Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy

INTRODUCTION — Several antihypertensive agents, including calcium channel blockers (eg, nifedipine), labetalol, methyldopa, and hydralazine, have a good 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 suggest 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 these clear warnings, these drugs continue to be prescribed to younger female patients [2], and new cases of adverse neonatal outcomes continue to be reported [3,4].

There is little controversy regarding the association between second- and third-trimester maternal ingestion of RAAS blockers and fetopathy; however, it remains somewhat uncertain whether the rate of fetal malformations is higher in patients exposed to these drugs in the first trimester when compared with those taking other antihypertensive drugs, or even untreated patients with hypertension.

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 — Because we are concerned about the possibility of teratogenesis, we are cautious about prescribing ACE inhibitors and ARBs to females capable of childbearing. Early studies of ACE inhibitor fetopathy emphasized the adverse effects with second- and third-trimester exposure (see 'Second- and third-trimester exposure' below), but reported little or unknown impact associated with first-trimester exposure. The most contemporary meta-analysis of observational studies of this issue 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 reported through November 2019 [5]. Compared with nonexposed controls, ACE inhibitor or ARB exposure in early pregnancy was associated with a higher risk of major congenital malformations (odds ratio [OR] 1.82, CI 1.42-2.34), cardiovascular malformations (OR 2.50, 95% CI 1.62-3.87), and stillbirths (OR 1.75, 95% CI 1.21-2.53), whereas 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). ACE inhibitor or ARB exposure in pregnancy was also associated with nonstatistically significant trends in preterm birth (OR 1.81, 95% CI 0.3-10.9) and miscarriage (OR 1.56, 95% CI 0.96-2.52).

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).

Second- and third-trimester exposure — The most common problems associated with second and third trimester exposure are related to impaired fetal/neonatal renal function, which results in oligohydramnios during pregnancy (amniotic fluid is largely derived from the fetal kidneys), and anuria and renal failure after delivery [6-10]. Histological lesions consistent with renal tubular dysgenesis have been observed in affected neonates [11].

Oligohydramnios is important because it increases the risk of umbilical cord compression and, in turn, nonreassuring findings on antepartum fetal assessment and fetal death. Severe oligohydramnios can lead to poor pulmonary development (pulmonary hypoplasia) and development of limb contractures and skeletal deformations [6,9,10] (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, renal insufficiency, 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 [12]. 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)

●Renal 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 beyond the first trimester [13]. The following major findings were reported:

●Fifty-nine pregnancies (31 percent) had evidence of RAAS inhibitor fetopathy (oligohydramnios, contractures, widened sutures, pulmonary hypoplasia, postnatal renal disease, neonatal thrombosis).

●All pregnancies affected with fetopathy were exposed after 20+0 weeks of gestation, and fetopathy was not observed if RAAS inhibitor exposure ceased before gestational week 20.

●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 renal abnormalities: 29 had renal insufficiency, 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 delivery.

●Five newborns had vena cava and/or renal thrombosis.

In addition, a case report described severe blinding retinopathy in twins exposed in utero to an ACE inhibitor [14].

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 taking these drugs should breastfeed and, if breast feeding, the infant should be monitored for adverse effects. There is no information on the use of ARBs during breastfeeding.

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 renal effects of renin-angiotensin-aldosterone system (RAAS) inhibitors are likely consequences of their ability to cross the placenta and interfere with fetal renal 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. In animal studies, loss of function mutations in renin-angiotensin system genes similarly results in abnormal renal development (eg, renal tubular dysgenesis), reduced fetal diuresis, and oligohydramnios [15].

Experimental evidence also suggests that angiotensin II may participate in the regulation of uteroplacental blood flow, perhaps by stimulating vascular production of vasodilator prostaglandins [16]. Thus, inhibition of angiotensin II could lead to fetal growth restriction. Angiotensin II may also play a direct role in fetal growth and development, particularly of the fetal kidney [17,18]. 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 [9,14].

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 [19]. 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 "Renal effects of ACE inhibitors in hypertension".)

LONG-TERM PROGNOSIS OF SYMPTOMATIC NEONATES — Renal 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 [12]. 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. The study reported that 23 percent had renal failure, 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 exposure required long-term renal replacement therapy [20].

Although data are sparse, they suggest that renal function should be monitored in children with a history of transient neonatal renal failure related to exposure to ACE inhibitors and ARBs in utero.

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 there are reasonable alternative antihypertensive drugs 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 these drugs are being 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 her menstrual period is delayed by more than two days, the patient should discontinue her ACE inhibitor or ARB, undergo a pregnancy test (blood is more sensitive than urine in very early pregnancy), and consult her physician. 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 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. Although well-conducted observational research, including the systematic review and large observational study described above [12,13], has questioned the association between first-trimester ACE inhibitor use and congenital (particularly cardiac) abnormalities, we believe that these drugs should be avoided throughout pregnancy because of the proven risks of exposure in the second and third trimesters. There is less information about the risk of congenital malformations associated with first-trimester exposure to ARBs [21,22], but the available literature suggests that these agents have similar physiologic effects as ACE inhibitors; thus, similar concerns apply. 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 [13], this drug has a similar mechanism of action and should not be administered to patients planning pregnancy or pregnant patients [23].

●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. (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 (ISA), have been associated with fetal growth restriction. Because labetalol does not possess ISA, there is a risk of fetal growth impairment with prolonged use.

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●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. (See 'Adverse fetal/neonatal effects' above.)

•In the second and third trimesters, ACE inhibitors 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 have renal failure, which usually improves 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 second- and third-trimester 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 first trimester exposure – The association of first-trimester exposure to ACE inhibitors (and probably ARBs) and congenital anomalies, and cardiovascular anomalies in particular, is less well documented than for exposure later in pregnancy, but continues to be a concern. (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 clearly available (eg, prevention of progression of proteinuric or microalbuminuric diabetic kidney disease), we counsel female patients to discontinue these medications if they are not using effective contraception. We also counsel about early detection of pregnancy, and in cases of possible unplanned pregnancy, we instruct patients to discontinue the ACE inhibitor or ARB if their menstrual period is delayed by more than two days, to have a sensitive pregnancy test, and to consult with their clinician. (See 'Clinical approach to use of RAAS inhibitors in females of childbearing potential' above.)

•We recommend discontinuation of an ACE inhibitor or ARB in patients who present in early pregnancy, with substitution of an alternate agent if necessary. We avoid use of all drugs that block the renin-angiotensin system during pregnancy, including renin inhibitors (aliskiren). (See 'Clinical approach to use of RAAS inhibitors in females of childbearing potential' above.)