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Chlorothiazide / methyldopa Pregnancy and Breastfeeding Warnings

Chlorothiazide / methyldopa is also known as: Aldoclor-150, Aldoclor-250

Chlorothiazide / methyldopa Pregnancy Warnings

Methyldopa crosses the placenta, and may cause mild hypotension in neonates of treated mothers. Because it has been safely and successfully used to treat hypertension during pregnancy, some experts consider it to be the drug of choice for the treatment of nonemergent hypertension during pregnancy. Of 3,248 children with any malformation related to a diuretic or a drug taken for a cardiovascular disorder from a population of 50,282 mother-child pairs in the Collaborative Perinatal Project (CPP), only one case associated with methyldopa was monitored, and no abnormalities were observed. An infant born with congenital heart disease, esophageal atresia, an absent kidney, and hypospadias whose mother received methyldopa throughout her pregnancy has been reported. In one study a decrease in the average head circumference of 202 neonates of mothers who were begun on methyldopa during gestation weeks 16 and 20 has been reported. Long-term follow-up of 98% of these children has not revealed abnormalities, and the developmental delay commonly seen in children of hypertensive mothers was less common in children whose mothers received methyldopa than in the children of untreated mothers. A review of 1,157 hypertensive pregnancies has revealed no evidence of teratogenicity or fetotoxicity associated with methyldopa. The Michigan Medicaid surveillance study showed no association between the use of methyldopa and congenital defects (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). This report is a summary of information from two studies, one in which 120 of 104,000 pregnant women from 1980 to 1983, and one in which 242 of 229,101 pregnant women from 1985 to 1992 received methyldopa during pregnancy. Eight and 11 total defects were observed in these studies, respectively (8 and 10 were expected, respectively). The one instance each of cardiovascular defect, cleft palate, and polydactyly in the second study did not achieve statistical significance. These data do not support an association between methyldopa and congenital defects. The various features of the fetal heart rate pattern, as evaluated in a controlled trial by computerized cardiotocography in human pregnancy, were not influenced by methyldopa 250 mg three times a day in 19 women with preeclampsia. Chlorothiazide readily crosses the human placenta, with umbilical cord blood levels approximately equivalent to maternal plasma. Of the 50,282 mother-child pairs from the CPP, 233 were exposed to thiazide or related diuretics during the first trimester. An increased risk of malformations was found for thiazide diuretics, although the fact that the population studied had underlying cardiovascular disease makes implication of drug use alone difficult. Use of thiazides after the first trimester does not seem to carry this risk. Thiazide diuretics may, however, pose metabolic risks to the mother and fetus (hyponatremia, hypokalemia, thrombocytopenia, hyperglycemia), and may have a direct effect on smooth muscle, resulting in inhibition of labor. The Michigan Medicaid surveillance study (noted above) showed no association between some thiazide diuretics and congenital defects. In the summary of information from the two studies, one in which 390 of 104,000 pregnant women from 1980 to 1983, and one in which 567 of 229,000 pregnant women from 1985 to 1992 received a related drug, hydrochlorothiazide (HCTZ). In the first study 28 total defects and 6 cardiovascular defects were observed (25 and 4 were expected, respectively). In the second study, 24 total defects and 7 cardiovascular defects were observed (22 and 6 were expected, respectively). Cleft palate was not observed in either study. These data do not support an association between HCTZ and congenital defects. These data are considered pertinent to other thiazide diuretics, although the number of exposures to chlorothiazide is too small to make definitive conclusions relative to this drug, per se. Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.

Methyldopa-chlorothiazide has been assigned to pregnancy category C by the FDA. Animal studies have failed to reveal evidence of teratogenicity or fetotoxicity, but the data regarding chlorothiazide are considered limited since visceral or skeletal abnormalities were not sought. Some retrospective reviews have shown an increased risk of malformations associated with thiazide diuretics. There are no controlled data from human pregnancy. Methyldopa-chlorothiazide should only be given during pregnancy when need has been clearly established, keeping in mind that the use of chlorothiazide during pregnancy in patients without heart disease is considered contraindicated by some experts.

Chlorothiazide / methyldopa Breastfeeding Warnings

Both methyldopa and chlorothiazide are excreted into human milk. Adverse effects in the nursing infant are unlikely. While a rare case of thrombocytopenia has been reported in one nursing infant whose mother was taking chlorothiazide, adverse effects in the nursing infant are unlikely. Chlorothiazide is considered compatible with breast-feeding by the American Academy of Pediatrics; however, the manufacturer recommends that due to the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Limited data from four nursing women who were taking methyldopa 750 to 2,000 mg per day reveal concentrations of drug in milk ranging from 0.1 to 0.9 mcg per mL. In one case, a single chlorothiazide 500 mg dose resulted in milk drug concentrations of less than 1 mcg per mL at 1, 2, and 3 hours. This should represent an insignificant amount of chlorothiazide to the infant such that adverse effects in the nursing infant are unlikely.

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