Toxicity of drugs during pregnancy : evaluation of statistical models and of perinatal health indicators – EToMeG

Prescribing drugs during pregnancy is common. However, the information available to prescribers on adverse effects on the fetus is often insufficient. Clinical trials rarely involve pregnant women and there are not enough pre-clinical animal studies on reproductive toxicity. Population studies have become a crucial resource. A key issue in pharmacoepidemiology is the prompt risk assessment of drug safety signals. To address this issue, recent interest has focused on available data resources, medico-administrative databases, in a context where large-scale databases as well as statistical questions on observational studies have emerged as prominent fields in epidemiological research. However, administrative health data contain limited clinical information raising concern about potential unmeasured confounding and biased risk estimation. We will investigate the use of the French SNIIRAM (health insurance claims linked to hospital data), to extend knowledge on the toxicity of drugs taken during pregnancy. From this database, it will be possible to determine the trimester of fetal exposure to drugs, condition of major importance to evaluate the responsibility of exposure to a drug in the occurrence of a neonatal disease.
Among potential endocrine disrupters, four therapeutic classes that are highly prevalent, yet with insufficiently known risks will be studied: NSAIDs, antihypertensive, antiepileptic, antidepressant drugs.

1- Published data regarding fetal exposure to NSAIDs are controversial. It was recently found that the use of NSAIDs in early pregnancy was associated with an increased risk of miscarriages and of malformations.
2- The safety of antihypertensive drugs is a major concern in obstetrics as hypertension is frequent event in pregnant women (4%) and blood pressure management is recommended to avoid maternal cerebro or cardiovascular compromise during pregnancy. ACE inhibitors and AT1 antagonists should be avoided throughout pregnancy. Regarding other antihypertensive drugs during early pregnancy, some studies showed some disturbing trends regarding exposure to ß-blockers, and calcium channel blockers.
3-The prevalence of depression is high (7%) and the use of anti-depressant drugs, such as selective serotonin reuptake inhibitors, is quite important during pregnancy. Published data regarding fetal exposure to anti-depressant drugs are controversial.
4- The risk for the fetus, including major congenital malformations, of prenatal exposure to AEDs has been questioned.
A recent study confirmed many other studies and found associations between exposure to valproate and spina bifida, malformations of the heart and major vessels, digits, skull bones and the brain. We will consider this association between exposure to valproate and these malformations as a positive reference.
However, more extensive data are necessary to confirm the effects of exposure to carbamazepine and topiramate.
Each therapeutic class will be studied to analyse:
- Incidence of fetal exposure to the drugs prescribed in France
- Adherence of prescribers to national/international prescription guidelines
- Excess of congenital malformations and neonatal diseases associated with fetal drug exposures
Two aspects will be addressed: we will study the metrological quality of hospital administrative (PMSI) data for certain perinatal health indicators (pathologies in the mother and infant), and assess the accuracy of discharge abstracts using medical records as the ‘gold standard’; we will also explore the interest of different statistical models (self-controlled case series, instrumental variables) to assess causal relationships between drug exposure and the outcome of pregnancy. Their assessment will be conducted on real data using an association considered to be known as a gold standard and with simulations.
The project is a pilot step for developing methodologies to be used for assessing risks induced by drugs taken during pregnancy from the SNIIRAM.