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Obstetrics & Gynecology 2001;98:427-433
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Treatment of Hypertension in Pregnancy: Effect of Atenolol on Maternal Disease, Preterm Delivery, and Fetal Growth

Thomas R. Easterling, MD, Darcy B. Carr, MD, Debra Brateng, RN, Cydney Diederichs, RN and Barbara Schmucker, RN

From the Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington.

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


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To assess the impact of antihypertensive therapy initiated early in pregnancy on maternal and fetal outcomes.

METHODS: A retrospective review of patients treated in early pregnancy with atenolol was conducted. Therapy was directed by measurements of cardiac output. Fetal growth was analyzed with reference to prior pregnancy outcome, treatment inconsistent with standards present at the end of the study period, and year of treatment. Data were analyzed by paired and unpaired t-test, analysis of variance for multiple comparisons, and linear regression.

RESULTS: Two hundred thirty-five pregnancies at risk for preeclampsia were studied. Ten percent (n = 22) received additional therapy with furosemide; 20% (n = 48) with hydralazine. Six and one half percent had treatment inconsistencies. Fifty-five percent had greater than 100 mg of proteinuria at baseline. One patient developed severe preeclampsia. Only 2.1% delivered before 32 weeks; 4.7% delivered before 34 weeks. Low percentile birth weight was strongly associated with a prior pregnancy with intrauterine growth restriction (P = 0.001), treatment inconsistency (P < .001), and a pregnancy earlier in our treatment experience (P < .001). Percentile birth weight increased from the 20th at the beginning of the study period to the 40th by the end (P = 0.002).

CONCLUSION: Early intervention with antihypertensive therapy was associated with a low rate of severe maternal hypertension and preterm delivery. The failure to adjust therapy in response to an excessive fall in cardiac output or increase in vascular resistance was associated with reduced fetal growth.

Hypertension is a common complication of pregnancy associated with significant maternal and neonatal complications. Although the importance of early, aggressive blood pressure control outside pregnancy is becoming increasingly clear,1–3 the role of blood pressure control during pregnancy remains controversial. Some assert that elevated blood pressure, in and of itself, is not associated with the intrinsic pathophysiology of preeclampsia.4 Alternatively, early treatment may significantly reduce the risk of severe maternal hypertension5 and may decrease the incidence of respiratory distress syndrome in the neonate.6 We have recently demonstrated that early treatment of pregnant women with hemodynamic risks for preeclampsia reduces the incidence of preeclampsia.7

Treatment of hypertension in pregnancy may be associated with a reduction in fetal growth. A meta-analysis of existing studies suggests that a reduction of mean arterial pressure by 10 mmHg can be expected to reduce fetal growth by approximately 145 g.8 Other studies have suggested an association with more concerning growth restriction.9 In our randomized trial of atenolol, we found a significant reduction in birth weight among nulliparas treated with atenolol but no increase in the rate of fetuses small for gestational age.7

In 1991, we initiated a clinical program at the University of Washington to identify women at risk for the development of preeclampsia in the community and to initiate antihypertensive therapy early in pregnancy. The goals of the program were: 1) prevent severe maternal hypertension, 2) prevent the need for preterm delivery because of maternal hypertension, and 3) maintain an environment supportive of fetal growth. Pharmacological treatment was based on individual maternal hemodynamic measurements. The purpose of this paper is to review the 8-year experience to define an appropriate strategy for care before a more rigorous clinical trial.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A retrospective review of pregnant patients treated in early pregnancy with antihypertensives was conducted. Patients were identified through a search of the hemodynamic database at the University of Washington. Criteria for inclusion were: 1) initial evaluation and treatment before 18 weeks of pregnancy, 2) initial therapy with atenolol, and 3) serial evaluations to term. Multiple gestations were excluded. The study was approved by the internal review board of the University of Washington.

