Reproductive Toxicology 28 (2009) 109–112

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Reproductive Toxicology

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Case report

Angiotensin II receptor blockers in pregnancy: A report of five cases

Ksenija Gersak ∗, Marta Cvijic, Lilijana Kornhauser CerarDepartment of Obstetrics and Gynaecology, University Medical Centre Ljubljana, Slajmerjeva 3, SI-1000 Ljubljana, Slovenia

a r t i c l e i n f o

Article history:Received 31 July 2008Received in revised form 3 December 2008Accepted 13 February 2009Available online 24 February 2009

Keywords:Angiotensin II receptor blockerSartans

a b s t r a c t

Objectives: To present cases exhibiting possible effects of angiotensin II receptor blockers (ARBs) receivedin pregnancy on the fetus.Methods: Retrospective analysis included women who delivered between 2002 and 2006 at Departmentof Obstetrics and Gynaecology Ljubljana.Results: Antihypertensive medications were prescribed to 346 of the 26,735 women. ARBs were givenin only five pregnancies: two women received losartan, and three irbesartan. The therapy was stoppedbetween 5 and 23 weeks of gestation. Two women delivered healthy babies at term; another term babyhad one additional finger and toe. Other two pregnancies were complicated with oligohydramnios andended in preterm delivery. One preterm infant had transient abnormal renal function tests.

Pregnancy

OligohydramniosFetusN

Conclusion: Women should be informed that ARB-antihypertensive therapy must be replaced/stoppedbefore planning their pregnancy or at least as soon as the pregnancy is confirmed. Fetal morphology scan

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. Background

Hypertensive disorders are the most common complications ofregnancy and importantly contribute to maternal, fetal and neona-al morbidity and mortality. A wide variety of agents are availableor the treatment of hypertension from the tested and safe methyl-opa to newer sartans. Sartans have been used in clinical practicerimarily in the treatment of chronic hypertension since the mid-le 1990s, when they began to supplant ACE inhibitors because of aenerally more favourable side effect profile. In 2001 the first reportf severe fetal toxicity of the sartans was published [1].

Sartans are specific angiotensin II receptor blocker (ARB). Theyre effective and generally well-tolerated medications used in thereatment of arterial hypertension and heart failure. This groupf agents modulates the renin–angiotensin–aldosterone system byelectively blocking type 1 angiotensin II receptor.

Data on fetal toxicity of ARBs in human are limited to small,ncontrolled series and case reports [1–9]. However, their use dur-

ng the second and/or third trimester of pregnancy can have aerious effect on the fetus. In utero exposure to ARBs during thiseriod is associated with impairment in fetal renal function that

an cause decreased amniotic fluid volume, neonatal renal failure,nuria, fetal hypotension, and fetal or neonatal death. Other abnor-alities reported in association with ARBs include pulmonary

ypoplasia, skull-bone hypoplasia, broadly spaced calvaria, cran-

∗ Corresponding author. Tel.: +386 14397590.E-mail address: ksenija.gersak@mf.uni-lj.si (K. Gersak).

890-6238/$ – see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.reprotox.2009.02.004

id volume should be obligatory, if ARBs are prescribed accidentally.© 2009 Elsevier Inc. All rights reserved.

iofacial dysmorphia, limb deformations, and joint contractures[1,4–9]. In contrast, exposure to ARBs in the first trimester of preg-nancy has been associated with low risk of fetopathy [2,4,7,9].

The purpose of our study was firstly to analyse retrospectivedata about women who were exposed to ARBs in pregnancy; andsecondly, to present cases with possible effects of treatment withARBs on the fetus.

2. Methods

All pregnant women who delivered during a 5-year period (between 1 January2002 and 31 December 2006) at the Department of Obstetrics and Gynaecology, Uni-versity Medical Centre Ljubljana were included in the study. Women who had beentreated for hypertension during pregnancy were identified in the National PerinatalInformation System of the Republic of Slovenia (NPISS). For those exposed to ARBs,personal medical records, detailed course of pregnancy, prescribed medications, andthe findings of ultrasound examinations were reviewed.

