Fetal Toxic Effects of Angiotensin II Receptor Antagonists: Case Report and Follow-Up after Birth

Bos-Thompson, Marie-Andrée; Hillaire‐Buys, Dominique; Müller, Françoise; Déchaud, H.; Mazurier, E.; Boulot, P.; Morin, Denis

doi:10.1345/aph.1e250

Cited by 49 publications

(22 citation statements)

References 17 publications

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“…[7][8]10,17,21,23,25,27,29,30,34,37,38,44,48,54,60,61,63,65,69 The mean age of the children described was 3.3Ϯ4.5 (range: 0.5 to 18) years. Fourteen children had prenatally been exposed to ACE-Is, and 12 had been exposed to ARBs.…”

Section: Follow-up At 6 or More Monthsmentioning

confidence: 99%

Pregnancy Outcome Following Exposure to Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Antagonists

Bullo

Tschumi²,

Bucher³

et al. 2012

Hypertension

293

152

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Abstract-The objective was to analyze the outcome following prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor antagonists (ARBs). For this purpose, a systematic review of published case reports and case series dealing with intrauterine exposure to ACE-Is or to ARBs using Medline as the source of data was performed. The publications retained for analysis included patients who were described individually, revealing, at minimum, the gestational age, substance used, period of medication intake, and the outcome. In total, 72 reports were included; 37 articles (118 well-documented cases) described the prenatal exposure to ACE-Is; and 35 articles (68 cases) described the prenatal exposure to ARBs. Overall, 52% of the newborns exposed to ACE-Is and 13% of the newborns exposed to ARBs did not exhibit any complications (PϽ0.0001). Neonatal complications were more frequent following exposure to ARBs and included renal failure, oligohydramnios, death, arterial hypotension, intrauterine growth retardation, respiratory distress syndrome, pulmonary hypoplasia, hypocalvaria, limb defects, persistent patent ductus arteriosus, or cerebral complications. The long-term outcome is described as positive in only 50% of the exposed children. Fetopathy caused by exposure to ACE-Is or ARBs has relevant neonatal and long-term complications. The outcome is poorer following exposure to ARBs. We propose the term "fetal renin-angiotensin system blockade syndrome" to describe the related clinical findings. Thirty years after the first description of ACE-I fetopathy, relevant complications are, at present, regularly described, indicating that the awareness of the deleterious effect of prenatal exposure to drugs inhibiting the renin-angiotensin system should be improved. A n undamaged renin-angiotensin system (RAS) is a prerequisite for normal prenatal renal development. Loss of function mutations in the genes encoding the RAS present with a disturbed renal development, characterized by reduced fetal diuresis, leading to oligohydramnios and, occasionally, skull-ossification defects. At birth, blood pressure is low, and death occurs in most cases.1 This clinical scenario resembles the findings, first reported by Guignard et al 2 and Duminy et al 3 in 1981, in infants exposed during pregnancy to drugs that block the RAS. This condition, which occurs following maternal treatment with either angiotensinconverting enzyme inhibitors (ACE-Is) or angiotensin receptor antagonists (ARBs), is usually termed fetal reninangiotensin system blockade syndrome (fetal RAS-blockade syndrome). Some data also indicate a possible association between the use of these drugs during the first trimester of pregnancy and congenital malformations.Because the adverse effects of drugs that block the RAS in the unborn child have been described only in single-case reports or in small case series, we performed a formal systematic analysis of the literature that addresses the intrauterine exposure to ACE-Is or ARBs. Our purposes in con...

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Section: Follow-up At 6 or More Monthsmentioning

confidence: 99%

Pregnancy Outcome Following Exposure to Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Antagonists

Bullo

Tschumi²,

Bucher³

et al. 2012

Hypertension

293

152

View full text Add to dashboard Cite

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“…Three trials [22,24,29] investigated add-on therapy of ARAs with ACEi and with proteinuria as the primary parameter (n= 19). We also found 12 articles about AEs [31][32][33][34][35][36][37][38][39][40][41][42], eight of which reported embryotoxic effects of ARAs given during [31][32][33][34][35][36][37][38], whereas one other was a pharmacokinetic study without efficacy data [43] .…”

Section: Study Characteristicsmentioning

confidence: 99%

“…Only a few benign courses are known. Bos-Thompson et al [33] reported a pregnant woman who was treated with losartan (80 mg/day) until the 28th week of gestation, after which losartan was withdrawn because of anhydramnion. The symptoms improved, and the newborn was followed up to the age of 2.5 years showing a mild chronic renal insufficiency.…”

