CHAPTER

13

Prevention of Preeclampsia

By Marie-Dominique Beaulieu

13

Prevention of Preeclampsia
Adapted by Marie-Dominique Beaulieu, MD, MSc, FCFP1 from the report prepared for the U.S. Preventive Services Task Force2

Blood pressure (BP) measurement should be part of the periodic health examinations of all pregnant women. The technique for BP measurement should be consistent, with the patient always in the same position (B Recommendation). There is no evidence to recommend low dose aspirin prophylaxis as a primary preventive measure in women at low risk of developing preeclampsia. Low dose aspirin prophylaxis can be considered in women at high risk of preeclampsia and intra-uterine growth retardation (IUGR) (C Recommendation).

Burden of Suffering
Hypertension is the most common medical complication of pregnancy, occurring in 6-8% of all pregnancies.<1,2> It is seen in a group of disorders that include preeclampsia-eclampsia, latent or chronic essential hypertension, a variety of renal diseases, and transient gestational hypertension. Preeclampsia, once called toxemia of pregnancy, is the most dangerous of these disorders, occurring in about 2.6% of pregnancies. Women with preeclampsia are at increased risk for abruptio placenta, acute renal failure, cerebral hemorrhage, disseminated intravascular coagulation, pulmonary edema, circulatory collapse, and eclampsia. The fetus may become hypoxic, increasing risk of low birthweight, premature delivery, or perinatal death.<3> Women who suffered from preeclampsia are not at increased risk of developing chronic hypertension. Risk factors for preeclampsia and eclampsia include black ancestry, nulliparity or first pregnancy with the actual partner, multiple gestations, chronic hypertension or diabetes, a family history of eclampsia or preeclampsia and possibly obesity.<4> Although definitions differ, many define preeclampsia as acute hypertension presenting after the 20th week of gestation accompanied by abnormal edema and/or proteinuria (more than 0.3 g/24h), or both.<5> BP over 140/90, or a rise of 15 mmHg or 30 mmHg above
1

Preeclampsia/eclampsia syndrome is the second leading cause of maternal death

Associate Professor, Department of Family Medicine, University of Montreal, Montreal, Quebec 2 By Michelle Berlin, MD, MPH, Assistant Professor of Obstetrics & Gynecology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania and A. Eugene Washington, MD, MSc, Co-director, Center for Reproductive Health Policy Research, University of California School of Medicine, San Francisco, California

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the usual diastolic and systolic BP respectively, is considered abnormal. The appearance of edema and proteinuria alone is unreliable because edema is common in normal pregnancies.<6> BP levels should be normalized 6 weeks post-partum. Transient gestational hypertension is defined as acute onset of hypertension in pregnancy or the early puerperium without proteinuria or abnormal edema and resolving within 10 days after delivery.<2> Chronic hypertension that had been latent prior to the pregnancy may become evident during gestation. Pregnant women with chronic hypertension are also at increased risk for stillbirth, neonatal death, and other fetal complications, but the risk is much lower than that of women with preeclampsia. Women with transient or latent chronic hypertension are more likely to develop chronic hypertension in later years.<4,5>

Maneuver
Two preventive maneuvers are considered. Screening for early signs of preeclampsia followed by appropriate clinical interventions has been for a long time the only strategy available. Recently, low dose aspirin prophylaxis has been evaluated as a primary prevention maneuver in low-risk and high-risk pregnancies.