Neonatal congenital abnormalities were registered according to the Interna-tional Classification of Diseases (ICD-10, Q00-Q99) [10].

3. Results

During the 5-year period, 26,735 women delivered at theDepartment of Obstetrics and Gynaecology Ljubljana, of whom346 received antihypertensive medications. ARBs were given infive pregnancies only (Table 1). Two women received losartan and

the others irbesartan. Two of them received only ARBs, while therest received other antihypertensive drugs (bisoprolol, metoprolol,nifedipine) as well. In all five women antihypertensive therapy withARBs was started at least 3 years before conception due to essentialhypertension and was stopped as soon as pregnancy was confirmed

110 K. Gersak et al. / Reproductive Toxicology 28 (2009) 109–112

Table 1Neonatal outcomes after ARBs exposure during pregnancy.

Case Medications ARBs exposure(weeks of gestation)

Gestational age (weeks),abnormal ultrasound findings

Gestational age atdelivery (weeks),pregnancy outcome,birth weight, Apgarscore (1–5 min)

Abnormalities

1 Irbesartan 150–300 mg/d,bisoprolol 5 mg/d

0–5 21: normal amniotic fluid,normal fetal anatomy scan; 27,33: normal amniotic fluid,normal fetal growth; 38:oligohydramnios

39, live birth, 2720 g,9–9

Small for gestational age

2 Losartan 50 mg/d, metoprolol100 mg/d

0–8 38: normal amniotic fluid,normal fetal growth

39, live birth, 3730 g,9–9

3 Irbesartan 2× 150 mg/d,methyldopa 3× 250 mg/d,lysine acetylsalicylate 100 mg/d

0–9 21, 28, 32, 40: normal amnioticfluid, normal fetal growth

40, live birth, 3860 g,9–9

Polydactyly

4 Irbesartan 300 mg/d,methyldopa 4× 500 mg/d,lysine acetylsalicylate 100 mg/d

0–25 18: oligohydramnios; 22:normal amniotic fluid, normalfetal anatomy scan; 29:oligohydramnios

29, live birth, deliveryby caesarean section,1275 g, 2–6

Respiratory distress,pneumothorax, apnoea ofprematurity, subependymalhaemorrhage

5 Losartan 50 mg/d, nifedipine 0–23 25: oligohydramnios, normaltomy sramni

27, live birth, 1040 g, Transitory decreased renal

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between 5 and 23 weeks of gestation). The therapy was modifiedo methyldopa in two cases.

.1. Case 1

A 30-year-old pregnant woman (105 kg, 167 cm, gravida 2) suf-ered from chronic hypertension for several years and was treatedith irbesartan 150–300 mg/d and bisoprolol 5 mg/d. The anti-

ypertensive therapy was discontinued at 5 weeks of gestation,hen the pregnancy was confirmed. The course of pregnancy wasormal; blood pressure was well-regulated without antihyperten-ive therapy. All ultrasound examinations showed normal fetalrowth. However, mild oligohydramnios was described (amnioticuid index [AFI] 4) at 38 weeks. A healthy female baby was deliv-red vaginally at 39 weeks of gestation. The birth weight was 2720 gsmall for gestational age, between the 5th and 10th percentile),ength 49 cm, and head circumference 33 cm (between the 10th and5th percentile).

.2. Case 2

A chronically hypertensive 36-year-old woman (102 kg, 175 cm,ravida 1), treated with losartan 50 mg/d and metoprolol 100 mg/dor 3 years, conceived spontaneously after been treated for pri-

ary sterility for 12 years. Antihypertensive therapy was stoppedt 8 weeks of gestation and during the rest of the pregnancy noedication was necessary to correct blood pressure. At 38 weeks

f gestation ultrasound examination showed normal fetal growthith normal amniotic fluid volume. At 39 gestational weeks, aealthy female baby was born weighing 3730 g, measuring 52 cm

n length and having head circumference of 33.5 cm.

