Chlorothiazide in Pregnancy and Breastfeeding

Risk Factor: CM*
Class: Diuretics

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Chlorothiazide is a member of the thiazide group of diuretics. The information in this monograph applies to all members of the group, including the pharmacologically and structurally related diuretics, chlorthalidone, indapamide, metolazone, and quinethazone.

Reproduction studies in mice (500 mg/kg/day), rats (60 mg/kg/day), and rabbits (50 mg/kg/day) revealed no external malformations or growth impairment, and no effect on fetal survival (1). However, these studies did not include a thorough examination for visceral anomalies and skeletal defects (1).

Data from published reports indicate that thiazide and related diuretics are infrequently administered during the 1st trimester. In the past, when these drugs were routinely given to prevent or treat toxemia, therapy was usually begun in the 2nd or 3rd trimester and adverse effects in the fetus were rare (2,3,4,5,6,7,8,9,10 and 11). No increases in the incidence of congenital defects were discovered, and thiazides were considered nonteratogenic (12,13,14 and 15).

In contrast, the Collaborative Perinatal Project monitored 50,282 mother-child pairs, 233 of whom were exposed in the 1st trimester to thiazide or related diuretics (16, pp. 371373). All of the mothers had cardiovascular disorders, which makes interpretation of the data difficult. However, an increased risk for malformations was found for chlorthalidone (20 patients) and miscellaneous thiazide diuretics (35 patients, excluding chlorothiazide and hydrochlorothiazide). For use anytime during pregnancy, 17,492 exposures were recorded and only polythiazide showed a slight increase in risk (16, p. 441). The statistical significance of these findings is unknown and independent confirmation is required.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, a number of newborns had been exposed to this class of diuretics during the 1st trimester: 20 (chlorothiazide), 48 (chlorthalidone), and 567 (hydrochlorothiazide) (Franz Rosa, personal communication, FDA, 1993). The number of major birth defects observed, the number expected, and the incidence for each drug were: 2/1/10.0%, 2/2/4.2%, and 24/22/4.2%, respectively. Specific data were available for six defect categories (observed/expected): cardiovascular defects 0/0, 1/0.5, and 7/6; oral clefts 0/0, 0/0, and 0/1; spina bifida, 0/0, 0/0, and 0/0.5; polydactyly, 0/0, 0/0, and 1/2y; limb reduction defects 0/0, 0/0, and 0/1; and hypospadias 1/0, 0/0, and 1/1, respectively. Although the number of exposures is small for two of the diuretics, these data do not support an association between the drug and congenital defects.

Many investigators consider diuretics contraindicated in pregnancy, except for patients with heart disease or chronic hypertension, because they do not prevent or alter the course of toxemia and they may decrease placental perfusion (8, 17,18,19,20 and 21). A 1984 study determined that the use of diuretics for hypertension in pregnancy prevented normal plasma volume expansion and did not change perinatal outcome (22). In 4,035 patients treated for edema in the last half of the 3rd trimester (hypertensive patients were excluded), higher rates were found for induction of labor, stimulation of labor, uterine inertia, meconium staining, and perinatal mortality (20). All except perinatal mortality were statistically significant compared with 13,103 controls. In another study, a decrease in endocrine function of the placenta as measured by placental clearance of estradiol was found in three patients treated with hydrochlorothiazide (23).

Chlorothiazide readily crosses the placenta at term, and fetal serum levels may equal those of the mother (24). In 10 women following 2 weeks of hydrochlorothiazide, 50 mg/day, the cord:maternal plasma ratio determined 213 hours after the last dose ranged from 0.10 to 0.80 (25). Chlorthalidone also crosses the placenta (26). Other diuretics probably cross to the fetus in similar amounts, although specific data are lacking.

Thiazides are considered mildly diabetogenic because they can induce hyperglycemia (18). Several investigators have noted this effect in pregnant patients treated with thiazides (27,28,29 and 30). Other studies have failed to show maternal hyperglycemia (31,32). Although apparently a low risk, newborns exposed to thiazide diuretics near term should be observed closely for symptoms of hypoglycemia resulting from maternal hyperglycemia (30).

