furosemide

FUROSEMIDE

Fetal Risk Summary

Furosemide is a potent diuretic. The drug has caused maternal deaths and abortions in rabbits at doses 2, 4, and 8 times the maximum recommended human dose of 600 mg/day (1). An increase in the incidence and severity of hydronephrosis (distention of the renal pelvis and in some cases of the ureters) has also been observed in the offspring of mice and rabbits (1). Wavy ribs and some skeletal defects have been observed in the offspring of rats given furosemide during organogenesis (2). These effects appeared to be caused directly or indirectly by the diuretic action of the drug (2).

Cardiovascular disorders, such as pulmonary edema, severe hypertension, or congestive heart failure, are probably the only valid indications for this drug in pregnancy. Furosemide crosses the placenta (3). Following oral doses of 25–40 mg, peak concentrations in cord serum of 330 ng/mL were recorded at 9 hours. Maternal and cord levels were equal at 8 hours. Increased fetal urine production after maternal furosemide therapy has been observed (4,5). Administration of furosemide to the mother has been used to assess fetal kidney function by provoking urine production, which is then visualized by ultrasonic techniques (6,7). Diuresis was found more often in newborns exposed to furosemide shortly before birth than in controls (8). Urinary sodium and potassium levels in the treated newborns were significantly greater than in the nonexposed controls.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 350 newborns had been exposed to furosemide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 18 (5.1%) major birth defects were observed (15 expected). Specific data were available for six defect categories, including (observed/expected) 2/4 cardiovascular defects, 1/1 oral clefts, 0/0 spina bifida, 1/1 polydactyly, 1/1 limb reduction defects, and 3/1 hypospadias. Only with the latter defect is there a suggestion of an association, but other factors, including the mother's disease, concurrent drug use, and chance, may be involved.

After the 1st trimester, furosemide has been used for edema, hypertension, and toxemia of pregnancy without causing fetal or newborn adverse effects (9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 and 31). Many investigators now consider diuretics contraindicated in pregnancy, except for patients with cardiovascular disorders, since they do not prevent or alter the course of toxemia and they may decrease placental perfusion (32,33,34 and 35). A 1984 study determined that the use of diuretics for hypertension in pregnancy prevented normal plasma volume expansion and did not change perinatal outcome (36). Thus, diuretics are not recommended for the treatment of pregnancy-induced hypertension because of the maternal hypovolemia characteristic of this disease.

Administration of the drug during pregnancy does not significantly alter amniotic fluid volume (30). Serum uric acid levels, which are increased in toxemia, are further elevated by furosemide (37). No association was found in a 1973 study between furosemide and low platelet counts in the neonate (38). Unlike the thiazide diuretics, neonatal thrombocytopenia has not been reported for furosemide.

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

Breast Feeding Summary

Furosemide is excreted into breast milk (1,39). No reports of adverse effects in nursing infants have been found. Thiazide diuretics have been used to suppress lactation (see Chlorothiazide).

