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METOPROLOL

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Fetal Risk Summary

Metoprolol, a cardioselective b-adrenergic blocking agent, has been used during pregnancy for the treatment of maternal hypertension and tachycardia (1,2,3,4,5,6,7,8,9 and 10). Reproductive studies in mice and rats have found no evidence of impaired fertility or teratogenicity (11). In rats, however, increases in fetal loss and decreases in neonatal survival were observed at doses up to 55.5 times the maximum daily human dose (11).

The drug readily crosses the placenta, producing approximately equal concentrations of metoprolol in maternal and fetal serum at delivery (1,2 and 3). The serum half-lives of metoprolol determined in five women during the 3rd trimester and repeated 3–5 months after delivery were similar (1.3 vs. 1.7 hours, respectively), but peak levels during pregnancy were only 20%–40% of those measured later (4). Neonatal serum levels of metoprolol increase up to 4-fold in the first 2–5 hours after birth, then decline rapidly during the next 15 hours (2,3).

No fetal malformations attributable to metoprolol have been reported, but experience during the 1st trimester is limited. Twins, exposed throughout gestation to metoprolol 200 mg/day plus other antihypertensive agents for severe maternal hypertension, were reported to be doing well at 10 months of age (7).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 52 newborns had been exposed to metoprolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (5.8%) major birth defects were observed (two expected). 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.

A 1978 study described 101 hypertensive pregnant patients treated with metoprolol alone (57 patients) or combined with hydralazine (44 patients) compared with 97 patients treated with hydralazine alone (1). The duration of pregnancy at the start of antihypertensive treatment was 34.1 weeks (range 13–41 weeks) for the metoprolol group and 32.5 weeks (range 12–40 weeks) for the hydralazine group. The metoprolol group experienced a lower rate of perinatal mortality (2% vs. 8%) and a lower incidence of intrauterine growth retardation (11.7% vs. 16.3%). No signs or symptoms of b-blockade were noted in the fetuses or newborns in this or other studies (1,2,5).

The use of metoprolol in a pregnant patient with pheochromocytoma has been reported (5). High blood pressure had been controlled with prazosin, an a-adrenergic blocking agent, but the onset of maternal tachycardia required the addition of metoprolol during the last few weeks of pregnancy. No adverse effects were observed in the newborn.

The acute effects of metoprolol on maternal hemodynamics have been studied (12). Nine women at a mean gestational age of 36.7 ± 3.0 weeks with a diagnosis of pregnancy-induced hypertension were given a single oral dose of 100 mg of metoprolol. Statistically significant (p<0.01) decreases were observed in maternal heart rate, systolic and diastolic blood pressure, and cardiac output. No significant change was noted in mean blood volume or intervillous blood flow. An improvement was observed in four women for the latter parameter, but a reduction occurred in another four. The intervillous blood flow did not change in the ninth patient.

Cardiac palpitations, accompanied by lightheadedness and dyspnea but without syncope, developed in a previously healthy 33-year-old woman at 10 weeks' gestation (13). A diagnosis of ventricular tachycardia and mitral valve prolapse with mild mitral regurgitation was diagnosed at 22 weeks and treatment with metoprolol, 50 mg twice daily, was begun. Four weeks later, quinidine was added to the regimen because of recurrent palpitations. Intrauterine growth retardation was noted during her obstetric care and she eventually gave birth at term to a healthy, 4-pound 15-ounce (about 2242-g) newborn. Follow-up of the infant was not mentioned.

New-onset ventricular tachycardia was diagnosed in seven pregnant women, among whom four were treated with metoprolol (250–450 mg/day) throughout the remainder of their pregnancy (14). Metoprolol therapy in a fifth patient did not resolve the arrhythmia and it was discontinued. Treatment was started in the 1st trimester in one, during the 2nd trimester in one, and in the 3rd trimester in two. All four were delivered at term of healthy newborns with birth weights (in grams) (daily metoprolol dose shown in parenthesis) of 3380 (250 mg), 3462 (350 mg), 3560 (250 mg), and 2535 (450 mg).

A retrospective study published in 1992 reported the follow-up of 35 very low-birth-weight (£1500 g) infants who had been exposed in utero to maternal antihypertensive therapy (15). Nineteen of the infants (mean birth weight 1113 g) had been exposed to b-blockers (metoprolol N=15, propranolol N=4; combination with hydralazine or clonidine in 17 cases) whereas in 16 cases (mean birth weight 1102 g), other antihypertensives (hydralazine alone N=11, hydralazine plus clonidine N=3, hydralazine plus methyldopa N=1, and diuretics N=1) had been used. The metoprolol dose ranged from 100 to 200 mg/day, while that of hydralazine varied from 30 to 150 mg/day. The mean duration of therapy was similar in both groups (12 vs. 11 days). Among the 19 b-blocker-exposed infants, 7 died, 4 within 15 days of birth, compared with no deaths in the other group (p=0.006). The authors speculated that the b-blockade may have impaired the infant's adaptation to the postnatal environment by inhibition of the sympathoadrenal system (15).