.3. Case 3

A 31-year-old woman (61 kg, 169 cm, gravida 2) with irregularenstrual cycle and hypertension of several years’ duration treatedith irbesartan 2× 150 mg/d presented herself to the gynaecolo-

ist 8 weeks after her last menstrual period. An ultrasound scanevealed a pregnancy of 9 weeks and 3 days and irbesartan treat-ent was immediately discontinued. Methyldopa 3× 250 mg/d and

ysine acetylsalicylate 100 mg/d were prescribed at 23 weeks ofestation for increased hypertensive problems. Ultrasound exam-

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9–9 function, apnoea ofprematurity, subependymalhaemorrhage, small umbilicalhernia, increased muscle tone

inations showed normal amniotic fluid volume and normal fetalgrowth. Delivery occurred spontaneously at 40 gestational weeks.A male baby weighed 3860 g, had a length of 54 cm, a head circum-ference of 37.5 cm and polydactyly, which was the only abnormalityfound at physical examination. The baby had a supernumerary fin-ger on the right hand and a supernumerary toe on the left foot,which were ligated in the maternity hospital. A family history onany dysmorphological syndromes was negative.

3.4. Case 4

A 26-year-old woman (60 kg, 163 cm, gravida 3) was treatedfor chronic hypertension with irbesartan 300 mg/d for severalyears. She presented to her gynaecologist initially at 18 gestationalweeks, irbesartan was withdrawn and substituted by methyldopa4× 500 mg/d. Ultrasound examination performed at the sametime revealed reduced amniotic fluid volume and appropriatefetal growth for gestational age. At 20 weeks of gestation womanwas admitted to the Department for Obstetrics and GynaecologyLjubljana where methyldopa was reduced to 3× 250 mg/d and addi-tionally lysine acetylsalicylate 100 mg/d was prescribed. Two weekslater she was discharged with methyldopa 3× 250 mg/d; the con-trol ultrasound examination showed normal amniotic fluid volume.At 29 weeks of gestation she was rehospitalized with a diagnosisof severe pre-eclampsia, her blood pressure was 220/130 mmHg,therefore methyldopa was elevated to 4× 500 mg/d. The ultrasoundscan revealed reduced amniotic fluid volume (the largest pocketwas 2 cm). An emergency caesarean section was performed due topathologic cardiotocography tracing. A female baby was extractedwith the birth weight of 1275 g (appropriate for gestational age,between the 40th and 50th percentile for gestational age), thelength of 41 cm and the head circumference of 27.5 cm. The Apgarscores were 2 and 6 at 1 and 5 min, respectively. After initial resus-citation with mask and bag ventilation she was transferred to theneonatal intensive care unit where she showed signs of respiratorydistress and was treated with continuous positive airway pressure(CPAP) by nasal prongs. After deterioration caused by spontaneous

right-side pneumothorax she was intubated and thoracal drainagewas performed. As radiographic signs of hyaline membrane dis-ease grades II–III were present, she was treated with two doses ofsurfactant. Support with positive pressure ventilation was neces-sary for 6 days and additional oxygen until day 22. Due to apnoea

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K. Gersak et al. / Reproducti

f praematurity, she was treated with aminophyilline until day 37.he levels of plasma creatinine and urea on day 2 were 96 �mol/Lnd 9.0 mmol/L, respectively. The head ultrasound revealed a smallyst after subependymal haemorrhage on the left side; there wereo signs of hypoxia. Neurological examinations were normal. Theutcome was favourable and she was discharged home on the 47thay of life.

.5. Case 5

A 42-year-old woman (58 kg, 157 cm, gravida 4), a known case ofhronic renal failure with arterial hypertension and hydronephro-is, had been taking losartan 50 mg/d and nifedipine 2× 20 mg/dor several years. Past medical history included bronchial asthmand recovered hepatitis A and B as well. She presented to herynaecologist with an unknown date of the last menstrual period.he patient had an undiagnosed pregnancy, estimated to be at 25ompleted weeks of gestation. The antihypertensive therapy wasmmediately discontinued. An ultrasound examination revealed aregnancy of 25/26 weeks with reduced amniotic fluid volume.he control ultrasound examination 1 week later showed a dete-ioration of oligohydramnios (AFI 1.5), one amniotic fluid area of5 mm was observed only in the fundus. During hospitalizationhe also suffered from urinary infection with hydronephrosis evi-ent on ultrasound scan, therefore, she was prescribed cefazolineg/12 h for 4 days and cefuroxime 500 mg/12 h for additional 5ays; for maturation of fetal lungs, she received dexamethasonemg/12 h for 2 days. Blood pressure ranged between 115–135 and5–90 mmHg. Delivery occurred spontaneously at 27 gestationaleeks. The mother gave birth to a girl weighing 1040 g, measur-

