A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy Baha M. Sibai, MD, William C. Mabie, MD, Falah Shamsa, PhD, Marco A. Villar, MD, and Garland D. Anderson, MD Memphis, Tennessee Three hundred women with mild chronic hypertension at 6 to 13 weeks' gestation were randomly allocated to receive either methyldopa or labetalol or be in the control group. Thirty-seven women (12%) were excluded for various reasons. Of the remaining 263 patients, 90 received no drug, 87 received methyldopa, and 86 received labetalol. All 263 were followed throughout pregnancy with serial renal function tests and serial assessment of fetal status. There were no differences among the three groups in mean systolic or diastolic blood pressures, mean gestational age, or initial laboratory findings at time of entry. Patients treated with medications had significantly lower (p < 0.0001) systolic and diastolic blood pressures throughout gestation compared with the no-medication group. Among the control group there was a spontaneously significant lowering (p < 0.0001) of both systolic and diastolic blood pressures at 14 to 26 weeks' gestation. However, there were no differences among the three groups regarding the incidences of either superimposed preeclampsia (15.6%, 18.4%, and 16.3%, respectively), abruptio placentae (2.2%, 1.1 %, and 2.3%, respectively), or preterm delivery (10%, 12.5%, and 11.6%, respectively). In addition, there were no differences among the groups regarding gestational age at delivery, birth weight, incidence of fetal growth retardation, or neonatal head circumference. There was one midtrimester loss in the methyldopa group and one stillbirth in each of the other groups. We conclude that treatment of maternal blood pressure in mild chronic hypertension during pregnancy did not improve perinatal outcome. (AM J OBSTET GVNECOL 1990;162:960-7.)
Key words: Mild hypertension, pregnancy, methyldopa, labetalol Pregnancies concurrent with chronic hypertension are associated with increased perinatal death and morbidity (increased incidence of infants with low birth weight).!. 2 Most of these perinatal risks are related to decreased uteroplacental blood flow. In addition, these pregnancies are associated with a high incidence of superimposed preeclampsia and abruptio placentae!' 3 These morbidity and mortality rates may be reduced with proper obstetric and neonatal management. However, the ideal management of these pregnancies is controversial, especially in regard to antihypertensive medication. Numerous clinical studies (controlled and uncontrolled) described fetal-neonatal benefits from treating mild to moderate hypertension during pregnancy!·IO However, it is almost impossible to evaluate or compare the results of these studies because of differences in the technique of measuring blood pressure and the initial blood pressure level at the time therapy is started. In addition, both the populations studied and the duration of antihypertensive therapy are highly From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis. Presented at the Eighth Annual Meeting of the American Gynecological and Obstetrical Society, Hot Springs, Virginia, September 7-9,1989. Reprint requests: Baha M. Sibai, MD, 853 jefferson Avenue, E-102, Memphis, TN 38163. 6/6118252
960
variable. American investigators usually use strict criteria for the diagnosis of chronic hypertension. In contrast, European and Australian investigators tend to include a heterogenous group of patients with essential hypertension, pregnancy-induced hypertension, or chronic hypertension with superimposed preeclampsia. Furthermore, most patients in these studies were ascertained only at or beyond 20 weeks' gestation. Thus there are actually minimal data describing the effects of antihypertensive therapy on patients seen during the first trimester. Methyldopa is presently the most commonly used drug to treat hypertension during pregnancy. However, newer antihypertensive agents may have potential advantages compared with methyldopa. Labetalol is a nonselective l3-blocker with some 160 mm Hg or diastolic pressure> 110 mm Hg) were treated with methyldopa to keep blood pressure below the above-stated levels. For analysis, these patients remained in the notreatment group. Blood pressure was monitored closely throughout the pregnancy. Measurements of systolic and diastolic pressures were then pooled to determine the mean blood pressure for each patient at 6 to 13 weeks' (initial entry), 14 to 26 weeks', 27 to 29 weeks', 30 to 32 weeks', 33 to 36 weeks', and 37 to 41 weeks' gestation. Superimposed preeclampsia was diagnosed on the basis of proteinuria (at least I gm/24 hr) or elevated uric acid
962
Sibai et al.
April 1990 Am J Obstet Gynecol
100
150
• Control • Methyldopa
• Control • Methyldopa .. Labetalol
-
.& Labetalol
-
140
~
~
-
E E
E E
Q.
Q.
ED
ED
.2
"0 en >C/)
90
C)
C)
-
.2 15
130
80
en
CIS
is
70
120
o
0-13
14-26
27-29
30-32
33-36
37-41
Weeks' Gestation
o
i
0-13
•
14-26
i i i '
27-29
30-32
33-36
37-41
Weeks' Gestation
Fig. 1. Systolic blood pressure (BP) changes throughout gestation. Results are expressed as mean ± SEM. *P < 0.001 by analysis of variance for repeated measurements among the three groups at the respective gestational age periods.