References

1. Product information. Furosemide. Mylan Pharmaceuticals, 2000.
2. Shepard TH. Catalog of Teratogen Agents. 9th ed. Baltimore, MD:The Johns Hopkins University Press, 1998:215.
3. Beermann B, Groschinsky-Grind M, Fahraeus L, Lindstroem B. Placental transfer of furosemide. Clin Pharmacol Ther 1978;24:560–2.
4. Wladimiroff JW. Effect of furosemide on fetal urine production. Br J Obstet Gynaecol 1975;82:221–4.
5. Stein WW, Halberstadt E, Gerner R, Roemer E. Effect of furosemide on fetal kidney function. Arch Gynekol 1977;224:114–5.
6. Barrett RJ, Rayburn WF, Barr M Jr. Furosemide (Lasix) challenge test in assessing bilateral fetal hydronephrosis. Am J Obstet Gynecol 1983;147:846–7.
7. Harman CR. Maternal furosemide may not provoke urine production in the compromised fetus. Am J Obstet Gynecol 1984;150:322–3.
8. Pecorari D, Ragni N, Autera C. Administration of furosemide to women during confinement, and its action on newborn infants. Acta Biomed (Italy) 1969;40:2–11.
9. Pulle C. Diuretic therapy in monosymptomatic edema of pregnancy. Minerva Med 1965;56:1622–3.
10. DeCecco L. Furosemide in the treatment of edema in pregnancy. Minerva Med 1965;56:1586–91.
11. Bocci A, Pupita F, Revelli E, Bartoli E, Molaschi M, Massobrio A. The water-salt metabolism in obstetrics and gynecology. Minerva Ginecol 1965;17:103–10.
12. Sideri L. Furosemide in the treatment of oedema in gynaecology and obstetrics. Clin Ter 1966;39:339–46.
13. Wu CC, Lee TT, Kao SC. Evaluation of new diuretic (furosemide) on pregnant women. A pilot study. J Obstet Gynecol Republ China 1966;5:318–20.
14. Loch EG. Treatment of gestosis with diuretics. Med Klin 1966;61:1512–5.
15. Buchheit H, Nicolai KH. Influence of furosemide (Lasix) on gestational edemas. Med Klin 1966;61:1515–8.
16. Tanaka T. Studies on the clinical effect of Lasix in edema of pregnancy and toxemia of pregnancy. Sanka To Fujinka 1966;41:914–20.
17. Merger R, Cohen J, Sadut R. Study of the therapeutic effects of furosemide in obstetrics. Rev Fr Gynecol 1967;62:259–65.
18. Nascimento R, Fernandes R, Cunha A. Furosemide as an accessory in the therapy of the toxemia of pregnancy. Hospital (Portugal) 1967;71:137–40.
19. Finnerty FA Jr. Advantages and disadvantages of furosemide in the edematous states of pregnancy. Am J Obstet Gynecol 1969;105:1022–7.
20. Das Gupta S. Frusemide in blood transfusion for severe anemia in pregnancy. J Obstet Gynaecol India 1970;20:521–5.
21. Kawathekar P, Anusuya SR, Sriniwas P, Lagali S. Diazepam (Calmpose) in eclampsia: a preliminary report of 16 cases. Curr Ther Res 1973;15:845–55.
22. Pianetti F. Our results in the treatment of parturient patients with oedema during the five years 1966–1970. Atti Accad Med Lomb 1973;27:137–40.
23. Azcarte Sanchez S, Quesada Rocha T, Rosas Arced J. Evaluation of a plan of treatment in eclampsia (first report). Ginecol Obstet Mex 1973;34:171–86.
24. Bravo Sandoval J. Management of pre-eclampsia-eclampsia in the third gyneco-obstetrical hospital. Cir Cirjjands 1973;41:487–94.
25. Franck H, Gruhl M. Therapeutic experience with nortensin in the treatment of toxemia of pregnancy. Munch Med Wochenschr 1974;116:521–4.
26. Cornu P, Laffay J, Ertel M, Lemiere J. Resuscitation in eclampsia. Rev Prat 1975;25:809–30.
27. Finnerty FA Jr. Management of hypertension in toxemia of pregnancy. Hosp Med 1975;11:52–65.
28. Saldana-Garcia RH. Eclampsia: maternal and fetal mortality. Comparative study of 80 cases. In VIII World Congress of Gynecology and Obstetrics. Int Cong Ser 1976;396:58–9.
29. Palot M, Jakob L, Decaux J, Brundis JP, Quereux C, Wahl P. Arterial hypertensions of labor and the postpartum period. Rev Fr Gynecol Obstet 1979;74:173–6.
30. Votta RA, Parada OH, Windgrad RH, Alvarez OH, Tomassinni TL, Patori AA. Furosemide action on the creatinine concentration of amniotic fluid. Am J Obstet Gynecol 1975;123:621–4.
31. Clark AD, Sevitt LH, Hawkins DF. Use of furosemide in severe toxaemia of pregnancy. Lancet 1972;1:35–6.
32. Pitkin RM, Kaminetzky HA, Newton M, Pritchard JA. Maternal nutrition: a selective review of clinical topics. Obstet Gynecol 1972;40:773–85.
33. Lindheimer MD, Katz AI. Sodium and diuretics in pregnancy. N Engl J Med 1973;288:891–4.
34. Christianson R, Page EW. Diuretic drugs and pregnancy. Obstet Gynecol 1976;48:647–52.
35. Gant NF, Madden JD, Shteri PK, MacDonald PC. The metabolic clearance rate of dehydroisoandrosterone sulfate. IV. Acute effects of induced hypertension, hypotension, and natriuresis in normal and hypertensive pregnancies. Am J Obstet Gynecol 1976;124:143–8.
36. Sibai BM, Grossman RA, Grossman HG. Effects of diuretics on plasma volume in pregnancies with long-term hypertension. Am J Obstet Gynecol 1984;150:831–5.
37. Carswell W, Semple PF. The effect of furosemide on uric acid levels in maternal blood, fetal blood and amniotic fluid. J Obstet Gynaecol Br Commonw 1974;81:472–4.
38. Jerkner K, Kutti J, Victorin L. Platelet counts in mothers and their newborn infants with respect to antepartum administration of oral diuretics. Acta Med Scand 1973;194:473–5.
39. Product information. Lasix. Hoechst-Roussel Pharmaceuticals, 1990.
    
    

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