Do Major Pharmacovigilance Databases Support Evidence of Second Trimester NSAID and Third Trimester Paracetamol Fetotoxicity?

Abstract

Background: Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used during pregnancy. Due to their fetotoxicity, NSAIDs are contraindicated during the third trimester. There is ongoing controversy about the extent to which NSAIDs may cause cardiovascular and renal impairment in the fetus earlier in the second trimester. Paracetamol, used as an effective treatment for closure of patent ductus arteriosus (PDA) after birth, is suspected to cause similar but unwanted effects during the third trimester of pregnancy. Methods: Three major pharmacovigilance databases (VigilanceCentral, EudraVigilance, and VigiBase) were searched for Individual Case Safety Reports (ICSRs; n = 1288) on fetotoxic effects that have been shown to result from NSAID exposure in late pregnancy. Results: In 219/1288 cases, an NSAID and/or paracetamol was taken after the first trimester, and the ICSR was not related to other reported risk factors. Out of these 219 ICSRs, 48 were exposed to NSAIDs in the second but not the third trimester or to paracetamol in the third trimester. Causality assessment was "probable or likely" in four NSAID reports and none of the paracetamol reports. Conclusions: The scarcity of adverse drug reactions (ADRs) in our study and in the literature, despite decades of pharmaceutical marketing and worldwide use of paracetamol as an analgesic of choice in the third trimester and the absence of formal contraindications against NSAIDs in the second trimester, speaks against a substantial cardiovascular and nephrotoxic risk of temporary use of NSAIDs in the second trimester or paracetamol in the third trimester. NSAIDs continue to be contraindicated in the third trimester.

Keywords: acetaminophen [MeSH] pregnancy trimester; anti-inflammatory agents; drug-related side effects and adverse reactions [MeSH]; ductus arteriosus [MeSH]; non-steroidal [MeSH]; oligohydramnios [MeSH]; persistent fetal circulation syndrome [MeSH]; pregnancy trimester; renal insufficiency [MeSH]; second [MeSH]; stillbirth [MeSH]; third [MeSH].

Figure 1

Flow chart of the selection process for generating the final study cohort. Filter 1 and filter 2 criteria are listed in detail in Table S1. ICSR, Individual Case Safety Report; n, number of cases; Both, co-exposed to NSAID/PCM; NSAID, non-steroidal anti-inflammatory drug; PCM, paracetamol.