Version July 2025
INTRODUCTION —
Several antihypertensive agents, including nifedipine, labetalol, methyldopa, and hydralazine, have a favorable safety profile for use in pregnant patients, based on many years of experience documented in observational studies and clinical trials [1]. By contrast, animal and human data have conclusively demonstrated that drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) are associated with an increased risk of fetopathy (defined as a disease or disorder seen in the fetus). These drugs include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors. The US Food and Drug Administration has added a boxed warning to use of these drugs: "Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected." Despite this clear warning, these drugs continue to be prescribed to younger female patients [2], and cases of adverse neonatal outcomes continue to be reported [3-5].
Although a relationship between maternal use of RAAS blockers in the second- and third-trimesters and fetopathy is well established, a relationship with first-trimester use has been reported less consistently and thus is less certain. Observations that the rate of fetal anomalies is higher than expected in pregnant patients with untreated hypertension and those with hypertension treated with other antihypertensive drugs has confounded analyses of this issue.
This topic will review the known adverse effects of RAAS inhibitors in pregnancy. The treatment of hypertension in pregnant and breastfeeding patients is discussed separately. (See "Treatment of hypertension in pregnant and postpartum patients".)
ADVERSE FETAL/NEONATAL EFFECTS
First-trimester exposure — We are cautious about prescribing ACE inhibitors and ARBs to females capable of childbearing and avoid them throughout pregnancy because of our concerns about known adverse fetal and neonatal effects.
A 2021 meta-analysis of observational studies included 6234 pregnancies exposed to ACE inhibitors or ARBs in the first trimester, 4104 pregnancies exposed to other oral antihypertensives, and over 1.8 million pregnancies without exposure to antihypertensive drugs [6]. Compared with nonexposed controls, ACE inhibitor or ARB exposure in early pregnancy was associated with higher risks of:
●Major congenital anomalies (odds ratio [OR] 1.82, CI 1.42-2.34)
●Cardiovascular anomalies (OR 2.50, 95% CI 1.62-3.87)
●Stillbirth (OR 1.75, 95% CI 1.21-2.53)
●Preterm birth (OR 1.81, 95% CI 0.3-10.9) and miscarriage (OR 1.56, 95% CI 0.96-2.52), although not statistically significant.
Pregnancies exposed to other antihypertensive drugs appeared to have a similar risk of congenital malformations as nonexposed controls (OR 0.96, 95% CI 0.69-1.33).
A 2011 study from the United Kingdom not included in the analysis found no convincing excess of congenital anomalies in patients taking angiotensin-blocking drugs in early pregnancy [7].
An important limitation of most studies is that the investigators were not able to assess the rate of anomalies among miscarriages, pregnancy terminations, and stillbirths, or assess confounding by characteristics of the underlying disease (eg, severity of hypertension) or indication for the ACE inhibitor or ARBs (eg, hypertension, diabetes mellitus, heart failure, myocardial infarction). Although the duration of fetal exposure to ACE inhibitors was throughout pregnancy in several of the earliest reports, another limitation of some reports is that it was not well documented consistently.
Second- and third-trimester exposure — The most common problems associated with second- and third-trimester ACE inhibitor or ARB exposure are related to impaired fetal/neonatal kidney function, which results in oligohydramnios during pregnancy (amniotic fluid is largely derived from the fetal kidneys), and anuria and kidney failure after birth [8-12]. Histological lesions consistent with renal tubular dysgenesis have been observed in affected neonates [13].
Oligohydramnios is important because it increases the risk of umbilical cord compression and, in turn, abnormal fetal heart rate patterns on antepartum assessment and fetal death. Severe oligohydramnios can lead to poor pulmonary development (pulmonary hypoplasia) and development of limb contractures and skeletal deformations [8,11,12] (see "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations"). Other adverse effects, such as growth restriction and preterm birth, are difficult to evaluate since the underlying maternal conditions for which ACE inhibitors and ARBs are commonly prescribed (eg, hypertension, chronic kidney disease, heart failure) are also associated with these adverse outcomes.
