Risk Factor: CM*
Class: Cardiovascular drugs/ Antihypertensives/ Angiotensin ii receptor antagonists
Fetal Risk Summary
Valsartan is a selective angiotensin II receptor antagonist that is used, either alone or in combination with other antihypertensive agents, for the treatment of hypertension. Valsartan blocks 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 mice, rats, and rabbits (1). No teratogenic effects were observed in these species at oral doses up to 9, 18, and 0.5 times the maximum recommended human dose of 320 mg/day based on body surface area (MRHD), respectively. The highest dose caused rat maternal toxicity (reduction in body weight gain and food consumption). At this dose, administration during organogenesis or late gestation and lactation resulted in significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones (1). In rabbits, maternal toxic doses (0.25 and 0.5 times the MRHD) resulted in fetal resorptions, litter loss, abortions, and low fetal body weight as well as maternal mortality. The no-observed-adverse-effect doses in mice, rats, and rabbits were 9, 6, and 0.1 times the MRHD, respectively (1). No adverse effects on reproductive performance of male and female rats were noted at oral doses up to 6 times the MRHD (1).
It is not known if valsartan crosses the human placenta to the fetus. The molecular weight (about 436) is low enough that passage to the fetus should be expected.
A 2001 case report described the pregnancy outcome of a 40-year-old woman with well-controlled chronic hypertension and diet-controlled type 2 diabetes mellitus who was treated with valsartan (80 mg/day) and atenolol (75 mg/day) until presentation at 24 weeks’ gestation (2). Anhydramnios (amniotic fluid index zero), most likely due to valsartan, was diagnosed by ultrasound, but fetal growth was appropriate for gestational age. Valsartan was stopped and atenolol was continued at the same dose. The amniotic fluid volume normalized within 2 weeks. The blood pressure, without evidence of toxemia, and the diabetes remained under adequate control. Intrauterine fetal death was diagnosed at 31 weeks’ gestation. At autopsy, very small, hypoplastic lungs were found (weight 18 g/expected 44 g), as were heavy kidneys (31 g/expected 18 g). The placenta was below the 10th percentile for gestational age (148 g/expected weight for gestational age at the 10th percentile 311 g). No other anomalies were detected. The very small placenta was thought to be primarily due to atenolol, but valsartan may have contributed to the condition. Death of the female fetus probably resulted from chronic placental insufficiency induced by the combination of valsartan and atenolol (2).
The antihypertensive mechanisms of action of valsartan 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 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, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to valsartan. 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 valsartan during human lactation have been located. The drug is excreted into the milk of lactating rats (1). Because the molecular weight (about 436) 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).
- Product information. Diovan. Novartis Pharmaceuticals, 2001.
- Briggs GG, Nageotte MP. Fatal fetal outcome with the combined use of valsartan and atenolol. Ann Pharmacother 2001;35:85961.