naloxone and Fetal-Death

Long-term oral administration of the long-acting opiate 1-alpha-acetylmethadol (LAAM) to female rats beginning on the day of conception interfered with the dams' ability to carry litters to term. When treatment was initiated 3 weeks prior to mating this effect was not observed. Daily administration of the opiate antagonist naloxone from day 14 of gestation through term, to precipitate withdrawal in utero, resulted in increased stillbirths, decreased pup weight and size, and weight loss 24 hours after birth. These data question the validity of animal experiments which purport to be models for methadone maintenance programs but in which treatment is started immediately prior to or soon after conception. They also suggest that withdrawal in utero may be responsible for many of the adverse effects of opiates on human and animal development.

Topics: Animals; Drug Tolerance; Embryo Implantation; Female; Fetal Death; Humans; Litter Size; Methadone; Methadyl Acetate; Naloxone; Opioid-Related Disorders; Pregnancy; Pregnancy, Animal; Rats; Substance Withdrawal Syndrome

Morphine was injected subcutaneously in doses of 2.5 to 10 mg/kg every 6 hours into pregnant rabbits from early pregnancy until delivery by hysterotomy on the 27th, 28th or 29th day. Pregnant control animals received 0.9% NaC1 injections. Abortions occurred in 34% of the morphine-treated does as a doserelated effect and in 6.5% of the controls. In preserved pregnancies the prevalence of intrauterine death was identical in both samples. Fetuses of treated animals weighed significantly less than those of the controls.However, the normally present effect of intrauterine position on fetal growth was not altered in fetuses of treated animals, so that growth-retarded as well as normal fetuses weighed more when located in the ovarium rather than the cervical portion of the uterus. The fetal lungs were inflated to 35 cm H2O and the remaining air at a deflation pressure of 10 cm H2O (V10) was determined as a measure of lung stability. There were no differences in this indicator of fetal lung maturity between fetuses of treated and control animals. It was found that the lecithin/sphingomyelin (L/S) ratio in the amniotic fluid of rabbits does not correlate with lung maturity; there were no differences between fetuses of treated and control animals. Morphine, when administered to pregnant rabbits does not accelerate fetal lung development. Therefore, the observed reduction in the incidence of respiratory distress syndrome in infants of heroin-addicted women has no direct equivalent in this animal model.

Topics: Abortion, Spontaneous; Amniotic Fluid; Animals; Birth Weight; Body Weight; Dose-Response Relationship, Drug; Embryo Implantation; Female; Fetal Death; Fetus; Gestational Age; Humans; Injections, Subcutaneous; Lung; Morphine; Naloxone; Phosphatidylcholines; Pregnancy; Pregnancy, Animal; Rabbits; Residual Volume; Sphingomyelins; Substance Withdrawal Syndrome