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Obstetrics & Gynecology 2000;96:956-961
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Low-Dose, Short-Acting, Angiotensin-Converting Enzyme Inhibitors as Rescue Therapy in Pregnancy

THOMAS R. EASTERLING, MD, DARCY B. CARR, MD, CONNIE DAVIS, MD, CYDNEY DIEDERICHS, DEBRA A. BRATENG and BARBARA SCHMUCKER

From the Departments of Obstetrics and Gynecology and Medicine, University of Washington, Seattle, Washington.

Address reprint requests to: Thomas R. Easterling, MD, Department of Obstetrics and Gynecology, Box 35-6460, University of Washington, Seattle, WA 98195-6460, E-mail: easter{at}u.washington.edu


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To assess the risks and potential benefits of low-dose angiotensin-converting enzyme (ACE) inhibitor treatment in pregnancies complicated by severe hypertension.

Methods: A retrospective review of pregnant women treated with ACE inhibitors was conducted. Hemodynamics before and after treatment were assessed by using Doppler technique to measure cardiac output. Data were analyzed by using the Wilcoxon signed-rank test. Maternal and neonatal outcomes were assessed by chart review and phone interview.

Results: Ten pregnancies were identified in which ACE inhibitor therapy was initiated in pregnancy for severe, unresponsive vasoconstricted hypertension; three were complicated by severe chronic hypertension, 4 by renal insufficiency, and 3 by severe preeclampsia. Treatment was limited to a low-dose, short-acting ACE inhibitor (captopril, 12.5 to 25 mg/day). Treatment was associated with an increase in cardiac output from 5.7 ± 1.5 L/minute to 7.4 ± 1.4 L/minute (P<.01) and a reduction in total peripheral resistance from 1770 ± 670 to 1222 ± 271 dyne • sec • cm-5 (P = .005). No fetal or neonatal complications were observed. The probability of observing one or more adverse neonatal outcome in this sample, based on an assumed true risk of 5% and 10%, was calculated to be 12% and 50%, respectively.

Conclusion: Low-dose captopril therapy was associated with improvement in maternal hemodynamics and, in cases complicated by severe hypertension and renal insufficiency, successful continuation of pregnancy. Fetal and neonatal complications were not experienced, but complication rates of 5–10% could have been missed because of the small number of exposed pregnancies.

Angiotensin-converting enzyme (ACE) inhibitors are potent antihypertensive agents that, in nonpregnant patients, have been demonstrated to have positive hemodynamic effects beyond their antihypertensive actions. Use of ACE inhibitors in pregnancy has been associated with adverse fetal outcomes, characterized by oligohydramnios and pulmonary hypoplasia, and adverse neonatal outcomes, characterized by hypotension and anuria.1–13 In contrast to these studies, pregnancies have been reported in which ACE inhibitors were used without adverse outcome.6,14–22

Given the cardiovascular benefits of treatment with ACE inhibitors and the incidence of cardiovascular complications in pregnancy, treatment during pregnancy could positively affect maternal and neonatal health. However, these potential benefits are limited by potential fetal and neonatal complications. We review our experience with low-dose, short-acting ACE inhibitors in pregnancy, with emphasis on evidence of potential maternal benefit and adverse fetal and neonatal outcomes.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
A retrospective review of pregnant patients treated with ACE inhibitors at the University of Washington Medical Center was conducted. Patients treated with ACE inhibitors were identified through a search of the hemodynamic database. The decision to initiate treatment with captopril in pregnancy was individualized on the basis of the potential for harm and benefit in each case. In general, patients treated with captopril were remote from term, when delivery would have resulted in certain neonatal mortality or significant morbidity. Before initiation of therapy, a senior specialist in maternal-fetal medicine discussed the risks and potential benefits with each patient. Patients were considered candidates for treatment if they had severe vasocon-stricted hypertension that was not responding to aggressive vasodilator therapy or if they had significant renal insufficiency for which ACE inhibitor treatment might be renal protective.

Hemodynamic measurements were made before treatment and 2 to 3 days after initiation of therapy. Blood pressure (BP) was measured by using an automated cuff, (Accutorr; Datascope, Paramus, NJ). Cardiac output was measured by using a previously validated Doppler technique23,24 (UltraCOM Cardiac Output Monitor; Lawrence Medical, Redmond, WA). Data were analyzed by using the Wilcoxon signed-rank test. Expected probabilities of adverse outcomes were calculated by using binomial approximation.

Mothers and neonates were monitored for complications. Worsening renal function and hyperkalemia were considered maternal complications of ACE inhibitor therapy. Oligohydramnios was considered a fetal complication. Anuria, hypotension, pulmonary hypoplasia, and skull hypoplasia were considered neonatal complications. Birth weight percentile for each infant was calculated by using Portland birth weight standards.25 Long-term follow-up was performed through a phone interview with the mother.