Although the use of metoprolol for maternal disease does not seem to pose a major risk to the fetus, the long-term effects of in utero exposure to b-blockers have not been studied. Persistent b-blockade has been observed in newborns exposed near delivery to other members of this class (see Acebutolol, Atenolol, and Nadolol). Thus, newborns exposed in utero to metoprolol should be closely observed during the first 24–48 hours after birth for bradycardia and other symptoms.

Some b-blockers may cause intrauterine growth retardation, as may have occurred in some of the cases above, and reduced placental weight (e.g., see Atenolol and Propranolol). Treatment beginning early in the 2nd trimester results in the greatest weight reductions. 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 documented 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 trimesters.]

Breast Feeding Summary

Metoprolol is concentrated in breast milk (1,3,16,17 and 18). Milk concentrations are approximately 3 times those found simultaneously in the maternal serum (reported range 2.0–3.7). No adverse effects have been observed in nursing infants exposed to metoprolol in milk. Based on calculations from a 1984 study, a mother ingesting 200 mg/day of metoprolol would only provide about 225 µg in 1000 mL of her milk (3). To minimize this exposure even further, one Reference suggested waiting 3–4 hours after a dose to breast-feed (18). Although these levels are probably clinically insignificant, nursing infants should be closely observed for signs or symptoms of b-blockade. The long-term effects of exposure to b-blockers from milk have not been studied but warrant evaluation. The American Academy of Pediatrics considers the drug to be compatible with breast feeding (19).

References

1. Sandstrom B. Antihypertensive treatment with the adrenergic beta-receptor blocker metoprolol during pregnancy. Gynecol Invest 1978;9:195–204.
2. Lundborg P, Agren G, Ervik M, Lindeberg S, Sandstrom B. Disposition of metoprolol in the newborn. Br J Clin Pharmacol 1981;12:598–600.
3. Lindeberg S, Sandstrom B, Lundborg P, Regardh CG. Disposition of the adrenergic blocker metoprolol in the late-pregnant woman, the amniotic fluid, the cord blood and the neonate. Acta Obstet Gynecol Scand 1984;118(Suppl):61–4.
4. Hogstedt S, Lindberg B, Rane A. Increased oral clearance of metoprolol in pregnancy. Eur J Clin Pharmacol 1983;24:217–20.
5. Venuto R, Burstein P, Schneider R. Pheochromocytoma: antepartum diagnosis and management with tumor resection in the puerperium. Am J Obstet Gynecol 1984;150:431–2.
6. Robson DJ, Jeeva Ray MV, Storey GAC, Holt DW. Use of amiodarone during pregnancy. Postgrad Med J 1985;61:75–7.
7. Coen G, Cugini P, Gerlini G, Finistauri D, Cinotti GA. Successful treatment of long-lasting severe hypertension with captopril during a twin pregnancy. Nephron 1985;40:498–500.
8. Gallery EDM. Hypertension in pregnant women. Med J Aust 1985;143:23–7.
9. Hogstedt S, Lindeberg S, Axelsson O, Lindmark G, Rane A, Sandstrom B, Lindberg BS. A prospective controlled trial of metoprolol-hydralazine treatment in hypertension during pregnancy. Acta Obstet Gynecol Scand 1985;64:505–10.
10. Frishman WH, Chesner M. Beta-adrenergic blockers in pregnancy. Am Heart J 1988;115:147–52.
11. Product information. Lopressor. CibaGeneva Pharmaceuticals, 1997.
12. Suonio S, Saarikoski S, Tahvanainen K, Paakkonen A, Olkkonen H. Acute effects of dihydralazine mesylate, furosemide, and metoprolol on maternal hemodynamics in pregnancy-induced hypertension. Am J Obstet Gynecol 1985;155:122–5.
13. Braverman AC, Bromley BS, Rutherford JD. New onset ventricular tachycardia during pregnancy. Int J Cardiol 1991;33:409–12.
14. Brodsky M, Doria R, Allen B, Sato D, Thomas G, Sada M. New-onset ventricular tachycardia during pregnancy. Am Heart J 1992;123:933–41.
15. Kaaja R, Hiilesmaa V, Holma K, Jarvenpaa A-L. Maternal antihypertensive therapy with beta-blockers associated with poor outcome in very-low birthweight infants. Int J Gynecol Obstet 1992;38:195–9.
16. Sandstrom B, Regardh CG. Metoprolol excretion into breast milk. Br J Clin Pharmacol 1980;9:518–9.
17. Liedholm H, Melander A, Bitzen PO, Helm G, Lonnerholm G, Mattiasson I, Nilsson B. Accumulation of atenolol and metoprolol in human breast milk. Eur J Clin Pharmacol 1981;20:229–31.
18. Kulas J, Lunell NO, Rosing U, Steen B, Rane A. Atenolol and metoprolol. A comparison of their excretion into human breast milk. Acta Obstet Scand 1984;118(Suppl):65–9.
19. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
    
    

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