Low Dose Aspirin Prophylaxis

Endothelial dysfunction caused by the systemic effects of decreased placental blood flow is postulated to be the pathophysiologic mechanism for preeclampsia. Compared to women with normal pregnancies, women with preeclampsia have a relative excess of thromboxane A2 compared to prostacyclin. It has been hypothesized that the correction of the thromboxane: prostacyclin ratio by aspirin could prevent preeclampsia and its complications. The aspirin dosage proposed varies between 60 to 150 mg per day and has been initiated between 13 to 26 weeks of pregnancy, in different studies.<7-9>

Screening for Early Signs of Preeclampsia

Much research has been done to identify screening tests that would predict the risk of developing preeclampsia before the classical triad of symptoms appears. The validity of proposed tests is difficult to evaluate due to the absence of a gold standard to confirm the diagnosis. Glomerular endotheliosis, the renal lesion characteristic of preeclampsia, is present in only 54% of patients who meet the clinical criteria for the disease,<10> and is not specific for preeclampsia. For practical reasons, most studies of potential screening tests for preeclampsia have relied on clinical criteria to confirm the diagnosis.

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Measurable proteinuria usually occurs late in the course of the illness and therefore is not useful for early detection.<2> However, screening for bacteriuria in pregnancy is recommended at 12 to 16 weeks (see Chapter 9). In a prospective study of women between 24 and 34 weeks of gestation, a urine albumin concentration 11 mcg/L had a sensitivity of 50% in predicting subsequent preeclampsia.<11> The conventional dipstick test is unreliable in detecting the moderate and highly variable elevations in albumin that occur early in the course of preeclampsia but it can help ascertain the diagnosis when it is present.<12> Other screening tests that have been suggested, include the angiotensin II infusion test and the supine pressor rollover examination, but these have also been found to be unsuitable, as the former is impractical and the latter lacks adequate sensitivity, specificity and positive predictive value.<1,12> BP measurement remains the cornerstone of early diagnosis, although it has limitations. First, there are the usual sources of measurement errors associated with sphygmomanometry. In addition, maternal posture can affect BP in pregnant women significantly.<12> The results can be erroneous, for example, if BP is measured with the woman in the supine position. Most important, a single elevated BP reading is neither diagnostic of nor a reliable predictor of preeclampsia. Absence of the normal decline in BP that occurs in the middle trimester or an increase in BP during the second trimester may be an early indicator of increased risk for preeclampsia.<3,13> Some experts recommend using the middle trimester mean arterial pressure (MAP), defined as ((2 x diastolic BP) + systolic BP)/3 as a screening test.<3> Studies indicate that a middle trimester MAP above 90 mmHg has a sensitivity of 61-71% and a specificity of 62-74% in predicting preeclampsia.<3,14>

To be valid, the blood pressure must be measured in a consistent manner at each visit

Effectiveness of Prevention and Treatment

Low Dose Aspirin Prophylaxis
The effectiveness of prophylactic acetylsalicylic acid (ASA) at doses ranging between 60 and 150 mg has been the object of some randomized controlled trials. Most were conducted in women at high risk for preeclampsia. All showed that low-dose aspirin can effectively reduce pregnancy-induced hypertension and preeclampsia and IUGR associated with the conditions. The decrease in the incidence of preeclampsia was not, however, associated with a decrease in neonatal mortality but the cesarian section rate was significantly lower in the aspirin group in two studies.<8,9>

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A large randomized controlled trial was conducted recently in 3,135 low-risk nulliparous women.<7> In this trial 60 mg of ASA was effective in reducing preeclampsia incidence from 6.3% to 4.6% but was associated with a statistically significant increase in abruptio placenta which was not observed in a much larger study (CLASP).<15> The beneficial effect of ASA was observed only in women whose BP was >120 mmHg at recruitment.<7>

