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Prevention of Preeclampsia: A Randomized Trial of Atenolol in Hyperdynamic Patients Before Onset of Hypertension

From the Departments of Obstetrics and Gynecology, and the Probability, Statistics, and Information, University of Washington, Seattle, Washington.

Address reprint requests to: Thomas R. Easterling, MD Department of Obstetrics and Gynecology Box 356460, University of Washington 1959 Pacific Street, NE Seattle, WA 98195 E-mail: easter{at}u.washington.edu

	Abstract

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Objective: To determine if assessment of maternal hemodynamics could predict women at risk for the development of preeclampsia, if treatment directed at hemodynamic abnormalities before the onset of hypertension could prevent preeclampsia, and if mothers could be treated in a way that protects fetal growth.

Methods: A double-blinded, randomized controlled trial was conducted. Subjects were considered to be at risk for preeclampsia if their cardiac output was greater than 7.4 L/min before 24 weeks’ gestation. Nulliparous and diabetic subjects at risk were treated with 100 mg of atenolol or placebo. Cardiac output was measured by Doppler technique. Inulin and para-aminohippurate clearances were performed.

Results: Treatment with atenolol reduced the incidence of preeclampsia from 5 of 28 (18%) to 1 of 28 (3.8%), (P = .04). Nulliparous women determined to be at risk for preeclampsia were similar to diabetic women at risk. Each was significantly heavier and had inulin and para-aminohippurate clearances greater than the control group. Treatment with atenolol was associated with infants weighing 440 g less than infants in the nulliparous placebo group, (P = .02). No effect on birth weight was seen in the diabetic patients. Mothers of the smallest infants who were treated with atenolol could be identified by unexpectedly large reductions in cardiac output.

Conclusion: Measurement of cardiac output in the second trimester identified women at risk for preeclampsia. Treatment with atenolol decreased the incidence of preeclampsia. Nulliparous and diabetic women at risk for preeclampsia were similar with regard to maternal hemodynamics, maternal weight, and renal function. Treatment with atenolol was associated with reduced infant birth weight.

Preeclampsia is a condition unique to pregnancy, characterized by the sudden onset of hypertension and proteinuria. Although the clinical manifestations of preeclampsia appear abruptly, physiologic changes in women in whom preeclampsia develops can be detected as early as the first and second trimesters.^1–3 The natural history of preeclampsia without adequate prenatal care results in substantial maternal morbidity and mortality. Current management based on early detection and delivery protects the mother but can result in significant perinatal morbidity and mortality associated with prematurity, fetal growth restriction (FGR), and fetal demise.

Ideally, early identification of patients at risk for preeclampsia and effective treatment would permit the safe completion of pregnancy for the mother and her infant. Aspirin and calcium supplementation have been suggested as prophylactic agents, but clinical trials have not demonstrated the efficacy of these agents to improve outcomes.^4–6

In longitudinal studies, we have found the hemodynamics of women in whom preeclampsia develops to be characterized by increased cardiac output, which is present as early as the first and second trimesters and persists postpartum.⁷ Some women with worsening disease experience a crossover in hemodynamics to a high resistance condition. In a cohort study of early-onset hypertension with a mixture of individual hemodynamics, we have demonstrated that reduced fetal growth is concentrated among women with hypertension mediated by increased vascular resistance; fetal growth is preserved largely in women whose hypertension is mediated by increased cardiac output.⁸ We have investigated the hemodynamic effect of atenolol on women with high–cardiac output hypertension and found that atenolol reduces blood pressure and cardiac output that is associated with a small increase in vascular resistance.⁹

Treatment of new-onset hypertension with atenolol has been demonstrated to reduce the development of new proteinuria and the need for maternal hospitalization.¹⁰ Other studies have raised questions regarding the impact of atenolol on fetal growth.¹¹ Early treatment of hypertension in pregnancy reduces the incidence of malignant maternal hypertension.¹²

If abnormal maternal hemodynamics and subsequent overt hypertension are integral to the pathophysiologic pathway and progression of preeclampsia, early treatment should impact favorably the course of the disease. This study was designed to address the following primary questions: can the assessment of maternal cardiac output predict women at risk for the development of preeclampsia; will treatment directed at abnormalities of hemodynamics before the development of hypertension reduce the incidence of preeclampsia; and can mothers be treated in a way that protects fetal growth?

