Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Prostaglandin synthesis inhibitors can cause constriction of the ductus arteriosus in utero (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). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (3) (see also Indomethacin), and in animals (4). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including fenoprofen, because of the findings in various animal models that indicate these agents block blastocyst implantation (5,6). Moreover, nonsteroid 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
Fenoprofen is an NSAID in the same subclass (propionic acids) as five other agents (flurbiprofen, ibuprofen, ketoprofen, naproxen, and oxaprozin). It is indicated for the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis (7).
Fenoprofen given to rats during pregnancy and continued until labor resulted in prolonged parturition (7).
It is not known if fenoprofen crosses the human placenta. The molecular weight (about 559) is low enough that passage to the fetus should be expected. However, in one study, the drug was used during labor (8). No data were given except that the drug could not be detected in cord blood or amniotic fluid.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 191 newborns had been exposed to fenoprofen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of six (3.1%) major birth defects were observed (eight expected), including (observed/expected) 1/2 cardiovascular defects and 1/1 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. These data do not support an association between the drug and congenital 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 (9). 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 (10). In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (11) (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 cyclooxygenase-2 (COX-2) affinity, had a lower risk of this toxicity in humans than aspirin (12).
BREASTFEEDING SUMMARY
Fenoprofen passes into breast milk in very small quantities. The milk:plasma ratio in nursing mothers given 600 mg every 6 hours for 4 days was approximately 0.017 (8). Although the clinical significance of this amount is unknown, another NSAID in the same subclass is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Ibuprofen).
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.Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
4.Powell JG, Cochrane RL. The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat. Prostaglandins 1982;23:469–88.
5.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.
6.Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
7.Product information. Nalfon. Dista Products, 2001.
8.Rubin A, Chernish SM, Crabtree R, Gruber CM Jr, Helleberg L, Rodda BE, Warrick P, Wolen RL, Ridolfo AS. A profile of the physiological disposition and gastro-intestinal effects of fenoprofen in man. Curr Med Res Opin 1974;2:529–44.
9.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.
10.Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.
11.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.
12.Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 2003;68:3–4.