Clomiphene citrate ups chances of multiple pregnancy, perinatal complications

Women exposed to clomiphene citrate (CC) have fourfold greater odds of becoming pregnant with multiples, and this seems to come with adverse perinatal outcomes, as shown in a French cohort study.

Compared with nonexposure, exposure to CC was associated with a higher occurrence of multiple pregnancy (5.2 percent vs 1.4 percent; odds ratio [OR], 3.9, 95 percent confidence interval [CI], 3.7–4.1), such as twins (5.1 percent vs 1.4 percent; OR, 3.9, 95 percent CI, 3.7–4.1) and triplets or more (0.13 percent vs 0.03 percent; OR, 4.3, 95 percent CI, 2.9–6.5). [Fertil Steril 2025;124:334-343]

However, adverse outcomes for mothers and babies occurred more frequently in CC-exposed pregnancies, even in singletons.

Among singleton pregnancies, CC exposure was associated with stillbirth (adjusted OR [aOR], 1.28, 95 percent CI, 1.01–1.61), medical termination of pregnancy (aOR, 1.35, 95 percent CI, 1.03–1.77), gestational diabetes (aOR, 1.14, 95 percent CI, 1.11–1.17], placenta previa (aOR, 1.38, 95 percent CI, 1.20–1.59), pre-eclampsia (aOR, 1.25, 95 percent CI, 1.18–1.33), preterm birth (aOR, 1.30, 95 percent CI, 1.25–1.35), and small for gestational age (aOR, 1.13, 95 percent CI, 1.10–1.17).

Among multiple pregnancies, greater odds of placenta previa (aOR, 2.00, 95 percent CI, 1.26–3.25), preterm birth (aOR, 1.16, 95 percent CI, 1.07–1.26), and SGA (aOR, 1.19, 95 percent CI, 1.10–1.30) were observed with CC exposure.

“Our findings indicate that the perinatal complications observed in pregnancies resulting from CC treatment are probably not solely attributable to the multiple gestation birth rate,” given that the complications also occurred in singleton pregnancies, according to the investigators.

They acknowledged uncertainty over whether the increased risks of obstetric and neonatal complications were primarily because of CC itself, the underlying infertility or polycystic ovarian syndrome, or a combination of both factors.

“[In light of the] observations, it is critical that CC be prescribed and monitored by gynaecologists or fertility specialists who can provide appropriate patient selection, dose adjustment, and thorough monitoring throughout the treatment and pregnancy,” they said.

In conclusion, the investigators emphasized “thoughtful consideration and monitoring [of] women before and during pregnancies” when using CC treatment. They called for additional studies, such as surveys of current monitoring practices, to support more consistent and safer use of CC in ovulation induction. “The risk of multiple gestation pregnancies and perinatal complications [should also be explored] in alternative therapies, such as letrozole, which has shown benefits in ovulation induction.” [Reprod Sci 2024;31:883-905]

The analysis included 31,934 CC-exposed pregnancies and 159,670 control pregnancies without CC exposure. These two groups were matched based on maternal age (mean age at delivery 30.1 years), history of hypertension (1.6 percent), and history of diabetes (1.7 percent), among others. None of the women received assisted reproductive treatment within the 12 months before the beginning of the pregnancy.