Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy, as is inhibition of labor, prolongation of pregnancy, and suppression of fetal renal function (see also Indomethacin) (1). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (1,2). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including oxaprozin, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (3,4). Moreover, as noted below, nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with spontaneous abortions (SABs) and congenital malformations. The absolute risk for these defects, however, appears to be low.
FETAL RISK SUMMARY
Oxaprozin is an NSAID used in the treatment of acute and chronic arthritis. It is in the same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ibuprofen, ketoprofen, and naproxen).
The drug produced infrequent congenital malformations in rabbits treated with doses in the usual human range, but not in mice and rats (5). No teratogenic effects were observed in two other studies of pregnant rats and rabbits (6–9). A dose-dependent constriction of the ductus arteriosus, similar to that produced by other nonsteroidal anti-inflammatory agents, was observed in fetal rats (9).
It is not known if oxaprozin crosses the human placenta. The molecular weight (about 293) is low enough that passage to the fetus should be expected.
A combined 2001 population-based observational cohort study and a case–control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (10). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with SABs. A similar study, also published in 2001, failed to find a relationship, in general, between NSAIDs and congenital malformations, but did find a significant association with cardiac defects and orofacial clefts (11). In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (12). (See Ibuprofen for details on these three studies.)
A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, and specifically those with greater COX-2 affinity, had a lower risk of this toxicity in humans than aspirin (13).
BREASTFEEDING SUMMARY
No reports describing the use of oxaprozin during human lactation have been located. The molecular weight (about 293) is low enough that excretion into breast milk should be expected. One reviewer listed several NSAIDs (diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, and tolmetin) that were considered safer alternatives to other agents (oxaprozin not mentioned) if a NSAID was required while nursing (14). Because of the long terminal elimination half-life (approximately 42 hours or longer) in adults and the unknown amount of oxaprozin that is excreted into milk, any of these choices is probably preferable.
References
1.Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
2.Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.
3.Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93.
4.Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
5.Product information. Daypro. G.D. Searle, 2001.
6.Yamada T, Nishiyama T, Sasajima M, Nakane S. Reproduction studies of oxaprozin in the rat and rabbit. Iyakuhin Kenkyu 1984;15:207–92. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: The Johns Hopkins University Press, 1992:299–300.
7.Yamada T, Norariya T, Sasajima M, Nakane S. Reproduction studies of oxaprozin. II. Teratology study in rats. Iyakuhin Kenkyu 1984;15:225–49. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:132–3.
8.Yamada T, Uchida H, Sasajima M, Nakane S. Reproduction studies of oxaprozin. III. Teratogenicity study in rabbits. Iyakuhin Kenkyu 1984;15:250–64. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:132–3.
9.Yamada T, Inoue T, Hara M, Ohba Y, Nakame S, Uchida H. Reproductive studies of oxaprozin and studies on the fetal ductus arteriosus. Clin Report 1984;18:514–25, 528–36. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: The Johns Hopkins University Press, 1992:299–300.
10.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. Br Med J 2001;322:266–70.
11.Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.
12.Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. Br Med J 2003;327:368–71.
13.Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res (Part B) 2003;68:3–4.
14.Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.