Effects of ibuprofen, diclofenac, naproxen, and piroxicam on ... - Sigo

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Nezvalova-Henriksen et al. achieved in previous studies. Another strength <strong>of</strong> our study was the accuracy <strong>of</strong> registration <strong>of</strong> major congenital malformations, which is confirmed to be high. 32,33 Finally, recall bias was avoided by the prospective collection <strong>of</strong> the majority <strong>of</strong> the data. Interpretation <strong>of</strong> results This study, like previous ones, 2–8 has shown that NSAID use, <strong>and</strong> ibupr<strong>of</strong>en use in particular, was quite common during pregnancy. We found that approximately one out <strong>of</strong> 14 women reported such use. Furthermore, a relatively high proportion <strong>of</strong> NSAID users were on sick leave, suffered from medical complications during pregnancy, <strong>and</strong> used other analgesics concomitantly. Despite the fact that NSAID use from gestational week 28 is essentially contraindicated, 34 1.3% used any <strong>of</strong> the four NSAIDs during the third trimester, <strong>and</strong> more than half <strong>of</strong> these initiated NSAID therapy during this period. It is not unlikely that these women needed NSAID therapy during the third trimester because exacerbations <strong>of</strong> musculoskeletal conditions may occur during this period. It has also been shown that many women are still not sufficiently informed about the safety <strong>of</strong> NSA- IDs during pregnancy, 35 <strong>and</strong> there is a possibility that at least some <strong>of</strong> the women continued taking these drugs during the third trimester without their doctor’s knowledge. With regards to congenital malformations, the results from this large prospective cohort study are generally reassuring. No significant associations were found between the use <strong>of</strong> ibupr<strong>of</strong>en, dicl<strong>of</strong>enac, <strong>naproxen</strong>, or <strong>piroxicam</strong> during the first trimester <strong>of</strong> pregnancy <strong>and</strong> an increased risk <strong>of</strong> overall or major congenital malformations. This is in accordance with the findings <strong>of</strong> other studies. 14,17,18 In addition, <strong>and</strong> contrary to the results presented by two previous studies, 15,16 no significant association was found between first-trimester use <strong>of</strong> any <strong>of</strong> the four NSAIDs <strong>and</strong> an increased risk <strong>of</strong> structural heart defects. This result is <strong>of</strong> particular interest given the nature <strong>and</strong> number <strong>of</strong> confounding factors we have been able to adjust for in our analyses (Appendix S1). In relation to vaginal bleeding <strong>and</strong> postpartum haemorrhage, there was some association with dicl<strong>of</strong>enac use towards the end <strong>of</strong> pregnancy. Even though dicl<strong>of</strong>enac has a relatively high selectivity for the cyclooxygenase–2 (COX– 2) enzyme, 70% <strong>of</strong> COX–1, the enzyme associated with platelet aggregation, is also inhibited at therapeutic levels <strong>of</strong> the drug. 36 In addition, dicl<strong>of</strong>enac has been shown to decrease uterine contractility in vitro, 37 a factor implicated in postpartum haemorrhage. It should be noted that dicl<strong>of</strong>enac use in the second trimester only, <strong>and</strong> not in the third trimester, was associated with postpartum haemorrhage. This last association thus seems pharmacologically implausible, <strong>and</strong>, taking Hill’s criteria for causality into consideration, 38 may indicate that the association could be a coincidence, <strong>and</strong> possibly subject to residual confounding. We found a significantly increased risk <strong>of</strong> low birthweight after exposure to ibupr<strong>of</strong>en <strong>and</strong> dicl<strong>of</strong>enac in the second trimester, but not after exposure to <strong>naproxen</strong> or <strong>piroxicam</strong>. This pregnancy outcome could at least in part be a result <strong>of</strong> underlying disease: for example, studies evaluating the effect <strong>of</strong> rheumatoid arthritis on pregnancy outcome have found an association with low birthweight. 39–41 Nevertheless, we adjusted for maternal musculoskeletal disease in our analyses, so an independent effect <strong>of</strong> these drugs on low birthweight cannot be ruled out. On the other h<strong>and</strong>, it was not possible to adjust for the severity <strong>of</strong> the diseases, so a confounding effect might still exist, <strong>and</strong> because <strong>of</strong> this we cannot state with certainty that there is a direct causative effect <strong>of</strong> the two drugs. 