METHYLDOPA

Fetal Risk Summary

Methyldopa is a central acting, antiadrenergic agent used in the treatment of hypertension. It has been used frequently in pregnancy for this indication.

Reproduction studies in mice, rats, and rabbits at doses 1.4, 0.2, and 1.1 times, respectively, the maximum recommended human dose (MRHD)on a body surface area basis, revealed no fetal harm (1). No impairment of fertility was noted in male or female rats at 0.2 times the MRHD. At higher doses (0.5 and 1 times the MRHD) in male rats, however, methyldopa decreased sperm count, sperm motility, the number of late spermatids, and the male fertility index (1).

Methyldopa crosses the placenta and achieves fetal concentrations similar to the maternal serum concentration (2,3 and 4). The Collaborative Perinatal Project monitored only one mother-child pair in which 1st trimester exposure to methyldopa was recorded (5). No abnormalities were found.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 242 newborns had been exposed to methyldopa during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 11 (4.5%) major birth defects were observed (10 expected). Specific data were available for six defect categories, including (observed/expected) 1/2 cardiovascular defects, 1/0 oral clefts, 0/0 spina bifida, 1/1 polydactyly, 0/0 limb reduction defects, and 0/1 hypospadias. These data do not support an association between the drug and congenital defects.

A decrease in intracranial volume has been reported after 1st trimester exposure to methyldopa (6,7). Children evaluated at 4 years of age showed no association between small head size and retarded mental development (8). Review of 1,157 hypertensive pregnancies demonstrated no adverse effects from methyldopa administration (9,10,11,12,13,14,15,16,17,18,19,20 and 21). A reduced systolic blood pressure of 4–5 mm Hg in 24 infants for the first 2 days after delivery has been reported (22). This mild reduction in blood pressure was not considered significant. An infant born with esophageal atresia with fistula, congenital heart disease, absent left kidney, and hypospadias was exposed to methyldopa throughout gestation (23). The mother also took clomiphene early in the 1st trimester.

Breast Feeding Summary

Methyldopa is excreted into breast milk in small amounts. In four lactating women taking 750–2000 mg/day, milk levels of free and conjugated methyldopa ranged from 0.1 to 0.9 µg/mL (2). A milk:plasma ratio could not be determined because simultaneous plasma levels were not obtained. The American Academy of Pediatrics considers methyldopa to be compatible with breast feeding (24).

References

1. Product information. Aldomet. Merck, 2000.
2. Jones HMR, Cummings AJ. A study of the transfer of a-methyldopa to the human foetus and newborn infant. Br J Clin Pharmacol 1978;6:432–4.
3. Jones HMR, Cummings AJ, Setchell KDR, Lawson AM. Pharmacokinetics of methyldopa in neonates. Br J Clin Pharmacol 1979;8:433–40.
4. Cummings AJ, Whitelaw AGL. A study of conjugation and drug elimination in the human neonate. Br J Clin Pharmacol 1981;12:511–5.
5. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:372.
6. Myerscough PR. Infant growth and development after treatment of maternal hypertension. Lancet 1980;1:883.
7. Moar VA, Jefferies MA, Mutch LMM, Dunsted MK, Redman CWG. Neonatal head circumference and the treatment of maternal hypertension. Br J Obstet Gynaecol 1978;85:933–7.
8. Dunsted M, Moar VA, Redman CWG. Infant growth and development following treatment of maternal hypertension. Lancet 1980;1:705.
9. Redman CWG, Beilin LJ, Bonnar J, Ounsted MK. Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 1976;2:753–6.
10. Hamilton M, Kopelman H. Treatment of severe hypertension with methyldopa. Br Med J 1963;1:151–5.
11. Abramowsky CR, Vegas ME, Swinehart G, Gyves MT. Decidual vasculopathy of the placenta in lupus erythematosus. N Engl J Med 1980;303:668–72.
12. Gallery EDM, Sounders DM, Hunyor SN, Gyory AZ. Randomised comparison of methyldopa and oxprenolol for treatment of hypertension in pregnancy. Br Med J 1979;1:1591–4.
13. Gyory AZ, Gallery ED, Hunyor SN. Effect of treatment of maternal hypertension with oxprenolol and a-methyldopa on plasma volume, placental and birth weights. Eighth World Congress of Cardiology, Tokyo, 1978; abstract No. 1098.
14. Arias F, Zamora J. Antihypertensive treatment and pregnancy outcome in patients with mild chronic hypertension. Obstet Gynecol 1979;53:489–94.
15. Redman CWG, Beilin LJ, Bonnar J. A trial of hypotensive treatment in pregnancy. Clin Sci Mol Med 1975;49:3–4.
16. Tcherdakoff P, Milliez P. Traitement de l'hypertension arterielle par alphamethyldopa au cours de la grossesse. Proc Premier Symposium National, Hypertension Arterielle, Cannes, 1970:207–9.
17. Lselve A, Berger R, Vial JY, Gaillard MF. Alpha-methyldopa/Aldomet and reserpine/Serpasil: treatment of pregnancy hypertensions. J Med Lyon 1968;1369–75.
18. Leather HM, Humphreys DM, Baker P, Chadd MA. A controlled trial of hypotensive agents in hypertension in pregnancy. Lancet 1968;2:488–90.
19. Hamilton H. Some aspects of the long-term treatment of severe hypertension with methyldopa. Postgrad Med J 1968;44:66–9.
20. Skacel K, Sklendvsky A, Gazarek F, Matlocha Z, Mohapl M. Therapeutic use of alpha-methyldopa in cases of late toxemia of pregnancy. Cesk Gynekol 1967;32:78–80.
21. Kincaid-Smith P, Bullen M. Prolonged use of methyldopa in severe hypertension in pregnancy. Br Med J 1966;1:274–6.
22. Whitelaw A. Maternal methyldopa treatment and neonatal blood pressure. Br Med J 1981;283:471.
23. Ylikorkala O. Congenital anomalies and clomiphene. Lancet 1975;2:1262–3.
24. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.