ng 36 cm in length, and having head circumference of 26.5 cm.pgar score at one and 5 min of life was 9. The baby was trans-

erred to the neonatal intensive care unit where apnoea attacksere observed few hours later and she was treated with methylx-

nthines. The levels of plasma creatinine and urea were elevatedn the first 4 days (on day 2, creatinine was 185 �mol/L, urea0 mmol/L; on day 4 creatinine 125.6 �mol/L, urea 12.2 mmol/L),hen the levels spontaneously decreased to normal (on the day 6,reatinine was 92 �mol/L and urea 7.2 mmol/L). The renal ultra-ound examination was normal at the age of 9 days. The outcomeas favourable and she was discharged home on day 52. The headltrasound scan revealed a small cyst in the caudothalamic areas a result of subependymal haemorrhage. On the discharge day,small umbilical hernia was discovered. At neurological examina-

ion, slightly increased muscle tone and mild tremor were noted,eonatal reflexes were present.

. Discussion

In this survey we found only five women, who were treated withRBs during pregnancy and delivered between 2002 and 2006 at

he Department of Obstetrics and Gynaecology, University Medi-al Centre Ljubljana. Two healthy babies were delivered at term;nother term baby had one additional finger and toe. Other tworegnancies were complicated with oligohydramnios and ended inreterm delivery. One preterm infant had transient abnormal renalunction tests.

Very few case reports are available regarding a possible toxicffect of ARBs on the fetus in mothers treated with these antihy-ertensive drugs during the first trimester of pregnancy [4,9,11]. In

ur review, we report two healthy babies and one baby with poly-actyly born to mothers who were exposed to irbesartan until 9eeks and 3 days of gestation. Musculoskeletal malformations after

arly fetal exposure to ARBs were described by Serreau et al. [4]. Heeported seven cases of early fetal exposure; in one of them, the

icology 28 (2009) 109–112 111

pregnancy was electively terminated due to ultrasonographicallyvisible abnormalities. Fetal examination revealed craniofacial dys-morphia with macrocrania, retrognathia and large fontanelle, andshort arms with hypoplastic terminal phalanges. The mother of thisfetus was treated with irbesartan until 13th week of gestation [4].

No large studies have been made to determine whether thefirst-trimester maternal sartan treatment increases the risk ofmalformations. However, the effects of ARBs and angiotensin-converting-enzyme (ACE) inhibitors on renin–angiotensin systemare similar, as they both impair angiotensin II mediated effect. Addi-tionally, the angiotensin II receptors are widely expressed in thefetal tissue and may have an important role in the fetal growthand development. The first large study of possible major con-genital malformations after the first-trimester exposure to ACEinhibitors found an increased risk of major congenital malforma-tions in infants exposed to ACE inhibitor compared to infants withno exposure [12]. Therefore, it is possible that exposure to ARBs inthe first trimester also increases the risk of malformations.

The time of exposure to ARBs in our cases extended over the earlystage of limb development. The pattern of digits develops on day46 for upper limbs and on day 49 for lower limbs when the notchesbetween the digital rays are formed [13]. While the inhibition of therenin–angiotensin system early in the pregnancy could affect earlyembriologic development, our case might be linked to maternalexposure to losartan in the first trimester.

