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Nezvalova-Henriksen et al. Table 3. Self-reported maternal health <strong>and</strong> pregnancy complications <strong>of</strong> the study population Women who used ibupr<strong>of</strong>en, dicl<strong>of</strong>enac, <strong>naproxen</strong>, <strong>and</strong>/or <strong>piroxicam</strong> anytime during pregnancy (n = 6511) Women who did not use any NSAID during pregnancy (n = 83 906) n % n % Maternal health during pregnancy Musculoskeletal pain 6206 95.3* 76 429 91.1 Headache including migraine 4289 65.9* 27 543 32.8 Temperature > 38.5°C 1342 21.8* 14 172 16.9 Proteinuria 890 13.7* 9714 11.6 Urinary tract infection <strong>and</strong>/or pyelonephritis 464 7.1** 5291 6.3 Hospitalisation*** 417 6.4* 3958 4.7 Involved in an accident 293 4.5* 2839 3.4 Pre-eclampsia <strong>and</strong>/or eclampsia 294 4.5* 3061 3.6 High blood pressure during the first trimester**** 284 4.4** 2998 3.6 Maternal health prior to pregnancy Musculoskeletal pain 3701 56.8* 40 565 48.3 Rheumatoid arthritis/systemic lupus erythematosus/ 551 8.5* 2614 3.1 fibromyalgia Depression 637 9.8* 5120 6.1 Asthma 517 7.9 6184 7.4 Cardiac disease 62 1.0 741 0.9 Thyroid disorder 191 2.9 2173 2.6 Diabetes (type I or II) 32 0.5 387 0.5 *Pearson’s v 2 test P < 0.001, when compared with the unexposed control group. **Pearson’s v 2 test P < 0.01 when compared with the unexposed control group. ***Excluding hospitalisation because <strong>of</strong> vaginal bleeding <strong>and</strong> high blood pressure. ****Defined as systolic blood pressure 140 mmHg. formed stratified analyses <strong>and</strong> found no effect modification from underlying medical conditions most commonly associated with NSAID use (musculoskeletal pain, headache, <strong>and</strong>/or migraine; results not presented). Discussion The principal finding in the present study is that there were no associations between the use <strong>of</strong> any <strong>of</strong> the four NSAIDs <strong>and</strong> congenital malformations. There was an increased risk <strong>of</strong> maternal vaginal bleeding associated with dicl<strong>of</strong>enac use late in pregnancy. Finally, there was a significant association between asthma in the child <strong>and</strong> ibupr<strong>of</strong>en use late in pregnancy. Strengths <strong>and</strong> limitations This study has several weaknesses that must be taken into consideration. The participation rate in the Norwegian Mother <strong>and</strong> Child Cohort Study was 38.5%, <strong>and</strong> this may have caused selection bias, especially with regard to prevalence estimates (women under the age <strong>of</strong> 25 years, without a partner, multipara, smokers, stillbirth, <strong>and</strong> neonatal death were all under-reported, whereas folic acid <strong>and</strong> multivitamin users were over-represented). However, two previous studies have concluded that only minor differences were found (under 2% in absolute differences in socio-demographic variables) between the Norwegian Mother <strong>and</strong> Child Cohort Study participants <strong>and</strong> the general Norwegian population <strong>of</strong> pregnant women, <strong>and</strong> no differences in the estimates <strong>of</strong> association measures were reported between the participants <strong>and</strong> the general population <strong>of</strong> pregnant women. 26,27 As shown in Figure 1, 13% <strong>of</strong> the women were excluded from the study because they did not complete questionnaire Q1 <strong>and</strong>/or Q2. We have no reason to believe that these women differed from the women who completed these questionnaires, but even so, we consider that although it might have affected the prevalence <strong>of</strong> medication use, it is unlikely that this factor has affected the associations between NSAID exposure <strong>and</strong> pregnancy outcomes. Notwithst<strong>and</strong>ing, the risk <strong>of</strong> misclassification errors arising from the possible under-reporting <strong>of</strong> NSAID use during pregnancy might bias the effect 6 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 Table 4. Adjusted odds ratios (ORs) for congenital malformations detected at birth in children <strong>of</strong> women who used