Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The antihypertensive mechanisms of action of candesartan and angiotensin-converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1receptors, 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, prematurity, and patent ductus arteriosus. Stillbirth or neonatal death may occur. 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 candesartan cilexetil. Newborn renal function and blood pressure should be closely monitored.
FETAL RISK SUMMARY
The prodrug, candesartan cilexetil, is hydrolyzed to the active drug, candesartan, during absorption from the gastrointestinal tract. Candesartan 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. It blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by preventing angiotensin II from binding to AT1 receptors (1).
Reproduction studies have been conducted with candesartan cilexetil in mice, rats, and rabbits at oral doses up to approximately 138, 2.8, and 1.7 times the maximum recommended human dose of 32 mg based on BSA (MRHD), respectively (1). Rat offspring, exposed to the drug during late gestation and through lactation, had decreased survival and an increased incidence of hydronephrosis, whereas no maternal toxicity or fetal harm was observed in pregnant mice. In pregnant rabbits, maternal toxicity (decreased body weight and death) was noted, but, in the offspring of surviving dams, no adverse effects were seen on fetal survival, fetal weight, or on external, visceral, or skeletal development (1). No effects on fertility or reproductive performance were observed in male and female rats given oral doses up to 83 times the MRHD (1).
It is not known if candesartan crosses the human placenta to the fetus. The molecular weight of candesartan (about 440 after hydrolysis of the prodrug, candesartan cilexetil) is low enough such that passage to the fetus should be expected.
In a 2001 case report, candesartan (7 mg/day) was used for mild hypertension throughout gestation (2). Amniotic fluid was reduced at term. The female infant (birth weight not given) had left-sided facial palsy, plexus paresis, and was anuric. On ultrasound, the kidneys were hyperechogenic with poor corticomedullary differentiation. Urine production started at 5 days of age and the sonographic appearance of the kidneys normalized during the following month. At 8 months of age, the infant was developing normally and only a discrete facial and plexus palsy remained (2).
A 41-year-old woman was treated with candesartan throughout a 32-week gestation (3). Because of anhydramnios, she was delivered of a 1120-g (0.4th percentile) male infant in poor condition. The infant had defective ossification of the roof of the calvarium, joint contractures, mild hypospadias, rocker bottom feet, a large abdominal left kidney and absent right kidney. He developed intractable hypotension, unresponsive to hydration, and remained anuric until he died (3).
In a 2003 report, the outcomes of 42 pregnancies exposed to ARAs were described (4). The outcomes of 37 pregnancies (1 set of twins) exposed in the 1st trimester were 3 spontaneous abortions (drugs not specified), 4 elective abortions (one for exencephaly; candesartan until 4 3/7 weeks, carbimazole, hydrochlorothiazide, maternal obesity), 1 stillbirth (no anomalies; valsartan until week 4, cigarette smoking, other antihypertensives), 1 minor malformation (undescended testicles; drug not specified), and 28 healthy newborns. There was one major malformation (cleft palate, patent ductus arteriosus, modest coarctation of the aorta, growth restriction; valsartan until week 13, hydrochlorothiazide, metoprolol, cigarette smoking). Five cases involved late exposure to ARAs and their outcomes involved one or more of the following: oligohydramnios/anhydramnios, anuria, hypoplastic skull bones, limb contractions, lung hypoplasia, and neonatal death (4).
A 2005 article reviewed the mechanism of ARA-induced fetal toxicity (5). This toxicity, observed in 15 case reports, was similar to that observed with angiotensin-converting enzyme (ACE) inhibitors. The primary effect is suppression of the fetal renin–angiotensin system that results in disruption of the fetal vascular perfusion and renal dysfunction (5).
A 38-year-old pregnant woman with chronic hypertension was treated with candesartan (16 mg/day) and propranolol (160 mg/day) (6). Oligohydramnios was diagnosed at 23 weeks and candesartan was stopped and methyldopa was started. At 26 weeks, no amniotic fluid was noted, the fetal kidneys were small and the bladder was empty. An elective abortion delivered a 860-g male fetus with deformities of the extremities and face due to oligohydramnios. The kidneys had severe tubular dysgenesis with a reduced number and poor differentiation of proximal tubules (6).
A 2007 review cited 64 published cases of pregnancies exposed to ARAs, 42.2% of which had unfavorable outcomes (7). The duration of ARA exposure was longer in the cases with poor outcomes compared with those with good outcomes, 26.3 ± 10.5 vs. 17.3 ± 11.6 weeks.
A 2010 case report described the outcome of an unplanned pregnancy that was exposed to aspirin 75 mg/day, metoprolol 25 mg/day, and candesartan 4 mg/day in the first 22 weeks (8). At that time, ultrasound revealed edematous fetal kidneys and reduced levels of amniotic fluid, and candesartan was discontinued. Five weeks later, normal amniotic fluid and a visible fetal bladder were noted, but the kidneys remained enlarged. At 31 weeks, she gave birth to a 2200-g male infant with Apgar scores of 9 and 9. Renal function studies in the 1-day-old infant were within normal limits. However, at 1 and 2 weeks, ultrasound of the kidneys showed bilateral marked calices, small cysts, and parenchymal increased echogenety. There was complete sonographic normalization of the kidneys at 6 weeks of age. At 6 months of age, a urine analysis was normal. The infant had a systolic murmur related to a patent ductus arteriosus. Based on experimental evidence, concern was expressed for renal dysfunction and arterial hypertension in adulthood (8).
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 (9). The factors that typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use of candesartan cilexetil during human lactation have been located. Because the molecular weight of the active drug, candesartan, is about 440, 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. Atacand. AstraZeneca LP, 2000.
2.Hinsberger A, Wingen AM, Hoyer PF. Angiotensin-II-receptor inhibitors in pregnancy. Lancet 2001;357:1620.
3.Cox RM, Anerson JM, Cox P. Defective embryogenesis with angiotensin II receptor antagonists in pregnancy. Br J Obstet Gynaecol 2003;110:1038–40.
4.Schaefer C. Angiotensin II-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity. Birth Defects Res (Part A) 2003;67:591–4.
5.Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res (Page A) 2005;73:123–30.
6.Vendemmia M, Garcia-Meric P, Rizzotti A, Boubred F, Lacroze V, Liprandi A, Simeoni U. Fetal and neonatal consequences of antenatal exposure to type 1 angiotensin II receptor-antagonists. J Matern Fetal Neonatal Med 2005;19:137–40.
7.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.
8.Munk PS, von Brandis P, Larsen AI. Reversible fetal renal failure after maternal treatment with candesartan: a case report. Reprod Toxicol 2010;29:381–2.
9.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.