Screening for Preeclampsia Followed by Early Intervention

Delivery is the only specific, definitive treatment of preeclampsia. However, early detection of hypertension during pregnancy permits clinical monitoring and prompt therapeutic intervention should severe preeclampsia or eclampsia develop. Although some studies support the use of bedrest, pharmacologic agents, and early delivery of the fetus to prevent complications, there is little conclusive evidence that these measures improve outcome.<12,16,17> A randomized controlled trial found that antihypertensive therapy and hospitalization, when compared with hospitalization alone, did not improve maternal or fetal outcome.<18> There have been no clinical trials to determine whether hypertensive women treated early in pregnancy have a better prognosis than those who are not detected early. Nonetheless, most obstetrical experts believe, based on clinical experience, that early detection and preventive non-pharmacologic treatment of preeclampsia may be beneficial to both mother and fetus.<1,6,18,19> This view is based in part on inferences drawn from the apparent effectiveness of regular prenatal care in reducing the risk of preeclampsia-eclampsia. Studies conducted as early as the 1940s suggested an inverse relationship between the extent of prenatal care and the incidence of eclampsia, perhaps reflecting a beneficial effect due to early detection.<20> These findings do not provide direct evidence, however, that improved outcome is due solely to BP measurement itself, rather than to other components of prenatal care or to the characteristics of women who receive regular prenatal care.

Recommendations of Others
The Canadian and American Colleges of Obstetricians and Gynecologists recommend BP measurements at the initial visit, every 4 weeks until 28 weeks gestation, every 2-3 weeks until 36 weeks gestation, and weekly thereafter.<21,22> In 1989, the U.S. Preventive Services Task Force recommended that all pregnant women should receive systolic and diastolic blood pressure measurements at the first prenatal visit and periodically until delivery or throughout the three trimesters.<23>

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Conclusions and Recommendations

There is no evidence to recommend universal low-dose ASA prophylaxis in nulliparous women (C Recommendation). Although there is grade I evidence of its capacity to reduce the incidence of preeclampsia, it has not been shown to decrease neonatal mortality, and has been associated with adverse outcome in some studies. The safety of aspirin prophylaxis must be carefully evaluated. However, this treatment may be considered for women at high risk for the condition. To date, the only readily available screening strategy for preeclampsia is the early detection of an abnormal BP trend over time. A diagnosis of preeclampsia should not be made solely on the presence of elevated BP. There is no experimental evidence that these efforts will result in reduced maternal or perinatal morbidity and mortality. However, there is grade II-2 evidence that regular prenatal care is associated with a reduced incidence of preeclampsia. Systolic and diastolic pressures should be measured on all obstetric patients at the first prenatal visit and periodically throughout the remainder of pregnancy (B Recommendation). The optimal frequency for measuring BP in pregnant women has not been determined and is therefore left to clinical discretion. The collection of reliable BP data requires consistent use of correct technique and a cuff of appropriate size encircling at least 2/3 of the upper arm length. The patient should consistently be in the same position, and the BP should be measured in the sitting position, after the patients arm has rested at heart level for 5 minutes.<5> For additional guidelines, see Chapter 53 on Screening for Hypertension. Further diagnostic evaluation and clinical monitoring, including frequent BP monitoring and urinalysis, are indicated if BP does not decrease normally during the third trimester, if the diastolic pressure increases 15 mmHg above baseline or the systolic pressure increases 30 mmHg above baseline, or if the BP exceeds 140/90. Medical interventions upon the suspicion of a diagnosis of preeclampsia must include hospital admission to substantiate the diagnosis and its severity.

Blood pressure should be measured at each prenatal visit. There is insufficient data to recommend routine aspirin prophylaxis

Unanswered Questions Research Agenda

The following have been identified as research priorities: 1. 2. The identification of biologic markers to predict early detection of preeclampsia. The identification of women likely to benefit from prophylactic aspirin prophylaxis.

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Evidence
The literature was identified with a MEDLINE search in the English language for the years 1966 to July 1993 using the following key words: preeclampsia, prevention and control. The review was initiated by the Task Force in December 1993 and the Recommendations finalized in January 1994.