ibupr<strong>of</strong>en, dicl<strong>of</strong>enac, <strong>naproxen</strong>, or <strong>piroxicam</strong> during pregnancy, compared with the unexposed control group Any congenital malformation* Use during pregnancy (total) Use during the first trimester n % OR 95% CI n % OR 95% CI Women who did not use any 4010/83 906 4.8 ref. ref. 4010/83 906 4.8 ref. ref. NSAIDs during pregnancy Ibupr<strong>of</strong>en 247/5325 4.6 1.0 0.8–1.1 140/3034 4.6 1.0 0.8–1.1 Dicl<strong>of</strong>enac 17/491 3.5 0.7 0.4–1.2 5/192 2.6 0.5 0.2–1.3 Naproxen 14/354 4.0 0.8 0.5–1.4 9/168 5.4 1.1 0.6–2.2 Piroxicam 6/150 4.0 0.8 0.4–1.9 4/82 4.9 1.0 0.4–2.8 Major congenital malformation* Women who did not use any 2203/83 906 2.6 ref. ref. 2203/83 906 2.6 ref. ref. NSAIDs during pregnancy Ibupr<strong>of</strong>en 130/5325 2.4 0.9 0.8–1.1 73/3034 2.4 0.9 0.7–1.2 Dicl<strong>of</strong>enac 12/491 2.4 0.9 0.5–1.6 2/192 1.0 0.4 0.1–1.5 Naproxen 9/354 2.5 1.0 0.5–1.9 7/168 4.2 1.6 0.7–3.5 Piroxicam 3/150 2.0 0.7 0.2–2.3 2/82 2.4 0.9 0.2–3.8 Structural heart defect detected during the first 18 months <strong>of</strong> age** Women who did not use any 1001/83 906 1.2 ref. ref. 1001/83 906 1.2 ref. ref. NSAIDs during pregnancy Ibupr<strong>of</strong>en 65/5325 1.2 1.0 0.8–1.3 44/3034 1.5 1.2 1.0–1.6 Dicl<strong>of</strong>enac 9/491 1.8 1.4 0.7–2.8 2/192 1.0 0.8 0.2–3.5 Naproxen 2/354 0.6 0.9 0.5–1.9 1/168 0.6 – – Piroxicam 4/150 2.7 2.3 0.8–6.2 2/82 2.4 2.3 0.5–9.3 *Data registered in the Medical Birth Registry <strong>of</strong> Norway. **Data self-reported by mother. Only infants referred to a specialist were included. estimates towards 1.0. On the other h<strong>and</strong>, some misclassification in the opposite direction may also have occurred because <strong>of</strong> the way multiple medications were coded when used in multiple time periods. We could not assess dosage <strong>and</strong> duration <strong>of</strong> NSAID use in detail: data that would have given us information about possible dose–response effects. The higher frequency <strong>of</strong> concomitant medication among NSAID users also merits attention; however, co-medication with potential teratogens <strong>and</strong> other medications with possible effects on certain pregnancy outcomes, <strong>and</strong> commonly used by the women, have been controlled for in the analyses. Despite the large sample size, we lacked power in this study to detect a possible increase in specific congenital anomalies (<strong>and</strong> rare pregnancy outcomes). Finally, because <strong>of</strong> the large number <strong>of</strong> analyses performed we cannot exclude the possibility that the associations we did find were caused by mass significance, although some <strong>of</strong> these associations were significant at the 1% level. Our results must be interpreted with these limitations in mind. On the other h<strong>and</strong>, the fact that our study included such a large number <strong>of</strong> participants made it possible to analyse the effect <strong>of</strong> individual NSAIDs on pregnancy outcome, instead <strong>of</strong> evaluating the group effect <strong>of</strong> these drugs. Few studies have achieved this so far. We included both overthe-counter <strong>and</strong> prescription NSAID use in our study, <strong>and</strong> the control group consisted <strong>of</strong> women who did not use any NSAIDs during pregnancy. Previous studies have used data from prescription registries, so that only prescribed NSAID use could be taken into account. In addition, in their control groups, women using over-the-counter NSAIDs were not excluded. 14,15,19 In the present study, we were able to avoid these potential limitations. Because <strong>of</strong> the vast quantity <strong>of</strong> data in The Norwegian Mother <strong>and</strong> Child Cohort Study <strong>and</strong> the MBRN, many important confounding factors, in particular underlying medical conditions, pregnancy complications, <strong>and</strong> lifestyle <strong>and</strong> medical characteristics <strong>of</strong> the infant were adjusted for in our study. This rigorous control for confounding factors has not been ª 2013 The Authors BJOG An International Journal <strong>of</strong> Obstetrics <strong>and</strong> Gynaecology ª 2013 RCOG 7
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