Cardiac output was measured by Doppler technique previously validated in pregnancy.10,11 (Lawrence Medical, Redmond, WA). Blood pressure was measured by automated cuff (Accutorr Datascope Corp., Paramus, NJ). The choice of antihypertensive therapy was based on maternal hemodynamics using the chart in Figure 1Go where the effects of therapy can be characterized by a vector of change. ß-blockers produce changes parallel to isometric lines of resistance; vasodilators, such as hydralazine, produce changes perpendicular to isometric lines of resistance.12 This report is limited to patients whose initial hemodynamic assessment suggested the need for atenolol. All patients were treated with 25 to 100 mg of atenolol. Although standards evolved over time, we attempted to reduce cardiac output to one standard deviation above the mean and to lower mean arterial pressure to less than 90 mmHg. If an insufficient response was achieved and the heart rate remained above 70 beats per minute, the dose of atenolol was increased. If an insufficient response was caused by an elevation in stroke volume associated with a reduction in heart rate, furosemide at 20 mg per day was added. If vascular resistance increased towards 1150 dyne · sec · cm-5, hydralazine, 10–50 mg every 6 hours was added.



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  		Figure 1. Mean arterial pressure is plotted against cardiac output. Isometric lines of vascular resistance permit visualization of each hemodynamic variable. Vasodilators such as hydralazine produce vectors of change perpendicular to lines of resistance. Drugs such as atenolol and furosemide produce vectors of change roughly parallel to lines of resistance but with some increase in resistance.

Easterling. Treatment of Hypertension. Obstet Gynecol 2001.

 
A 12-hour urine collection was requested from each patient to assess creatinine clearance and urinary protein excretion at her initial visit. These specimens were analyzed in the laboratories used by the referring physicians.

Over the course of our initial experience, strategies of management evolved. To maintain an environment to support fetal growth we realized the importance of maintaining a cardiac output above the mean for gestational age and maintaining a vascular resistance less than 1150 dyne · sec · cm-5. In a previous randomized study, we found that all small for gestational age infants were associated with a reduction in cardiac output below the mean for gestational age.7 In a study of preterm hypertension, we had found that an elevated vascular resistance was strongly associated with reduced fetal growth.13 Furthermore, we realized the need to anticipate hemodynamic changes and adjust medications early. As pregnancy progressed, we found that some patients would continue to experience a fall in cardiac output despite the same dose of atenolol. In these, the dose of atenolol was reduced by 50%. Others experienced increasing blood pressure associated with a fall in cardiac output caused by a rise in vascular resistance. In these, hydralazine was added. All hemodynamic charts were reviewed blinded from clinical outcomes and categorized for the presence or absence of treatment inconsistencies: 1) cardiac output below the mean for gestational age, and 2) vascular resistance at least 1150 dyne · sec · cm-5.

Clinical outcomes were derived from a review of the patients’ clinical charts. When patients were delivered outside the University system, copies of antenatal records and delivery records were obtained for review. Preeclampsia was defined by diastolic blood pressures greater than 90 mmHg and 1+ or greater proteinuria. Severe preeclampsia was defined by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 110 mmHg or by evidence of significant end organ disease such as thrombocytopenia (less than 100,000 per mL), elevated liver function tests, or proteinuria greater than 5 g per 24 hours. Chronic hypertension was defined by the presence of diastolic blood pressures greater than 90 mmHg predating the pregnancy or before 20 weeks’ gestation. Deliveries were considered to be preterm if they occurred before 37 weeks’ gestation. Percentile birth weights were calculated from Portland-based neonatal growth data.14

Data were analyzed by paired and unpaired t-test, analysis of variance for multiple comparisons, and linear regression. Proteinuria was compared after log transformation. Multivariable linear regression was used to evaluate the association between birth weight percentile and the variables of interest (maternal age, history of severe preeclampsia, prior pregnancy complicated by intrauterine growth restriction, year of treatment, treatment inconsistency, and use of additional antihypertensive agents). The strongest predictors of birth weight percentile were determined by simple linear regression. Model building by the forward selection procedure was performed. First, the relationships among variables were assessed for collinearity. The strongest predictors were then determined and included in the model. Other variables were added separately to test for confounding, increased precision, and interactions. Birth weight percentile was analyzed after log transformation.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Two hundred thirty-five pregnancies were identified where atenolol therapy was initiated before 18 weeks’ gestation. Table 1Go summarizes maternal characteristics. The majority of patients, 69.4%, were treated for chronic hypertension. Many women with prior pregnancies had been preeclamptic or delivered an infant with growth restriction.