38 An association was found between ibupr<strong>of</strong>en use during the second <strong>and</strong> third trimester <strong>and</strong> infant asthma at 18 months <strong>of</strong> age. The association remained significant even after adjustment for several potentially important confounding factors, including: preterm delivery, smoking during pregnancy, in utero exposure to paracetamol, maternal asthma, breastfeeding, infant exposure to cigarette smoke, <strong>and</strong> postpartum infant exposure to ibupr<strong>of</strong>en <strong>and</strong> paracetamol, both directly <strong>and</strong> concurrently with breastfeeding. Terminal bronchioles are not developed before gestational week 28, <strong>and</strong> as postulated in one <strong>of</strong> the studies on the effect <strong>of</strong> paracetamol exposure in utero on the development <strong>of</strong> asthma in children, 42–44 fetal lungs are more likely to be influenced by external factors later in pregnancy, from the end <strong>of</strong> the second trimester onwards. 45 It has also been shown that it is COX–1 that is the prevailing is<strong>of</strong>orm in the airways, <strong>and</strong> its inhibition leads to bronchoconstriction. 46 Ibupr<strong>of</strong>en inhibits 90% <strong>of</strong> COX–1 at maximum plasma concentration. 47 In addition, bronchial hyperresponsiveness at 4 weeks <strong>of</strong> age is associated with asthma in the 6- <strong>and</strong> 11–year-old child. 48 All these factors support a possible causal relationship between ibupr<strong>of</strong>en use late in pregnancy <strong>and</strong> asthma in the 18–month-old child. Based upon a common mechanism <strong>of</strong> action among all NSAIDs, it is interesting that exposure to the other three drugs was not associated with asthma. This difference could be explained by a lack <strong>of</strong> power in the study for the other drugs, as the numbers <strong>of</strong> subjects exposed were considerably lower for these. This finding warrants further investigation. Conclusion The lack <strong>of</strong> associations with congenital malformations in the present study is particularly reassuring, despite the borderline association found between ibupr<strong>of</strong>en use in the first trimester <strong>and</strong> congenital heart defects. Maternal vaginal bleeding during pregnancy <strong>and</strong> postpartum was associated with dicl<strong>of</strong>enac use. In addition, asthmatic 10 ª 2013 The Authors BJOG An International Journal <strong>of</strong> Obstetrics <strong>and</strong> Gynaecology ª 2013 RCOG
Safety <strong>of</strong> individual NSAIDs during pregnancy symptoms in the child at 18 months <strong>of</strong> age were associated with ibupr<strong>of</strong>en use, <strong>and</strong> this could be a result <strong>of</strong> the mechanism <strong>of</strong> action <strong>of</strong> these drugs. The increased risk <strong>of</strong> low birthweight associated with both ibupr<strong>of</strong>en <strong>and</strong> dicl<strong>of</strong>enac may, at least in part, be attributable to underlying inflammatory conditions, <strong>and</strong> was, reassuringly, within the normal baseline risk range for low birthweight. Disclosure <strong>of</strong> interests None to declare. Contribution to authorship KNH performed the statistical analysis <strong>and</strong> wrote the article. KNH, OS, <strong>and</strong> HN planned the study, interpreted the results, revised the article, <strong>and</strong> approved the final draft. H.N. had overall responsibility for the study. Details <strong>of</strong> ethics approval The study was approved by the Regional Committee for Ethics in Medical Research, Region South, <strong>and</strong> the Norwegian Data Inspectorate. Acknowledgements The Norwegian Mother <strong>and</strong> Child Cohort Study is supported by the Norwegian Ministry <strong>of</strong> Health <strong>and</strong> the Ministry <strong>of</strong> Education <strong>and</strong> Research, National Institutes <strong>of</strong> Health/National Institute <strong>of</strong> Environmental Health Sciences (grant no. NO-ES-75558), National Institutes <strong>of</strong> Health/ National Institute <strong>of</strong> Neurological Disorders <strong>and</strong> Stroke (grant no. 1 UO1 NS 047537–01), <strong>and</strong> the Norwegian Research Council/Functional Genomics (grant no. 151918/ S10). We are grateful to all <strong>of</strong> the participants <strong>and</strong> their families for taking part in this study. Supporting Information Additional Supporting Information may be found in the online version <strong>of</strong> this article: Appendix S1. Overview <strong>of</strong> confounding factors controlled for in the logistic regression analyses. & References 1 Li D, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy <strong>and</strong> risk <strong>of</strong> miscarriage: population based cohort study. BMJ 2003;327:368–72. 