Nonsteroidal anti-inflammatory drugs for rheumatoid arthritis during pregnancy

Ana Florescu MSC, Gideon Koren MD, FRCPC

July 2005

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease of the joints. It affects women of reproductive age, so pregnancy complicated by RA is not uncommon. Most pregnant women find that RA tends to improve during pregnancy; it most often improves during the second and third trimesters.

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

1. Ostensen M, Ostensen H. Safety of nonsteroidal antiinflammatory 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 conventional nonsteroidal anti-inflammatory 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 miscarriage in pregnant users of non-steroidal anti-inflammatory 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. Effects of aspirin consumption 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 indomethacin 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 comparison 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. Efficacy and safety of indomethacin 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.

Published Motherisk Updates are available on the College of Family Physicians of Canada website.

Copyright Canadian Family Physician 2005;51:961-2.