Maternal treatment with ARBs in the second and third trimesterof pregnancy is associated with suppression of fetal renal function,and consequently leads to either oligohydramnios or anhydram-nios. It is unclear if ARBs’ toxicity reflects primary structural injury,the secondary consequences of hypotension related to major dys-function of renin–angiotensin system, combination of mechanismsor some other mechanism. The hystopathological renal changes,including tubular dysgenesis, abnormalities of glumeruli and renalvasculature, a strong and diffuse exposure of renin in the jux-taglomerular apparatus and renal hypoperfusion may produceoligohydramnios with associated deformation of extremities andskull ossification and secondary pulmonary hypoplasia [1,4,14–16].Reduced amniotic fluid volume was reported in 21 of the 23 cases ofmaternal treatment with ARBs in late pregnancy [1,3–9,11,14–17]. Innine cases, the therapy was discontinued between 20 and 31 weeksof gestation—at the time when decreased level of amniotic fluidwas diagnosed [4,5,7–9,15,16]. In most reports, amniotic fluid vol-ume normalized between 2 and 4 weeks after the therapy had beendiscontinued [7–9,16]. In only one case, 7 weeks were needed andthe newborn infant had mild transient renal insufficiency [5]. Bothour cases, where the mothers were treated with ARBs in late preg-nancy, were associated with reduced amniotic fluid volume; onlyin one case stopping of medication led to normalization of the fluidvolume in 2 weeks. As after discontinuation of ARBs the volumeof amniotic fluid could be restored, fetal renal injury is probablyreversible [5,7–9,16].

The time needed for normalization of the amniotic fluid volumecould be a good predictor of fetal renal injury. Persisting oligohy-dramnios might be related to serious renal failure [4,15]. In ourlimited number of cases, the shorter outcome was favourable, how-ever, the time between discontinuation of ARBs and delivery wasvery short in both cases (2 weeks and 3.5 weeks) and babies weredelivered before term [4].

In addition to fetal renal injury caused by exposure to ARBsduring the pregnancy, we found no reports that document fetalrenal impairment, polydactyly, respiratory distress and subependy-

mal haemorrhage associated with other two antihypertensivemedication, nifedipine and methyldopa [18,19]. According to ourknowledge, there are also no similar toxic effect of using the com-bination of losartan and nifedipine. The use of high-dose aspirinduring the second-half of the pregnancy is associated with adverse

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utcome including fetal and neonatal cerebral bleeding, howeverow dose aspirin (50–150 mg/d), which was also used in our cases100 mg/d in case 4), is considered to be safe throughout the preg-ancy [20,21].

Limited number of our cases does not allow to find any cor-elation between the level of maternal hypertension and renalmpairment in the newborn. Other morbidities of the infant in cases

and 5 (respiratory distress, apnoea and subependymal haemor-hage) could be attributed to low gestation age. Nevertheless, largertudies from the literature [22,23] confirm increased probability ofhese adverse outcomes in infants of mothers who had hypertensiveisorder during pregnancy, even if delivered in higher gestationalge [24].

In conclusion, exposure to ARBs during first trimester of preg-ancy is probably associated only with low risk of adverse fetalutcome when compared to the risk when exposure is extendedo the second or third trimester. Nevertheless, large numbers ofases are needed to evaluate possible toxic effects of ARBs in preg-ancy. Persistent exposure to ARBs throughout pregnancy is relatedo well describe adverse effects on the fetal development, kidneyn particular. Therefore, women who are treated with ARBs, shoulde informed that their antihypertensive therapy must be replacedr stopped before planning their pregnancy or at least as soon ashe pregnancy is confirmed. Fetal morphology scan and monitor-ng of the amniotic fluid volume should be obligatory, if ARBs areccidentally prescribed to a pregnant woman.

onflict of interest

The authors declare that there are no conflicts of interest.

eferences

[1] Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects [letter].Lancet 2001;357(9253):363.

[2] Velázquez-Armenta EY, Han JY, Choi JS, Yang KM, Nava-Ocampo AA. AngiotensinII receptor blockers in pregnancy: a case report and systematic review of the

literature. Hypertens Pregnancy 2007;26:51–66.

[3] Bass JK, Faix RG. Gestational therapy with an angiotensin II receptor antagonistand transient renal failure in a premature infant. Am J Perinatol 2006;23:313–7.

[4] Serreau R, Luton D, Macher MA, Delezoide AL, Garel C, Jacqz-Aigrain E. Develop-mental toxicity of the angiotensin II type 1 receptor antagonists during humanpregnancy: a report of 10 cases. BJOG 2005;112:710–2.