A 2012 systematic review reported findings from 186 cases of intrauterine exposure to ACE inhibitors or ARBS, mostly after the first trimester [14]. Adverse outcomes in offspring were more common with ARB exposure compared with ACE inhibitor exposure and included:
●Oligohydramnios: 55 (30 percent)
●Anuria: 51 (27 percent)
●Kidney failure/dialysis: 62 (33 percent)
●Hypotension: 30 (16 percent)
●Pulmonary hypoplasia: 17 (9 percent)
●Respiratory distress syndrome: 41 (22 percent)
●Persistent patent ductus: 13 (7 percent)
●Hypocalvaria: 32 (17 percent)
●Limb defect: 31 (17 percent)
●Fetal growth restriction: 29 (16 percent)
●Cerebral complications: 12 (6 percent)
●Miscarriage or perinatal death: 46 (25 percent)
More recently, a study of data obtained from the databases of six teratology information services in Europe and Israel reported fetal outcomes from 89 pregnancies exposed to ACE inhibitors and 101 pregnancies exposed to ARBs during the second and/or third trimester [15]. The following major findings were reported:
●Fifty-nine pregnancies (31 percent) had evidence of RAAS inhibitor fetopathy (oligohydramnios, joint contractures, hypocalvaria/widened skull sutures, pulmonary hypoplasia, postnatal renal disease, neonatal thrombosis).
●Although most exposed fetuses had both first- and second-trimester exposure, only those with exposure that extended after 20+0 weeks of gestation were diagnosed with fetopathy. If RAAS inhibitor exposure ceased before gestational week 20, fetopathy was not observed.
●In prospectively enrolled cases with exposure at ≥20+0 weeks, the rate of fetopathy for ACE inhibitors was lower than that for ARBs: 1 out of 31 (3.2 percent) and 7 out of 24 (29.2 percent), respectively. There were no data from an unexposed control group, but the background rate of congenital malformations in the general obstetric population is 3 to 4 percent and may be higher in pregnant patients with hypertension. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Background'.)
●The shortest duration of exposure in a fetopathy pregnancy was 15 days (losartan from gestational weeks 28 to 30).
●Fifty-three of the 59 pregnancies (90 percent) had oligohydramnios, two cases had normal amniotic fluid volume (AFV), AFV was not assessed in two cases, and data regarding AFV were conflicting in two cases. In 15 cases, oligohydramnios was the only sign of fetopathy, and in 12 of these cases, AFV normalized within 2.0 to 5.5 weeks following drug discontinuation.
●Thirty-eight newborns had kidney abnormalities: 29 had kidney failure, and 17 had transient or permanent oliguria/anuria, with peritoneal dialysis required in 10 cases.
●Pulmonary hypoplasia occurred in 11 of the 59 fetopathy cases, resulting in eight neonatal deaths, one pregnancy termination due to poor prognosis, and two survivors. RAAS inhibitor therapy was continued in 7 of 11 pregnancies until or almost until birth.
●Five newborns had thrombosis of the vena cava and/or renal vein.
In addition, a case report described severe blinding retinopathy in twins exposed in utero to an ACE inhibitor [16].
Lastly, early studies of ACE inhibition in animal models reported high levels of fetal mortality in ewes, rabbits, and rodents exposed in mid- to late pregnancy [8].
Postnatal exposure from breast milk — ACE inhibitors are transferred into breast milk, but have very low levels in the milk. Captopril and enalapril are not expected to cause adverse effects in breastfed infants. However, newborns may be more susceptible to the hemodynamic effects of these drugs, such as hypotension, and sequelae, such as oliguria and seizures. Therefore, the hemodynamic status of the infant should be taken into account when deciding whether patients on these drugs should breastfeed and, if breast feeding, the infant should be monitored for adverse effects. There is little information on the use of ARBs during breastfeeding, although one study showed that candesartan transferred into breast milk in minute quantities and was not detectable in the plasma of the breastfeeding infants [17].
Clinicians are advised to check LactMed or the UpToDate drug database for up to date information on specific drugs.
