Risk Factor: BM*
Class: Central nervous system drugs/ Nonsteroidal anti-inflammatory drugs
Fetal Risk Summary
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used in the management of the signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and juvenile arthritis. It is in same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ibuprofen, ketoprofen, and oxaprozin). Drugs in this class have been shown to inhibit labor and to prolong the length of pregnancy (1).
At 0.230.28 times the human systemic exposure at the recommended dose, no evidence of impaired fertility or fetal harm was seen in mice, rats, and rabbits (2). A 1990 report described an investigation on the effects of several nonsteroidal antiinflammatory agents on mouse palatal fusion both in vivo and in vitro (3). The compounds, including naproxen, were found to induce cleft palate.
Consistent with the relatively low molecular weight (about 230), naproxen readily crosses the placenta to the fetal circulation. In a mother treated with 250 mg of naproxen every 8 hours for four doses, cord blood levels in twins 5 hours after the last dose were 59.5 and 68 g/mL (4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,448 newborns had been exposed to naproxen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 70 (4.8%) major birth defects were observed (62 expected). Specific data were available for six defect categories, including (observed/expected) 14/14 cardiovascular defects, 2/2 oral clefts, 0/1 spina bifida, 3/4 polydactyly, 2/2 limb reduction defects, and 3/3 hypospadias. 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 (5). 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 (SABs) (see Ibuprofen for details).
Prostaglandin synthesis inhibitors may cause constriction of the ductus arteriosus in utero, which may result in primary pulmonary hypertension of the newborn (6,7). The dose, duration, and period of gestation are important determinants of these effects. Most studies of NSAIDs used as tocolytics have indicated that the fetus is relatively resistant to premature closure of the ductus before the 34th or 35th week of gestation (see Indomethacin). However, three fetuses (one set of twins) exposed to naproxen at 30 weeks for 26 days in an unsuccessful attempt to halt premature labor had markedly decreased plasma concentrations of prostaglandin E (5,8). Primary pulmonary hypertension of the newborn with severe hypoxemia, increased blood clotting times, hyperbilirubinemia, and impaired renal function were observed in the newborns. One infant died 4 days after birth, probably because of subarachnoid hemorrhage. Autopsy revealed a short and constricted ductus arteriosus. Use in other patients for premature labor at 34 weeks or earlier has not result in neonatal problems (9,10).
In a case report published in 2000, a mother took an over-the-counter preparation of naproxen 220 mg twice a day over the 4 days immediately preceding birth of a term 3790-g male infant (11). Within 2 hours of birth the infant developed typical signs and symptoms of primary pulmonary hypertension with a closed ductus arteriosus. Conservative management was initiated and the infant was improving by the sixth postnatal day. At 6 weeks of age, the infant was doing well clinically without cyanosis.
Because of the potential newborn toxicity, naproxen should not be used late in the 3rd trimester (2,5,12). Moreover, women attempting to conceive should not use any prostaglandin synthesis inhibitor, including naproxen, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (13,14). In addition, as noted above, NSAIDs have been associated with SABs.
[*Risk Factor D if used in 3rd trimester or near delivery.]
Breast Feeding Summary
Naproxen passes into breast milk in very small quantities. The milk:plasma ratio is approximately 0.01 (2). Following 250 or 375 mg twice daily, maximum milk levels were found 4 hours after a dose and ranged from 0.7 to 1.25 g/mL and 1.76 to 2.37 g/mL, respectively (15,16). The total amount of naproxen excreted in the infant’s urine was 0.26% of the mother’s dose. The effect on the infant from these amounts is unknown. The American Academy of Pediatrics considers naproxen to be compatible with breast feeding (17).
- Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:80920.
- Product information. Naprosyn. Roche Laboratories, 2000.
- Montenegro MA, Palomino H. Induction of cleft palate in mice by inhibitors of prostaglandin synthesis. J Craniofac Genet Del Biol 1990;10:8394.
- Wilkinson AR. Naproxen levels in preterm infants after maternal treatment. Lancet 1980;2:5912.
- 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;322:26670.
- Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:3544.
- Rudolph AM. The effects of nonsteroidal antiinflammatory compounds on fetal circulation and pulmonary function. Obstet Gynecol 1981;58(Suppl):63s7s.
- Wilkinson AR, Aynsley-Green A, Mitchell MD. Persistent pulmonary hypertension and abnormal prostaglandin E levels in preterm infants after maternal treatment with naproxen. Arch Dis Child 1979;54:9425.
- Gerris J, Jonckheer M, Sacre-Smits L. Acute hyperthyroidism during pregnancy: a case report and critical analysis. Eur J Obstet Gynecol Reprod Biol 1981;12:27180.
- Wiqvist N, Kjellmer I, Thiringer K, Ivarsson E, Karlsson K. Treatment of premature labor by prostaglandin synthetase inhibitors. Acta Biol Med Germ 1978;37:92330.
- Talati AJ, Salim MA, Korones SB. Persistent pulmonary hypertension after maternal naproxen ingestion in a term newborn: a case report. Am J Perinatol 2000;17:6971.
- Anonymous. PG-synthetase inhibitors in obstetrics and after. Lancet 1980;2:1856.
- 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.
- Jamali F, Tam YK, Stevens RD. Naproxen excretion in breast milk and its uptake by suckling infant (abstract). Drug Intell Clin Pharm 1982;16:475.
- Jamali F, Stevens DRS. Naproxen excretion in milk and its uptake by the infant. Drug Intell Clin Pharm 1983;17:91011.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.