth rate and perinatal outcomes RESULTS: Of 3,173,013 pregnancies, 32,010 (1%) occurred in women exposed to CC, of which 31,934 were assigned to 159,670 unexposed control pregnancies. The multiple pregnancy rate was significantly higher in CC-exposed pregnancies (5.2% versus 1.4%; odds ratio (OR) 3.9, 95% CI [3.7-4.1]) such as twin pregnancies ( 5.1% versus 1.4%; OR 3.9, 95% CI [3.7-4.1]) and triple or more pregnancies (0.13% versus 0.03%; OR 4.3, 95% CI [2.9-6.5]) compared to the unexposed control cohort. Women exposed to CC presented significantly more adverse obstetrical and perinatal outcomes, including stillbirths, premature delivery threats, premature rupture of membranes, gestational diabetes, placenta previa, gravid hypertension, pre-eclampsia, preterm birth, small for gestational age (SGA) and C-section rate. After stratification on multiple pregnancy and adjustment on confounders (history of psychiatric disease, obesity and embryo reduction during pregnancy), exposure to CC remains associated with adverse outcomes in both singleton and multiple pregnancies. CONCLUSION A four-fold risk of multiple gestation births was found in pregnancies exposed to CC, along with perinatal adverse events, even in singletons. Although it remains uncertain whether these adverse events are due to the medication itself or to the treated medical condition, these findings should provide awareness of practitioners and patients about its use. It also underscores the importance of attentively monitoring follicular growth during the treatment process to avoid multiple pregnancies.