Risk estimation of fetal adverse effects after short-term second trimester exposure to non-steroidal anti-inflammatory drugs: a literature review
- 36 Downloads
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.
KeywordsAnti-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.
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.
- 5.Holmes RP, Stone PR (2000) Severe oligohydramnios induced by cyclooxygenase-2 inhibitor nimesulide. Obstet Gynecol 96(5 Pt 2):810–811Google Scholar
- 6.Lopes LM, Carrilho MC, Francisco RP, Lopes MA, Krebs VL, Zugaib M (2016) Fetal ductus arteriosus constriction and closure: analysis of the causes and perinatal outcome related to 45 consecutive cases. J Matern Fetal Neonatal Med 29(4):638–645. https://doi.org/10.3109/14767058.14762015.11015413 CrossRefGoogle Scholar
- 14.Gouyon JB, Petion AM, Sandre D, Sgro C, Bavoux F (1991) Neonatal kidney insufficiency and intrauterine exposure to ketoprofen. Arch Fr Pediatr 48(5):347–348Google Scholar
- 24.Truter PJ, Franszen S, van der Merwe JV, Coetzee MJ (1986) Premature closure of the ductus arteriosus causing intra-uterine death. A case report. S Afr Med J 70(9):557–558Google Scholar
- 25.Van den Veyver IB, Moise KJ Jr, Ou CN, Carpenter RJ Jr (1993) The effect of gestational age and fetal indomethacin levels on the incidence of constriction of the fetal ductus arteriosus. Obstet Gynecol 82(4 Pt 1):500–503Google Scholar
- 26.Vermillion ST, Scardo JA, Lashus AG, Wiles HB (1997) The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age. Am J Obstet Gynecol 177(2):256–259Google Scholar
- 27.Hickok DE, Hollenbach KA, Reilley SF, Nyberg DA (1989) The association between decreased amniotic fluid volume and treatment with nonsteroidal anti-inflammatory agents for preterm labor. Am J Obstet Gynecol 160(6):1525–1530Google Scholar
- 28.Jacqz-Aigrain E, Guillonneau M, Boissinot C, Bavoux F, Hartmann JF, Blot P (1993) Maternal and neonatal effects of indomethacin administrated during pregnancy. Apropos of 18 cases. Arch Fr Pediatr 50(4):307–312Google Scholar
- 30.World Health Organization (2015) WHO guidelines approved by the guidelines review committee. WHO recommendations on interventions to improve preterm birth outcomesGoogle Scholar
- 31.Pham JT, Carlos MA (2002) Current treatment strategies of symptomatic patent ductus arteriosus. J Pediatr Health Care 16(6):306–310Google Scholar
- 33.Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, Zea AM, Zhang Y, Sadeghirad B, Thabane L (2018) Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA 319(12):1221–1238. https://doi.org/10.1001/jama.2018.1896 CrossRefGoogle Scholar
- 40.Marti Sole JJ, Pasarisas Sala M (1996) A possible association between the maternal administration of metamizole and persistent pulmonary hypertension in a newborn infant. An Esp Pediatr 44(4):387–388Google Scholar
- 42.Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF (1996) Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 97(5):658–663Google Scholar
- 43.Abramov Y, Nadjari M, Weinstein D, Ben-Shachar I, Plotkin V, Ezra Y (2000) Indomethacin for preterm labor: a randomized comparison of vaginal and rectal-oral routes. Obstet Gynecol 95(4):482–486Google Scholar
- 45.Gardner MO, Owen J, Skelly S, Hauth JC (1996) Preterm delivery after indomethacin. A risk factor for neonatal complications? J Reprod Med 41(12):903–906Google Scholar
- 47.Uslu T, Ozcan FS, Aydin C (1992) Oligohydramnios induced by maternal indomethacin therapy. Int J Clin Pharmacol Ther Toxicol 30(7):230–232Google Scholar