	Materials and Methods

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This study was a double-blinded, randomized controlled trial to test the hypothesis that early identification and treatment of women at risk for preeclampsia would reduce the incidence of preeclampsia. The intent of the study was to investigate the physiology of the relationship between a reduction in blood pressure and cardiac output and the subsequent development of preeclampsia, as characterized by the onset of hypertension and proteinuria. The study was not anticipated to be large enough to determine whether this clinical treatment protocol could improve fetal outcomes.

Pregnant women from the Maternal Infant Care Clinic at the University of Washington Medical Center were recruited for the study. Informed consent was obtained from each subject. Nulliparous women with singleton gestations and without histories of significant medical complications, and insulin-requiring diabetic women with less than 1.0 g of proteinuria per 24 hours were considered candidates for the study.

Women were screened with a measurement of cardiac output between 22 and 25 weeks’ gestation. Our previous work indicated that a cardiac output greater than 7.4 L/min in the second trimester would have captured all women in a cohort of 179 nulliparous women in whom preeclampsia developed.⁷ From that work, we would expect preeclampsia to develop in approximately 18% of women with a cardiac output greater than 7.4 L/min. Nulliparas and diabetic women with a cardiac output greater than 7.4 L/min were enrolled as "at risk" and were candidates for randomization. Nulliparas with a cardiac output less than or equal to 7.4 L/min were enrolled as low-risk controls. Three groups of patients were included in the study: nulliparas—at risk for preeclampsia, nulliparas—not at risk (control), and women with diabetes—at risk for preeclampsia.

Nulliparous and diabetic women at risk for preeclampsia were randomized in separate blocks of 20 by a random numbers chart through the Pharmacy Department at the University of Washington Medical Center. Subjects randomized to the treatment arms were treated with 100 mg of atenolol per day. Placebo and atenolol capsules were prepared in the pharmacy to appear identical. Pill counts were performed to assess compliance during the course of the study. Heart rate response was used as a measure of compliance at the end of the study.

Maternal blood pressure was measured by automated cuff (Accutorr Datascope Corp., Paramus, NJ). Cardiac output was determined by Doppler technique (UltraCOM Cardiac Output Monitor, Lawrence Medical, Redmond, WA). Each was measured in the left lateral recumbent position after a period of rest. We have validated this technique in pregnancy previously.^13,14 Hemodynamic measurements were made at intervals of routine clinic visits. All measurements after the screening measurement were blinded from the clinical management team and from members of the study team not actually making the measurements.

The effect of treatment on renal function was made by measuring glomerular filtration rate (inulin clearance) and renal blood flow (para-aminohippurate clearance) before the initiation of therapy, at 4–6 weeks and 10–12 weeks after the initiation of therapy. The first 20 nulliparous subjects enrolled, all of the diabetic subjects, and all of the control subjects were studied. Clearances were performed under conditions of water loading to ensure adequate passage of newly formed urine through the dilated maternal collecting system. Water load was initiated by drinking 15–20 mL/kg of water over 30 minutes and was maintained by replacing 80% of urine output with oral water. Urine outputs of 200 to 300 mL per 20 minutes were achieved. Intravenous inulin and para-aminohippurate loading doses and infusion rates were 8 mg/kg and 50 mg/kg and 5.7 mg/min and 17 mg/min, respectively. Three sequential 20-minute clearances were performed to assess the steady-state conditions assumed by the methodology. Urine and plasma para-aminohippurate levels were measured using dimethylaminocinnamaldehyde in ethanol.¹⁵ Urine and plasma inulin levels were measured by the Anthrone method.¹⁶

At the conclusion of pregnancy, the clinical chart of each subject was reviewed by two investigators who had remained blinded from the hemodynamic data. Using data in the clinical chart, each subject was classified as normal or as having gestational hypertension or preeclampsia. A subject was classified as hypertensive if two diastolic blood pressures at least 6 hours apart were greater than 90 mm Hg or were 15 mm Hg above baseline in the first half of pregnancy. Subjects who were hypertensive and had consistent 1+ or greater proteinuria determined by dipstick (Combistix; Miles, Elkhart, IN) were classified as preeclamptic. In the absence of proteinuria, they were classified as having gestational hypertension.¹⁷ If the two reviewers did not agree on classification, patient data were reviewed jointly to achieve concordance in diagnosis.

