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ATENOLOL

Fetal Risk Summary

Atenolol is a cardioselective b-adrenergic blocking agent used for the treatment of hypertension. The drug did not cause structural anomalies in pregnant rats and rabbits, but a dose-related increase in embryo and fetal resorptions in rats was observed at doses up to and greater than 25 times the maximum recommended human dose (MRHD) (1). This effect was not seen in rabbits at doses up to 12.5 times the MRHD.

Atenolol readily crosses the placenta to the fetus, producing steady state fetal levels that are approximately equal to those in the maternal serum (2,3,4,5,6,7,8 and 9). Atenolol transfer was one third to one fourth the transfer of the more lipid-soluble b-blockers propranolol, timolol, and labetalol in an in vitro experiment using perfused human placentas (10). In 11 pregnant patients treated with 100 mg/day, the serum half-life (8.1 hours) and the 24-hour urinary excretion (52 mg) were similar to those in nonpregnant women (7).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 105 newborns had been exposed to atenolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 12 (11.4%) major birth defects were observed (4 expected). Specific data were available for six defect categories, including (observed/expected) 3/1 cardiovascular defects, 1/0 oral clefts, 0/0 spina bifida, 0/0 polydactyly, 1/0 limb reduction defects, and 4/0 hypospadias. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother's disease, concurrent drug use, and chance, may be involved.

A 1997 abstract (11) and later full report (12) described a case of retroperitoneal fibromatosis in a fetus exposed in utero to atenolol from the 2nd month of gestation through delivery at 37 weeks. The obese (134 kg at term), 25-year-old mother, in her third pregnancy, was treated for hypertension with 100 mg atenolol daily until giving birth to the 3790-g male infant. Other drug therapy included magnesium supplements and occasional metoclopramide. The mother had no familial history of cancer and both of her other children were normal. Treatment of the tumor with chemotherapy during the first 3 months of life was successful, but a severe scoliosis was present in the child at 4 years of age. The authors attributed the rare tumor to the drug because, among other reasons, the location of the mass was similar to fibroses reported in adults exposed to atenolol (11,12).

Use of atenolol for the treatment of hypertension in pregnant women has been described by several investigators (6,9,13,14,15,16,17,18, 19,20,21 and 22). No fetal malformations attributable to atenolol were reported in these trials, but treatment with atenolol in most cases did not occur during the 1st trimester. Intrauterine growth retardation and persistent b-blockade in the newborn have been observed after atenolol exposure. In one study in which therapy for mild essential hypertension was begun at a mean gestational age of 15.9 weeks, the newborns in the treated group (N=15) had a significantly lower birth weight (2620 g vs. 3530 g) than untreated controls (N=14) (20). Moreover, in the treated group, 5 of the newborns had weights below the 5th percentile and 10 were below the 10th percentile, compared with 1 newborn below the 25th percentile in controls.

A 1992 report described the outcomes of 29 women with pregnancy-induced hypertension in the 3rd trimester (23). The women were randomized to receive either the cardioselective b-blocker, atenolol (N=13), or the nonselective b-blocker, pindolol (N=16). The decrease in mean maternal arterial blood pressure in the two groups did not differ statistically, 9 and 7.8 mm Hg. In comparing before and after therapy, several significant changes were measured in fetal hemodynamics with atenolol but, except for fetal heart rate, no significant changes were measured with pindolol. The atenolol-induced changes included a decrease in fetal heart rate, increases in the pulsatility indexes (and thus, the peripheral vascular resistance) of the fetal thoracic descending aorta, the abdominal aorta, and the umbilical artery, and a decrease in the umbilical venous blood flow (23). Although no difference was observed in the birth weights in the two groups, the placental weight in atenolol-treated pregnancies was significantly less, 529 g vs. 653 g, respectively.

Interestingly, a 1987 study had used Doppler ultrasound to evaluate maternal and fetal circulation during atenolol therapy in 14 women with pregnancy-induced hypertension at a mean gestational age of 35 weeks (range 33–38 weeks) (24). The results suggested that peripheral vascular resistance was increased on both the maternal and fetal sides of the placenta. However, the study design and techniques used have been criticized based on concerns for reproducibility, including day-to-day variability in Doppler measurements, the lack of controls in the study, and the uncertainty of the clinical significance of velocity waveform measurements (25).

A 1997 report described an open, prospective survey on the use of antihypertensives in 398 consecutive pregnant women who attended an antenatal hypertension clinic between 1980 and 1995 (26). Atenolol was used by 76 of the women and compared to those using calcium channel blockers (N=22), diuretics (N=26), methyldopa (N=17), other b-blockers (N=12), or no drug therapy (N=235). The newborns exposed in utero to atenolol had the lowest mean birth weight (p<0.001), and, along with those who received calcium channel blockers, the lowest mean ponderal index and mean placental weight.

In a group of pregnant women with symptomatic mitral valve stenosis, 11 were treated with atenolol and 14 with propranolol (27). The mean birth weight of the 25 infants was 2.8 kg (range 2.1–3.5 kg). Atenolol, 25 mg twice daily, was administered from 18 weeks' gestation to term in a normotensive woman who had suffered a myocardial infarction (28). She delivered a 2720-g infant with normal Apgar scores and blood gases.

