Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (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 tolmetin, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (5,6). Moreover, as noted above, 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
Tolmetin is an NSAID used for the relief of the signs and symptoms of rheumatoid arthritis, juvenile arthritis, and osteoarthritis. It is in the same subclass (acetic acids) as three other NSAIDs (diclofenac, indomethacin, and sulindac).
Tolmetin is not teratogenic in rats and rabbits (7,8). The doses used in some of the studies were up to 1.5 times the maximum clinical dose based on a body weight of 60 kg (8).
It is not known if tolmetin crosses the human placenta. The molecular weight of the sodium salt (about 315) is low enough 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, 99 newborns had been exposed to tolmetin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (1.0%) infant had a major birth defect (four expected) consisting of a cardiovascular defect (one expected) and polydactyly (none 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 (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 COX-2 affinity, had a lower risk of this toxicity in humans than aspirin (12).
BREASTFEEDING SUMMARY
Tolmetin is excreted into breast milk (8,13). In the 4 hours following a single 400-mg oral dose, milk levels varied from 0.06 to 0.18 mcg/mL with the highest concentration occurring at 0.67 hour. Milk:plasma ratios were 0.005–0.007. The clinical significance of these levels to the nursing infant is unknown. The American Academy of Pediatrics classifies tolmetin as compatible with breastfeeding (14).
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.Nishimura K, Fukagawa S, Shigematsu K, Makumoto K, Terada Y, Sasaki H, Nanto T, Tatsumi H. Teratogenicity study of tolmetin sodium in rabbits. (Japanese) Iyakuhin Kenkyu 1977;8:158–64. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: The Johns Hopkins University Press, 1989:625.
8.Product information. Tolectin. Ortho-McNeil Pharmaceutical, 2001.
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 (Part B) 2003;68:3–4.
13.Sagraves R, Waller ES, Goehrs HR. Tolmetin in breast milk. Drug Intell Clin Pharm 1985;19:55–6.
14.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into breast milk. Pediatrics 2001;108:776–89.