| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Academic Department of Obstetrics and Gynaecology, North Staffordshire Hospital Trust/Keele University, Staffordshire; Nottingham University Medical School, Nottingham; Department of Obstetrics and Gynaecology, Birmingham Women’s Hospital, Birmingham; and the Department of Mathematics, Keele University, Stoke-on-Trent Staffordshire, United Kingdom.
Address reprint requests to: P. M. Shaughn O’Brien, MD North Staffordshire Hospital Maternity Unit, City General Hospital Newcastle Road Stoke-on-Trent, ST4 6QG United Kingdom
 |
Abstract |
|---|
Top
 Abstract MethodsResultsDiscussionReferences |
|---|
Methods: Over a 2-year period, we recruited 325 unselected, normotensive primigravidas from the hospital antenatal department after their routine 20-week scan appointments. Each woman had a singleton pregnancy, was normotensive at the time of entry into the study, and had an unremarkable medical history. Ninety-three nonpregnant women were recruited from the hospital staff for comparison. Platelet angiotensin II binding was measured in all participants. After delivery, the case notes were screened to determine pregnancy outcome.
Results: Two hundred sixty-seven women remained normotensive to delivery, 30 developed nonproteinuric pregnancy-induced hypertension, 23 developed proteinuric pregnancy-induced hypertension, four had transient hypertension, and one was diagnosed subsequently as having essential hypertension. The median platelet angiotensin II binding for the nonpregnant subjects was 15.7 fmol/109 platelets, which differed significantly from the value for normotensive pregnant subjects (4.8 fmol/109 platelets, P < .001) and from the value for those who developed either nonproteinuric pregnancy-induced hypertension (4.95 fmol/109 platelets) or proteinuric pregnancy-induced hypertension (7.2 fmol/109 platelets, P < .001). There was no significant difference between pregnant women who remained normotensive and those who developed nonproteinuric or proteinuric pregnancy-induced hypertension.
Conclusion: Measurement of angiotensin II binding in the second trimester has no value as a screening test for nonproteinuric or proteinuric pregnancy-induced hypertension.
The term "hypertensive disorders of pregnancy" encompasses several disorders associated with high blood pressure (BP). Nonproteinuric pregnancy-induced hypertension, which affects approximately 10% of primigravidas,1 is usually a mild complication that appears not to increase perinatal mortality, whereas proteinuric pregnancy-induced hypertension remains the largest single cause of perinatal mortality in the developed world, accounting for 18.6% of maternal deaths in the United Kingdom.2
In the present study, nonproteinuric pregnancy-induced hypertension was defined as BP of at least 140/90 mmHg, measured on two separate occasions more than 6 hours apart, in a previously normotensive woman, after the 20th week of pregnancy, which resolved by the 6th week postpartum. Proteinuric pregnancy-induced hypertension was defined as just described, accompanied by at least 300 mg of total protein in 24 hours. Transient hypertension was defined as BP of at least 140/90 mmHg that did not persist for more than 6 hours, and essential hypertension as BP of at least 140/90 mmHg before the 20th week of pregnancy or after 12 weeks postpartum.
A predictive test for pregnancy-induced hypertension would allow targeting of the at-risk group for increased surveillance and prophylaxis. More than 100 clinical, biophysical, and biochemical tests have been described for predicting the development of pregnancy-induced hypertension, but none has sufficient sensitivity or specificity for clinical use.3,4 The angiotensin II infusion test,5 which depends on changes in vascular reactivity, has been considered the criterion standard for predicting pregnancy-induced hypertension in the research setting. However, the technique is invasive and time consuming, making it unsuitable as a routine clinical procedure. Recent studies, in particular a study by Kyle et al,6 question its validity as a screening test for nonproteinuric and proteinuric pregnancy-induced hypertension.
The clinical signs of pregnancy-induced hypertension usually do not appear until the third trimester. However, the underlying pathophysiologic changes are present months before the onset of overt disease. They are associated with inadequate placentation and failure or inhibition of the second wave of endovascular trophoblast migration into the myometrial segments of the uteroplacental arteries.7 The vascular smooth muscle response to vasoactive substances, such as angiotensin II, decreases during normotensive pregnancy. However, the response decreases less in women who develop pregnancy-induced hypertension, with these changes preceding any change in arterial BP.5
There is also a characteristic imbalance in the endovascular thromboxane A2/prostacyclin ratio toward thromboxane dominance, which is seen in pregnancy-induced hypertension.8 This imbalance could lead to the increased vasoconstriction, increased platelet aggregation, and reduced uteroplacental perfusion seen in pregnancy-induced hypertension.
