Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in the 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
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 restriction (IUGR), prematurity, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, which 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.
FETAL RISK SUMMARY
Losartan is a selective angiotensin II receptor blocker (ARB) 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 (1–3). At oral doses greater than three times the maximum recommended human dose of 100 mg based on BSA (MRHD), reduced body weight, delayed physical and behavioral development, mortality, and renal toxicity were observed in rat fetuses and neonates (1–3). These adverse effects were attributed to exposure during late pregnancy (gestational days 15–20) and/or during lactation (1,2). 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 postimplantation loss, or live pups/litter at parturition were observed at an oral dose approximately 12 times the MRHD (1–3).
It is not known if losartan or its active metabolite crosses the human placenta to the fetus. Because the molecular weight of losartan (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 (4). 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-restricted 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 6–8 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 (4).
In a 2001 case report, anhydramnios was diagnosed at 31 weeks’ gestation in a 31-year-old woman with periarteritis nodosa (5). 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 (5).
A 42-year-old woman was treated with losartan (dose not specified), hydrochlorothiazide, felodipine, and metoprolol throughout gestation (6). Oligohydramnios was diagnosed at 33 weeks’ gestation. A 2180-g female infant was born at 36 weeks’ with limb deformities (varus of left foot, right clubfoot, and fixed external rotation of the right knee). Potter’s facies, pulmonary hypertension, and anuria were present and the infant died of respiratory distress on day 4. Autopsy revealed a patent ductus arteriosus and abnormal kidneys (6).
In another case, a 35-year-old woman with hypertension was treated with losartan (50 mg/day) throughout gestation (7). An examination at 22 weeks’ was normal, but oligohydramnios was noted at 34 weeks’. Losartan was stopped and an amnioinfusion was given, but the woman developed signs of infection and a hypotonic male infant (weight not given) was delivered. Apgar scores were 1, 4, and 4 at 1, 5, and 10 minutes, respectively. The infant had persistent hypotension, anuria, and multivisceral failure and died on day 4 (7).
In an unusual case, a 45-year-old woman with type 2 diabetes and chronic hypertension developed anhydramnios (amniotic fluid index [AFI] 0) at about 28 weeks’ gestation while receiving losartan (8). Losartan was discontinued and 4 days later, a transabdominal amnioinfusion produced an AFI of 6. Normal amniotic fluid levels were maintained for the remainder of the pregnancy. At 32 weeks’, ultrasound revealed a thrombus in the fetal vena cava at the level of the right renal vein. Labor was induced at 38 weeks’ to deliver 2960-g male infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Further ultrasound studies revealed an inclusive inferior vena cava thrombus with up to three collateral vessels providing flow around the clot. At 10 days of age, additional examination of the asymptomatic infant revealed a single dominant collateral vessel (8).
A 41-year-old woman with hypertension was treated throughout gestation with losartan (9). At 29 weeks’ gestation, anhydramnios was detected. A cesarean section delivered a 1223-g (50th–60th percentile) female infant was delivered with Apgar scores of 2, 5, and 7 at 1, 5, and 10 minutes, respectively. The flaccid newborn had apnea, bradycardia, and was cyanotic. The neonatal course was complicated by marked renal impairment, hypotension, respiratory depression, joint contractures, and a large anterior fontanelle with widely separated sutures. Follow-up at 7 months of age revealed a growth-restricted infant (≤5th percentile) and renal disease, including apparent renal tubular acidosis (9).
A brief teratogen update in 2005 summarized the adverse outcomes of pregnancies exposed to losartan and three other similar agents (10). Exposure in the second half of pregnancy resulted in fetal toxicity that was very similar to that observed with ACE inhibitors. Although the number of reported 1st trimester exposures was limited, there was no suggestion of an increased risk of major congenital defects (10).
A 2009 report described two cases of losartan exposure before and during pregnancy (11). The drug was used to treat hypertension and was stopped at 8 and 23 weeks’ gestation, respectively. The pregnancy outcome in the first patient was a healthy, 3.730-kg female infant born at 39 weeks. In the second woman, pregnancy woman was diagnosed at 25 weeks’ and losartan was stopped, but oligohydramnios was noted on ultrasound. A repeat ultrasound 1 week later showed worsening oligohydramnios (AFI 1.5). At 27 weeks’, she spontaneously gave birth to a 1.040-kg female infant with Apgar scores of 9 and 9. In addition to the complications of prematurity, impaired renal function was noted but spontaneously resolved by day 6 of age. A renal ultrasound on day 9 was normal. The infant was discharged home on day 52, at which time a small umbilical hernia was discovered. A neurological examination revealed slightly increased muscle tone and mild tremor (11).
A 2012 review of the use of ACE inhibitors and ARBs in the 1st trimester concluded that there may be an elevated teratogenic risk, but the risk appeared to be related to other factors (12). The factors, which typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use of losartan during human lactation have been located. Because the molecular weight (about 461) of losartan is low enough, excretion into human breast milk should be expected. The effects of this exposure on a nursing infant are unknown. The American Academy of Pediatrics, however, classifies ACE inhibitors, a closely related group of antihypertensive agents, as compatible with breastfeeding (see Captopril or Enalapril).
References
1.Product information. Cozaar. Merck, 2001.
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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.
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12.Polifka JE. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence. Birth Defects Res (Part A) 2012;94:576–98.