FETAL RISK SUMMARY

Labetalol, a combined α/β-adrenergic blocking agent, has been used for the treatment of hypertension occurring during pregnancy (1–29). No teratogenicity was observed in rats and rabbits at oral doses 6 and 4 times the maximum recommended human dose (MRHD), respectively (30). However, increased fetal resorptions occurred in both species at doses approximately equivalent to the MRHD. In rabbits, IV doses ≤1.7 times the MRHD revealed no drug-related fetal harm (30).

Labetalol crosses the human placenta to produce cord serum concentrations averaging 40%–80% of peak maternal levels (1–5). Maternal serum and amniotic fluid concentrations are approximately equivalent 1–3 hours after a single IV dose (4). After oral dosing (1–42 days) in eight women, amniotic fluid concentrations of labetalol were in the same range as, but lower than, the plasma concentrations in six of the women (6). The pharmacokinetics of labetalol in pregnant patients has been reported (7,8).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 29 newborns had been exposed to labetalol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Four (13.8%) major birth defects were observed (one expected). Details on the malformations were not available, but no anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. Although the number of exposures is small, the incidence of malformations is suggestive of an association, but other factors, including the mother’s disease, concurrent drug use, and chance, may be involved.

No published reports of fetal malformations attributable to labetalol have been located, but experience during the 1st trimester, except for the surveillance study described above, is lacking. Most reports have found no adverse effects on birth weight, head circumference, Apgar scores, or blood glucose control after in utero exposure to labetalol (9–13). One case of neonatal hypoglycemia has been mentioned, but the mother was also taking a thiazide diuretic (2). Offspring of mothers treated with labetalol had a significantly higher birth weight than infants of atenolol-treated mothers, 3280 vs. 2750 g, respectively (14). However, in a study comparing labetalol plus hospitalization with hospitalization alone for the treatment of mild preeclampsia presenting at 26–35 weeks’ gestation, labetalol treatment did not improve perinatal outcome, and a significantly higher number of labetalol-exposed infants were growth restricted, 19.1% (18 of 94) vs. 9.3% (9 of 97), respectively (15).

Fetal heart rate is apparently unaffected by labetalol treatment of hypertensive pregnant women. However, two studies have observed newborn bradycardia in five infants (16,17). In one of these infants, bradycardia was marked (<100 beats/minute) and persistent (17). All five infants survived. Hypotension was noted in another infant delivered by cesarean section at 28 weeks’ gestation (1). In a study examining the effects of labetalol exposure on term (≥37 weeks) newborns, mild transient hypotension, which resolved within 24 hours, was observed in 11 infants compared with 11 matched controls (18). Maternal dosage varied from 100 to 300 mg 3 times daily with the last dose given within 12 hours of birth. The mean systolic blood pressures at 2 hours of age in exposed and nonexposed infants were 58.8 and 63.3 mmHg (p <0.05), respectively. Other measures of β-blockade, such as heart and respiratory rates, palmar sweating, blood glucose control, and metabolic and vasomotor responses to cold stress, did not differ between the groups. The investigators concluded that labetalol did not cause clinically significant β-blockade in mature newborn infants (18).

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