Clomiphene citrate medication for infertility and risk of stillbirth or neonatal death: a population-based cohort study

CONTEXT: Women achieving pregnancy with infertility treatment may be at increased risk of stillbirth and neonatal death.

OBJECTIVE: To assess associations between clomiphene citrate (CC) use and perinatal death.

DESIGN: Whole of population data linkage cohort.

SETTING: South Australia.

PARTICIPANTS: All women giving birth between July 2003 and December 2015 (n=242,077).

METHODS: All births of at least 20 weeks were linked to government records of dispensed medications. A pregnancy was considered exposed to CC if a prescription was dispensed from 90 days before through to the end of a conception window. Descriptive statistics for stillbirths and neonatal deaths were stratified by multiplicity. For singletons, multivariable logistic regression models were used to examine the association of CC exposure with the combined outcome of perinatal death.

MAIN OUTCOME MEASURES: Stillbirths and neonatal deaths (with 28 days of birth) combined as perinatal deaths.

RESULTS: Among singletons, the prevalence of stillbirth was 6.6 per 1,000 births, with neonatal deaths of 2.1 per 1,000 live births. Among singletons conceived with CC, stillbirth and neonatal death had prevalence of 10.2 and 3.1 per 1,000, respectively. For the combined outcome of perinatal death, the odds ratio was 1.54 (95% confidence interval 1.15, 2.07), stable upon adjustment for factors conveying biological (e.g. obesity, pre-gestational diabetes) and social (e.g. disadvantage) risks for perinatal death.

CONCLUSION: Risk of perinatal death may be increased in pregnancies that follow use of CC. While established confounding factors related to infertility were taken into account, there may be some residual contribution of underlying infertility.