Sympatholytic (Antihypertensive)
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The use of labetalol for the treatment of maternal hypertension does not appear to pose a risk to the fetus, except possibly in the 1st trimester, and may offer advantages over the use of agents with only β-blocker activity. Most studies have found no effect on fetal growth, but one did find fetal growth restriction when used for the treatment of mild preeclampsia. Some β-blockers may cause intrauterine growth restriction (IUGR) and reduced placental weight, especially those lacking intrinsic sympathomimetic activity (ISA) (i.e., partial agonist). Labetalol does not possess ISA. IUGR and reduced placental weight may potential occur with all agents within this class and can be a consequence of maternal hypertension. Although IUGR is a serious concern, the benefits of maternal therapy with labetalol outweigh the risks to the fetus. If used near delivery, the newborn infant should be closely observed for 24–48 hours for signs and symptoms of β-blockade. Long-term effects of in utero exposure to labetalol have not been studied but warrant evaluation.
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).
Several investigations have shown a lack of effect of labetalol treatment on uterine contractions (1–3,16,19–21). One study did report a higher incidence of spontaneous labor in labetalol-treated mothers (6 of 10) than in a similar group treated with methyldopa (2 of 9) (22). In another report, 3 of 31 patients treated with labetalol experienced spontaneous labor, one of whom delivered prematurely (23). The authors attributed the uterine activity to the drug because no other causes were found. However, because most trials with labetalol in hypertensive women have not shown this effect, it is questionable whether the drug has any direct effect on uterine contractility.
Labetalol does not change uteroplacental blood flow despite a drop in blood pressure (2,4,5,24,25). The lack of effect on blood flow was probably caused by reduced peripheral resistance.
Labetalol apparently reduces the incidence of hyaline membrane disease in premature infants by increasing the production of pulmonary surfactant (1,2,4,16,26). The mechanism for this effect may be mediated through β2-adrenoceptor agonist activity that the drug partially possesses (1,2,4,16,26).
Follow-up studies have been completed at 6 months of age on 10 infants exposed in utero to labetalol (27). All infants demonstrated normal growth and development. In addition, no ocular toxicity was observed in newborns, even though labetalol has an affinity for ocular melanin (1,2,26).
The experience with labetalol in pregnancy was briefly reviewed in a 1988 article (31). A 2000 meta-analysis concluded that IV labetalol for late-onset hypertension in pregnancy was safer than IV hydralazine or diazoxide in terms of drug-induced maternal hypotension and fewer cesarean sections (32).
BREASTFEEDING SUMMARY
Labetalol is excreted into breast milk (1,6). In 24 lactating women at 3 days postpartum, administration of 330–800 mg/day produced a mean milk level of 33 ng/mL. No adverse effects were observed in the nursing infants. One patient, consuming 1200 mg/day, had a mean milk concentration of 600 ng/mL, but this woman did not breastfeed. Three women at 6–9 days postpartum consumed daily doses of labetalol of 600, 600, and 1200 mg and produced peak milk concentrations of the drug of 129, 223, and 662 ng/mL, respectively (6). Peak concentrations of labetalol in the milk occurred between 2 and 3 hours after a dose. Measurable plasma concentrations of labetalol were found in only one infant: 18 ng/mL at 4 hours and 21 ng/mL at 8 hours. Although no adverse effects have been reported, nursing infants should be closely observed for bradycardia, hypotension, and other symptoms of α/β-blockade. Long-term effects of exposure to labetalol from milk have not been studied but warrant evaluation. The American Academy of Pediatrics classifies labetalol as compatible with breastfeeding (33).
References
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