   Results
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Abstract
 Materials and Methods
 Results
Discussion
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Ten women were identified who had been treated with captopril over a 2-year period (1996–1998). Captopril was chosen because of its short half-life. Patients were treated with 3.125 mg or 6.25 mg every 6 hours. Table 1Go describes each of these pregnancies, including representative BPs. Patients 1–3 had severe chronic hypertension. Their hemodynamics were characterized by marked increases in total peripheral resistance that had not responded to high doses of at least two other vasodilators. Patient 1 was the first patient treated. At 22 weeks, her BP was severely elevated despite treatment with three antihypertensive drugs. The patient was offered treatment with captopril as "salvage therapy" for a nonviable and potentially life-threatening pregnancy. The success of this pregnancy led to use of captopril in subsequent pregnancies.


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  		Table 1. Patients Treated With Captopril
 
Patients 4–7 had significant renal disease and hypertension. Patients 4–6 had class F diabetes mellitus. Patient 7 had renal transplantation with significant renal insufficiency (serum creatinine concentration, 1.9 to 2.2 mg/dL).

Patients 8–10 had severe preeclampsia and persistent vasoconstriction despite aggressive therapy with traditional vasodilators. Despite significant reductions in BP, only modest prolongations in pregnancy were achieved in these women. Delivery was required for fetal indications.

Table 2Go summarizes the hemodynamic effects associated with treatment with low-dose captopril. A clinically significant reduction in total peripheral resistance was achieved that was associated with a significant increase in cardiac output. Reductions in BP were modest and not consistent among patients. Figure 1Go shows the hemodynamic vector of change associated with treatment. The vector is perpendicular to isometric lines of resistance, demonstrating that low-dose captopril provided significant afterload reduction.


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  		Table 2. Hemodynamic Changes Associated With Captopril Treatment
 


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  		Figure 1. Hemodynamic changes associated with treatment with captopril. Mean arterial pressure is plotted against cardiac output. Total peripheral resistance (TPR) is designated by isometric diagonal lines.

 
Gestational age at delivery and birth weight are shown in Table 1Go. None of the pregnancies were complicated by severe oligohydramnios. None of the infants were hypotensive or anuric after delivery. None had pulmonary hypoplasia. Birth weight compared with gestational age for each infant is shown in Figure 2Go. The mean percentile for gestational age was 18.2. This degree of growth lag is consistent with that in a larger group of hypertensive, vasoconstricted pregnancies on which we reported previously (18%).26



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  		Figure 2. Birth weight of infants exposed to captopril in utero.

 
The infant of one woman with severe preeclampsia died of complications of prematurity (birth weight, 595 g). Eight of the nine women with surviving infants were contacted 6 months to 1 year after discharge. None of the infants have been identified as having renal complications. Given that our experience is limited to 10 pregnancies, a significant risk associated with low-dose captopril may not have been observed. If the true baseline risk of adverse outcome is 5%, we would have had a 12% chance of observing one or more outcomes; if the true risk is 10%, we would have had a 50% chance of observing one or more adverse outcomes.


   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
The potential benefit on pregnancy outcome of ACE inhibitor therapy was suggested by Hod et al.27 Eight nephrotic insulin-dependent diabetic women were treated with captopril for at least 6 months before conception. During therapy, mean proteinuria decreased from 1633 ± 666 mg/day to 273 ± 146 mg/day. Maximum mean proteinuria during subsequent pregnancy reached 1000 ± 1185 mg/day and decreased to 619 ± 411 mg/day 3 months postpartum. If antenatal treatment with captopril reduced proteinuria in subsequent pregnancies, would maintenance of ACE inhibition during pregnancy be of greater benefit?

The risks associated with ACE inhibitor therapy have been extensively documented. Table 3Go summarizes cases in which use of ACE inhibitors resulted in adverse outcome.1–14 These outcomes are largely associated with severe oligohydramnios, pulmonary hypoplasia, neonatal hypotension, and neonatal anuria. Calvarial hypoplasia has also been reported. Table 4Go summarizes cases in which these complications were not observed.6,19–22 Several relevant differences emerge from comparison of these two groups. First, early, severe oligohydramnios was frequently reported in the group with adverse outcomes and was absent in the group with favorable outcomes. Second, the doses of ACE inhibitors used in the group with adverse outcomes were substantially higher than those used in the group with favorable outcomes. Third, long-acting ACE inhibitors, such as enalapril or lisinopril, were commonly used in the group with adverse outcomes, particularly in cases of neonatal hypotension and anuria, but were rarely used in the group with favorable outcomes.


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  		Table 3. Adverse Outcomes Attributable to Angiotensin-Converting Enzyme Inhibitor Use in Pregnancy
 

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  		Table 4. Outcomes Not Attributable to Angiotensin-Converting Enzyme Inhibitor Use in Human Pregnancy
 
The effects of ACE inhibitor use in pregnancy have been investigated in animal models.28–31 Excess rates of fetal and neonatal loss are reported in association with a reduction in uterine blood flow of 22–33%. In the studies by Broughton Pipkin et al,28 Binder and Faber,29 and Ferris and Weir,30 the doses of ACE inhibitor used were high. Using more modest dosing, Woods31 reported a less severe reduction in uterine blood flow of 11%, suggesting a dose-dependent effect.

