Risk Factor: CM*
Class: Central nervous system drugs/ Nonsteroidal anti-inflammatory drugs
Fetal Risk Summary
Diflunisal is a nonsteroidal antiinflammatory agent (NSAID) used in the treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. The drug is teratogenic and embryotoxic in rabbits administered 4060 mg/kg/day, the highest dose equivalent to 2 times the maximum human dose (1). Similar results were not observed in mice and rats treated with 45100 mg/kg/day (1,2) or in monkeys treated with 80 mg/kg during organogenesis (3). No published reports describing the use of this drug in human pregnancy have been located.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 258 newborns had been exposed to diflunisal during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 19 (7.4%) major birth defects were observed (10 expected). Specific data were available for six defect categories, including (observed/expected) 1/3 cardiovascular defects, 1/0.4 oral clefts, 0/0 spina bifida, 1/1 polydactyly, 0/0 limb reduction defects, and 1/1 hypospadias. It remains to be investigated whether an unusual frequency distribution of the other 15 defects is in the overall excess of birth defects.
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 (4). 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 spontaneous abortions (see Ibuprofen for details).
Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (see also Indomethacin) (5). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (5). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (6) (see also Indomethacin), and in animals (7). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including diflunisal, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (8,9).
[*Risk Factor D if used in 3rd trimester or near delivery.]
Breast Feeding Summary
Diflunisal is excreted into human milk. Milk concentrations range from 2% to 7% of the levels in the mother’s plasma (1). No reports describing the use of this agent during lactation have been located.
- Product information. Dolobid. Merck Sharpe & Dohme, 1993.
- Nakatsuka T, Fujii T. Comparative teratogenicity study of diflunisal (MK-647) and aspirin in the rat. Oyo Yakuri 1979;17:5517. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:222.
- Rowland JM, Robertson RT, Cukierski M, Prahalada S, Tocco D, Hendrickx AG. Evaluation of the teratogenicity and pharmacokinetics of diflunisal in cynomolgus monkeys. Fund Appl Toxicol 1987;8:518. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:222.
- Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of nonsteroidal anti-inflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:26670.
- Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:3544.
- Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:80920.
- Powell JG, Cochrane RL. The effects of a number of nonsteroidal anti-inflammatory compounds on parturition in the rat. Prostaglandins 1982;23:46988.
- Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Witorsch RJ, editor. Reproductive Toxicology. 2nd ed. New York, NY:Raven Press, 1995:17593.
- Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:125565.