Fig. 2. Diastolic blood pressure (BP) changes throughout gestation. Results are expressed as mean ± SEM. *P < 0.001 by analysis of variance for repeated measurements among the three groups at the respective gestational age periods.
levels (~6 mg/ dl) during the second half of pregnancy. Maternal laboratory studies included serial measurements of hematocrit, serum creatinine, uric acid, endogenous creatinine clearance, and 24-hour urinary excretion of protein. Antepartum fetal surveillance included serial ultrasonograms and antepartum fetal heart rate tests as described previously. I All clinical decisions regarding management and timing of delivery were left to the attending faculty and house staff. Outcome variables included changes in renal function test results, adequacy of blood pressure control, necessity for additional antihypertensive drugs, average days of antepartum maternal hospitalization, and incidences of superimposed preeclampsia and abruptio placentae. Perinatal outcomes included gestational age at delivery, birth weight, incidence of preterm delivery, incidence of fetal growth retardation, proportion of infants admitted to the special-care neonatal unit, and neonatal outcome. Data analysis. Serial changes in blood pressures among the groups and within each treatment group were first analyzed by analysis of variance for repeated measurements followed by Fisher's least square significant difference testing and Bonferroni tests. We next combined the two drug groups (methyldopa and labetalol) into a single treatment group and compared this combined group with the control group. A similar analysis was then performed to compare changes in blood pressures at various stages of gestation between treated and not-treated groups. One-way analysis of
variance was used to evaluate clinical characteristics and pregnancy outcome among the three groups. A X2 analysis was used to evaluate the assumption of equal proportions of various clinical and outcome variables among the three groups. A p value 0.05). However, systolic blood pressure was significantly lower in both drug groups compared with the control group. The overall weighted means of the drug groups and the control group were also significantly different (P < 0.0001). Fig. 2 shows significant lowering (P < 0.0001) of maternal diastolic pressures at various stages of gestation in both drug groups compared with the control group. The two drug groups were then combined and data were reanalyzed to compare treatment to no treatment (Fig. 3). The overall systolic mean (weighted averages) in the treated group was significantly lower (128 ± 0.5vs.136 ± 0.7mm Hg;p < 0.0001). Among the no-treatment group there was significant lowering (P < 0.0001) of systolic blood pressure by 14 to 26 weeks' gestation. Thereafter there were no differences between successive stages of gestation, except for a significant increase in systolic pressures at 33 to 36 weeks' (P < 0.003) and at or beyond 37 weeks' gestation (P < 0.0001). Fig. 4 shows the overall diastolic mean (weighted averages) in the treated group to be significantly
964
Sibai et al.
April 1990
Am.J Obstet Gym'col
Table III. Pregnancy outcome None Outcome
No.
Need for additional drugs Superimposed preeclampsia Abruptio placentae Cesarean delivery for fetal distress
10 14 2 29 4
I
Methyldopa
%
No.
11 15.6 2.2 32.2 404
5 16 1 31 5
Labetalol
I
%
No.
5.7 1804 1.1 35.2 5.7
5 14 2 30 7
I
% 5.8 16.3 2.3 34.9 8.1
Table IV. Perinatal complications None Complication
Preterm gestation
Key words: Mild hypertension, pregnancy, methyldopa, labetalol Pregnancies concurrent with chronic hypertension are associated with increased perinatal death and morbidity (increased incidence of infants with low birth weight).!. 2 Most of these perinatal risks are related to decreased uteroplacental blood flow. In addition, these pregnancies are associated with a high incidence of superimposed preeclampsia and abruptio placentae!' 3 These morbidity and mortality rates may be reduced with proper obstetric and neonatal management. However, the ideal management of these pregnancies is controversial, especially in regard to antihypertensive medication. Numerous clinical studies (controlled and uncontrolled) described fetal-neonatal benefits from treating mild to moderate hypertension during pregnancy!·IO However, it is almost impossible to evaluate or compare the results of these studies because of differences in the technique of measuring blood pressure and the initial blood pressure level at the time therapy is started. In addition, both the populations studied and the duration of antihypertensive therapy are highly From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis. Presented at the Eighth Annual Meeting of the American Gynecological and Obstetrical Society, Hot Springs, Virginia, September 7-9,1989. Reprint requests: Baha M. Sibai, MD, 853 jefferson Avenue, E-102, Memphis, TN 38163. 6/6118252
960
variable. American investigators usually use strict criteria for the diagnosis of chronic hypertension. In contrast, European and Australian investigators tend to include a heterogenous group of patients with essential hypertension, pregnancy-induced hypertension, or chronic hypertension with superimposed preeclampsia. Furthermore, most patients in these studies were ascertained only at or beyond 20 weeks' gestation. Thus there are actually minimal data describing the effects of antihypertensive therapy on patients seen during the first trimester. Methyldopa is presently the most commonly used drug to treat hypertension during pregnancy. However, newer antihypertensive agents may have potential advantages compared with methyldopa. Labetalol is a nonselective l3-blocker with some 160 mm Hg or diastolic pressure> 110 mm Hg) were treated with methyldopa to keep blood pressure below the above-stated levels. For analysis, these patients remained in the notreatment group. Blood pressure was monitored closely throughout the pregnancy. Measurements of systolic and diastolic pressures were then pooled to determine the mean blood pressure for each patient at 6 to 13 weeks' (initial entry), 14 to 26 weeks', 27 to 29 weeks', 30 to 32 weeks', 33 to 36 weeks', and 37 to 41 weeks' gestation. Superimposed preeclampsia was diagnosed on the basis of proteinuria (at least I gm/24 hr) or elevated uric acid
962
Sibai et al.
