Impact of clomiphene citrate on multiple gestation births and perinatal outcomes: a nationwide cohort study

To evaluate the occurrence of multiple gestation birth and perinatal adverse outcomes in pregnancies resulting from clomiphene citrate (CC) treatment compared with nonexposed pregnancies.

Nationwide cohort study in a university hospital-based research center.

Pregnancies lasting >22 weeks of gestation, in women aged 18-43 years between 2013 and 2019, recorded in the French health data warehouse (Système National des Données de Santé).

Pregnancies exposed to CC were assigned to a 1:5 unexposed control cohort on the basis of maternal age, calendar year of childbirth, French social deprivation index, history of hypertension, and history of diabetes. The exclusion criteria were in vitro fertilization/intracytoplasmic sperm injection treatment or gonadotropins within 12 months before pregnancy and pregnancies occurring in women with the dispensing of CC between 12 and 2 months and/or less 11 days before the beginning of the pregnancy.

Multiple gestation birth rate and perinatal outcomes.

Of 3,173,013 pregnancies, 32,010 (1%) occurred in women exposed to CC, of whom 31,934 were assigned to 159,670 unexposed control pregnancies. The multiple pregnancy rate was significantly higher in CC-exposed pregnancies (5.2% vs. 1.4%; odds ratio [OR], 3.9; 95% confidence interval [CI], 3.7-4.1) such as twin pregnancies (5.1% vs. 1.4%; OR, 3.9; 95% CI, 3.7-4.1) and triple or more pregnancies (0.13% vs. 0.03%; OR, 4.3; 95% CI, 2.9-6.5) than in the unexposed control cohort. Women exposed to CC presented significantly more adverse obstetric and perinatal outcomes, including stillbirths, premature delivery threats, premature rupture of membranes, gestational diabetes, placenta previa, gravid hypertension, preeclampsia, preterm birth, small for gestational age, and cesarean 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.

A fourfold 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 because of 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.