Risk Factor: BM*
Class: Central nervous system drugs/ Nonsteroidal anti-inflammatory drugs
Fetal Risk Summary
Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. It is in the same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ibuprofen, naproxen, and oxaprozin).
Reproductive studies in mice and rats at about 0.2 times the maximum recommended human dose based on body surface area revealed no teratogenic or embryotoxic effects (1). In rabbits, maternally toxic doses were embryotoxic but not teratogenic (1). Shepard reviewed four animal studies using mice, rats, and monkeys and found no adverse fetal effects or congenital malformations (2).
It is not known if ketoprofen crosses the human placenta. The molecular weight (about 254) is low enough, however, that passage to the fetus should be expected.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 112 newborns had been exposed to ketoprofen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (2.7%) major birth defects were observed (five expected), including (expected/observed) 1/1 cardiovascular defect and 1/0.3 polydactyly. No anomalies were observed in four other categories of defects (oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available.
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 (3). 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) (4). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (4). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (5) (see also Indomethacin) and in animals (6). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ketoprofen, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (7,8). Moreover, as noted above, NSAIDs have been associated with SABs.
[*Risk Factor D if used in 3rd trimester or near delivery.]
Breast Feeding Summary
No reports on the use of ketoprofen in lactating humans have been located. The low molecular weight (about 254) suggests that the drug will be excreted into breast milk. The effects of this exposure on a nursing infant are unknown. Ketoprofen is excreted into the milk of lactating dogs, with milk concentrations about 4%5% of plasma levels (1). Another NSAID in the same subclass is considered compatible with breast feeding by the American Academy of Pediatrics (see Ibuprofen).
- Product information. Orudis, Oruvail. Wyeth-Ayerst Pharmaceuticals, 2000.
- Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:364.
- Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal antiinflammatory 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 non-steroidal 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.