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Ana Florescu MSC, Gideon Koren MD, FRCPC
July 2005
QUESTION
I am treating two pregnant patients who have rheumatoid arthritis with nonsteroidal anti-inflammatory drugs. Are these medications safe at high doses during pregnancy?
ANSWER
While these medications do not appear to increase overall rates of congenital malformations, they do increase the risk of ductus arteriosus constriction or closure.
QUESTION
Je traite deux patientes enceintes qui souffrent d'arthrite rhumatoïde avec des anti-inflammatoires non stéroïdiens. Ces médicaments sont-ils sûrs à fortes doses durant la grossesse?
RÉPONSE
Il ne semble pas que ces médicaments augmentent les taux globaux de malformations congénitales mais ils accroissent effectivement le risque de constriction ou d'obstruction du canal artériel.
Treating RA during pregnancy is particularly challenging. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy, despite reported and confirmed adverse effects on both mothers and fetuses when they are used for long periods. The principal mode of action of this class of anti-inflammatory drugs is their non-selective inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition to the desired effect of reducing inflammation, non-selective COX inhibitors also inhibit gastric, platelet, and renal production of prostaglandin.1
All NSAIDs cross the human placenta and are distributed to the fetus at term. Prenatal exposure to NSAIDs has been shown to increase the incidence of pulmonary hypertension, premature closure of the ductus arteriosus, and periventricular hemorrhage, and to impair fetal renal function leading to oligohydramnios.2 These effects have been reported for indomethacin, ibuprofen, ketoprofen, and diclofenac.1 Although risk of ductal closure increases during late pregnancy in women exposed to NSAIDs, closure is frequently resolved within 24 hours of stopping therapy.
Fetuses exposed to NSAIDs often have decreased urinary output,1 but as with ductal closure, the amniotic fluid usually returns to normal after therapy is stopped. Renal complications appear to be rare, considering the number of women treated with NSAIDs.3 Adverse renal effects reported include fatal anuria, renal failure, oliguria, and oligohydramnios.
A population-based retrospective study on use of NSAIDs showed that they did not increase adverse birth outcomes, but did increase risk of miscarriage.4 Although the sample size was large with no apparent selection bias, the study's retrospective design limits the reliability of its results.
Ostensen and Ostensen1 prospectively studied pregnant women with rheumatic disease to compare the incidence of adverse fetal effects between women exposed and not exposed to NSAIDs. They found no increased risk of teratogenicity or neonatal adverse outcomes in the group exposed to NSAIDs. Fetal echocardiographic studies were not conducted, however, so risk of transient ductal closure and reduced amniotic fluid volume could not be evaluated.
The only two NSAIDs extensively studied in pregnant women are acetylsalicylic acid and indomethacin. The Motherisk team recently reviewed ASA therapy5 and concluded that, overall, there was no increased risk of congenital malformations among fetuses exposed to ASA in utero. Case-control studies, however, showed an association between ASA and the rare condition gastroschisis. In most of these studies, ASA was used for upper respiratory tract infections, so it is possible that gastroschisis was induced by respiratory viruses. This possibility is attractive because gastroschisis has been associated also with a different drug used for upper respiratory tract infections, n-propanalamine.
Indomethacin has been linked to a variety of adverse fetal effects, documented in several trials.6-9 One study,6 found an increased incidence of pulmonary hypertension in the indomethacin group. Eronen et al9 also found an increased incidence of respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis in their indomethacin-exposed group.
A recent meta-analysis completed by Motherisk10 found a 15-fold increased risk of ductal constriction after brief (up to 48 hours) exposure to NSAIDs near term. No such risk seems to exist with use of NSAIDs during the first two trimesters. These data suggest a cautious approach, as it is likely that chronic use of NSAIDs in high doses, such as is necessary in the treatment of RA, is associated with an increased risk of adverse fetal effects.
References
Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Ms Florescu is a member and Dr Koren is Director of the Motherisk Program. Dr Koren is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation and, in part, by a grant from the Canadian Institutes of Health Research. He holds the Ivey Chair in Molecular Toxicology at the University of Western Ontario in London.
Published Motherisk Updates are available on the College of Family Physicians of Canada website.
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The information on this website is not intended as a substitute for the advice and care of your doctor or other health-care provider. Always consult your doctor if you have any questions about exposures during pregnancy and before you take any medications.
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