Fetal Risk Summary
Reproductive studies with phenylbutazone in rats and rabbits have not revealed teratogenicity or adverse fetal effects (1,2). However, an increase in stillbirths and decreased survival of newborns have been observed in these species (3).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 27 newborns had been exposed to phenylbutazone during the 1st trimester (F. Rosa, personal communication, FDA, 1993). The total number of major birth defects observed was not available, but at least two (7.4%) occurred (one expected), including (observed/expected) 1/0.3 cardiovascular defects and 1/0 spina bifida. No anomalies were observed in four other defect categories (oral clefts, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
Two reports have been located that describe congenital defects in the offspring of mothers consuming phenylbutazone during pregnancy (4,5). A causal relationship was not established in either case. One review on the use of antirheumatic drug treatment during pregnancy stated that phenylbutazone is nonteratogenic in humans (6). The drug is known to cross the placenta to the human fetus (7,8 and 9).
Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (see also Indomethacin) (10). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (10). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (11) (see also Indomethacin) and in animals (12). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including phenylbutazone, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (13,14). In addition, a possible association between this class of agents and abortion may exist (see Ibuprofen).
[*Risk Factor D if used in 3rd trimester or near delivery.]
Breast Feeding Summary
Phenylbutazone is excreted into breast milk in low concentrations, although some investigators failed to detect the drug 3 hours after maternal administration (15). The drug has been measured in infant serum after breast feeding, but no adverse effects in the nursing infant have been reported. The American Academy of Pediatrics considers phenylbutazone to be compatible with breast feeding (16).
- Larsen V, Bredahl E. The embryotoxic effects on rabbits of monophenylbutazone (Monazen) compared with phenylbutazone and thalidomide. Acta Pharmacol Toxicol 1966;24:4535. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:500.
- Schardein JL, Blatz AT, Woosley ET, Kaup DH. Reproductive studies on sodium meclofenamate in comparison to aspirin and phenylbutazone. Toxicol Appl Pharmacol 1969;15:4655. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:500.
- Product information. Butazolidin. Geigy Pharmaceuticals, 1993.
- Tuchmann-Duplessis H. Medication in the course of pregnancy and teratogenic malformation. Concours Med 1967;89:211920.
- Kullander S, Kallen B. A prospective study of drugs in pregnancy. Acta Obstet Gynecol Scand 1976;55:28995.
- Ostensen M, Husby G. Antirheumatic drug treatment during pregnancy and lactation. Scand J Rheumatol 1985;14:17.
- Leuxner E, Pulver R. Verabreichung von irgapryin bei schwangeren und wochnerinnen. Munchen Med Wochenschr 1956;98:846.
- Strobel S, Leuxner E. Uber die zullassigkeit der verabreichung von butazolidin bei schwangeren und wochnerinnen. Med Klin 1957;39:170810.
- Akbaraly R, Leng JJ, Brachet-Liermain A, White P, Laclau-Lacrouts B. Trans-placental transfer of four anti-inflammatory agents. A study carried out by in vitro perfusion. J Gynecol Obstet Biol Reprod (Paris) 1981;10:711.
- 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, ed. 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.
- Wilson JT. Milk/plasma ratios and contraindicated drugs. In Wilson JT, ed. Drugs in Breast Milk. Balgowlah, Australia: ADIS Press, 1981:789.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.