Intervention studies have been aimed at increasing vasodilation and reducing platelet aggregation. Aspirin at low doses selectively inhibits thromboxane production, with a sparing effect on prostacyclin. However, recent trials9,10 showed aspirin to have little benefit in preventing proteinuric pregnancy-induced hypertension, except in a small high-risk group. This emphasizes the need for a predictive test to target a group more precisely for studies of prophylaxis.
Platelets share many structural and biochemical characteristics with vascular smooth muscle, and they provide an easily sampled model of vascular smooth muscle cells. Platelets have angiotensin II binding sites, the density of which decreases in normotensive pregnancy and increases in women with pregnancy-induced hypertension.11 The increase in platelet angiotensin II binding was shown to be due to an increase in receptor number rather than to an increase in receptor affinity.12 These studies reinforce the idea that platelet binding changes might be representative of vascular change in angiotensin II receptors found in pregnancy.
Baker and colleagues13 compared platelet angiotensin II binding and the angiotensin II sensitivity test as predictors of pregnancy-induced hypertension in 34 primigravidas between 28 and 32 weeks’ gestation. They reported that platelet angiotensin II binding was a good predictor of pregnancy-induced hypertension and suggested that colinearity existed between the two. They concluded that a much larger study was needed to assess the prospective use of platelet angiotensin II binding to determine the risk of developing pregnancy-induced hypertension.
The aim of this study was to assess whether platelet angiotensin II binding at 20 weeks’ gestation is a useful predictor of pregnancy-induced hypertension.
|
Methods |
|---|
|
Top
AbstractMethodsResultsDiscussionReferences |
|---|
Three BP measurements were made by two investigators (PKS and TJW) at 5-minute intervals, using a standard mercury sphygmomanometer. Readings were taken from the right arm with the woman supine. The systolic pressure was recorded at the first Korotkoff sound and diastolic pressure at the fourth Korotkoff sound.
Blood was collected and was transferred into two 10-mL polypropylene tubes, each containing 1 mL of 3.13% (w/v) trisodium citrate and 400 µL of acetylacetic acid (25 mmol/L). The samples were placed in ice and transferred immediately to the laboratory for platelet angiotensin II binding assay. If more than one patient was seen at the time, the samples were refrigerated at 4C for a maximum of 1 hour before they were transferred in ice to the laboratory.
Platelets were prepared as described by Mann et al.14 The platelet angiotensin II binding assay was performed as previously described by Baker et al.11 All platelet angiotensin II assays were performed in triplicate (by PKS and TJW). The intra-assay variation assessed by calculating the coefficient of variation of each sample was 14%.
For comparative platelet angiotensin II binding data, blood was collected from 93 nonpregnant women between days 1 and 3 of their menstrual cycles. Each of these women was in good health, was not taking any medications (including oral contraceptives), and had regular menstrual cycles. Ethical approval was obtained for all of the work described in this study from the local research ethics committee, and all participants gave written informed consent.
Platelet binding data were analyzed for the dichotomous outcome using logistic regression of all of the antenatal variables recorded at the time of entry into the study. We also analyzed these data using a stepwise routine in a multivariate analysis. The Mann-Whitney U test was used to compare measurements between several independent groups, with a two-sided significance level of 5%. The Kruskal-Wallis one-way analysis of variance was used to compare measurements between several independent groups at a significance level of 5%. These nonparametric tests were used because of the skewness of the data; consequent summaries are given in terms of medians and ranges. The data were analyzed using Number Crunching Statistical System 6 (J. L. Hintze, Kaysville, UT).
|
Results |
|---|
|
Top
AbstractMethodsResultsDiscussionReferences |
|---|
).
|
We performed logistic regression for the dichotomous outcome on all of the antenatal variables recorded at the time of entry into the study. We also analyzed these data using a stepwise routine in a multivariate analysis. Platelet angiotensin II binding was not picked out by either of these models as a significant predictor of pregnancy-induced hypertension.
|
Discussion |
|---|
|
Top
AbstractMethodsResultsDiscussionReferences |
|---|
Our research confirmed the diminution of platelet angiotensin II binding in normotensive pregnancy at 20 weeks’ gestation, compared with nonpregnancy as previously reported.15 We found no significant differences in platelet angiotensin II binding between women who were normotensive to delivery and those who developed pregnancy-induced hypertension. These data are in agreement with a recent, similar study by Pouliot et al,16 which confirmed the findings of the earlier study of Baker et al,13 concluding that platelet angiotensin II binding site density does not predict preeclampsia in the second or third trimester. Although Pouliot et al16 reported a significant difference in binding between women with normotensive pregnancies and nonpregnant women, they recorded lower levels of binding in the hypertensive groups than those reported by Baker et al13 and those found in the present study. In contrast to Baker et al and the present investigators, Pouliot and colleagues16 used several concentrations of iodine-125–angiotensin II to generate a full Scatchard plot. This is considered by some to be a more accurate method than the single-ligand estimation used in the present study, but it is less practical as a routine screening test than the simplified version established by Baker and colleagues.11
We chose 20 weeks’ gestation for our study because pregnancy-induced hypertension, by definition, occurs after the 20th week of pregnancy. The study by Gant et al5 showed that loss of resistance to the pressor effect of infused angiotensin II was apparent by the 20th week of gestation. If the test had proved to be a sensitive predictor of pregnancy-induced hypertension, this would be early enough in the pregnancy to allow for increased surveillance and possible prophylaxis. If the test had proved clinically useful, sampling of blood at the 20-week anomaly scan appointment would have been convenient to clinician and patient.