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  		Table 1. Maternal Characteristics (Mean ± SD)
 
Three quarters of the patients were managed as consultants where the majority of care was provided by referring physicians. The majority of patients were managed with atenolol alone; approximately 10% received additional therapy with furosemide; 20% received additional therapy with hydralazine. When judged by management strategies, which had evolved by the end of the experience, 15 patients (6.5%) were identified who had treatment inconsistencies. Either cardiac output was permitted to fall below the mean for gestational age, or vascular resistance increased above 1150 dyne · sec · cm-5 without the initiation of vasodilator therapy.

Maternal hemodynamics and renal function are described in Table 2Go. Cardiac output and mean arterial pressure decreased significantly between baseline and the early third trimester. Urine collections were obtained from 179 women (77%). The mean glomerular filtration rate, 163 ± 65 mL per min, was elevated above what might be expected from a group of uncomplicated nulliparous patients who did not develop preeclampsia (125 ± 19.7 mL per min).7 A significant number of patients were proteinuric before 18 weeks’ gestation. Fifty-five percent had more than 100 mg per 24 hours; 9.6% had more than 300 mg per 24 hours. These patients presumably carried baseline proteinuria into the pregnancy.


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  		Table 2. Hemodynamic Changes Associated With Therapy and Baseline Renal Condition (Mean ± SD)
 
Table 3Go summarizes obstetric outcomes. Only one patient developed severe preeclampsia; she was also the only patient who required delivery at less than or equal to 28 weeks’ gestation. She was treated with atenolol alone but never experienced a therapeutic response to atenolol as judged by a reduction in heart rate. The rate of preterm delivery was low: 2.1% of patients delivered before 32 weeks; 4.7% before 34 weeks.


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  		Table 3. Obstetric Outcomes (Mean ± SD)
 
A prior pregnancy complicated by severe preeclampsia or intrauterine growth restriction, a pregnancy in an earlier year of our experience, and treatment inconsistency were significantly associated with reduced birth weight percentile in the simple regression analyses. Multivariable regression was performed adjusting for potential confounders, precision variables, and effect modification. The overall statistics for the final model were: F statistic 10.56, P < .001, and R2 0.2. In the final model, low birth weight percentile remained strongly associated with an earlier year of treatment, treatment inconsistency, and prior pregnancy complicated by intrauterine growth restriction. The results of the final analysis are described in Table 4Go. Collinearity was not observed between the variables in the final model. Mean percentile birth weight increased over the course of the experience from 20th percentile in the first year to 40th percentile in the last year (P = .002) (Figure 2Go). In the last 3 years of the experience, only two patients experienced treatment inconsistencies.


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  		Table 4. Regression Analysis for Predictors of Low Birth Weight Percentile
 


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  		Figure 2. The percentile birth weight of each patient is plotted by year of entry into the treatment program. Percentile birth weight increased from approximately 20 in 1992 to 40 in 1999 (P < .001).

Easterling. Treatment of Hypertension. Obstet Gynecol 2001.

 
All patients reviewed in this experience were initially treated with atenolol. Over the course of pregnancy, the clinical need for additional therapy divided the cohort into three groups: 1) those who continued to be treated with atenolol alone (n = 165), 2) atenolol and furosemide (n = 22), and 3) atenolol and hydralazine (n = 48). When analyzed retrospectively, the initial hemodynamics of these three groups were different; the cardiac output of the group that needed hydralazine was less than that of the group needing atenolol alone. The cardiac output of the group needing furosemide was greater than that of the group treated with atenolol alone (Table 5Go). Despite the significant differences, the overlap between groups was too large to permit discrimination at the initial reading. Figure 3Go describes the change in cardiac output of each of the three groups. In Figure 4Go, cardiac output is plotted against mean arterial pressure. Vascular resistance is represented by diagonal isometric lines. Hemodynamic changes entirely caused by changes in vascular resistance will be perpendicular to these lines; those entirely caused by changes in cardiac output will be parallel to the lines. The changes in each hemodynamic parameter can then be seen for each group. Note the modest fall in vascular resistance in the atenolol plus hydralazine group at the third measurement after initiation of hydralazine. At baseline, the group that subsequently needed hydralazine therapy had more proteinuria than the atenolol group (P < .001).


