Sympatholytic (Antihypertensive)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Some β-blockers may cause growth restriction, including intrauterine growth restriction (IUGR), and reduced placental weight, especially those lacking intrinsic sympathomimetic activity (ISA) (i.e., partial agonist). Treatment beginning early in the 2nd trimester results in the greatest weight reductions, whereas treatment restricted to the 3rd trimester primarily affects only placental weight. Acebutolol does possess ISA. However, IUGR and reduced placental weight may potentially occur with all agents within this class. Although growth restriction is a serious concern, the benefits of maternal therapy with β-blockers, in some cases, might outweigh the risks to the fetus and must be judged on a case-by-case basis.
FETAL RISK SUMMARY
Acebutolol, a cardioselective β-adrenergic blocking agent, has been used for the treatment of hypertension occurring during pregnancy (1–5). The drug undergoes extensive first-pass hepatic metabolism after oral administration (absolute bioavailability about 40%). The major metabolite, diacetolol, is equipotent to acebutolol (6).
In animal reproduction studies, no teratogenic effects were observed in pregnant rats and rabbits with doses up to about 32 times the maximum recommended human dose (MRHD) and up to about 7 times the MRHD, respectively. The maximum dose in rabbits produced slight intrauterine growth restriction that was thought to be secondary to maternal toxicity (6).
Acebutolol crosses the placenta, producing a maternal:cord ratio of 0.8 (3). The corresponding ratio for the active metabolite, diacetolol, was 0.6. Newborn serum levels of acebutolol and the metabolite were <5–244 and 17–663 ng/mL, respectively (3). A cord:maternal ratio of 0.7 for acebutolol has also been reported (4).
No human malformations attributable to acebutolol have been observed, but experience with the drug during the 1st trimester is lacking. In a study comparing three β-blockers, the mean birth weight of 56 newborns was slightly lower than 38 pindolol-exposed infants but higher than 31 offspring of atenolol-treated mothers (3160 vs. 3375 vs. 2745 g) (2). Growth restriction has been associated with β-blockers and the weight reduction may have been drug induced.
In a comparison of 20 pregnant women treated with either acebutolol or methyldopa for mild-to-moderate hypertension, no differences between the drugs were found for pregnancy duration, birth weight, Apgar scores, or placental weight (5). In addition, no evidence of bradycardia, hypoglycemia, or respiratory problems was found in the acebutolol-exposed newborns. In an earlier study, however, 10 newborns exposed to acebutolol near term had blood pressures and heart rates significantly lower than similar infants exposed to methyldopa (7). The hemodynamic differences were still evident 3 days after birth. Mean blood glucose levels were not significantly lower than those of similar infants exposed to methyldopa, but transient hypoglycemia was present 3 hours after birth in four term newborns (5). The mean half-life of acebutolol in the serum of newborns has been calculated to be 10.1 hours, but the half-life based on urinary excretion was 15.6 hours (7). The manufacturer cites the elimination half-life of acebutolol in newborns as 6–14 hours, compared with a half-life for diacetolol of 24–30 hours during the first 24 hours, then 12–16 hours thereafter (6). Therefore, newborn infants of women consuming the drug near delivery should be closely observed for signs and symptoms of β-blockade for at least 3–4 days to allow for elimination of the parent and active metabolite from the infant. Long-term effects of in utero exposure to β-blockers have not been studied but warrant evaluation.
BREASTFEEDING SUMMARY
Acebutolol and its active metabolite, diacetolol, are excreted into breast milk (3,8). Milk:plasma ratios for the two compounds were 7.1 and 12.2, respectively (3). Absorption of both compounds was demonstrated in breastfeeding infants, but no adverse effects were mentioned (3).
In a study of seven nursing, hypertensive mothers treated with 200–1200 mg/day within 13 days of delivery, milk:plasma acebutolol ratios in three of the mothers varied from 2.3 to 9.2, whereas similar ratios of the metabolite ranged from 1.5 to 13.5 (8). The highest milk concentration of acebutolol, 4123 ng/mL, occurred in a mother taking 1200 mg/day. Two to three days after treatment was stopped, milk:plasma ratios of acebutolol and the metabolite in the seven women were 1.9–9.8 and 2.3–24.7, respectively. Symptoms of β-blockade (hypotension, bradycardia, and transient tachypnea) were observed in one nursing infant, although the time of onset of the adverse effects was not given. Neonatal plasma concentrations of the drug and metabolite (specific data not given), which were already high from in utero exposure, rose sharply after nursing commenced. The mother was taking 400 mg/day, and her milk:plasma ratios of acebutolol and metabolite during treatment were 9.2 and 13.5, respectively, the highest observed in this study (8).
Breastfed infants of mothers taking acebutolol should be closely observed for hypotension, bradycardia, and other signs or symptoms of β-blockade. Long-term effects of exposure to β-blockers from milk have not been studied but warrant evaluation. The American Academy of Pediatrics classifies acebutolol as a drug that has been associated with adverse effects in nursing infants (9).
References
1.Dubois D, Petitcolas J, Temperville B, Klepper A. Beta blockers and high-risk pregnancies. Int J Biol Res Pregnancy 1980;1:141–5.
2.Dubois D, Petitcolas J, Temperville B, Klepper A, Catherine P. Treatment of hypertension in pregnancy with beta-adrenoceptor antagonists. Br J Clin Pharmacol 1982;13(Suppl):375S–8S.
3.Bianchetti G, Dubruc C, Vert P, Boutroy MJ, Morselli PL. Placental transfer and pharmacokinetics of acebutolol in newborn infants (abstract). Clin Pharmacol Ther 1981;29:233–4.
4.Boutroy MJ. Fetal and neonatal effects of the beta-adrenoceptor blocking agents. Dev Pharmacol Ther 1987;10:224–31.
5.Williams ER, Morrissey JR. A comparison of acebutolol with methyldopa in hypertensive pregnancy. Pharmatherapeutica 1983;3:487–91.
6.Product information. Sectral. Wyeth-Ayerst Pharmaceuticals, 2000.
7.Dumez Y, Tchobroutsky C, Hornych H, Amiel-Tison C. Neonatal effects of maternal administration of acebutolol. Br Med J 1981;283:1077–9.
8.Boutroy MJ, Bianchetti G, Dubruc C, Vert P, Morselli PL. To nurse when receiving acebutolol: is it dangerous for the neonate? Eur J Clin Pharmacol 1986;30:737–9.
9.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.