Patients in whom significant hypertensive disease developed, including sufficient criteria for the diagnosis of preeclampsia, could, upon request of their clinical care team, have their randomization code broken. Alternatively, the clinical team could initiate treatment, including antihypertensive therapy, without regard to randomization. In either case, the subject remained in the original arm of randomization for the purpose of analysis.

Infants of all mothers were evaluated after delivery; gestational age based on best obstetric criteria, birth weight, and admission to the intensive care unit were recorded. Infants were determined to be greater than the 90th percentile or smaller than the 10th percentile for gestational age using Portland birth weight standards.¹⁸

Sample size calculations were based on an expected rate of preeclampsia of 18% in the subjects with a cardiac output greater than 7.4 L/min and on a reduction of the incidence of preeclampsia to 4% in the treated group (the incidence of preeclampsia in an unscreened nulliparous population). Thirty-five subjects treated with atenolol and with placebo would be required to achieve a power of 60% at P = .05. (A power of 60% was chosen because of the preliminary nature of the study.) Data were analyzed using ², Fisher exact test, analysis of variance, and longitudinal analysis using maximum-likelihood estimation.^19,20 Briefly, longitudinal analysis of hemodynamic data involves the generation of a line for each subject’s results over time. From the family of lines formed by the individual lines of the subjects in a group, a best-fit line is generated. The best-fit lines are then compared statistically. The protocol was reviewed and approved by the Human Subjects Committee of the University of Washington.

	Results

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The distribution of enrolled subjects is described in Figure 1. Although a total of 204 at-risk patients were eligible for randomization, only 68 agreed to enroll in the atenolol trial; 56 completed the trial. These 56 and the 18 controls who completed the protocol are the subject of analysis. In general, those who declined to enroll were unwilling to expend the time and anticipated discomfort associated with the para-aminohippurate and inulin clearances. Some had concerns regarding the effects of medication on their baby. Of the 16 subjects who withdrew from the study, outcomes are available for 13. None of these subjects had preeclampsia. Table 1 describes the characteristics of the four randomized groups and the control group. No differences were found at enrollment between treated and placebo nulliparous or diabetic subjects. The diabetic subjects were older by 4 to 5 years and heavier by 19 kg than the control patients. Patients with diabetes were delivered 1.5 to 2.5 weeks earlier, consistent with our policy of scheduled delivery of patients with diabetes after determination of pulmonary maturity. Nulliparas at risk for preeclampsia differed from controls with regard to weight. They were 14 kg heavier, more closely resembling the diabetic subjects than the controls. Among women whose diabetes was treated with atenolol, we did not identify any episodes of unrecognized hypoglycemia in association with ß-blockade.

View larger version (24K): [in this window] [in a new window]   Figure 1. Trial profile. The reasons that subjects did not complete the study and deviations from study protocols are listed. Subjects with protocol deviations remained in their randomized groups. CO = cardiac output; rx htn PE = hypertension treated, diagnosis preeclampsia; rx htn GH = hypertension treated, diagnosis gestational hypertension.

View larger version (27K): [in this window] [in a new window]   Figure 2. Means and standard deviations of each parameter are plotted. The control group is represented by the simple line and shaded area. The placebo and atenolol groups are represented by the dashed and solid lines, respectively. The first two measurements represent control points.

View larger version (15K): [in this window] [in a new window]   Figure 3. Mean and standard deviations of inulin and para-aminohippurate clearances. PAH = para-aminohippurate.

View larger version (46K): [in this window] [in a new window]   Figure 4. The effect of treatment on inulin clearance, mean ± standard deviation. NS = not significant.

View larger version (20K): [in this window] [in a new window]   Figure 5. Birth weight of each infant is plotted for each group; mean and standard deviation are superimposed. Infants born at >90th percentile are represented by large circles; those born at <10th percentile are represented by small circles. (In the control group, seven weights are plotted in the cluster around the mean. In the nulliparous placebo group, 11 weights are plotted in the cluster around the mean. In the nulliparous atenolol group, ten weights are plotted in the cluster around the mean, and three are plotted in the cluster at 3500 g.) LGA = large for gestational age; SGA = small for gestational age.

