Clomiphene citrate dose and reproductive and perinatal outcomes in fresh autologous in vitro fertilization cycles, United States, 2004-2021

Objective Having demonstrated that clomiphene citrate (CC) is related to multiple pregnancy, prematurity, birth defects & perinatal death (NEJM, PLOS One, JCEM), and recapitulated these observations experimentally in a dose-dependent way within a murine model (Endocrinology), we sought to confirm a cumulative dose-response relationship of clomiphene citrate (CC) across courses on the risk for fetal death among fresh autologous IVF cycles. Study design Population cohort study of 21,004 fresh, autologous IVF embryo transfer cycles that were performed in US fertility clinics between 2004 and 2021 where clomiphene citrate was used for ovulation induction. Frozen cycles were not available. Materials and methods We created 4 categories of total clomiphene dosage (<500mg, 500-749mg, 750-999mg, and ≥1000mg) and used robust Poisson regression models to estimate adjusted risk ratios (aRR) and 95% confidence intervals (CI) for perinatal outcomes. Models adjusted for age, parity, prior assisted reproductive technology cycles, infertility diagnosis, race/ethnicity, and body mass index (BMI). Main results The median total clomiphene citrate dose was 500mg, with 4,476 cycles (21.3%) using <500mg, 14,241 (67.8%) using 500-749mg, 1,517 (7.2%) using 750-999mg, and 770 (3.7%) using 1000mg or greater. After adjustment, rates of spontaneous abortion were higher for patients using 500-749mg and 750-999mg of clomiphene citrate, relative to those using <500mg (11.8% vs 10.3%, aRR 1.12, CI 1.02-1.25 and 14.4% vs 10.3%, aRR 1.38, CI 1.18-1.62, respectively). There was a 3-fold increased rate of stillbirth for the ≥1000mg group compared with the <500mg group; however, the estimate was imprecise due to small sample size and the confidence interval included the null (0.7% vs 0.2%, aRR 3.30, CI 0.88-12.39). Multiple birth risk was significantly higher for all clomiphene citrate dosage categories compared with the <500mg group (15.7%): 21.8%, aRR 1.38, CI 1.16-1.64 for the 500-749mg group, 23.8%, aRR 1.47, CI 1.14-1.89 for the 750-999mg group, and 28.3%, aRR 1.47, CI 1.25-2.22 for the ≥1000mg group. Conclusion Rates of spontaneous abortion, stillbirth, and multiple birth increased monotonically with cumulative clomiphene citrate dose; however, effect estimates became imprecise at the upper extreme dose.