PROPOXYPHENE

Fetal Risk Summary

Four case reports, involving five patients, have described the use of propoxyphene during pregnancies that resulted in infants with congenital abnormalities (1,2,3 and 4). However, other drugs were used in each case and any association may be fortuitous: Pierre Robin syndrome, arthrogryposis, severe mental and growth retardation (1 infant) (1) Absence of left forearm and radial two digits, syndactyly of ulnar three digits and left fourth and fifth toes, hypoplastic left femur (1 infant) (2) Omphalocele, defective anterior left wall, diaphragmatic defect, congenital heart disease with partial ectopic cordis because of sternal cleft, dysplastic hips (1 infant) (2) Micrognathia, widely spaced sutures, beaked nose, bifid uvula, defects of toes, withdrawal seizures (1 infant) (3) Bilateral anophthalmia (1 infant) (4) A 1982 study of 350 patients with congenital contractures of the joints (arthrogryposis) concluded that only 15 had been exposed to a possible teratogen) (5). One of the 15 cases involved a 24-year-old woman who had consumed, at 2 months' gestation, propoxyphene (65 mg) and methocarbamol (750 mg) 2–3 times daily for 3 days to treat severe back pain. The term female infant was noted at birth to have multiple joint contractures involving the thumbs, wrists, elbows, knees, and feet. The latter were described as a bilateral equinovarus deformity. There were practically no foot creases. Other abnormalities present were frontal bosselation, a midline hemangioma, and weak abdominal musculature. Development was normal at 3 years of age except for the joint contractures, which had improved with time, and a grade I/VI systolic murmur. The cause of the malformations was unknown, although the authors speculated that there may have been a link to methocarbamol (5).

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 686 of which had 1st trimester exposure to propoxyphene (6, pp. 287–295). For use anytime during pregnancy, 2,914 exposures were recorded (6, p. 434). No evidence was found in either group to suggest a relationship to large categories of major or minor malformations or, in the 1st trimester, to individual defects. Five possible associations with individual defects after anytime use were observed (6, p. 484): Microcephaly (6 cases) Ductus arteriosus persistens (5 cases) Cataract (5 cases) Benign tumors (12 cases) Clubfoot (18 cases) The statistical significance of these associations is unknown and independent confirmation is required.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,029 newborns had been exposed to propoxyphene during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 41 (4.0%) major birth defects were observed (43 expected). Specific data were available for six defect categories, including (observed/expected) 10/10 cardiovascular defects, 2/2 oral clefts, 0/1 spina bifida, 3/3 polydactyly, 0/2 limb reduction defects, and 1/2 hypospadias. These data do not support an association between the drug and congenital defects.

Neonatal withdrawal has been reported in five infants (3,7,8,9 and 10). The relationship between heavy maternal ingestion of this drug and neonatal withdrawal seems clear. The infants were asymptomatic with normal Apgar scores until 3.5–14 hours after delivery. Withdrawal was marked by the onset of irritability, tremors, diarrhea, fever, high-pitched cry, hyperactivity, hypertonicity, diaphoresis, and, in two cases, seizures. Symptoms began to subside by day 4, usually without specific therapy. Examinations after 2–3 months were normal.

Propoxyphene has been used in labor without causing neonatal respiratory depression (11). However, a significant shortening of the first stage of labor occurred without an effect on uterine contractions.

[*Risk Factor D if used for prolonged periods.]

Breast Feeding Summary

Propoxyphene passes into breast milk, but the amounts and clinical significance are unknown. In one case, a nursing mother attempted suicide with propoxyphene (12). The concentration of the drug in her breast milk was found to be 50% of her plasma level. By calculation, the authors predicted a mother consuming a maximum daily dose of the drug would provide her infant with 1 mg/day. The American Academy of Pediatrics considers propoxyphene to be compatible with breast feeding (13).

References

1. Barrow MV, Souder DE. Propoxyphene and congenital malformations. JAMA 1971;217:1551–2.
2. Ringrose CAD. The hazard of neurotrophic drugs in the fertile years. Can Med Assoc J 1972;106:1058.
3. Golden NL, King KC, Sokol RJ. Propoxyphene and acetaminophen: possible effects on the fetus. Clin Pediatr 1982;21:752–4.
4. Golden SM, Perman KI. Bilateral clinical anophthalmia: drugs as potential factors. South Med J 1980;73:1404–7.
5. Hall JG, Reed SD. Teratogens associated with congenital contractures in humans and in animals. Teratology 1982;25:173–91.
6. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
7. Tyson HK. Neonatal withdrawal symptoms associated with maternal use of propoxyphene hydrochloride (Darvon). J Pediatr 1974;85:684–5.
8. Klein RB, Blatman S, Little GA. Probable neonatal propoxyphene withdrawal: a case report. Pediatrics 1975;55:882–4.
9. Quillan WW, Dunn CA. Neonatal drug withdrawal from propoxyphene. JAMA 1976;235:2128.
10. Ente G, Mehra MC. Neonatal drug withdrawal from propoxyphene hydrochloride. NY State J Med 1978;78:2084–5.
11. Eddy NB, Friebel H, Hahn KJ, Halbach H. Codeine and its alternatives for pain and cough relief. 2. Alternates for pain relief. Bull WHO 1969;40:1–53.
12. Catz C, Guiacoia G. Drugs and breast milk. Pediatr Clin North Am 1972;19:151–66.
13. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.