View larger version (38K): [in this window] [in a new window]   Figure 6. Cardiac outputs of the four smallest infants treated with atenolol. The mean and standard deviation of the control group are represented by the dark line and the shaded area, respectively. CO = cardiac output.

Ten newborns required observation in or admission to the neonatal intensive care unit (NICU). Four were diagnosed with hypoglycemia (diabetic placebo—two, diabetic atenolol—one, nulliparous atenolol—one). Four newborns were admitted to rule out sepsis and were treated with antibiotics (nulliparous placebo, nulliparous atenolol, diabetic atenolol, control). None had positive cultures. Two newborns from the diabetic atenolol group were admitted to the NICU: one after a delivery complicated by shoulder dystocia, and one for transient tachypnea. None of the admissions were attributed to participation in the study protocol.

In three cases, the treatment protocol was interrupted or the randomization code was broken (Figure 1). Two diabetic patients in the placebo group were each admitted at 31 weeks’ gestation for hypertension. The code was broken at the request of the clinical management team, and the patients were treated with antihypertensives. They delivered at 35 and 36 weeks and were diagnosed as preeclamptic and as having gestational hypertension. The third (diabetic atenolol) was admitted to the hospital at 34 weeks for hypertension. She was treated with hydralazine without breaking the code and delivered at 36 weeks with the diagnosis of preeclampsia.

	Discussion

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Identification of women at risk for preeclampsia was accomplished by measuring cardiac output in the second trimester. Nulliparous women with a cardiac output greater than 7.4 L/min were twice as likely to experience preeclampsia. The only woman in the control group to experience preeclampsia had an elevated cardiac output of 8 L/min at her second reading, which was blinded until the completion of the study. The enrichment of patients at risk for preeclampsia in the screen-positive group supports the association of high cardiac output with preeclampsia. However, a positive predictive value of only 16–22% would result in substantial overtreatment of those not at risk if used broadly. A combination of cardiac output screening in the context of clinical criteria such as a history of severe preeclampsia, renal insufficiency, or diabetes might be more useful.

Treatment with atenolol reduced the incidence of any hypertensive diagnosis in pregnancy from 71% to 29% (P < .001). Given that atenolol is an effective antihypertensive, these findings are not surprising. If hypertension is only a diagnostic criterion for preeclampsia and not an integral link in the pathophysiology, normalization of blood pressure may mask the clinical presentation while allowing the disease process to progress. If hemodynamic control is efficacious, the primary pharmacologic effect, blood pressure control, as well as a secondary physiologic effect, reduction in proteinuria, should be demonstrated.

Treatment reduced the incidence of preeclampsia from 18% to 3.8% (P < .04). The effect was equally present in nulliparous and diabetic groups. Our findings are consistent with those of Rubin et al,¹⁰ where treatment of new-onset hypertension with atenolol reduced the incidence of new proteinuria and antenatal hospitalization. Steyn et al²¹ randomized a group of pregnant women who had diastolic pressures greater than 80 mm Hg before 20 weeks’ gestation to placebo compared with ketanserin, a selective serotonin-2 receptor antagonist. Many subjects had previous pregnancies complicated by preeclampsia. Preeclampsia was reduced from 18% in the control group to 2.9% in the treatment group,²¹ comparable to the reduction found in our study.

Three subjects experienced significant modifications of their treatment by the clinical management team. In a small study, these changes in care could potentially change results. Biases introduced by protocol deviation operated in the direction to lessen the beneficial effects of atenolol demonstrated by this study.

To examine a potential mechanism of a reduction in proteinuria, we measured para-aminohippurate and inulin clearances. As expected, the diabetic subjects had clearances significantly higher than the control group, consistent with hyperfiltration. Unexpectedly, nulliparous subjects also had baseline clearances higher than controls, similar to the diabetic subjects. We have demonstrated previously that maternal weight and cardiac output are each associated with the diagnosis of preeclampsia.²² We observed that the nonpregnant hemodynamics of women in whom preeclampsia developed are very similar to the hemodynamics of nonpregnant, insulin-resistant subjects.

This study found women at risk for preeclampsia to have renal hemodynamic characteristics of hyperperfusion similar to those of patients with uncomplicated diabetes. We again confirmed that those at risk are heavier, similar to patients with type 2 diabetes mellitus. We believe that these findings strengthen the suggestion that insulin resistance may be associated with the development of preeclampsia. Women destined to subsequently express syndrome X (hyperinsulinemia, hypertension, and hyperlipidemia) may be at risk for preeclampsia earlier in life.

