New review of analgesics in pregnancy advises minimum dose for shortest time

Study results suggest that around 50% of women take over-the-counter analgesics during pregnancy.

Published 24 February 2021

Review of over-the-counter analgesics taken in pregnancy finds their prevalent use ‘high’ and increasing, with knowledge gaps apparent relating to fetal exposure and offspring health.

Over-the-counter analgesics are increasingly used by pregnant women, with as many as 50% using at least one medication in one European study. Now, a new review of OTC analgesic use during pregnancy describes this high prevalence as a ‘pressing issue’ - and with wide knowledge gaps relating to fetal exposure and the health of children.(1)

Prevalent use in pregnancy, which was one of the study’s objectives, is deemed ‘hard to quantify’, particularly as paracetamol and aspirin are routinely recommended for the relief of common pregnancy symptoms. Usually, report the reviewers, paracetamol is used for its analgesic and antipyretic properties in pregnant women, while NSAIDs, such as ibuprofen, are to treat mild to moderate pain and fever. Aspirin, they add, ‘is often prescribed to treat conditions such as pre-eclampsia, recurrent miscarriages and foetal growth restriction’. Measuring consumption, however, is complicated by their non-prescription status and varied reasons for use. Thus, a plethora of studies cited in the review fail to find a consensus level of consumption, but with many suggesting that around 50% of pregnant women use OTC paracetamol. Overall, however, the review reports that global use of OTC analgesics is ‘high’ and no doubt increasing.

So why should this matter? First, let’s not forget that several authorities have declared paracetamol ‘safe’ for use during pregnancy. For example, a 2019 report on behalf the UK’s Royal College of Obstetricians and Gynaecologists concluded that ‘paracetamol remains safe for use during pregnancy and breastfeeding, and its use in any trimester does not appear to increase the risk of major birth defects’.(2) However, on the broader front the same paper added that ‘analgesics should be used at the lowest effective dose for the shortest possible duration to minimise any potential risks to the mother, developing fetus or neonate’.

Nevertheless, a concern remains that many analgesics cross the placenta and reach the developing fetus, as confirmed in several studies measuring compounds and their metabolites in fetal plasma and amniotic fluid. What is not known, however – and one of the knowledge gaps identified by the reviewers – is whether all metabolites cross the placenta to the same degree and how that might relate to any apparent adverse outcomes from toxicity. This, say the authors, may affect different fetal organ systems, possibly at different levels of exposure. Thus, from the many studies explored, associated adverse effects have been reported for gastroschisis or miscarriage – though many others found no significant associations with birth defects or miscarriage.

Thus, the search for causation seems more about hypotheses than facts and the reviewers report that no definite conclusions can be drawn: ‘We cannot say confidently that OTC analgesics are indeed a direct cause of all observed offspring outcomes.’ The research presented in the review illustrates the challenges of these exposure studies, and underlines the need for follow-up studies on larger pregnancy cohorts in a wider time window – and there seems no research on OTC analgesics in such cohorts. So the reviewers echo the RCOG conclusions, that one realistic approach is ‘to caution against their indiscriminate use to ensure the minimum effective dose is administered for the shortest possible time’.

Nevertheless, despite the safety caveats, several recent studies have raised warning flags. A 2018 small meta-analysis of three rodent studies suggested that paracetamol taken in pregnancy has the potential to reduce fertility in female offspring (as seen in reduction of primordial follicles and irregular menstrual cycles).(3) Just a few weeks later, another study, performed on fetuses obtained from induced terminations of pregnancy, found a ‘dramatic loss’ of ovarian germ cells in those exposed to ibuprofen during the first trimester of pregnancy – but not in those unexposed.(4) A press statement released with this study and accompanying comments noted that ‘paracetamol should be preferred to any anti-inflammatory drug up to 24 gestational weeks’, and otherwise for as short a time as necessary.

1. Zafeiri A, Mitchell RT, Hay DC, et al. Over-the-counter analgesics during pregnancy: a comprehensive review of global prevalence and offspring safety. Hum Reprod Update 2021; 27: 67-95.
2. Bisson DL, Newell SD, Laxton C. Antenatal and postnatal analgesia. BJOG 2019; 126: e114-e124.
3. Arendrup FS, Mazaud-Guittot S, Jégou B, Kristensen DM. Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development? Endocrin Connect 2018; doi: 10.1530/EC-17-0298.
4. Leverrier-Penna S, Mitchell RT, Becker E, et al. Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo. Hum Reprod 2018; 33: 482-493.

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