Chlorthalidone / reserpine Pregnancy and Breastfeeding Warnings

Brand names: Demi-Regroton, Regroton

Chlorthalidone / reserpine Pregnancy Warnings

Reserpine-chlorthalidone has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of teratogenicity after reserpine doses 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 reserpine was given in doses 10 times the MRHD early or late in pregnancy. Animal studies have failed to reveal evidence of teratogenicity associated with chlorthalidone. Some retrospective reviews have shown an increased risk of malformations associated with thiazide diuretics. There are no controlled data from human pregnancy. Reserpine-chlorthalidone should only be used during pregnancy when there are no alternatives and benefit outweighs risk.

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.

One prospective study, one retrospective study, and rare cases of the use of chlorthalidone during pregnancy have been reported. A series of 211 pregnant women who were given chlorthalidone to prevent toxemia of pregnancy has been reported. Patients were entered into the study at gestation week 16, and were given chlorthalidone 50 mg once a day or placebo in a single-blinded fashion. There were significant decreases in the serum sodium and potassium in the treated patients, especially between gestation months four through nine. There appeared to be no benefit from the drug since there were no differences in blood pressure or the incidence of edema or proteinuria between the groups. The average height and weight of the offspring of treated patients was significantly higher; there were no deaths and no malformations. Placental weights were significantly greater among women who received chlorthalidone, but no differences in the amount or nature of amniotic fluid, placental calcification, or number of placental infarctions between the groups was found. The authors speculated whether the increased placental size in the treated group was related to alterations in glycogen metabolism.

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. 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 gave 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, and are considered pertinent to other thiazide diuretics.

Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.

See references

Chlorthalidone / reserpine Breastfeeding Warnings

Both reserpine and chlorthalidone are excreted into human milk. There are no reports of adverse effects on the nursing infant. However, galactorrhea has been associated with reserpine. 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.

There are no data on the safety of chlorthalidone during breast-feeding. There are data regarding the excretion of a related drug, hydrochlorothiazide (HCTZ) into human milk. A peak milk concentration of 125 ng/mL was measured 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/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 mean milk HCTZ level is approximately 80 ng/mL, the infant would be exposed to approximately 0.05 mg of HCTZ daily. This usually represents an insignificant amount of HCTZ to the infant such that adverse effects in the nursing infant are unlikely.

See references

Further information

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