Chlorothiazide / reserpine Pregnancy and Breastfeeding Warnings

Brand names: Diupres-250, Diupres-500

Chlorothiazide / reserpine Pregnancy Warnings

Reserpine-chlorothiazide has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of teratogenicity after doses of reserpine 125 to 250 times the maximum recommended human dose (MRHD, 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 of reserpine 10 times the MRHD were given early or late in pregnancy. Animal data have failed to reveal evidence of teratogenicity associated with chlorothiazide, but the data 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 regarding either component of this combination drug. Reserpine-chlorothiazide should only be used during pregnancy when there are no alternatives and benefit outweighs risk, keeping in mind that use of chlorothiazide during pregnancy is considered contraindicated by some experts.

There are three relevant sources of information regarding reserpine: a case report and two retrospective studies.

In one case, 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. No significant relationship between congenital anomalies and the use of reserpine was found. 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 had 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.

Chlorothiazide readily crosses the human placenta, with umbilical cord blood levels approximately equivalent to maternal plasma.

Of the 50,282 mother-child pairs in the study mentioned above, 233 were exposed to thiazide or related diuretics during the first trimester. An increased risk of malformations was found for thiazide diuretics, although the high incidence of underlying cardiovascular disease in the population studied 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 showed no association between reserpine or thiazide diuretics and congenital defects (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). Of 229,101 completed pregnancies between 1985 and 1992, 15 were exposed to reserpine at some time during the first trimester, and 42 were exposed to the drug at any time during pregnancy. No birth defects were observed. Regarding thiazide diuretics, this report is a summary of information from 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 reserpine or 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.

See references

Chlorothiazide / reserpine Breastfeeding Warnings

Reserpine is excreted into human milk. There are no reports of adverse effects on the nursing infant. There is a report of galactorrhea associated with reserpine. Chlorothiazide is excreted into human milk in low concentrations. 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.

In one case, a single chlorothiazide 500 mg dose resulted in milk drug concentrations of less than 1 mcg/mL at one, two, and three hours after administration. This usually represents an insignificant amount of chlorothiazide to the infant such that adverse effects in the nursing infant are unlikely.

See references

Further information

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