Section: Aesmentioning

confidence: 99%

Efficacy and safety of angiotensin II receptor type 1 antagonists in children and adolescents

et al. 2009

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Our purpose was to evaluate the effects of angiotensin II receptor type 1 antagonists (ARAs) in children and adolescents with hypertension or/and several kinds of nephropathies on blood pressure (BP) and proteinuria and to evaluate related safety issues. Data sources were Medline, Embase, The Cochrane Library, BIOSIS Previews, contact with investigators and manufacturers, personal bibliography of the lead author, and manual searches. We selected randomized controlled trials (RCTs), uncontrolled trials, and case series investigating ARAs in children and adolescents, as well as case reports about adverse events and the embryotoxic effects of ARAs in children. In four RCTs with 698 individuals, mean systolic blood pressure (BP) decreased by 10.5 mmHg [95% confidence interval (CI) 9.8-11.2] and mean diastolic BP by 6.4 mmHg (95% CI 5.8-7.0). Proteinuria decreased by 30-64% (range) in two RCTs and four case series. Safety data were comparable with adult safety data. ARAs can be considered effective and safe in lowering BP and proteinuria in the pediatric age group. The correlation between the surrogate parameters BP and proteinuria with clinical endpoints is documented to a large degree. The evidence is based on RCTs and also on lower evidence levels, such as case series. In some conditions, RCTs in children are not feasible. Registers could provide more evidence in the future.

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“…In humans, oligohydramnios, renal failure, pulmonary hypoplasia, limb contractures, and fetal or neonatal death have been associated with sartan exposure late in pregnancy, because expression of angiotensin type 1 receptors is low during the early stages of renal development and increases later in pregnancy (3,4). These complications were not observed in our patient, likely due to discontinuation of the medication before the third trimester.…”

Section: Discussionmentioning

confidence: 60%

A case report of prenatal exposure to rosuvastatin and telmisartan

Trakadis

Blasér²,

Hahn

et al. 2009

Paediatrics and Child Health

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A vailable information regarding the outcome of human pregnancies during which the fetus was exposed to statins and sartans is limited and inconclusive.Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, which catalyzes the formation of mevalonic acid from 3-hydroxy-3-methylglutaryl coenzyme A -the ratelimiting step in cholesterol synthesis. Statins are considered to be the standard treatment for hyperlipidemia, but are contraindicated during pregnancy because of potential teratogenic effects (1).Telmisartan is an antihypertensive medication, which acts as an angiotensin II receptor antagonist, and has an inhibitory effect on the renin-angiotensin system. Telmisartan is contraindicated in pregnancy; adverse effects have been reported in both animal and human pregnancies (2). CASE prESEntAtionThe propositus was a 15-month-old boy born to a nonconsanguineous 31-year-old mother with hypertension and hyperlipidemia, and a healthy 29-year-old father, both of northern European descent. Other siblings included a healthy five-year-old brother and a 13-year-old maternal half brother with a history of pyloric stenosis and attention-deficit hyperactivity disoder. Neither sibling was exposed to statins or sartans in the prenatal period.The patient was conceived naturally, and the pregnancy was not detected until the third trimester due to irregular maternal menstrual periods. There was occasional spotting during the first half of the pregnancy but no frank vaginal bleeding. The fetus was exposed to telmisartan (80 mg/day) during the first seven months and to rosuvastatin (10 mg/day) during the entire gestational period. The mother also reported smoking one-half pack of cigarettes per day, but she denied any alcohol intake. Fetal movements were reportedly absent, but prenatal ultrasounds were normal. Spontaneous vaginal delivery occurred at 39 weeks; the infant's birth weight was 3.6 kg and there were no complications at birth. There were no anomalies noted at birth, except for microcephaly. The initial presentation to medical care was for global developmental delay.On initial examination at 15 months, the patient was very irritable, appeared much smaller than his chronological age and was extremely microcephalic. His length was 75 cm (10th percentile for age), weight was 6.95 kg (less than the fifth percentile for age; 50th percentile for four months) and head circumference was 41.5 cm (less than the third Statins are considered to be a standard treatment for hyperlipidemia. Central nervous system, limb and midline defects have been reported in newborns exposed to statins in utero, although causality has been questioned. A 22-month-old boy with severe microcephaly, growth retardation, dysmorphic features, profound global developmental delay and peri-Sylvian polymicrogyria on brain imaging is presented. He was born to a mother exposed to telmisartan during the first seven months and rosuvastatin throughout the entire pregnancy. There were no features of fetopathy associated with sartans including telmisartan, su...

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Fetal Toxic Effects of Angiotensin II Receptor Antagonists: Case Report and Follow-Up after Birth

Cited by 49 publications

References 17 publications

Pregnancy Outcome Following Exposure to Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Antagonists

Pregnancy Outcome Following Exposure to Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Antagonists

Efficacy and safety of angiotensin II receptor type 1 antagonists in children and adolescents

A case report of prenatal exposure to rosuvastatin and telmisartan

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