Neonatal thrombocytopenia has been reported following the use near term of chlorothiazide, hydrochlorothiazide, and methyclothiazide (15,27,33,34,35,36,37 and 38). Other studies have not found a relationship between thiazide diuretics and platelet counts (39,40). The positive reports involve only 11 patients; however, although the numbers are small, 2 of the affected infants died (27,34). The mechanism of the thrombocytopenia is unknown, but the transfer of antiplatelet antibody from the mother to the fetus has been demonstrated (38). Thiazide-induced hemolytic anemia in 2 newborns was described in 1964 following the use of chlorothiazide and bendroflumethiazide at term (33). Thiazide diuretics may induce severe electrolyte imbalances in the mother's serum, in amniotic fluid, and in the newborn (41,42 and 43). In one case, a stillborn fetus was attributed to electrolyte imbalance and/or maternal hypotension (41). Two hypotonic newborns were discovered to be hyponatremic, a condition believed to have resulted from maternal diuretic therapy (42). Fetal bradycardia, 6570 beats/minute, was shown to be secondary to chlorothiazide-induced maternal hypokalemia (43). In a 1963 study, no relationship was found between neonatal jaundice and chlorothiazide (44). Maternal and fetal deaths in two cases of acute hemorrhagic pancreatitis were attributed to the use of chlorothiazide in the 2nd and 3rd trimesters (45).

In summary, the published experience with 1st trimester use of thiazides and related diuretics does not indicate these agents are teratogenic. One large study (the Collaborative Perinatal Project) did find an increased risk of defects when diuretics were used during the 1st trimester in women with cardiovascular disorders, but causal relationships cannot be inferred from these data without independent confirmation.

Diuretics are not recommended for the treatment of pregnancy-induced hypertension because of the maternal hypovolemia characteristic of this disease. Other risks to the fetus or newborn include hypoglycemia, thrombocytopenia, hyponatremia, hypokalemia, and death from maternal complications. Moreover, thiazide diuretics may have a direct effect on smooth muscle and inhibit labor.

[*Risk Factor D if used in pregnancy-induced hypertension.]

Breast Feeding Summary

Chlorothiazide is excreted into breast milk in low concentrations (46). Following a single 500-mg oral dose, milk levels were less than 1 mg/mL at 1, 2, and 3 hours. The authors speculated that the risks of pharmacologic effects in nursing infants would be remote. However, it has been stated that thrombocytopenia can occur in the nursing infant if the mother is taking chlorothiazide (47). Documentation of this is needed (48). Chlorthalidone has a very low milk:plasma ratio of 0.05 (26).

In one mother taking 50 mg of hydrochlorothiazide (HCTZ) daily, peak milk levels of the drug occurred 510 hours after a dose and were about 25% of maternal blood concentrations (49). The mean milk concentration of HCTZ was about 80 ng/mL. An infant consuming 600 mL of milk/day would thus ingest about 50 mg of the drug, probably an insignificant amount (49). The diuretic could not be detected in the serum of the nursing 1-month-old infant, and measurements of serum electrolytes, blood glucose, and blood urea nitrogen were all normal.

Thiazide diuretics have been used to suppress lactation (50,51). However, the American Academy of Pediatrics considers bendroflumethiazide, chlorthalidone, chlorothiazide, and hydrochlorothiazide to be compatible with breast feeding (52).

References

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Questions and Answers

what does chlorothiazide do to your phosphorus and calcium levels?,

Chlorothiazide is a "thiazide" diuretic. They can lower all your electrolytes except calcium. For some reason, you can get a high calcium.

Could prescription medicine negate the affects of the Plan-B pill?, The prescription medicine that I'm taking is labetalol, chlorothiazide, and lisinopril for my high-blood pressure. I want to make sure that these medicines could make the Plan-B pill not work if I took it.

I tried looking up information but I was unable to find anything. Anyone know anything?

There are no interactions that I know of between Plan B (levonorgestrel) and the medications you are taking.