[

icology 28 (2009) 109–112

[5] Bos-Thompson MA, Hillaire-Buys D, Muller F, Dechaud H, Mazurier E, Boulot P,et al. Fetal toxic effects of angiotensin II receptor antagonists: case report andfollow-up after birth. Ann Pharmacother 2005;39:157–61.

[6] Nayar B, Singhal A, Aggarwal R, Malhotra N. Losartan induced fetal toxicity.Indian J Pediatr 2003;70:923–4.

[7] Berkane N, Carlier P, Verstraete L, Mathieu E, Heim N, Uzan S. Fetal toxicity ofvalsartan and possible reversible adverse side effects. Birth Defects Res A ClinMol Teratol 2004;70:547–9.

[8] Briggs GG, Nageotte MP. Fatal fetal outcome with the combined use of valsartanand atenolol. Ann Pharmacother 2001;35:859–61.

[9] Schaefer C. Angiotensin II-receptor-antagonists: further evidence of fetotoxicitybut not teratogenicity. Birth Defects Res A Clin Mol Teratol 2003;67:591–4.

10] http://www.who.int/classifications/icd/en/. [accessed May 10, 2008].[11] Hinsberger A, Wingen AM, Hoyer PF. Angiotensin-II-receptor inhibitors in preg-

nancy [letter]. Lancet 2001;357(9268):1620.12] Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS,

et al. Major congenital malformations after first-trimester exposure to ACEinhibitors. N Engl J Med 2006;354:2443–51.

13] Moore K, Persaud TVN. The developing human: clinically oriented embryology.Philadelphia: Saunders; 2008.

[14] Daïkha-Dahmane F, Levy-Beff E, Jugie M, Lenclen R. Foetal kidney maldevel-opment in maternal use of angiotensin II type I receptor antagonists. PediatrNephrol 2006;21:729–32.

15] Vendemmia M, Garcia-Méric P, Rizzotti A, Boubred F, Lacroze V, Liprandi A, etal. Fetal and neonatal consequences of antenatal exposure to type 1 angiotensinII receptor-antagonists. J Matern Fetal Neonatal Med 2005;18:137–40.

16] Martinovic J, Benachi A, Laurent N, Daikha-Dahmane F, Gubler MC. Fetaltoxic effects and angiotensin-II-receptor antagonists [letter]. Lancet 2001;358(9277):241–2.

[17] Pietrement C, Malot L, Santerne B, Roussel B, Motte J, Morville P. Neonatalacute renal failure secondary to maternal exposure to telmisartan, angiotensinII receptor antagonist. J Perinatol 2003;23:254–5.

[18] Redman CW, Beilin LJ, Bonnar J, Ounsted MK. Fetal outcome in trial of antihy-pertensive treatment in pregnancy. Lancet 1976;2(7989):753–6.

19] Smith P, Antony J, Johanson R. Nifedipine in pregnancy. BJOG 2000;107(3):299–307.

20] Rumack CM, Guggenheim MA, Rumack BH, Peterson RG, Johanson ML, Brait-waite WR. Neonatal intracranial haemorrhage and maternal use of aspirin.Obstet Gynecol 1981;58(5 Suppl.):52S–6S.

21] CLASP: a randomised trial of low-dose aspirin for the prevention andtreatment of pre-eclampsia among 9364 pregnant women. CLASP (Collab-orative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet1994;343(8898):619–29.

22] Zetterström K, Lindeberg SN, Haglund B, Hanson U. The association of mater-nal chronic hypertension with perinatal death in male and female offspring: arecord linkage study of 866,188 women. BJOG 2008;115:1436–42.

23] Gilbert WM, Young AL, Danielsen B. Pregnancy outcomes in women

with chronic hypertension: a population-based study. Reprod Med2007;52:1046–51.

24] Habli M, Levine RJ, Qian C, Sibai B. Neonatal outcomes in pregnancies withpreeclampsia or gestational hypertension and in normotensive pregnanciesthat delivered at 35, 36, or 37 weeks of gestation. Am J Obstet Gynecol2007;197(406):e1–7.