Pratique clinique Clinical Pract ice
R
heumatoid arthritis (RA) is a systemic auto- immune infl ammatory disease of the joints. It aff ects women of reproductive age, so pregnancy complicated by RA is not uncommon. Most preg- nant women fi nd that RA tends to improve during pregnancy; it most often improves during the sec- ond and third trimesters.Treating RA during pregnancy is particularly challenging. Nonsteroidal anti-infl ammatory drugs (NSAIDs) are the mainstay of therapy, despite reported and confirmed adverse effects on both mothers and fetuses when they are used for long peri- ods. Th e principal mode of action of this class of anti- infl ammatory drugs is their non-selective inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition to the desired eff ect of reducing infl amma- tion, 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 inci- dence of pulmonary hypertension, premature clo- sure 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, keto- profen, 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 amni- otic fl uid usually returns to normal after therapy is stopped. Renal complications appear to be rare, con- sidering 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
Nonsteroidal anti-infl ammatory drugs for rheumatoid arthritis during pregnancy
Ana Florescu, MSC Gideon Koren, MD, FRCPC
ABSTRACT
QUESTION I am treating two pregnant patients who have rheumatoid arthritis with nonsteroidal anti-infl ammatory 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.
RÉSUMÉ
QUESTION Je traite deux patientes enceintes qui souff rent d’arthrite rhumatoïde avec des anti-infl ammatoires 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 eff ectivement le risque de constriction ou d’obstruction du canal artériel.
Motherisk Update
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Clinical Pract ice Pratique clinique
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miscarriage.4 Although the sample size was large with no apparent selection bias, the study’s retro- spective design limits the reliability of its results.
Ostensen and Ostensen1 prospectively studied pregnant women with rheumatic disease to com- pare the incidence of adverse fetal eff ects between women exposed and not exposed to NSAIDs. Th ey found no increased risk of teratogenicity or neo- natal adverse outcomes in the group exposed to NSAIDs. Fetal echocardiographic studies were not conducted, however, so risk of transient ductal clo- sure and reduced amniotic fl uid volume could not be evaluated.
The only two NSAIDs extensively studied in pregnant women are acetylsalicylic acid and indo- methacin. The Motherisk team recently reviewed ASA therapy5 and concluded that, overall, there was no increased risk of congenital malforma- tions among fetuses exposed to ASA in utero.
Case-control studies, however, showed an asso- ciation between ASA and the rare condition gas- troschisis. 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 tri- als.6-9 One study,6 found an increased incidence of pulmonary hypertension in the indomethacin group. Eronen et al9 also found an increased inci- dence of respiratory distress syndrome, broncho- pulmonary dysplasia, and necrotizing enterocolitis in their indomethacin-exposed group.
A recent meta-analysis completed by Motherisk10 found a 15-fold increased risk of duc- tal constriction after brief (up to 48 hours) expo- sure to NSAIDs near term. No such risk seems to exist with use of NSAIDs during the fi rst two tri- mesters. Th ese 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 eff ects.
References
1. Ostensen M, Ostensen H. Safety of nonsteroidal antiinfl ammatory drugs in pregnant patients with rheumatic disease. J Rheumatol 1996;23(6):1045-9.
2. Hernández-Díaz S, García-Rodríguez LA. Epidemiologic assessment of the safety of con- ventional nonsteroidal anti-infl ammatory drugs. Am J Med 2001;110(3 Suppl 1):20-7S.
3. Cuzzolin L, Dal Cere M, Fanos V. NSAID-induced nephrotoxicity from the fetus to the child. Drug Saf 2001;24(1):9-18.
4. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and mis- carriage in pregnant users of non-steroidal anti-infl ammatory drugs: population based observational study and case-control study. BMJ 2001;322(7281):266-70.
5. Kozer E, Costei AM, Boskovic R, Nulman I, Nikfar S, Koren G. Eff ects of aspirin consump- tion during pregnancy on pregnancy outcomes: meta-analysis. Birth Defects Res B Dev Reprod Toxicol 2003;68(1):70-84.
6. Besinger RE, Niebyl JR, Keyes WG, Johnson TR. Randomized comparative trial of indo- methacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol 1991;164(4):981-6. Discussion Am J Obstet Gynecol 1991;164(4):986-8.
7. Kurki T, Eronen M, Lumme R, Ylikorkala O. A randomized double-dummy compari- son between indomethacin and nylidrin in threatened preterm labor. Obstet Gynecol 1991;78(6):1093-7.
8. Morales WJ, Smith SG, Angel JL, O’Brien WF, Knuppel RA. Effi cacy and safety of indo- methacin versus ritodrine in the management of preterm labor: a randomized study. Obstet Gynecol 1989;74(4):567-72.
9. Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala O, Hallman M. Increased incidence of bronchopulmonary dysplasia after antenatal administration of indomethacin to prevent preterm labor. J Pediatr 1994;124(5 Pt 1):782-8.
10. Costei AM, Florescu A, Boskovic R, Koren G. NSAIDs during the third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. In press.
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.
Do you have questions about the safety of drugs, chemi- cals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at (416) 813-7562; they will be addressed in future Motherisk Updates.
Published Motherisk Updates are available on the College of Family Physicians of Canada website (www.cfpc.ca). These articles are also published on the Motherisk website (www.
motherisk.org).
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