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  		Table 5. Maternal Characteristics at Initiation of Therapy by Subsequent Antihypertensive Therapy (Mean ± SD)
 


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  		Figure 3. Mean cardiac output is plotted against gestational age for three groups of patients determined by antihypertensive therapy at delivery. Normal cardiac output (mean ± SD) over gestation is included for reference.

Easterling. Treatment of Hypertension. Obstet Gynecol 2001.

 


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  		Figure 4. Vectors of change for three groups of patients determined by antihypertensive therapy at delivery are plotted.

Easterling. Treatment of Hypertension. Obstet Gynecol 2001.

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The Maternal Hypertension Clinic at the University of Washington is a referral clinic supervised by single specialist in maternal fetal medicine. Referrals are encouraged for women with a diagnosis of chronic hypertension, a history of prior severe preeclampsia, a history of renal disease, or diastolic blood pressures greater than 80 mmHg in the second trimester. The relationship with referring physicians is consultative. Treatment of hypertension and fetal surveillance is directed from the clinic, but the majority of prenatal care and delivery of patients who remain uncomplicated is carried out in the community. Antihypertensive therapy is guided by noninvasive measurements of hemodynamics. Patients are evaluated from three to six times during pregnancy with total care being assumed by the referring doctor at approximately 34 weeks. Delivery records are obtained from all patients so that outcomes can be reviewed and treatment strategies adjusted along the lines of a quality improvement model. Based on history, this cohort of patients would be expected to have a significant rate of complications. The baseline rate of proteinuria supports the acuity of the patients.

The goals of therapy were: to prevent severe maternal hypertension, to prevent preterm delivery for maternal hypertension, and to preserve fetal growth. We were generally successful. Severe hypertension was avoided with the exception of a single patient who did not demonstrate a physiological heart rate response to atenolol therapy. The prematurity rate was very low, comparable with a rate that might be expected from an unselected pregnant population.

Fetal growth in this population was clearly less than expected from a normal population. Two conditions were strongly associated with reduced growth. First, a history of intrauterine growth restriction in the prior pregnancy predicted a second small baby. The unknown mediators of this association between births are probably intrinsic to the mother and her pregnancies rather than associated with a particular therapy. In contrast, what we have labeled "treatment inconsistencies" were also associated with impaired growth. Over the course of our experience, we were better able to maintain fetal growth; mean percentile weight increased from 20 to 40. Several changes in strategy can be identified. We attempt to maintain cardiac output at or just below one standard deviation above the mean for gestational age. In a substantial number of patients, we observed that after an initial fall in cardiac output attributable to the pharmacological action of ß-blockade, a secondary fall was observed 6 to 8 weeks after the initiation of therapy. We believe that these secondary changes represent an improvement in the underlying physiology of hypertension, a downregulation of disease. In these patients, we reduced the dose of atenolol. A smaller number of patients experienced a fall in cardiac output associated with increasing hypertension and increasing vascular resistance, a crossover of hemodynamics. We have previously reported that these changes pose a significant risk to the fetus and believe that they represent a worsening of maternal hypertension.13 In these patients, we add oral hydralazine in doses ranging from 10 to 50 mg every 6 hours. We also initiate intensive fetal monitoring at this time. Finally, although we have found that the addition of a diuretic is beneficial in some patients, we will usually discontinue diuresis after 28 weeks’ gestation.

The study has a number of weaknesses that should limit its use to direct clinical care. It is not randomized. The efficacy of our therapy must be judged against that expected for an untreated group with similar acuity but also in the context of our prior randomized trial.7 Although the absence of significant maternal disease and prematurity rates approaching that of a normal population is encouraging, confirmation in a rigorous trial is needed. We had hoped to develop sufficient insight into the hemodynamic process that serial hemodynamic monitoring would not be required. We found that attention to subtle hemodynamic changes improved our ability to protect fetal growth and that monitoring on a continuing basis was more important than we had previously anticipated.

Our experience confirms a complexity of disease and change in disease over time that we had not previously appreciated. Despite the appearance that hypertension was well controlled, cardiac output and vascular resistance exhibited changes that were not reflected in changes in blood pressure. Attention to these changes was important to maintain fetal growth. As previously described, some patients’ hemodynamics "crossed over" from a high cardiac output state to one of high resistance. Appreciation of these subtleties in care was associated with an increase in mean percentile birth weight from the 20th percentile in the first year to the 40th percentile by the last year.

