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Hydralazine / hydrochlorothiazide / reserpine Pregnancy and Breastfeeding Warnings

Hydralazine / hydrochlorothiazide / reserpine is also known as: Diuretic Ap-Es, HHR, Hydrap-ES, Marpres, Ser-Ap-Es, Serathide, Serpazide, Serpex, Tri-Hydroserpine, Uni Serp, Unipres

Hydralazine / hydrochlorothiazide / reserpine Pregnancy Warnings

Reserpine-hydralazine-hydrochlorothiazide (HCTZ) has been assigned to pregnancy category C by the FDA. Animal studies with reserpine have revealed evidence of teratogenicity after doses 125 to 250 times the maximum recommended daily human dose (MRDHD, on a per kg basis) were given to rats. Abnormalities included anophthalmia, absence of the axial skeleton, and hydronephrosis. Pregnancy in rabbits was interrupted when doses 10 times the MRDHD were given early or late in pregnancy. Animal studies with hydralazine have revealed evidence of teratogenicity after doses 20 to 30 times the MRDHD (on a per kg basis) were given to mice. Teratogenicity was possibly related to hydralazine after doses 10 to 15 times the MRDHD (on a per kg basis) were given to rabbits. Retrospective reviews of hydrochlorothiazide have shown an increased risk of malformations associated with thiazide diuretics. There are no controlled data on the use of reserpine-hydralazine-hydrochlorothiazide in human pregnancy. Reserpine-hydralazine-hydrochlorothiazide should only be given during pregnancy when there are no alternatives and benefit outweighs risk.

Reserpine: There are three relevant sources of information on the use of reserpine during human pregnancy. In one case report, a stillborn female was born at gestation week 30 to a hypertensive, 30-year-old mother who had taken reserpine from days 13 to 41. Abnormalities included cleft lip and palate and bilateral anophthalmia, marked scoliosis, a thoracolumbar open defect, and diaphragmatic agenesis. The mother had also been exposed to tobacco and ampicillin. Cziezel summarized the Hungarian experience with reserpine from 1980 to 1984. During this period, 52 of 6,227 pregnant women were exposed to reserpine. Neither the total group nor subgroups of congenital anomalies indicated a significant increase associated with reserpine treatment during pregnancy. There was no evidence of a congenital reserpine syndrome. Of 50,282 mother-child pairs monitored by the Collaborative Perinatal Project, 48 had first trimester exposure to reserpine and 475 has exposure to reserpine at anytime during pregnancy. Of the 48, four defects (8%) were observed, which was more than expected. Of the 475, microcephaly (7), hydronephrosis (3), inguinal hernia (12), and hydroureter (3), were observed. None of these anomalies occurred significantly more than expected. Hydralazine: 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 instances of the use of hydralazine during pregnancy were found. Of the 136 pairs, eight malformed children had been exposed to the drug during pregnancy (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. HCTZ: The Collaborative Perinatal Project monitored 50,282 mother-child pairs, of whom 233 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. Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.

Hydralazine / hydrochlorothiazide / reserpine Breastfeeding Warnings

The milk to maternal serum hydralazine concentration ratio was 1.4 in one case in which a woman was taking hydralazine 50 mg three times a day. These data indicate concentration of hydralazine in milk. Even so, the amount of drug exposed to the nursing infant was relatively small, and no adverse effects in the nursing infant were observed. HCTZ is excreted into human milk in low concentrations. In one case, a peak milk concentration of 125 ng per mL was measured between 4 and 12 hours after a daily dose in a woman who was taking HCTZ 50 mg daily. 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. If a 1-month-old infant takes approximately 600 mL of milk per day, and the mean milk HCTZ level is calculated to approximate 80 ng per mL, the infant would be exposed to approximately 0.05 mg of HCTZ each day. This should represent an insignificant amount of HCTZ to the infant such that adverse effects in the nursing infant are unlikely.

Reserpine, hydralazine and hydrochlorothiazide are excreted into human milk. There are no reports of adverse effects on the nursing infant. There is a report of galactorrhea associated with reserpine. 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.

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