HYPOTHESES FOR PATHOGENESIS OF ADVERSE EFFECTS —
The adverse fetal kidney effects of renin-angiotensin-aldosterone system (RAAS) inhibitors are likely consequences of their ability to cross the placenta and interfere with fetal kidney hemodynamics. Because the fetal circulation is characterized by low perfusion pressures, high angiotensin II levels are needed to maintain the glomerular filtration rate (GFR). ACE inhibitors and ARBs rapidly reduce angiotensin II levels, thereby reducing intraglomerular pressure and inducing a decline in GFR, which is reflected by oligohydramnios in utero and anuria after birth.
Even when the total GFR is relatively well maintained, fetal hypotension from an impaired response to angiotensin II can lead to ischemic kidney injury. Kidney histology, when available, has demonstrated renal tubular dysplasia [11]. This lesion is not unique to ACE inhibitor exposure; it is also found in fetuses exposed to prolonged hypotension in utero. In animal studies, loss of function mutations in renin-angiotensin system genes similarly results in abnormal kidney development (eg, renal tubular dysgenesis), reduced fetal diuresis, and oligohydramnios [18].
Experimental evidence also suggests that angiotensin II may participate in the regulation of uteroplacental blood flow, perhaps by stimulating vascular production of vasodilator prostaglandins [19]. Thus, inhibition of angiotensin II could lead to fetal growth restriction [20,21].
Retinopathy and hypocalvaria in exposed fetuses has been attributed to drug-related reductions in normal retinal and cranial vascularization during fetal development rather than to oxygen toxicity or deformation [11,16].
In addition to these effects, AT1 receptor blockade results in the disinhibition of renin release by angiotensin II and increased formation of all angiotensin peptides [22]. These peptides could activate the AT2 receptor, which is highly expressed in the fetus. However, the consequences of this effect are unknown. A brief review of the actions of angiotensin II on glomerular hemodynamics can be found separately. (See "Kidney effects of ACE inhibitors and ARBs in hypertension".)
LONG-TERM PROGNOSIS OF SYMPTOMATIC NEONATES —
Kidney function may appear to improve over time in infants, but the long-term outcome in survivors has not been well described. In a 2012 systematic review of 186 cases of prenatal exposure to ACE inhibitors or ARBs, long-term (≥6 month) follow-up was only available in 26 children [14]. The mean age of the 26 children was 3.3 +/- 4 years and 22 were exposed during the second and third trimesters or during the entire pregnancy. Kidney failure occurred in 23 percent of the children, with two requiring dialysis; 15 percent had proteinuria; and 15 percent had hypertension. Outcomes were significantly better in children only exposed in the first trimester. Subsequently, the Midwest Pediatric Nephrology Consortium reported that 8 out of 17 patients with second-trimester, third-trimester, or throughout-pregnancy in utero RAAS blocker exposure required long-term kidney replacement therapy [23].
Although data are sparse, they suggest that kidney function should be monitored in children with a history of transient neonatal kidney failure related to in utero exposure to ACE inhibitors and ARBs.
CLINICAL APPROACH TO USE OF RAAS INHIBITORS IN FEMALES OF CHILDBEARING POTENTIAL
●We suggest avoidance of ACE inhibitors or ARBs in females of childbearing age for whom reasonable alternative antihypertensive drugs exist that are effective for blood pressure control and would be safer for the fetus. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Preconception management of chronic hypertension'.)
●When effective alternatives are not clearly available (eg, prevention of progression of proteinuric chronic kidney disease), the patient should be counseled about the potential fetal risks associated with renin-angiotensin-aldosterone system (RAAS) inhibitors and the importance of consistent and correct use of effective contraception when pregnancy is not desired and these drugs are taken. The Centers for Disease Control and Prevention have published evidenced-based recommendations for options of hormonal contraceptives in females with cardiovascular disease.
●Pregnancy is not absolutely contraindicated if these drugs are continued. For patients planning pregnancy who continue their use, very early detection of pregnancy is important to minimize embryonic exposure (figure 1). If the menstrual period is delayed by more than two days, the patient should discontinue their ACE inhibitor or ARB, undergo a pregnancy test (blood is more sensitive than urine in very early pregnancy), and consult their physician about further management. The diagnosis of very early pregnancy can be challenging, given the normal variation in menstrual cycle length and the frequency of irregular menstrual cycles. A negative pregnancy test should be repeated in a few days if menses have not resumed (see "Clinical manifestations and diagnosis of early pregnancy"). Abrupt cessation of an ACE inhibitor or ARB does not result in rebound hypertension.
