TRIAMTERENE

Fetal Risk Summary

Triamterene is a potassium-conserving diuretic. It is a weak folic acid antagonist. Reproduction studies in rats at doses up to 6 times the maximum recommended human dose based on body surface area found no evidence of fetal harm (1).

The drug crosses the placenta in animals (1). The molecular weight (about 253) is low enough that transfer to the human fetus should be expected.

No defects were observed in five infants exposed to triamterene in the 1st trimester (2, p. 372). For use anytime during pregnancy, 271 exposures were recorded without an increase in malformations (2, p. 441).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 318 newborns had been exposed to triamterene during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 15 (4.7%) major birth defects were observed (13 expected). Three cases of cardiovascular defects (three expected) and one case of polydactyly (one expected) were observed, but specific information was not available for the other defects. No anomalies were observed in four other categories of defects (oral clefts, spina bifida, limb-reduction defects, and hypospadias) for which data were available. These data do not support an association between the drug and congenital defects.

The effects of exposure (at any time during the 2nd or 3rd month after the last menstrual period) to folic acid antagonists on embryo/fetal development were evaluated in a large, multicenter, case-control surveillance study published in 2000 (3). The report was based on data collected between 1976 and 1998 by the Slone Epidemiology Unit Birth Defects Study from 80 maternity or tertiary care hospitals in Boston, Philadelphia, Toronto, and Iowa. Mothers were interviewed within 6 months of delivery about their use of drugs during pregnancy. Folic acid antagonists were categorized into two groups: group I—dihydrofolate reductase inhibitors (aminopterin, methotrexate, sulfasalazine, pyrimethamine, triamterene, and trimethoprim); group II—agents that affect other enzymes in folate metabolism, impair the absorption of folate, or increase the metabolic breakdown of folate (carbamazepine, phenytoin, primidone, and phenobarbital) (3). The case subjects were 3,870 infants with cardiovascular defects, 1,962 with oral clefts, and 1,100 with urinary tract malformations. Infants with defects associated with a syndrome were excluded, as were infants with coexisting neural tube defects (NTDs; known to be reduced by maternal folic acid supplementation). Too few infants with limb-reduction defects were identified to be analyzed. Controls (N=8,387) were infants with malformations other than oral clefts and cardiovascular, urinary tract, and limb-reduction defects and NTDs, but included infants with chromosomal and genetic defects. The risk of malformations in control infants would not have been reduced by vitamin supplementation, and none of the controls used folic acid antagonists (3). For group I cases, the relative risks (RRs) of cardiovascular defects and oral clefts were 3.4 (95% confidence interval [CI] 1.8–6.4) and 2.6 (95% CI 1.1–6.1), respectively. For group II cases, the RRs of cardiovascular and urinary tract defects, and oral clefts were 2.2 (95% CI 1.4–3.5), 2.5 (95% CI 1.2–5.0), and 2.5 (95% CI 1.5–4.2), respectively. Maternal use of multivitamin supplements reduced the risks in group I cases, but not in group II cases (3).

Many investigators consider diuretics to be contraindicated in pregnancy, except for patients with heart disease, because they do not prevent or alter the course of toxemia, and they may decrease placental perfusion (4,5 and 6). In general, diuretics are not recommended for the treatment of pregnancy-induced hypertension because of the maternal hypovolemia characteristic of this disease.

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

Breast Feeding Summary

No reports describing the use of triamterene during lactation have been located. The molecular weight (about 253) is low enough that excretion into breast milk should be expected. The diuretic is excreted in animal milk (1). The potential effects of this exposure on a nursing infant are unknown.

References

1. Product information. Dyrenium. WellSpring Pharmaceuticals, 2001.
2. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
3. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608–14.
4. Pitkin RM, Kaminetzky HA, Newton M, Pritchard JA. Maternal nutrition: a selective review of clinical topics. Obstet Gynecol 1972;40:773–85.
5. Lindheimer MD, Katz AI. Sodium and diuretics in pregnancy. N Engl J Med 1973;288:891–4.
6. Christianson R, Page EW. Diuretic drugs and pregnancy. Obstet Gynecol 1976;48:647–52.