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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.

See references

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.

See references

References for pregnancy information

  1. Pritchard JA, Pritchard SA "Standardized treatment of 154 consecutive cases of eclampsia." Am J Obstet Gynecol 123 (1975): 543-52
  2. Pauli RM, Pettersen BJ "Is reserpine a human teratogen?" J Med Genet 23 (1986): 267-8
  3. De Swiet M "Antihypertensive drugs in pregnancy." Br Med J (Clin Res Ed) 291 (1985): 365-6
  4. "Product Information. Ser-Ap-Es (Cam-ap-es)." Ciba Pharmaceuticals, Summit, NJ.
  5. Kuzniar J, Skret A, Piela A, Szmigiel Z, Zaczek T "Hemodynamic effects of intravenous hydralazine in pregnant women with severe hypertension." Obstet Gynecol 66 (1985): 453-8
  6. Yemini M, Shoman (Schwartz) Z, Dgani R, et al. "Lupus-like syndrome in a mother and newborn following administration of hydralazine; a case report." Eur J Obstet Gynecol Reprod Biol 30 (1989): 193-7
  7. Mabie WC, Gonzalez AR, Sibai BM, Amon E "A comparative trial of labetalol hydralazine in the acute management of severe hypertension complicating pregnancy." Obstet Gynecol 70 (1987): 328-33
  8. Bott-Kanner G, Schwitzer A, Schoenfeld A, Joel-Cohen J, Rosenfeld JB "Treatment with propranolol and hydralazine throughout pregnancy in a hypertensive patient." Isr J Med Sci 14 (1978): 466-8
  9. Johnson GT, Thompson RB "A clinical trial of intravenous apresoline in the management of toxaemia of late pregnancy." J Obstet Gynaecol 65 (1958): 360-6
  10. Heinonen O, Slone D, Shapiro S; Kaufman DW ed. "Birth Defects and Drugs in Pregnancy." Littleton, MA: Publishing Sciences Group, Inc. (1977): 297
  11. Lodeiro JG, Feinstein SJ, Lodeiro SB "Fetal premature atrial contractions associated with hydralazine." Am J Obstet Gynecol 160 (1989): 105-7
  12. Czeizel A "Reserpine is not a human teratogen." J Med Genet 25 (1988): 787
  13. Rodriguez SU, Sanford LL, Hiller MC "Neonatal thrombocytopenia associated with ante-partum administration of thiazide drugs." N Engl J Med 270 (1964): 881-4
  14. Rosenfeld J, Bott-Kanner G, Boner G, et al. "Treatment of hypertension during pregnancy with hydralazine monotherapy or with combined therapy with hydralazine and pindolol." Eur J Obstet Gynecol Reprod Biol 22 (1986): 197-204
  15. Widerlov E, Karlman I, Storsater J "Hydralazine-induced neonatal thrombocytopenia." N Engl J Med 303 (1980): 1235
  16. Liedholm H, Wahlin-Boll E, Hanson A, Ingemarsson I, Melander A "Transplacental passage and breast milk concentrations of hydralazine." Eur J Clin Pharmacol 21 (1982): 417-9
  17. Chapman ER, Strozier WE, Magee RA "The clinical use of apresoline in the toxemias of pregnancy: a preliminary report." Am J Obstet Gynecol 68 (1954): 1109-7
  18. Lindheimer MD, Katz AI "Sodiuim and diuretics in pregnancy." N Engl J Med 288 (1973): 891-4

References for breastfeeding information

  1. Committee on Drugs, 1992 to 1993 "The transfer of drugs and other chemicals into human milk." Pediatrics 93 (1994): 137-50
  2. Liedholm H, Wahlin-Boll E, Hanson A, Ingemarsson I, Melander A "Transplacental passage and breast milk concentrations of hydralazine." Eur J Clin Pharmacol 21 (1982): 417-9
  3. Werthmann MW, Krees SV "Excretion of chlorothiazide in human breast milk." J Pediatr 81 (1972): 781-3
  4. "Product Information. Ser-Ap-Es (Cam-ap-es)." Ciba Pharmaceuticals, Summit, NJ.
  5. Ananth J "Side effects in the neonate from psychotropic agents excreted through breast-feeding." Am J Psychiatry 135 (1978): 801-5
  6. Miller ME, Cohn RD, Burghart PH "Hydrochlorothiazide disposition in a mother and her breast-fed infant." J Pediatr 101 (1982): 789-91

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