●ACE inhibitors and ARBs should be discontinued immediately in patients who present in early pregnancy on these drugs. An alternate agent is initiated, if necessary.
We avoid use of all drugs that block the renin-angiotensin system during all trimesters of pregnancy because of the proven risks of exposure in the second and third trimesters and conflicting but suggestive information about the risk of congenital malformations associated with exposure limited to the first trimester. These concerns apply to both ACE inhibitors and ARBs. Although recent data suggest that fetopathy may be more likely to occur with ARBs than ACE inhibitors, these agents have similar physiologic effects, thus similar concerns apply for both drugs. We are not aware of cases of exposure to direct renin inhibitors during pregnancy (eg, aliskiren); however, given the similar impact on the renin-angiotensin system, we avoid these drugs during pregnancy. Valsartan/sacubitril is the newest drug of this type and is a combination of an ARB and an angiotensin receptor-neprilysin inhibitor (ARNI). Although minimal data are available in pregnancy [15], this drug has a similar mechanism of action and should not be administered to patients planning pregnancy or pregnant patients [24].
●Patients with diabetes with micro- or macro-proteinuria who are planning pregnancy/pregnant may be switched to diltiazem or verapamil since these drugs have been reported to reduce proteinuria and have not been associated with fetopathy. (See "Treatment of diabetic kidney disease".)
●Patients with nondiabetic proteinuric and nonproteinuric kidney disease should be managed using a similar approach to those with diabetic kidney disease. ACE inhibitors, ARBs, and direct renin inhibitors should be discontinued prior to conception and alternative antihypertensive and antiproteinuric strategies should be used. Labetalol, nifedipine, and methyldopa can be used for blood pressure control, with no or low risk. Nondihydropyridine calcium channel blockers may be used in pregnancy, although their ability to reduce proteinuria is variable, and they are not as effective as ACE inhibitors or ARBs. We are not aware of any data on the use of direct renin inhibitors (eg, aliskiren) in pregnancy; however, we assume they would have similar adverse effects as ACE inhibitors and ARBs and should not be used in this setting.
Some beta-blockers, especially those lacking intrinsic sympathomimetic activity , have been associated with fetal growth restriction. Because atenolol does not possess intrinsic sympathomimetic activity, there is a risk of fetal growth impairment with prolonged use. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Choice and safety by drug class'.)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: High blood pressure and pregnancy (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Risks associated with second- and third-trimester exposure
•There are significant fetal risks associated with the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in the second and third trimesters of pregnancy. These drugs can interfere with fetal renal hemodynamics, resulting in a fall in GFR. Oligohydramnios may occur due to decreased fetal urine production; possible consequences include fetal pulmonary hypoplasia, deformational abnormalities, and death. After birth, the neonate may develop kidney failure, which may improve over time. The long-term outcome in survivors has not been well described. (See 'Second- and third-trimester exposure' above.)
•Despite the clear warnings regarding fetal exposure to ACE inhibitors and ARBs, new cases continue to be reported. Health care providers should be vigilant and continue to emphasize the risks of these drugs. (See 'Second- and third-trimester exposure' above.)
●Risks associated with isolated first-trimester exposure – The association of isolated first-trimester exposure to ACE inhibitors or ARBs and congenital anomalies (and cardiovascular anomalies in particular) is a concern. Although less well documented than fetopathy associated with exposure extending later in pregnancy, we avoid exposure during all trimesters. (See 'First-trimester exposure' above.)
●Management recommendations
•We avoid ACE inhibitors and ARBs in females capable of pregnancy when other antihypertensive drugs with a better fetal safety profile are available. (See 'Clinical approach to use of RAAS inhibitors in females of childbearing potential' above.)
•When effective alternatives are not available (eg, prevention of progression of proteinuric or microalbuminuric diabetic kidney disease), we counsel female patients to use effective contraception if pregnancy is not desired. Patients on ACE inhibitors and ARBs should discontinue the drug if their menstrual period is delayed by more than two days and have a sensitive pregnancy test and consult with their clinician about further management. (See 'Clinical approach to use of RAAS inhibitors in females of childbearing potential' above.)