2 Olesen C, Steffensen F, Nielsen G. de Jong-van den Berg L, Olsen J. Drug use in first pregnancy <strong>and</strong> lactation: a population-based survey among Danish women. Eur J Clin Pharmacol 1999;55:139–44. 3 Werler M, Mitchell A, Hern<strong>and</strong>ez-Diaz S, Honein M. <strong>and</strong> The National Birth Defects Prevention Study. Use <strong>of</strong> over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193:771–7. 4 Bonati M, Bortulus R, Marchetti F, Romero M, Tognoni G. Drug use in pregnancy: an overview <strong>of</strong> epidemiological (drug utilization) studies. Eur J Clin Pharmacol 1990;38:325–8. 5 Nordeng H, Eskild A, Nesheim B, Aursnes I, Jacobsen G. Drug use during early pregnancy. Eur J Clin Pharmacol 2001;57:529–63. 6 Nezvalova-Henriksen K, Spigset O, Nordeng H. Maternal characteristics <strong>and</strong> migraine pharmacotherapy during pregnancy: Cross sectional analysis <strong>of</strong> data from a large cohort study. Cephalalgia 2009; 29: 1267–76. 7 Nezvalova-Henriksen K, Spigset O, Nordeng H. Triptan exposure during pregnancy <strong>and</strong> the risk <strong>of</strong> major congenital malformations <strong>and</strong> adverse pregnancy outcomes: results from the Norwegian Mother <strong>and</strong> Child Cohort Study. Headache 2010;50:563–75. 8 Nezvalova-Henriksen K, Spigset O, Nordeng H. <strong>Effects</strong> <strong>of</strong> codeine on pregnancy outcome: results from a large population-based cohort study. Eur J Clin Pharmacol 2011;67:1253–62. 9 Ertresvag J, Zwart J-A, Helde G, Johnsen H-J, Bovim G. Headache <strong>and</strong> transient focal neurological symptoms during pregnancy, a prospective cohort. Acta Neurol Sc<strong>and</strong> 2005;111:233–7. 10 Marcus D, Scharff L, Turk D. Longitudinal prospective study <strong>of</strong> headache during pregnancy <strong>and</strong> postpartum. Headache 1999; 39:625–32. 11 Fast A, Shapiro D, Ducommun E, Friedmann L, Bouklas T, Floman Y. Low-back pain in pregnancy. Spine 1987;12:368–71. 12 Mantle M, Greenwood R, Currey H. Backache in pregnancy. Rheumatol Rehabil 1977;16:95–101. 13 Østensen M. Prescribing in pregnancy – Rheumatological disorders. Best Pract Res Clin Obstet Gynecol 2001;15:953–69. 14 Nielsen G, Sørensen H, Larsen H, Pedersen L. Risk <strong>of</strong> adverse birth outcome <strong>and</strong> miscarriage in pregnant users <strong>of</strong> non-steroidal antiinflammatory drugs: population based observational study <strong>and</strong> casecontrol study. BMJ 2001;322:266–70. 15 Ofori B, Oraichi D, Blais L, Rey E, Berard A. Risk <strong>of</strong> congenital anomalies in pregnant users <strong>of</strong> non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol 2006;77:268–79. 16 Ericson A, Kallen B. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5. 17 Kallen B, Olausson P. Maternal drug use in early pregnancy <strong>and</strong> infant cardiovascular defect. Reprod Toxicol 2003;17:255–61. 18 Cleves M, Savell V, Raj S. Maternal use <strong>of</strong> acetaminophen <strong>and</strong> nonsteroidal anti-inflammatory drugs (NSAIDs), <strong>and</strong> muscular ventricular septal defects. Birth Defects Res A 2004;70:107–13. 19 Daniel S, Matok I, Gorodischer R, Koren G, Uziel E, Wiznitzer A, et al. Major Malformations Following Exposure to Nonsteroidal Antiinflammatory Drugs During the First Trimester <strong>of</strong> Pregnancy. J Rheumatol 2012;39:2163–9. 20 Koren G, Florescu A, Costei A, Boskovic R, Moretti M. Nonsteroidal antiinflammatory drugs during third trimester <strong>and</strong> the risk <strong>of</strong> premature closure <strong>of</strong> the ductus arteriosus: a meta-analysis. Ann Pharmacother 2006;40:824–9. 21 Ostensen M, Skomsvoll J. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opin Pharmacother 2004;5:571–80. 22 Alano M, Ngougmna E, Ostrea E, Konduri G. Analysis <strong>of</strong> Nonsteroidal Antiinflammatory Drugs in Meconium <strong>and</strong> Its Relation to Persistent Pulmonary Hypertension <strong>of</strong> the Newborn. Pediatrics 2001; 107: 519–23. 23 Cuzzolin L. Dal Cere M, Fanos V. NSAID-induced nephrotoxicity from the fetus to the child. Drug Saf 2001;24:9–18. 24 Keaney N. Drug-induced lung disease. In: Walker R, Edwards C editors. Clinical Pharmacy <strong>and</strong> Therapeutics, 3rd edn. London: Churchill Livingstone; 2003. pp 414–5. 25 Norwegian Institute <strong>of</strong> Public Health. The Norwegian Mother <strong>and</strong> Child Cohort Study. Oslo, Norway: http://www.fhi.no/eway/default. aspx?pid=238&trg=MainArea_5811&MainArea_5811=5895:0:15,30 46:1:0:0:::0:0; 2012. ª 2013 The Authors BJOG An International Journal <strong>of</strong> Obstetrics <strong>and</strong> Gynaecology ª 2013 RCOG 11
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