How pregnancy incites or aggravates hypertension remains unsolved despite decades of intensive research. A variety of biochemical markers, based primarily on rationales implicated in the pathophysiology of hypertensive disorders due to pregnancy, have been proposed for the purpose of predicting or assessing the development of preeclampsia later in pregnancy.1 Recently, inhibin-A, a glycoprotein produced by the syncytiotrophoblast of the human placenta has been evaluated both for the prediction of preeclampsia2–7 as well as assessment of severity.8–10 The control of inhibin secretion from the placenta has not been fully elucidated.11 However, there is convincing evidence that inhibin secretion is enhanced during normal pregnancy, and serves to regulate placental production of gonadotropin-releasing hormone, human chorionic gonadotropin, and steroids.12 Abnormal levels of inhibin-A have been recently reported in women with molar pregnancies13 as well as preeclampsia8–10,14,15 suggesting the possibility that placental derangements in the form of either insufficiency or hyper-placentosis may be reflected in inhibin-A levels measured in maternal serum.
This study was undertaken to measure maternal serum inhibin-A levels in a consecutive series of women evaluated for preeclampsia in the third trimester to determine if knowledge of a patient's inhibin-A level might be useful in categorizing the severity of an individual patient's hypertensive disorder due to pregnancy. Further study will explore the slope of inhibin-A increase throughout pregnancy in women destined to develop preeclampsia.
MATERIALS AND METHODS
Serum for measurement of inhibin-A levels was obtained from all women admitted to Parkland Hospital for evaluation of hypertensive disorders due to pregnancy between July 17, 2000, and September 22, 2000. Classification of hypertensive disorders was performed as shown in Table 1.
Evaluation for hypertensive disorders included admission to the labor and delivery unit where maternal blood pressure was measured serially using standard aneroid sphygmomanometers. Korotkoff 5 was used to determine the diastolic blood pressure. Routine evaluation included assessment for symptoms of impending eclampsia, to include visual disturbances, epigastric discomfort, and unrelenting headache. Routine laboratory evaluation included measurement of urinary protein using specimens obtained by catheterization. Dipsticks (Bayer Corp., Elkhart, IN) were used to quantitate proteinuria as follows: 1+ = 30 mg/dL, 2+ = 100 mg/dL, 3+ = 300 mg/dL, and 4+ = ≧2 g/dL or more. Routine laboratory evaluation included measurement of hematocrit, platelets, serum creatinine, and aspartate transaminase. A sample for inhibin-A was also drawn at admission. Delivery was effected in women diagnosed to have severe preeclampsia. Women found to be hypertensive, but without criteria for severe disease, were hospitalized in the high-risk pregnancy unit generally until 38 weeks and were then delivered unless severe preeclampsia supervened earlier.
Inhibin-A was measured using an enzyme-linked immunosorbent assay kit (Serotec, Oxford, England). The inhibin-A detection limit was less than 3.9 pg/mL. Standard serum control samples were run with each assay. The inter- and intraplate coefficients of variation were less than 10%. There was less than 1% cross-reactivity with inhibin-B.
An upper limit threshold for abnormally increased inhibin-A levels was defined as the mean value plus two standard deviations of the log. This threshold was developed using specimens obtained from 83 women evaluated for hypertension but found to be normotensive and remained for the remainder of their pregnancies.
Statistical analysis was performed using χ2, Wilcoxon rank sum, Student t test, analysis of variance, and Kruskal-Wallis test with Dunn's multiple comparison. All tests were two-sided; statistical significance was inferred for P values < .05. Analysis was performed using SAS statistical software 8.2 (Cary, NC).
A total of 232 women were admitted for evaluation of hypertensive disorders due to pregnancy during the study period. The demographic characteristics of these women are summarized in Table 2, which also shows the distribution of women according to their classification of hypertension. There were no cases of superimposed preeclampsia. Using women with no hypertension as the reference group, those with gestational hypertension or preeclampsia were more likely to be younger and nulliparous. Women with severe preeclampsia delivered infants with significantly lower birth weights (Table 3). This was due to both preterm birth and fetal growth restriction defined as birth weight less than or equal to the third percentile for gestational age.16
As shown in Table 4, inhibin-A levels were significantly associated with the severity of hypertensive disease due to pregnancy. Specifically, and using women with no hypertension as the reference group, inhibin-A levels were significantly increased in women with mild and severe preeclampsia. Conversely, women with chronic hypertension and those without proteinuria had inhibin-A levels similar to women without hypertension. Women with gestational hypertension also had inhibin-A levels similar to the reference group of women without hypertension. The distribution of actual inhibin-A levels in relation to classification of hypertension is shown in Figure 1. An upper limit threshold for inhibin-A was defined as the mean log concentration plus two standard deviations for women with no hypertension. This value was 3196 pg/mL. Analysis of the classification of hypertensive disorders with regard to inhibin-A levels greater than 3196 pg/mL is also shown in Table 4 and Figure 1. Such high inhibin-A levels were found in 23% of women with severe preeclampsia. However, such high inhibin-A levels were also seen in 2% of women with no hypertension. The sensitivity to detect proteinuric hypertension including both mild and severe preeclampsia was 15.6% (8.3, 25.6) using the 3196 pg/mL threshold. The specificity, using this same threshold was 96.8% (92.6, 98.9).
There are two primary findings in this population-based observational study of inhibin-A levels in women evaluated for hypertension due to pregnancy. First, inhibin-A levels are significantly increased in women with protein-uric hypertension, and especially in those with severe preeclampsia. Secondly, overtly high levels were not very sensitive (16%) for the diagnosis of proteinuric hypertension. Our results suggest to us that measurement of inhibin-A levels has little to offer in the assessment of the severity of hypertensive disorders due to pregnancy. This conclusion, however, does not preclude the possibility that measurement of inhibin-A levels much earlier in pregnancy might be of value for the prediction of preeclampsia later in gestation.
Muttukrishna et al10 studied inhibin-A levels in 20 women with preeclampsia matched to 20 women with normal pregnancies. Inhibin-A levels were significantly increased in the serum of preeclamptics, with virtually no overlap with levels measured in normotensive pregnant women. This report has prompted us and others to assess the potential of inhibin-A levels to better assess and classify hypertensive disorders due to pregnancy. Silver et al analyzed inhibin-A levels in 111 women with preeclampsia or gestational hypertension compared with 60 matched normotensive controls.8 Although inhibin-A levels were significantly higher in women with preeclampsia, there was limited utility to use such measurements to distinguish women with preeclampsia from those with gestational hypertension. Our results are very similar to those reported by Silver et al.8 Other investigators, usually comparing women with known preeclampsia14,15 with case-controls, have reported an association between elevated inhibin-A levels and preeclampsia. To our knowledge, our study is the first population-based investigation of inhibin-A levels as an adjunct in women systematically evaluated for hypertensive disorders due to pregnancy.
We conclude that inhibin-A levels, contrary to original expectations, are not useful for classifying hypertensive disorders due to pregnancy because of the overlap of normal and abnormal serum levels in women with and without preeclampsia.
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© 2002 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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