Unlike many medications of concern in pregnancy, ACE inhibitors are not known to be teratogenic.32,33 Adverse outcomes associated with use of ACE inhibitors in the first trimester have not been reported. The observed impact on the fetus seems to result from the pharmacologic effects of the drugs, which would be expected to be dose dependent. Angiotensin-converting enzyme inhibition reduces uterine prostaglandin E production and, therefore, uterine perfusion.30 Transplacental passage of ACE inhibitors to the fetus results in hypotension, reduced fetal renal perfusion, oligohydramnios, and subsequent pulmonary hypoplasia. Fetal hypotension impairs the growth of membranous bone, resulting in calvarial hypoplasia.34 Hypotension and anuria in the neonatal period are most commonly associated with use of long-acting ACE inhibitors and higher doses of captopril. These complications are consistent with those seen in adults with renal compromise, in which the anuric patient cannot clear long-acting drugs.

These observations directed our choice of medication and dosing. We limited treatment to very low doses of captopril, a short-acting ACE inhibitor. We attempted to deliver the fetuses remote from maternal dosing. We found that low-dose captopril had significant and beneficial hemodynamic effects in our patients. In patients 1–3, treatment with captopril dramatically improved hypertension control and facilitated safe prolongation of their pregnancies. In the nephrotic diabetic patients, we expected treatment with ACE inhibitors to be renal protective. However, given the sample size of our uncontrolled study, we cannot confirm this expectation. In the severely preeclamptic patients, we observed the most modest prolongation of pregnancy. Although control of hypertension was improved, fetal condition required delivery.

The decision to use ACE inhibitors in individual pregnancies must not be taken lightly, as the associated risks are clear. Discussion with patients of potential risks and benefits is required. Althought the absence of adverse outcomes in our experience is encouraging, our series is not large enough to exclude moderate rates of adverse outcome. If the risk was 5%, we would have only a 12% chance of observing one or more adverse outcomes. A risk of 10% would be associated with a 50% chance of one or more adverse events.

From our experience we can make recommendations about how ACE inhibitors should be used if the risk is thought to be balanced by potential benefit in an individual patient. First, we reserve ACE inhibitors for use as adjuvent antihypertensive agents in vasocon-stricted patients who are not responding to other classes of vasodilators. Our group is experienced in using maternal hemodynamic measurements to identify appropriate patients and to direct antihypertensive therapy. Empirical treatment could result in excessive use when other drugs might be as beneficial. Second, we avoid use of long-acting ACE inhibitors. Drugs with short half-lives facilitate discontinuation of therapy in the face of adverse events and avoid the possibility of excessively long pharmacologic effects after birth. Third, we restrict treatment to very low doses of captopril, 12.5 to 25 mg/day. Fourth, we follow all treated pregnancies with frequent assessments of amniotic fluid volume. Significant oligohydramnios indicates the need to withdraw therapy even if the oligohydramnios is suspected to result from the primary disease process. Finally, treated mothers must be followed for potential complications, such as reduction in renal function or hyperkalemia.

We accept the fact that treatment of pregnant women with ACE inhibitors is not risk free and will be controversial. However, given the well-established renal and cardiovascular benefits associated with this class of medications, treatment with ACE inhibitors should not be categorically denied to pregnant women.


   Footnotes
 
PII S0029-7844(00)01037-1

Received February 14, 2000. Received in revised form May 24, 2000. Accepted June 11, 2000.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Rosa F, Bosco L, Graham C, Milstein J, Dreis M, Creamer J. Neonatal anuria with maternal angiotensin-converting enzyme inhibition. Obstet Gynecol 1989;74:371–4.[Abstract/Free Full Text]

2. Cunniff C, Jones K, Phillipson J, Benirschke K, Short S, Wujek J. Oligohydramnios sequence and renal tubular malformation associated with maternal enalapril use. Am J Obstet Gynecol 1990;162: 187–9.[Medline]

3. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: Acute renal failure in a neonate. Ann Intern Med 1988;108:215–6.

4. Broughton Pipkin F, Baker P, Symonds E. ACE inhibitors in pregnancy. Lancet 1989;2:96–7.[Medline]

5. Thorpe-Beeston J, Armar N, Dancy M, Cochrane G, Ryan G, Rodeck C. Pregnancy and ACE inhibitors. Br J Obstet Gynaecol 1993;100:692–3.[Medline]

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P. G. Pryde, M. Barr Jr, and T. R. Easterling
LOW-DOSE, SHORT-ACTING,ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AS RESCUE THERAPY IN PREGNANCY
Obstet. Gynecol., May 1, 2001; 97(5): 799 - 800.
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