The glomerular filtration rate of subjects treated with atenolol and those treated with placebo were different from those of controls before therapy. The glomerular filtration rate of the placebo group remained significantly elevated, whereas that of the atenolol group approached the glomerular filtration rate of the control group. The renal protective effect of antihypertensive therapy in nonpregnant patients has been widely accepted. The normalization of glomerular filtration rate in the context of a reduction in proteinuria and the diagnosis of preeclampsia supports a similar role for antihypertensive therapy in pregnancy.

Previous studies²³ and most clinical experience indicate that overt preeclampsia is associated with a reduction in renal function and renal perfusion. Our study suggests that those at risk for preeclampsia have elevated glomerular filtration rate and renal blood flow before the onset of clinical disease. Although the study was not large enough to conclude confidently that the women in whom preeclampsia developed had elevated renal function, some individual subjects did. Three in whom preeclampsia developed had creatinine clearances at entry to the study higher than would be expected in normal pregnancy: 238, 195, and 172 mL/min. If this is true, then renal hemodynamics transition in some patients changes from a condition of overperfusion early in pregnancy to underperfusion with the development of preeclampsia. This crossover in renal hemodynamics would then parallel the central hemodynamics changes we have described in the development of severe preeclampsia^7,24 and those characteristics of diabetic nephropathy.

Atenolol affected the growth of fetuses born to nulliparous women, but not to the extent that they were clearly smaller than those of controls. Infants of diabetic mothers did not seem to be affected. Reasons for the differential effect are not clear. One could hypothesize that the tendency towards excessive fetal growth in pregnancies complicated by diabetes overwhelmed the impact of atenolol. Examining the distribution of birth weights in the nulliparous patients suggests that differences associated with treatment with atenolol were the result in a shift of the entire distribution rather than an effect on a few individual infants (Figure 5). The central two quartiles were shifted from 3000–4000 g in the placebo group to 2500–3500 g in the treated group. The control group was intermediate between the two experimental groups. The impact of the downward shift in birth weight is not clearly pathologic. The infants in the atenolol group did not have more complications in the neonatal period. The rate of SGA infants after treatment was 4.8%, less than expected (10%), and was equivalent to the rates in the placebo and control groups. In contrast, Butters et al¹¹ reported that 67% of babies weighed less than the 10th percentile at birth after mothers were treated empirically with atenolol for chronic hypertension. We hypothesize that selection of patients appropriate for treatment with atenolol, those with elevated cardiac output, resulted in the reduced rate of SGA in our study.

Our retrospective evaluation of hemodynamic profiles and associated birth weights suggests that infants destined to be small can be identified remote from delivery. If the atenolol dose was reduced, would larger babies be born? If the atenolol dose was reduced, would the prevention of preeclampsia be as effective? The current study certainly cannot answer these questions, but this treatment strategy seems to be a logical extension of our findings and deserves evaluation.

This study was designed to be a test of pathophysiology rather than a test of a treatment protocol. Although our protocol may seem attractive as a treatment regimen, we believe that the shortcomings of the trial must be considered. First, the trial was not large enough to demonstrate an improvement in neonatal outcome. The crossover of patients to antihypertensive treatment after the diagnosis of preeclampsia further reduced the potential to demonstrate improved outcome. The low incidence of severe outcomes in nulliparous, uncomplicated preeclampsia would require a very large study. Second, the trial confirmed the potential for atenolol to reduce fetal growth. Although the reductions in growth observed in this study could not be considered pathologic, a larger study might reveal a small increase in infants below the 10th percentile. Future studies should probably focus on those at highest risk for significantly abnormal outcome, such as those with a history of prior severe preeclampsia or medical complications such as diabetes, renal disease, or chronic hypertension.

The development of proteinuria in the presence of hypertension is, for most, the diagnostic hallmark of preeclampsia. Our study supports the hypothesis that hypertension itself is an important link in the pathophysiology of preeclampsia.

	Footnotes

 
Supported by the American Diabetes Association and the Clinical Research Center, University of Washington.

PII S0029-7844(98)00522-5

Received June 22, 1998. Received in revised form September 22, 1998. Accepted October 8, 1998.

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