Risk Factor: CM*
Class: Cardiovascular drugs/ Antihypertensives/ Other antihypertensives
Fetal Risk Summary
Propranolol, a nonselective b-adrenergic blocking agent, has been used for various indications in pregnancy: Maternal hyperthyroidism (1,2,3,4,5,6 and 7) Pheochromocytoma (8) Maternal cardiac disease (6,7,9,10,11,12,13,14,15,16,17,18,19 and 20) Fetal tachycardia or arrhythmia (21,22) Maternal hypertension (7,20,2324,25,26,27,28,29 and 30) Dysfunctional labor (31) Termination of pregnancy (32) Reproduction studies in rats revealed embryotoxicity (increased resorption sites and reduced litter sizes) and reduced neonatal survival at doses up to about 10 times the maximum recommended human dose (MRHD) (33). No embryotoxicity was observed in rabbits at doses up to about 20 times the MRHD. No teratogenicity was noted in either species.
The drug readily crosses the placenta (2,6,12,16,22,29,34,35). Cord serum levels varying between 19% and 127% of maternal serum have been reported (2,16,22,29). Oxytocic effects have been demonstrated following IV, extra-amniotic injections, and high oral dosing (17,31,32,36,37). IV propranolol has been shown to block or decrease the marked increase in maternal plasma progesterone induced by vasopressin or theophylline (38). The pharmacokinetics of propranolol in pregnancy have been described (39). Plasma levels and elimination were not significantly altered by pregnancy.
A number of fetal and neonatal adverse effects have been reported following the use of propranolol in pregnancy. Whether these effects were caused by propranolol, maternal disease, other drugs consumed concurrently, or a combination of these factors is not always clear. Daily doses of 160 mg or higher seem to produce the more serious complications, but lower doses have also resulted in toxicity. Analysis of 23 reports involving 167 liveborn infants exposed to chronic propranolol in utero is shown below (1,2,3 and 4,6,7,9,11,12,13 and 14,20,22,23 and 24,26,27,28 and 29,40,41,42 and 43): No. Cases % Intrauterine growth retardation
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 274 newborns had been exposed to propranolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 11 (4.0%) major birth defects were observed (12 expected), including (observed/expected) 3/3 cardiovascular defects and 2/1 hypospadias. No anomalies were observed in four other defect categories (oral clefts, spina bifida, polydactyly, and limb reduction defects) for which specific data were available.
Respiratory depression was noted in four of five infants whose mothers were given 1 mg of propranolol IV just before cesarean section (45). None of the five controls in the double-blind study was depressed at birth. The author suggested the mechanism may have been b-adrenergic blockade of the cervical sympathetic discharge that occurs at cord clamping.
Fetal bradycardia was observed in 2 of 10 patients treated with propranolol, 1 mg/minute for 4 minutes, for dysfunctional labor (31). No lasting effects were seen in the babies. In a retrospective study, 8 markedly hypertensive patients (9 pregnancies) treated with propranolol were compared with 15 hypertensive controls not treated with propranolol (25). Other antihypertensives were used in both groups. A significant difference was found between the perinatal mortality rates, with 7 deaths in the propranolol group (78%) and only 5 deaths in the controls (33%). However, a possible explanation for the difference may have been the more severe hypertension and renal disease in the propranolol group than in the controls (46).
Intrauterine growth retardation may be related to propranolol. Several possible mechanisms for this effect, if indeed it is associated with the drug, have been reviewed (47). Premature labor has been suggested as a possible complication of propranolol therapy in patients with pregnancy-induced hypertension (PIH) (42). In nine women treated with propranolol for PIH, three delivered prematurely. The author speculated that these patients were relatively hypovolemic and when a compensatory increase in cardiac output failed to occur, premature delivery resulted. However, another report on chronic propranolol use in 14 women did not observe premature labor (43).
In a randomized, double-blind trial, 36 patients at term were given either 80 mg of propranolol or placebo (48). Fetal heart rate reaction to a controlled sound stimulus was then measured at 1, 2, and 3 hours. The heart rate reaction in the propranolol group was significantly depressed, compared with placebo, at all three time intervals.
The reactivity of nonstress tests (NSTs) was affected by propranolol in two hypertensive women in the 2nd and 3rd trimesters (49). One woman was taking 20 mg every 6 hours and the other 10 mg 3 times daily. Repeated NSTs were nonreactive in both women, but immediate follow-up contraction stress tests were negative. The NSTs became reactive 2 and 10 days, respectively, after propranolol was discontinued.
In summary, propranolol has been used during pregnancy for maternal and fetal indications. The drug is apparently not a teratogen, but fetal and neonatal toxicity may occur. A 1988 review on the use of b-blockers, including propranolol, during pregnancy concluded that these agents are relatively safe (50), but some b-blockers, including propranolol, may cause intrauterine growth retardation and reduced placental weight (e.g., see also Atenolol). Treatment beginning early in the 2nd trimester results in the greatest weight reductions. This toxicity has not been consistently demonstrated in other agents within this class, but the relatively few pharmacologic differences among the drugs suggests that the reduction in fetal and placental weights probably occurs with all at some point. The lack of toxicity documentation may reflect the number and type of patients studied, the duration of therapy, or the dosage used, rather then a true difference among b-blockers. Although growth retardation is a serious concern, the benefits of maternal therapy with b-blockers may, in some cases, outweigh the risks to the fetus and must be judged on a case-by-case basis.
Newborn infants of women consuming the drug near delivery should be closely observed during the first 2448 hours after birth for bradycardia, hypoglycemia, and other symptoms of b-blockade. Long-term effects of in utero exposure to b-blockers have not been studied but warrant evaluation.
[*Risk Factor D if used in 2nd or 3rd trimesters.]
Breast Feeding Summary
Propranolol is excreted into breast milk. Peak concentrations occur 23 hours after a dose (12,20,43,51). Milk levels have ranged from 4 to 64 ng/mL, with milk:plasma ratios of 0.21.5 (12,20,29,50). Although such adverse effects as respiratory depression, bradycardia, and hypoglycemia have not been reported, nursing infants exposed to propranolol in breast milk should be closely observed for these symptoms of b-blockade. Long-term effects of exposure to b-blockers from milk have not been studied but warrant evaluation. The American Academy of Pediatrics considers propranolol to be compatible with breast feeding (52).
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