Risk estimation of fetal adverse effects after short-term second trimester exposure to non-steroidal anti-inflammatory drugs: a literature review

  • Katarina DatheEmail author
  • Stefanie Hultzsch
  • Lucas William Pritchard
  • Christof Schaefer



Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended in the 3rd trimester of pregnancy due to known fetal adverse effects in an advanced gestational age. This investigation was performed to assess whether there is a significant risk of NSAIDs being used as an analgesic or antipyretic medication in the 2nd trimester.


A systematic search for publications reporting 2nd trimester NSAID exposure was performed in MEDLINE. The search focused on case descriptions reporting defined adverse effects including prenatal ductus arteriosus constriction, oligohydramnios, neonatal renal failure, and primary pulmonary hypertension. Original articles published until February 2018 were considered for evaluation.


Out of 681 identified publications, 26 included relevant information on the defined adverse effects. Among these publications, premature labor was the major reason for 2nd trimester indomethacin treatment while other clinical indications and other NSAIDs were underrepresented. Narrowing or closure of the ductus arteriosus in the 2nd trimester was described in 33 fetuses. Only eight publications reported adverse effects after less than 7-day exposure during the 2nd trimester.


Based on these results, short-term use of NSAIDs as analgesics or antipyretics in the 2nd trimester does not appear to pose a substantial risk for fetal adverse effects. Long-term use in the late 2nd trimester, however, should always be monitored.


Anti-inflammatory agents, non-steroidal [MeSH] Pregnancy trimester, second [MeSH] “Fetus” [MeSh] Oligohydramnios [MeSH] Ductus arteriosus [MeSH] Renal insufficiency [MeSH] 



We thank Luisa Maria Köhler and Verena Linsenmeier who helped to obtain the required full-text publications. Part of the literature review will be included in the thesis of Lucas William Pritchard.

Authors’ contributions

KD and CS developed the approach. KD and LWP developed the search strategy and conducted the literature search. KD, LWP, and SH screened the articles. KD and SH extracted the data from the relevant literature and created the evidence tables. All the listed authors participated in the result interpretation. KD and CS wrote the first draft of the manuscript, and all authors critically revised subsequent manuscript drafts and contributed essential discussion points. LWP edited the manuscript. All the listed authors approved the final manuscript.


This work was funded by the German Federal Institute for Drugs and Medical Devices (BfArM).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

228_2019_2712_MOESM1_ESM.pdf (174 kb)
Supplementary Table 1 (PDF 174 kb)
228_2019_2712_MOESM2_ESM.pdf (180 kb)
Supplementary Table 2 (PDF 179 kb)
228_2019_2712_MOESM3_ESM.pdf (546 kb)
Supplementary Table 3 (PDF 545 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie, Institut für Klinische Pharmakologie und ToxikologieBerlinGermany

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