The study incidence of 16.3% for developing nonproteinuric or proteinuric pregnancy-induced hypertension was high, given the fact that the women were not selected on the grounds of being at high risk (although they were primigravidas). We expected around 10%1 to develop high BP during first pregnancy. We know no reason for this unexpectedly high percentage of hypertension.
Given these results, we conclude that platelet angiotensin II binding at 20 weeks’ gestation does not have sufficient sensitivity or specificity to be a useful predictor of pregnancy-induced hypertension. In the original study by Baker et al,13 women were recruited in the third trimester (28–32 weeks) and it was suggested that the modification in receptor number appears only after the 28th week of pregnancy. If platelet angiotensin II binding can predict pregnancy-induced hypertension only when measured after 28 weeks, its value as a predictor is limited, because the group of patients most difficult to manage would be missed, and selection of patients for prophylaxis would not be possible.
|
Footnotes |
|---|
Received March 26, 1998. Received in revised form July 29, 1998. Accepted August 13, 1998.
|
References |
|---|
|
Top
AbstractMethodsResultsDiscussionReferences |
|---|
2. Department of Health. Report on confidential enquiries into maternal deaths in the UK: 1988/1990. London: Department of Health, 1994:22–23.
3. O’Brien WF. Predicting preeclampsia. Obstet Gynecol 1990;75:445–52.
4. Masse J, Forest JC, Moutquin JM, Marcoux S, Brideau NA, Belanger M. A prospective study of several potential biological markers for early prediction of the development of preeclampsia. Am J Obstet Gynecol 1993;169:501–8.[Medline]
5. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest 1973;52:2682–9.
6. Kyle PM, Campbell S, Buckley D, Kissane J, de Swiet M, Albano J, et al. A comparison of the inactive urinary kallikrein:creatinine ratio and the angiotensin sensitivity test for the prediction of pre-eclampsia. Br J Obstet Gynaecol 1996;103:981–7.[Medline]
7. Brosens IA, Robertson WB, Dixon HB. The role of the spiral arteries in the pathogenesis of preeclampsia. In: Wynn RM, ed. Obstetrics and gynecology annual. New York: Appleton-Century-Crofts, 1972:177–91.
8. Walsh SW. Pre-eclampsia: An imbalance in placental prostacyclin and thromboxane production. Am J Obstet Gynecol 1985;152:335–40.[Medline]
9. CLASP: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619–29.[Medline]
10. ECPPA: Randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. ECPPA (Estudo Colaborativo para Prevençao da Pre-eclampsia com Aspirina) Collaborative Group. Br J Obstet Gynaecol 1996;103: 39–47.
11. Baker PN, Broughton-Pipkin F, Symonds EM. Platelet angiotensin II binding and plasma renin concentration, plasma renin substrate and plasma angiotensin II in human pregnancy. Clin Sci (Colch) 1990;79:403–8.[Medline]
12. Graves SW, Moore TJ, Seely EW. Increased platelet angiotensin II receptor number in pregnancy induced hypertension. Hypertension 1992;20:627–32.
13. Baker PN, Broughton-Pipkin F, Symonds EM. Comparative study of platelet angiotensin II binding and the angiotensin II sensitivity test as predictors of pregnancy induced hypertension. Clin Sci (Colch) 1992;83:89–95.[Medline]
14. Mann JFE, Sis J, Ritz E. Angiotensin II binding to human blood cells. J Hypertens 1985;3:131–7.[Medline]
15. Baker PN, Broughton-Pipkin F, Symonds EM. Longitudinal study of platelet angiotensin II binding in human pregnancy. Clin Sci (Colch) 1992;82:377–81.[Medline]
16. Pouliot L, Forest JC, Moutquin JM, Coulombe N, Masse J. Platelet angiotensin II binding sites and early detection of preeclampsia. Obstet Gynecol 1998;91:591–5.[Abstract]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
