MEPERIDINE

Fetal Risk Summary

Fetal problems have not been reported from the therapeutic use of meperidine in pregnancy except when it has been given during labor. Like all narcotics, maternal and neonatal addiction are possible from inappropriate use. Neonatal depression, at times fatal, has historically been the primary concern following obstetric meperidine analgesia. Controversy has now arisen over the potential long-term adverse effects resulting from this use.

Meperidine's placental transfer is very rapid, appearing in cord blood within 2 minutes following IV administration (1). It is detectable in amniotic fluid 30 minutes after IM injection (2). Cord blood concentrations average 70%–77% (range 45%–106%) of maternal plasma levels (3,4). The drug has been detected in the saliva of newborns for 48 hours following maternal administration during labor (5). Concentrations in pharyngeal aspirates were higher than in either arterial or venous cord blood.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 62 newborns had been exposed to meperidine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (4.8%) major birth defects were observed (three expected), including (observed/expected) 1/0 polydactyly and 1/0 hypospadias. No malformations were observed in four other defect categories (cardiovascular defects, oral clefts, spina bifida, and limb reduction defects) for which specific data were available.

Respiratory depression in the newborn following use of the drug in labor is time and dose dependent. The incidence of depression increases markedly if delivery occurs 60 minutes or longer after injection, reaching a peak around 2–3 hours (6,7). Whether this depression is caused by metabolites of meperidine (e.g., normeperidine) or the drug itself is currently not known (2,8,9 and 10). However, recent work suggests that these effects are related to unmetabolized meperidine and not to normeperidine (7).

Impaired behavioral response and electroencephalographic changes persisting for several days have been observed (11,12). These persistent effects may be partially explained by the slow elimination of meperidine and normeperidine from the neonate over several days (13,14). One group of investigators related depressed attention and social responsiveness during the first 6 weeks of life to high cord blood levels of meperidine (15). An earlier study reported long-term follow-up of 70 healthy neonates born to mothers who had received meperidine within 2 hours of birth (16,17). Psychologic and physical parameters at 5 years of age were similar in both exposed and control groups. Academic progress and behavior during the 3rd and 4th years in school were also similar.

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 268 of which had 1st trimester exposure to meperidine (18, pp. 287–95). For use anytime during pregnancy, 1,100 exposures were recorded (18, p. 434). No evidence was found to suggest a relationship to large categories of major or minor malformations. A possible association between the use of meperidine in the 1st trimester and inguinal hernia was found based on six cases (18, p. 471). The statistical significance of this association is unknown, and independent confirmation is required.

[*Risk Factor D if used for prolonged periods or in high doses at term.]

Breast Feeding Summary

Meperidine is excreted into breast milk (19,20). In a group of mothers who had received meperidine during labor, the breast-fed infants had higher saliva levels of the drug for up to 48 hours after birth than a similar group that was bottle-fed (5). In 9 nursing mothers, a single 50-mg IM dose produced peak levels of 0.13 µg/mL at 2 hours (20). After 24 hours, the concentrations decreased to 0.02 µg/mL. Average milk:plasma ratios for the 9 patients were greater than 1.0. No adverse effects in nursing infants were reported in any of the above studies. In their 1983 statement on drugs in breast milk, the American Academy of Pediatrics classified meperidine as compatible with breast feeding (21). However, the drug was not mentioned in the 1989 or 1994 revisions of their statement.

References

1. Crawford JS, Rudofsky S. The placental transmission of pethidine. Br J Anaesth 1965;37:929–33.
2. Szeto HH, Zervoudakis IA, Cederquist LL, Inturrise CE. Amniotic fluid transfer of meperidine from maternal plasma in early pregnancy. Obstet Gynecol 1978;52:59–62.
3. Apgar V, Burns JJ, Brodie BB, Papper EM. The transmission of meperidine across the human placenta. Am J Obstet Gynecol 1952;64:1368–70.
4. Shnider SM, Way EL, Lord MJ. Rate of appearance and disappearance of meperidine in fetal blood after administration of narcotic to the mother. Anesthesiology 1966;27:227–8.
5. Freeborn SF, Calvert RT, Black P, MacFarlane T, D'Souza SW. Saliva and blood pethidine concentrations in the mother and the newborn baby. Br J Obstet Gynaecol 1980;87:966–9.
6. Morrison JC, Wiser WL, Rosser SI, Gayden JO, Bucovaz ET, Whybrew WD, Fish SA. Metabolites of meperidine related to fetal depression. Am J Obstet Gynecol 1973;115:1132–7.
7. Belfrage P, Boreus LO, Hartvig P, Irestedt L, Raabe N. Neonatal depression after obstetrical analgesia with pethidine. The role of the injection-delivery time interval and the plasma concentrations of pethidine and norpethidine. Acta Obstet Gynecol Scand 1981;60:43–9.
8. Morrison JC, Whybrew WD, Rosser SI, Bucovaz ET, Wiser WL, Fish SA. Metabolites of meperidine in the fetal and maternal serum. Am J Obstet Gynecol 1976;126:997–1002.
9. Clark RB, Lattin DL. Metabolites of meperidine in serum. Am J Obstet Gynecol 1978;130:113–5.
10. Morrison JC. Reply to Drs. Clark and Lattin. Am J Obstet Gynecol 1978;130:115–7.
11. Borgstedt AD, Rosen MG. Medication during labor correlated with behavior and EEG of the newborn. Am J Dis Child 1968;115:21–4.
12. Hodgkinson R, Bhatt M, Wang CN. Double-blind comparison of the neurobehaviour of neonates following the administration of different doses of meperidine to the mother. Can Anaesth Soc J 1978;25:405–11.
13. Cooper LV, Stephen GW, Aggett PJA. Elimination of pethidine and bupivacaine in the newborn. Arch Dis Child 1977;52:638–41.
14. Kuhnert BR, Kuhnert PM, Prochaska AL, Sokol RJ. Meperidine disposition in mother, neonate and nonpregnant females. Clin Pharmacol Ther 1980;27:486–91.
15. Belsey EM, Rosenblatt DB, Lieberman BA, Redshaw M, Caldwell J, Notarianni L, Smith RL, Beard RW. The influence of maternal analgesia on neonatal behaviour. I. Pethidine. Br J Obstet Gynaecol 1981;88:398–406.
16. Buck C, Gregg R, Stavraky K, Subrahmaniam K, Brown J. The effect of single prenatal and natal complications upon the development of children of mature birthweight. Pediatrics 1969;43:942–55.
17. Buck C. Drugs in pregnancy. Can Med Assoc J 1975;112:1285.
18. Heinonen O, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
19. Vorherr H. Drug excretion in breast milk. Postgrad Med 1974;56:97–104.
20. Peiker G, Muller B, Ihn W, Noschel H. Excretion of pethidine in mother's milk. Zentralbl Gynaekol 1980;102:537–41.
21. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics 1983;72:375–83.