Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The human pregnancy experience with irbesartan is limited. However, the antihypertensive mechanisms of action of irbesartan 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, premature birth, 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 irbesartan. Newborn renal function and blood pressure should be closely monitored.
FETAL RISK SUMMARY
Irbesartan 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. Irbesartan 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 rats and rabbits (1). In the pregnant rat, doses approximately equal to or higher than the maximum recommended human dose of 300 mg/day based on BSA (MRHD) were associated with increased incidences of renal pelvic cavitation, hydroureter, and/or absence of renal papilla. At four times the MRHD, subcutaneous edema was observed in the fetuses. The anomalies appeared to be related to late, rather than early, gestational exposure (1). Doses approximately 1.5 times the MRHD in pregnant rabbits produced maternal mortality and abortion. Surviving rabbits had a slight increase in early resorptions (1). No adverse effects on fertility or reproductive performance were seen in male and female rats at an oral dose about 5 times the MRHD (1).
It is not known if irbesartan crosses the human placenta to the fetus. The molecular weight (about 429) is low enough that transfer to the fetus should be expected. The drug does cross the placentas of rats and rabbits in late gestation (1).
A 24-year-old woman with type 1 diabetes, hypothyroidism, and hypertension was being treated with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day, insulin (glargine and regular), levothyroxine 0.125 mg/day, and epoetin alfa (2). An unplanned pregnancy occurred that was diagnosed at 8 weeks and irbesartan and hydrochlorothiazide were replaced with methyldopa. The patient’s HbA1c was 7%. Ultrasonography at 13 weeks’ detected an exencephaly and the pregnancy was terminated. Autopsy revealed a partial exencephaly and unilateral renal agenesis. The cause of the defects could not be determined, but the authors suspected irbesartan (2). However, unilateral renal agenesis is possibly autosomal dominant inheritance with variable expressivity and penetrance (3).
A 35-year-old woman with hypertension was exposed to irbesartan, atorvastatin, and sibutramine from 6 weeks to 8 days before conception (4). She had a 1st trimester miscarriage. Examination of the embryo revealed delayed development of the upper extremities. The karyotype was 45,XO (Turner syndrome), a chromosomal abnormality.
A 2009 report described three cases of irbesartan exposure before and during pregnancy (5). In each case, the drug was used to treat hypertension and was stopped at 5, 9, and 18 weeks’ gestation, respectively. The three pregnancy (gestational age at birth) outcomes were small-for-gestational-age (39 weeks), polydactyly (40 weeks), and complications of prematurity (29 weeks), respectively. In the latter case, oligohydramnios was observed at 18 weeks. Other than the polydactyly, no structural malformations were reported (5).
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 (6). The factors, which typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use irbesartan during human lactation have been located. Because of the relatively low molecular weight (about 429), excretion into human breast milk should be expected. The effect of this exposure on a nursing infant is 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. Avapro. Bristol-Myers Squibb, 2000.
2.Boix E, Zapater P, Pico A, Moreno O. Teratogenicity with angiotensin II receptor antagonists in pregnancy. J Endocrinol Invest 2005;28:1029–31.
3.Moel DI. Renal agenesis, unilateral. In: Buyse ML, Editor-in-Chief. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, 1990:1461.
4.Velazquez-Armenta EY, Han JY, Choi JS, Yang KM, Nava-Ocampo AA. Angiotensin II receptor blockers in pregnancy: a case report and systematic review of the literature. Hypertens Pregnancy 2007;26:51–66.
5.Gersak K, Cvijic M, Cerar LK. Angiotensin II receptor blockers in pregnancy: a report of 5 cases. Reprod Toxicol 2009;28:109–12.
6.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.