April 1990 Am J Obstet Gynecol
100
150
• Control • Methyldopa
• Control • Methyldopa .. Labetalol
-
.& Labetalol
-
140
~
~
-
E E
E E
Q.
Q.
ED
ED
.2
"0 en >C/)
90
C)
C)
-
.2 15
130
80
en
CIS
is
70
120
o
0-13
14-26
27-29
30-32
33-36
37-41
Weeks' Gestation
o
i
0-13
•
14-26
i i i '
27-29
30-32
33-36
37-41
Weeks' Gestation
Fig. 1. Systolic blood pressure (BP) changes throughout gestation. Results are expressed as mean ± SEM. *P < 0.001 by analysis of variance for repeated measurements among the three groups at the respective gestational age periods.
Fig. 2. Diastolic blood pressure (BP) changes throughout gestation. Results are expressed as mean ± SEM. *P < 0.001 by analysis of variance for repeated measurements among the three groups at the respective gestational age periods.
levels (~6 mg/ dl) during the second half of pregnancy. Maternal laboratory studies included serial measurements of hematocrit, serum creatinine, uric acid, endogenous creatinine clearance, and 24-hour urinary excretion of protein. Antepartum fetal surveillance included serial ultrasonograms and antepartum fetal heart rate tests as described previously. I All clinical decisions regarding management and timing of delivery were left to the attending faculty and house staff. Outcome variables included changes in renal function test results, adequacy of blood pressure control, necessity for additional antihypertensive drugs, average days of antepartum maternal hospitalization, and incidences of superimposed preeclampsia and abruptio placentae. Perinatal outcomes included gestational age at delivery, birth weight, incidence of preterm delivery, incidence of fetal growth retardation, proportion of infants admitted to the special-care neonatal unit, and neonatal outcome. Data analysis. Serial changes in blood pressures among the groups and within each treatment group were first analyzed by analysis of variance for repeated measurements followed by Fisher's least square significant difference testing and Bonferroni tests. We next combined the two drug groups (methyldopa and labetalol) into a single treatment group and compared this combined group with the control group. A similar analysis was then performed to compare changes in blood pressures at various stages of gestation between treated and not-treated groups. One-way analysis of
variance was used to evaluate clinical characteristics and pregnancy outcome among the three groups. A X2 analysis was used to evaluate the assumption of equal proportions of various clinical and outcome variables among the three groups. A p value 0.05). However, systolic blood pressure was significantly lower in both drug groups compared with the control group. The overall weighted means of the drug groups and the control group were also significantly different (P < 0.0001). Fig. 2 shows significant lowering (P < 0.0001) of maternal diastolic pressures at various stages of gestation in both drug groups compared with the control group. The two drug groups were then combined and data were reanalyzed to compare treatment to no treatment (Fig. 3). The overall systolic mean (weighted averages) in the treated group was significantly lower (128 ± 0.5vs.136 ± 0.7mm Hg;p < 0.0001). Among the no-treatment group there was significant lowering (P < 0.0001) of systolic blood pressure by 14 to 26 weeks' gestation. Thereafter there were no differences between successive stages of gestation, except for a significant increase in systolic pressures at 33 to 36 weeks' (P < 0.003) and at or beyond 37 weeks' gestation (P < 0.0001). Fig. 4 shows the overall diastolic mean (weighted averages) in the treated group to be significantly
964
Sibai et al.
April 1990
Am.J Obstet Gym'col
Table III. Pregnancy outcome None Outcome
No.
Need for additional drugs Superimposed preeclampsia Abruptio placentae Cesarean delivery for fetal distress
10 14 2 29 4
I
Methyldopa
%
No.
11 15.6 2.2 32.2 404
5 16 1 31 5
Labetalol
I
%
No.
5.7 1804 1.1 35.2 5.7
5 14 2 30 7
I
% 5.8 16.3 2.3 34.9 8.1
Table IV. Perinatal complications None Complication
Preterm gestation