In a nonrandomized study comparing atenolol with two other b-blockers for the treatment of hypertension during pregnancy, the mean birth weight of atenolol-exposed babies was markedly lower than infants exposed in utero to either acebutolol or pindolol (2745 g vs. 3160 g vs. 3375 g) (18,29). A similar study comparing atenolol with labetalol found a significant difference in the birth weights of the two groups, 2750 g vs. 3280 g (p<0.001) (5). No difference was found in the birth weights of atenolol- vs. placebo-exposed infants (2961 g vs. 3017 g) in a randomized, double blind investigation of 120 pregnant women with mild to moderate hypertension (16). Additionally, in a prospective randomized study comparing 24 atenolol-treated women with 27 pindolol-treated women, no differences between the groups were found in gestational length, birth weight, Apgar scores, rates of cesarean section, or umbilical cord blood glucose levels (30). Treatment in both groups started at about 33 weeksí gestation. Intrauterine fetal deaths have been observed in women with severe hypertension treated with atenolol, but this has also occurred with other b-blockers and in hypertensive women not treated with drugs (5,16,31).

In eight mothers treated with atenolol or pindolol, a decrease in the basal fetal heart rate was noted only in atenolol-exposed fetuses (32). Before and during treatment, fetal heart rates in the atenolol patients were 136 and 120 beats/minute, respectively, whereas the rates for the pindolol group were 128 and 132 beats/minute, respectively. In 60 patients treated with atenolol for pregnancy-induced hypertension, no effect was observed on fetal heart rate pattern in response to uterine contractions (33). Accelerations, variables, and late decelerations were all easily distinguishable.

Persistent b-blockade was observed in a newborn whose mother was treated with atenolol, 100 mg/day, for hypertension (3). At 15 hours of age, the otherwise normal infant developed bradycardia at rest and when crying, and hypotension. Serum atenolol was 0.24 µg/ml. Urinary excretion of the drug during the first 7 days ranged from 0.085–0.196 µg/mL. In another study, 39% (18 of 46) of the newborns exposed to atenolol developed bradycardia compared to only 10% (4 of 39) of placebo-exposed newborns (p<0.01) (16). None of the infants required treatment for the lowered heart rate.

In summary, exposure to atenolol in utero may result in intrauterine growth retardation. The reduced fetal growth appears to be related to increased vascular resistance in both the mother and the fetus and is a function of the length of drug exposure. Treatment starting early in pregnancy, such as in the 2nd trimester, is associated with the greatest decrease in fetal and placental weights. In comparison, when therapy is initiated in the 3rd trimester, only placental weight appears to be significantly affected. 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. Infant behavior is apparently not affected by atenolol exposure as no differences were noted in the development at 1 year of age of offspring from mothers treated during the 3rd trimester for mild to moderate pregnancy-induced hypertension with either bed rest alone or rest combined with atenolol (34). The mean duration of therapy in the atenolol-treated patients was 5 weeks. Because only one case has been reported, an association between atenolol and fetal retroperitoneal fibromatosis requires confirmation.

Newborns exposed to atenolol near delivery should be closely observed during the first 24–48 hours for signs and symptoms of b-blockade. Although the results of the study cited above are reassuring, the long-term effects of prolonged in utero exposure to this class of drugs have not been studied but warrant evaluation.

Breast Feeding Summary

Atenolol is excreted into breast milk (4,7,9,35,36,37,38 and 39). The drug is a weak base, and accumulation in the milk occurs with concentrations significantly greater than corresponding plasma levels (4,35,36,37 and 38). Peak milk concentrations after single (50 mg) and continuous dosing (25–100 mg/day) regimens were 3.6 and 2.9 times greater than simultaneous plasma levels (37). Atenolol has been found in the serum and urine of breast-fed infants in some studies (4,7,35). Other studies have been unable to detect the drug in the infant serum (test limit 10 ng/mL) (36,37).

Symptoms consistent with b-adrenergic blockade were observed in a breast-fed, 5-day-old, full-term female infant, including cyanosis, hypothermia (35.5°C rectal), and bradycardia (80 beats/minute) (39). Blood pressure was 80/40 mm Hg. Except for these findings, physical examination was normal and bacterial cultures from various sites were negative. The mother had been treated orally with atenolol, 50 mg every 12 hours, for postpartum hypertension. Breast feeding was stopped 3 days after onset of the symptoms and 6 hours later the infantís symptoms had resolved. A milk sample, collected 10 days postpartum and 1.5 hours after a 50 mg dose, contained 469 ng/ml of atenolol. Concentrations in the infant's serum, 48 and 72 hours after breast feeding, were 2010 ng/mL and 140 ng/mL, respectively. The calculated serum half-life in the infant was 6.4 hours. By extrapolation, the minimum daily dose absorbed by the infant was estimated to be 8.97 mg, approximately 9% of the motherís daily dose (39). (These calculations have been questioned and defended [40,41].) In a 1994 Reference, the American Academy of Pediatrics classified atenolol as compatible with breast feeding, although the above adverse reaction report was not cited (42). This was called to their attention in two 1995 letters to the editor (43,44), and elicited a response that atenolol would be reclassified in a later revision (45).

Except for the single case cited above, adverse reactions in other infants have not been reported. However, because milk accumulation occurs with atenolol, nursing infants must be closely monitored for bradycardia and other signs and symptoms of b-blockade. Moreover, one author has recommended that water-soluble, low-protein-bound, renally excreted b-blockers, such as atenolol, should not be used during lactation (44). Because of the availability of safer alternatives (e.g., propranolol), this seems to be good advice. Long-term effects on infants exposed to b-blockers from breast milk have not been studied but warrant evaluation.

References

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