Diuretic (Carbonic Anhydrase Inhibitor)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Although some animal data have shown toxicity in offspring, a comparison to the human dose has not been provided and most studies found no adverse effects. Moreover, despite widespread use, the human data do not suggest a risk of developmental toxicity. The drug can be considered compatible in pregnancy.
FETAL RISK SUMMARY
Acetazolamide is an inhibitor of the enzyme carbonic anhydrase. It is indicated as adjunctive treatment of chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure. It also is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness despite gradual ascent (1). The drug also is used off-label for idiopathic intracranial hypertension (IIH) (2–5).
Shepard (6) reviewed six reproduction studies using acetazolamide in mice, rats, hamsters, and monkeys. Forelimb defects were observed in the fetuses of rodents, but not in those of monkeys. One of the studies found that potassium replacement reduced the risk of congenital defects in rats (6). A study with pregnant rabbits found that, with doses producing maternal acidosis and electrolyte changes, acetazolamide produced a dose-related increase in axial skeletal malformations (7). The combination of acetazolamide and amiloride was found to produce abnormal development of the ureter and kidney in fetal mice when given at the critical moment of ureter development (8).
It is not known if acetazolamide crosses the human placenta. However, the molecular weight (about 222) suggests that the drug will cross to the embryo–fetus.
Despite widespread usage, no reports linking the use of acetazolamide with congenital defects have been located. A single case of a neonatal sacrococcygeal teratoma has been described (9). The mother received 750 mg daily for glaucoma during the 1st and 2nd trimesters. A relationship between the drug and carcinogenic effects in the fetus has not been supported by other reports. Retrospective surveys on the use of acetazolamide during gestation have not demonstrated an increased fetal risk (10,11).
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 12 of whom had 1st trimester exposure to acetazolamide (12, p. 372). No anomalies were observed in the exposed offspring. For use anytime during pregnancy, 1024 exposures were recorded (12, p. 441), and 18 infants were found to have malformations (18.06 expected). Thus, no evidence was found to suggest a relationship to large categories of major or minor malformations or to individual defects.
A woman with glaucoma was treated throughout pregnancy with acetazolamide, 250 mg twice daily, and topical pilocarpine and timolol (13). Within 48 hours of birth at 36 weeks’ gestation, the infant’s condition was complicated by hyperbilirubinemia and asymptomatic hypocalcemia, hypomagnesemia, and metabolic acidosis. The deficiencies of calcium and magnesium resolved quickly after treatment, as did the acidosis, even though the mother continued her medications while breastfeeding the infant. Mild hypertonicity of the lower limbs requiring physiotherapy was observed at 1-, 3-, and 8-month examinations. Two healthy infants of an epileptic mother, treated throughout two pregnancies with acetazolamide 250 mg/day and carbamazepine, were delivered at term and showed no effects of exposure to the drugs (13).
Four reports described the use of acetazolamide for treatment of IIH in a large number of pregnant women (2–5). No embryo or fetal adverse effects attributable to the drug were noted in any of the cases.
BREASTFEEDING SUMMARY
Acetazolamide is excreted into breast milk (14). A mother, 6 days postpartum, was given 500 mg (sustained-release formulation) twice daily for glaucoma, and she breastfed her infant for the following week. Nursing was stopped after that time because of the mother’s concerns about exposing the infant to the drug. However, no changes attributable to drug exposure were noted in the infant. Breast milk levels of acetazolamide on the fourth and fifth days of therapy, 1–9 hours after a maternal dose, varied between 1.3 and 2.1 mcg/mL. A consistent relationship between concentration and time from last dose was not apparent. A milk:plasma ratio 1 hour after a dose was 0.25. Three plasma levels of acetazolamide in the infant were 0.2, 0.2, and 0.6 mcg/mL. The authors estimated that the infant ingested about 0.6 mg/day (i.e., 0.06% of the maternal dose) (15).
The American Academy of Pediatrics classifies acetazolamide as compatible with breastfeeding (15).
References
1.Product information. Acetazolamide. Teva Pharmaceuticals, 2009.
2.Lee AG, Pless M, Falardeau J, Capozzoli T, Wall M, Kardon RH. The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Am J Ophthalmol 2005;139:855–9.
3.Falardeau J, Lobb BM, Golden S, Maxfield SD, Tanne E. The use of acetazolamide during pregnancy in intracranial hypertension patients. J Neuroophthalmol 2013;33:9–12.
4.Kesler A, Kupferminc M. Idiopathic intracranial hypertension and pregnancy. Clin Obstet Gynecol 2013;56:389–96.
5.Golan S, Maslovitz S, Kupferminc MJ, Kesler A. Management and outcome of consecutive pregnancies complicated by idiopathic intracranial hypertension. Isr Med Assoc J 2013;15:160–3.
6.Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:5–6.
7.Nakatsuka T, Komatsu T, Fujii T. Axial skeletal malformations induced by acetazolamide in rabbits. Teratology 1992;45:629–36.
8.Miller TA, Scott WJ Jr. Abnormalities in ureter and kidney development in mice give acetazolamide–amiloride or dimethadione (DMO) during embryogenesis. Teratology 1992;46:541–50.
9.Worsham GF, Beckman EN, Mitchell EH. Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA 1978;240:251–2.
10.Favre-Tissot M, Broussole P, Robert JM, Dumont L. An original clinical study of the pharmacologic–teratogenic relationship. Ann Med Psychol 1964;1:389. As cited in Nishimura H, Tanimura T, eds. Clinical Aspects of the Teratogenicity of Drugs. New York, NY: Excerpta Medica, 1976:210.
11.McBride WG. The teratogenic action of drugs. Med J Aust 1963;2:689–93.
12.Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
13.Merlob P, Litwin A, Mor N. Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol 1990;35:85–8.
14.Soderman P, Hartvig P, Fagerlund C. Acetazolamide excretion into human breast milk. Br J Clin Pharmacol 1984;17:599–600.
15.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.