Effects of Propranolol during Pregnancy and Development of Rats. I. Adverse Effects during Pregnancy

Abstract

SummaryPregnant rats, treated with high doses of propranolol, gave birth to small for dates neonates. Litter size was affected in daily doses of 100 and 150 mg/kg/day. Propranolol markedly influenced the gain in weight normally observed in pregnant rats. The placentas of the rats which received the higher doses of propranolol weighed about 30% less than normal placentas. SpeculationPregnant rats, treated with propranolol, gave birth to small for dates neonates. This effect is possibly the result of a drug-induced reduction in transport across cellular membranes, resulting in malnutrition. Since similar effects were reported in humans, treatment with propranolol during pregnancy should be further reevaluated in laboratory animals.The administration of propranolol to pregnant women is slowly gaining acceptance. If the present trend continues it will possibly become one of the more extensively used drugs for a variety of conditions associated with pregnancy such as: Lypertension (2,6), hyperthyroidism (1, 12), cardiac arrhythmias (13,16,20), and hypertrophic obstructive cardiomyopathy (5,7,25). A relatively laree number of side effects on the Drocess of ~arturition and on Y 1 1 the newborn have been reported. One of these side effects is intrauterine growth retardation (2, 6, 16) often accompanied by a small or fibrotic placenta (6, 16). These findings are thought to be caused by sustained increase in uterine muscle tone or hemodynamic changes in the mother and in the fetus resulting from Padrenoceptor blockade by propranolol(l6). In previous investigations we have shown that high concentrations of propranolol partially inhibit the uptake of amino acids (17, 18), uridine and thymidine (19), and 2-deoxyglucose (3) by chick embryo liver cells in vitro. Preliminary experiments indicate that the same inhibition may occur in mammalian cells, both in vitro and in vivo. This creates a situation analogous to starvation, which would exert its effects mainly on rapidly dividing cells or tissues with a hiah metabolic rate.Propranolol cFosses the mammalian placenta (14) and its pharmacologic effects on the fetus are easily demonstrated (9, 10). In view of our previous laboratory findings and the reports of small placentas and fetuses in women receiving propranolol during pregnancy, a methodical investigation on the effects of this drug in pregnant rats was initiated. MATERIALS AND METHODS ANIMALSThe experiments were carried out using Wistar rats, randomly bred, and weighing 140-160 g. Timed pregnant rats were obtained by mating virgin females with experienced male rats for a 24-hr period. dl-Propranolol was administered starting the morning after impregnation.Oral administration of dl-propranolol was achieved by dissolving the drug in the water imbibed by the rats. The concentrations of propranolol in the drinking water were based upon long term measurements of the average consumption of water containing propranolol per rat per 24 hr, which was found to be about 25 & 7 ml/day. The concentrations were such that each group of ra...

Effect of prenatal propranolol exposure on development of the postnatal rat heart

“…The reduction observed in maternal weight gain at 25 mg/kg/day in this study differed from earlier results in that it was statistically significant, possibly due to better resolution resulting from a larger test population. Our finding that litter size was unaffected by maternal PRO treatment confirms the results reported by Schoenfeld et a1 [8] at these dose levels.…”

“…The largest absolute reductions were observed at the later ages, but they were not significant, due to increased variability at these ages. Other laboratories have also reported neonatal weight reductions after prenatal PRO exposure, but they measured weights only to 2.5 days postpartum [8,12]. The percent reductions seen in body and heart weights of PRO-exposed pups vs. controls are in good agreement with the percent reductions seen in dam weights on GD 20.…”

“…Maternal PRO treatment has been associated with several adverse effects in the fetus and neonate, both clinically [6,7] and in laboratory animals [8,9], but little information has been reported on its effects on neonatal heart growth and development [ 12,131. In the present study, pregnant rats received PRO during the last two trimesters of gestation, and several parameters of early postnatal heart growth and development were measured. Both dose levels of PRO resulted in a significant reduction in maternal weight gain in a fashion consistent with that reported previously [8,19]. The reduction observed in maternal weight gain at 25 mg/kg/day in this study differed from earlier results in that it was statistically significant, possibly due to better resolution resulting from a larger test population.…”

“…Several clinical reports, however, have associated maternal PRO treatment with a number of adverse effects in the fetus and neonate, including intrauterine growth retardation, neonatal bradycardia and hypoglycemia, and increased perinatal mortality [reviewed in 6,7]. Adverse effects have also been reported in animal studies: e.g., pregnant rats given PRO in their drinking water had smaller weight gains during pregnancy, as well as reduced placenta size and weight, litter size, total litter weight, and pup weight at birth [8].…”

Beta-Adrenergic Binding Sites in Fetal Rat Central Nervous System and Pineal Gland: Their Relation to Other Receptor Sites

“…Quite recently, maternal treatment with propranolol has become contro versial because of its adverse effects on fetal outcome both in humans and in rats. The drug was reported to produce growth retardation [Pruyn et al, 1979;Schoenfeld et al, 1985], In order to assess central nervous system (CNS) involvement, knowledge of the regional distribution of ß-adrenergic sites and of their dynamically changing pattern throughout development is a prerequisite. Prenatal distribution patterns of receptors have been found to change rapidly.…”