O-092 Prevalence of multiple gestation births and perinatal outcomes in pregnancies secondary to clomiphene citrate treatment: a nationwide cohort study
Authors: Bourdon M , Santulli P , Tsatsaris V , Treluyer J M , Beeker N , Pinson P , Chouchana L 
Published: July 2024

Abstract

Study question
Is the incidence of multiple gestation births higher in pregnancies obtained after clomiphene citrate (CC) treatment compared to spontaneous pregnancies?

Summary answer
The rate of multiple gestation births in pregnancies obtained after CC treatment is significantly increased compared to spontaneous pregnancies.

What is known already
CC is a selective estrogen modulator frequently used to induce ovulation in infertile women. Data regarding the prevalence of multiple gestation births and adverse perinatal outcomes after CC are contradicting and based on meta-analysis of small sample size studies. Multiple gestations are frequently associated with complications such as preeclampsia, premature labor, and growth restriction, which contribute to higher mortality and morbidity rates.

Study design, size, duration
Using the French National Health Data System (SNDS) spanning 2013 to 2019, we conducted a nationwide cohort study including all pregnancies lasting more than 22 weeks of gestation, in women aged between 18-43 years.

Participants/materials, setting, methods
For each women, the first pregnancy during study was included. Women with the dispensing of IVF/ICSI treatment and/or gonadotrophins were excluded. Pregnancies exposed to CC (during the period [-60days,-11days] before the beginning of the pregnancy) were 1:10 matched to unexposed pregnancies. Pregnancies exposed to CC between 12 to 2months or less than 11 days before the beginning of the pregnancy were excluded to mitigate misclassification bias. The primary outcome was the multiple gestation birth rate.

Main results and the role of chance
Of 3,173,013 pregnancies, 32,010 (10 ‰) occurred in women exposed to clomiphene. The multiple pregnancy rate was significantly higher in pregnant women exposed with CC compared to matched controls (odd ratio 4.1, 95% CI [3.9-4.3]) such as twin pregnancies (OR 4.1, 95% CI [3.9-4.3]) and triple or more pregnancies (OR 5.1, 95% CI [3.8-7.2]). 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), C-section rate, and major birth defect rate. After stratification on multiple pregnancy and adjustment on confounders (history of psychiatric disease, diabetes, arterial hypertension, obesity and embryo reduction during pregnancy), women exposed to CC had a significantly higher risk of stillbirth, gestational diabetes, placenta previa, pre-eclampsia, preterm delivery and SGA in case of singleton pregnancies. Additionally, in the case of multiple pregnancies, they had a higher risk of placenta previa, preterm delivery, and SGA compared to non-exposed women.

Limitations, reasons for caution
The use of filled prescriptions as a measure of drug exposure could be subject to bias such as misclassification bias, although we attempt to mitigate it.

Wider implications of the findings
Clomiphene use is strongly associated with multiple gestation births and with adverse obstetrical and perinatal outcomes even in singleton pregnancies. These findings should provide awareness of practitioners and patients about its use. It underscore the importance of attentively monitoring follicular growth during the treatment process to avoid multiple pregnancies.

Trial registration number
NA