The high rate of proteinuria in early pregnancy suggests the presence of microvascular disease predating pregnancy. Preconceptual evaluation would permit treatment without concern for the impact on the fetus and, through the use of drugs such as angiotensin-converting enzyme inhibitors, would offer the potential for improved microvascular health before conception.15 Women who eventually required treatment with hydralazine were at risk for poor fetal growth and seemed to have more advanced microvascular disease suggested by the level of proteinuria in early pregnancy. The presence of more significant microvascular disease in women who subsequently crossed over hemodynamically supports a dynamic model of hypertension where the hemodynamic character of the hypertension evolves as micro-vascular disease progresses.

Given the apparent need to individualize therapy and adjust therapy over time, the inconsistent results of trials based on uniform monotherapy are not surprising. Furthermore, mother and fetus seem to be at cross purposes. Therapy that may benefit the mother and permit her to carry a hypertensive pregnancy further into gestation may have the potential to impair fetal growth. Optimal care balances the potentially conflicting risks and benefits to mother and fetus. Changes in maternal and fetal condition in the context of advancing gestational age will result in a shift in that balance and therefore the optimal treatment over the course of an individual pregnancy.


   Footnotes
 
PII S0029-7844(01)01477-6

Received January 30, 2001. Received in revised form April 30, 2001. Accepted May 24, 2001.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Hansson L, Zanchetti A, Carruthers S, Dahlof B, Elmfeldt D, Julio S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principle results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755–62.[Medline]

2. Group UPDS. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–13.[Abstract/Free Full Text]

3. Group UPDS. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317: 317–20.

4. Roberts M, Redman C. Preeclampsia: More than pregnancy-induced hypertension. Lancet 1993;341:1447–51.[Medline]

5. Collins R, Wallenburg H. Pharmacological prevention and treatment of hypertensive disorders in pregnancy. In: Chalmers I, Enkin M, Keirse M, eds. Effective care in pregnancy and childbirth. New York: Oxford University Press, 1989:512–33.

6. Magee L, Elran E, Bull S, Logan A, Koren G. Risks and benefits of beta-receptor blockers for pregnancy hypertension: Overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol 2000;88:15–26.[Medline]

7. Easterling T, Brateng D, Schmucker B, Brown Z, Millard S. Prevention of preeclampsia: A randomized trial of atenolol in hyperdynamic patients prior to the onset of hypertension. Obstet Gynecol 1999;93:725–33.[Abstract/Free Full Text]

8. von Dadelszen P, Ornstein M, Bull S, Koren G, Magee L. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: A meta analysis. Lancet 2000; 355:87–92.[Medline]

9. Butters L, Kennedy S, Rubin P. Atenolol in essential hypertension during pregnancy. BMJ 1990;301:587–9.

10. Easterling T, Watts D, Schmucker B, Benedetti T. Measurement of cardiac output during pregnancy: Validation of Doppler technique and clinical observations in preeclampsia. Obstet Gynecol 1987;69:845–50.[Medline]

11. Easterling T, Carlson K, Schmucker B, Brateng D, Benedetti T. Measurement of cardiac output in pregnancy by Doppler technique. Am J Perinatol 1990;7:220–2.[Medline]

12. Easterling T, Benedetti T, Schmucker B, Carlson K. Anti-hypertensive therapy in pregnancy directed by noninvasive hemodynamic monitoring. Am J Perinatol 1989;6: 86–9.[Medline]

13. Easterling T, Benedetti T, Carlson K, Brateng D, Wilson J, Schmucker B. The effect of maternal hemodynamics on fetal growth in hypertensive pregnancies. Am J Obstet Gynecol 1991;165:902–6.[Medline]

14. Babson S, Behrman R, Lessel R. Fetal growth: Liveborn birth weights for gestational age of white middle class infants. Pediatrics 1970;45:937–43.[Abstract/Free Full Text]

15. Hod M, van Dijk D, Karp M, Wintraub N, Rabinerson D, Bar J, et al. Diabetic nephropathy and pregnancy: The effect of ACE inhibitors prior to pregnancy on fetomaternal outcome. Nephrol Dial Transplant 1995;10:2328–33.[Abstract/Free Full Text]




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