LOSARTAN

Fetal Risk Summary

Losartan is a selective angiotensin II receptor antagonist that is used, either alone or in combination with other antihypertensive agents, for the treatment of hypertension. Losartan, and its active metabolite, block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by preventing angiotensin II from binding to AT1 receptors.

Reproduction studies have been conducted in pregnant rats (1,2 and 3). At oral doses greater than 3 times the maximum recommended human dose of 100 mg on a body surface area basis (MRHD), reduced body weight, delayed physical and behavioral development, mortality, and renal toxicity were observed in rat fetuses and neonates (1,2 and 3). These adverse effects were attributed to exposure during late pregnancy (gestational days 15–20) and/or during lactation (1,2). A later study, however, found that the amounts of losartan and its active metabolite crossing to the rat fetus were much higher than those excreted in milk, suggesting that the renal toxicity was due to transplacental exposure (4). The irreversible renal abnormalities in the newborn pups included dilatation of the renal pelvis, edema of the renal papilla, medial hypertrophy of intracortical arterioles, chronic renal inflammation, and irregular scarring of the renal parenchyma (2).

In fertility and reproductive performance studies, a significant decrease in fetal implants in rats was noted at a maternally toxic oral dose, approximately 24 times the MRHD. No effects on implants/pregnant female, percent post-implantation loss, or live pups/litter at parturition were observed at an oral dose approximately 12 times the MRHD (1,2 and 3).

A study published in 1999 compared the effects of losartan (an AT1 receptor blocker) to an investigational agent, PD123319 (an AT2 receptor inhibitor), on the developing fetal rat heart (5). Both agents markedly decreased newborn cardiac collagen content, suggesting that angiotensin II receptors are involved in the development of cardiac tissue during gestation (5). The hearts, however, appeared normal in size, shape, and structure. Compared to controls, PD123319 had no effect on birth weight, whereas losartan caused intrauterine growth retardation.

It is not known if losartan or its active metabolite crosses the human placenta to the fetus. Both the drug and its active metabolite cross the rat placenta in significant amounts only during late gestation (1,4). Moreover, the amounts in the rat fetal plasma were significantly higher than those found in maternal milk during lactation (4). In sheep at 125–132 days' gestation (mean 130 days), a bioassay indicated that losartan (10 mg/kg IV) did not cross the placenta (6). The significance of this finding for humans is unknown because the sheep placenta is epitheliochorial whereas the human placenta is hemomonochorial (6). However, because the molecular weight of losartan potassium (about 461) is low enough, passage to the human fetus should be expected.

A postmarketing safety surveillance study of losartan, published in 1999, described the outcomes of four human pregnancies (7). Three of the pregnancies were exposed to the drug in the 1st trimester and the fourth pregnancy was diagnosed about 2 months after stopping the drug. In the first case, the woman became pregnant while taking losartan and the drug was discontinued at approximately 8 weeks' gestation. Because of worsening renal failure, dialysis was required during pregnancy. She delivered a growth-retarded infant at 29 weeks who died at 9 days of age. In the second case, losartan was stopped 6 weeks after the last menstrual period. The woman delivered prematurely at 30 weeks because of preeclampsia. The infant was reported to be doing well. The third pregnancy ended with a spontaneous abortion (no specific embryo data) at 6 to 8 weeks' gestation while the woman was receiving losartan. Finally, a spontaneous abortion (no specific embryo data) occurred at 6 weeks' gestation in a woman who had stopped losartan about 2 months before the pregnancy was diagnosed. Because of the timing of the exposures, none of the outcomes appear to be related to the use of losartan. They are probably a consequence of the women's severe hypertension.

In a 2001 case report, anhydramnios was diagnosed at 31 weeks' gestation in a 31-year-old woman with periarteritis nodosa (8). Hypertension had developed at 17 weeks' gestation and losartan, 50 mg/day, had been started. Therapy was changed to methyldopa (750 mg/day), but 2 days later the woman noticed no fetal movements. Ultrasound confirmed intrauterine fetal death and she delivered a stillborn 1592-g male infant the next day. The infant had facial and limb deformities characteristic of oligohydramnios. At autopsy, pulmonary hypoplasia and hypoplastic skull bones with wide sutures were observed, but no other apparent abnormalities, including the kidneys and urinary tract, were noted. The anhydramnios and resulting fatal fetal abnormalities were attributed to losartan (8).

The antihypertensive mechanisms of action of losartan and angiotensin converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1 receptors, whereas the latter prevents the formation of angiotensin II itself. Therefore, use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity that is identical to that seen with ACE inhibitors (e.g., see Captopril or Enalapril). Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth retardation, prematurity, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, that is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to losartan. Newborn renal function and blood pressure should be closely monitored.

[*Risk factor DM if used in 2nd or 3rd trimesters.]

Breast Feeding Summary

No reports describing the use of losartan during human lactation have been located. The drug and its active metabolite are found in the milk of lactating rats (1). Because the molecular weight (about 461) of losartan potassium is low enough, excretion into human breast milk should also be expected. The effects of this exposure on a nursing infant are unknown. The American Academy of Pediatrics, however, considers ACE inhibitors, a closely related group of antihypertensive agents, to be compatible with breast feeding (see Captopril or Enalapril).

References

1. Product information. Cozaar. Merck, 2001.
2. Spence SG, Allen HL, Cukierski MA, Manson JM, Robertson RT, Eydelloth RS. Defining the susceptible period of developmental toxicity for the AT1-selective angiotensin II receptor antagonist losartan in rats. Teratology 1995;51:367–82.
3. Spence SG, Cukierski MA, Manson JM, Robertson RT, Eydelloth RS. Evaluation of the reproductive and developmental toxicity of the AT1-selective angiotensin II receptor antagonist losartan in rats. Teratology 1995;51:383–97.
4. Spence SG, Zacchei AG, Lee LL, Baldwin CL, Berna RA, Mattson BA, Eydelloth RS. Toxicokinetic analysis of losartan during gestation and lactation in the rat. Teratology 1996;53:245–52.
5. Lamparter S, Sun Y, Weber KT. Angiotensin II receptor blockade during gestation attenuates collagen formation in the developing rat heart. Cardiovascular Res 1999;43:165–72.
6. Stevenson KM, Gibson KJ, Lumbers ER. Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep. Br J Pharmacol 1995;114:1495–1501.
7. Mann RD, Mackay F, Pearce G, Freemantle S, Wilton LV. Losartan: a study of pharmacovigilance data on 14 522 patients. J Hum Hyperten 1999;13:551–7.
8. Saji H, Yamanaka M, Hagiwara, Ijiri R. Losartan and fetal toxic effects. Lancet 2001;357:363.