Risk Factor: CM*
Class: Cardiovascular drugs/ Antihypertensives/ Other antihypertensives
Fetal Risk Summary
Nadolol is a nonselective b-adrenergic blocking agent used for hypertension and angina pectoris. The drug is not teratogenic in rats, hamsters, and rabbits, but embryotoxicity and fetotoxicity were observed in the latter species (1,2).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 71 newborns had been exposed to nadolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (1.4%) major birth defect was observed (three expected), a cardiovascular defect (one expected).
Only one published case of the use of nadolol in pregnancy has been located (3). A mother with immunoglobulin A nephropathy and hypertension was treated throughout pregnancy with nadolol, 20 mg/day, plus a diuretic (triamterene/hydrochlorothiazide) and thyroid. The infant, delivered by emergency cesarean section at 35 weeks’ gestation, was growth retarded and exhibited tachypnea (68 breaths/minute) and mild hypoglycemia (20 mg/dL). Depressed respirations (23 breaths/minute), slowed heart rate (112 beats/minute), and hypothermia (96.5F) occurred at 4.5 hours of age. The lowered body temperature responded to warming, but the cardiorespiratory depression, with brief episodes of bradycardia, persisted for 72 hours. Nadolol serum concentrations in cord blood and in the infant at 12 and 38 hours after delivery were 43, 145, and 80 ng/mL, respectively. The cause of some or all of the effects observed in this infant may have been b-blockade (3). However, maternal disease could not be excluded as the sole or contributing factor behind the intrauterine growth retardation and hypoglycemia (3). In addition, hydrochlorothiazide may have contributed to the low blood glucose (see Chlorothiazide).
The authors identified several characteristics of nadolol in the adult that could potentially increase its toxicity in the fetus and newborn, including a long serum half-life (1724 hours), lack of metabolism (excreted unchanged by the kidneys), and low protein binding (30%) (3). Because of these factors, other b-blockers may be safer for use during pregnancy, although persistent b-blockade has also been observed with acebutolol and atenolol. As with other agents in this class, long-term effects of in utero b-blockade have not been studied but warrant evaluation.
Some b-blockers may cause intrauterine growth retardation, such as may have occurred in the case above, and reduced placental weight (e.g., see also Atenolol and Propranolol). Because the number of patients treated in the 1st trimester is much lower than the number exposed later in pregnancy, the greatest weight reductions have been observed when treatment began early in the 2nd trimester. 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.
[*Risk Factor D if used in 2nd or 3rd trimester.]
Breast Feeding Summary
Nadolol is excreted into breast milk (3,4). A mother taking 20 mg of nadolol/day had a concentration in her milk of 146 ng/mL 38 hours after delivery (3). In 12 lactating women ingesting 80 mg once daily for 5 days, mean steady-state levels of nadolol, approximately 357 ng/mL, were attained at 3 days. This level was approximately 4.6 times higher than simultaneously measured maternal serum levels (4). By calculation, a 5-kg infant would have received 2%7% of the adult therapeutic dose, but the infants were not allowed to breast-feed (4).
Because experience is lacking, nursing infants of mothers consuming nadolol should be closely observed for 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 nadolol to be compatible with breast feeding (5).
- Product information. Corgard. Bristol Laboratories, 1993.
- Saegusa T, Suzuki T, Narama I. Reproduction studies of nadolol: a new b-adrenergic blocking agent. Yakuri to Chiryo 1983;11:511938. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:440.
- Fox RE, Marx C, Stark AR. Neonatal effects of maternal nadolol therapy. Am J Obstet Gynecol 1985;152:10456.
- Devlin RG, Duchin KL, Fleiss PM. Nadolol in human serum and breast milk. Br J Clin Pharmacol 1981;12:3936.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.