Hydralazine / hydrochlorothiazide Pregnancy and Breastfeeding Warnings
Hydralazine / hydrochlorothiazide Pregnancy Warnings
In general, hydralazine has been used extensively and safely for the treatment of maternal hypertension during pregnancy. There are reports of neonatal asymptomatic and symptomatic thrombocytopenia and maternal and fetal lupus-like toxicity associated with the maternal use of hydralazine, but there are no reports of associated teratogenicity. Among 50,282 mother-child pairs monitored in the Collaborative Perinatal Project, 136 pairs had been exposed to hydralazine during pregnancy. Of the 136 pairs, 8 malformed children were observed (3.8 were expected from the population studied), yielding a standardized relative risk of 2.09. Underlying preeclampsia makes implication of drug therapy alone difficult. Of 50,282 mother-child pairs in the Collaborative Perinatal Project, 233 pairs were exposed to thiazide or related diuretics during the first trimester. An increased risk of malformations was found for thiazide diuretics. 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. Data from the Michigan Medicaid Birth Defects Study (MMBDS) failed to reveal an association between the use of hydralazine and congenital abnormalities (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). The MMBDS is a retrospective study of 229,101 completed pregnancies between 1985 and 1992, of which 40 were exposed to hydralazine at some time during the first trimester and 341 were exposed to the drug at any time during pregnancy. These data do not support an association between hydralazine and birth defects. Data from the MMBDS has revealed an association between the use of hydrochlorothiazide (HCTZ) and congenital abnormalities. Between 1985 and 1992, 567 of 229,101 completed pregnancies were exposed to HCTZ at some time during the first trimester, and 1,173 were exposed to the drug at any time during pregnancy. Of the 567 pregnancies, there were 24 total and 7 cardiovascular birth defects (22 and 6 were expected, respectively). There were no observations of cleft palate, spina bifida, limb reduction, or hypospadias. The one instance of polydactyly did not achieve statistical significance. These data are consistent with an association between the use of HCTZ and birth defects, although other factors, including underlying disease(s) of the mother are not accounted for. Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.
Hydralazine-hydrochlorothiazide (HCTZ) has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of teratogenicity after doses 20 to 30 times the maximum recommended daily human dose (on a per kg basis) were given to mice. Teratogenicity was possibly related to hydralazine after doses 10 to 15 times the maximum recommended daily human dose (on a per kg basis) were given to rabbits. There are no controlled data in human pregnancy, but retrospective reviews have shown an increased risk of malformations associated with thiazide diuretics. Hydralazine-HCTZ should only be given during pregnancy when benefit outweighs risk.
Hydralazine / hydrochlorothiazide Breastfeeding Warnings
Both hydralazine and hydrochlorothiazide are excreted into human milk. Hydrochlorothiazide 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.
In one case report of a woman who was taking hydralazine 50 mg three times a day, the milk to maternal serum concentration ratio was 1.4, indicating concentration of hydralazine in milk. Even so, the amount of drug exposed to the nursing infant is relative small, and no adverse effects in the nursing infant were observed. In one case, a peak milk concentration of 125 ng/mL was observed between 4 and 12 hours after a daily dose in a woman who was taking HCTZ 50 mg/day. A simultaneously measured maternal serum HCTZ level was approximately 275 ng per mL. There were no detectable drug levels or electrolyte abnormalities in the baby's blood. The authors calculated that, if a 1-month-old infant takes approximately 600 mL of milk per day, and the average milk HCTZ level is approximately 80 ng per mL, the infant would be exposed to approximately 0.05 mg HCTZ daily. This should represent an insignificant amount of HCTZ to the infant such that adverse effect in the nursing infant are unlikely.
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