Methadone during pregnancy in the rat: dose level effects on maternal and perinatal mortality and growth in the...

Four groups of pregnant rats were administered methadone hydrochloride orally on days 8 through 22 of gestation. Each group initially received 5 mg/kg for 4 days. One group was maintained at this level and the remaining groups were increased to maintenance doses of 10, 15 or 20 mg/kg increments at 4-day intervals. An intubation control group received the vehicle only. Nontreated control mothers were left undisturbed. All offspring were fostered to other nontreated mothers at birth. Methadone, particularly at the higher dose levels, reduced maternal weight gain during pregnancy and increased both maternal mortality and total mortality among the young (resorptions plus stillbirths). Birth weight covaried with dose level and litter size: the 5, 10 and 15 mg/kg doses yielded litter sizes comparable, to, or somewhat smaller than, controls, but with lower birth weights; the 20 mg/kg doses yielded the smallest litter sizes but with birth weights greater than any other treated or control group. Beyond day 1 of life, treated and control offspring did not differ in mortality. By weaning, the low offspring weights seen at birth had been compensated for and were no longer evident. Body weights of offspring of mothers in the 20 mg/kg group remained well above average through weaning. In a second experiment, blood levels of methadone were determined for both mothers and litters in the 5, 10 and 15 mg/kg groups, sacrificed 24 hours before expected parturition. Blood levels were dose-related and corresponded to those found in human subjects receiving daily maintenance doses of approximately 30, 60 and 100 mg, respectively.