Acknowledgements
We would like to thank Jean-Marie Moutquin, MD, FRCPC, Professor, Department of Obstetrics and Gynecology, Universit e Laval, Qu bec City, Qu bec, for reviewing this chapter. e e

Selected References
1. DeVoe SJ, OShaughnessy R: Clinical manifestations and diagnosis of pregnancy-induced hypertension. Clin Obstet Gynecol 1984; 27: 836-853 Chesley LC: History and epidemiology of preeclampsiaeclampsia. Clin Obstet Gynecol 1984; 27: 801-820 Page EW, Christanson R: The impact of mean arterial pressure in the middle trimester upon the outcome of pregnancy. Am J Obstet Gynecol 1976; 125: 740-746 Roberts JM, Redman CW: Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 1993; 341: 1447-1451 National High Blood Pressure Education Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 1990; 163: 1691-1712 Wallenburg HCS: Detecting hypertensive disorders of pregnancy. In: Chalmers I, Enkin M, Kierse, ed: Effective care in pregnancy and childbirth. Oxford: Oxford University Press, 1989; 382-402 Sibai BM, Caritis SN, Thom E, et al : Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. N Engl J Med 1993; 329: 1213-1218 Beaufils M, Donsimoni R, Uzan S, et al : Prevention of preeclampsia by early antiplatelet therapy. Lancet 1985; 840-842 Benigni A, Gregorini G, Frusca T, et al : Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med 1989; 321: 357-362 Fisher KA, Luger A, Spargo BH, et al : Hypertension in pregnancy: clinical-pathological correlations and remote prognosis. Medicine-Baltimore 1981; 60: 267-276 Rodriguez MH, Masaki DI, Mestman J, et al : Calcium/creatinine ration and microalbuminuria in the prediction of preeclampsia. Am J Obstet Gynecol 1988; 159: 1452-1455 141 2. 3.

4. 5.

6.

7.

8. 9.

10.

11.

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Sibai BM: Pitfalls in diagnosis and management of preeclampsia. Am J Obstet Gynecol 1988; 159: 1-5 Fallis NE, Langford HG: Relation of second trimester blood pressure to toxemia of pregnancy in the primigravid patient. Am J Obstet Gynecol 1963; 87: 123-125 Moutquin JM, Rainville C, Giroux L, et al : A prospective study of blood pressure in pregnancy: prediction of preeclampsia. Am J Obstet Gynecol 1985; 151: 191-196 CLASP Collaborative Group: CLASP: a randomized controlled trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. Lancet 1994; 343: 619-629 Mathews DD, Shuttleworth TP, Hamilton EFB: Modern trends in management of non-albminuric hypertension in late pregnancy. Br Med J 1978; 2: 623-625 Gilstrap LC, Cunningham FG, Whalley PG: Management of pregnancy-induced hypertension in the nulliparous patient remote from term. Semin Perinatol 1978; 2: 73 Sibai BM, Gonzalez AR, Mabie WC, et al : A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol 1987; 70: 323-327 Redman CW, Roberts JM: Management of pre-eclampsia. Lancet 1993; 341: 1451-1454 Cunningham FG, Lindheimer MD: Hypertension in pregnancy. N Engl J Med 1992; 326: 927-932 Chelsey LC: Eclampsia at the Margaret Hague Maternity Hospital. Bull Marg Hague Hosp 1953; 6: 2-11 American College of Obstetricians and Gynecologists. Standards for obstetric-gynecologic services, 6th ed. Washington, D.C.: American College of Obstetricians and Gynecologists, 1985: 17-18 The Society of Obstetricians and Gynaecologists of Canada: Guidelines for prenatal care in Canada 1984. Bulletin 1984; 6(4): 1 U.S. Preventive Services Task Force: Guide to Clinical Preventive Services: an Assessment of the Effectiveness of 169 Interventions. Williams & Wilkins, Baltimore, Md, 1989: 95-103

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19. 20. 21. 22.

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24.

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R Y

1 3

Prevention of Preeclampsia
MANEUVER
Routine prenatal care with blood pressure measurement

EFFECTIVENESS
Early detection and non-specific preventive treatment is beneficial to the mother and fetus.

LEVEL OF EVIDENCE <REF>

Cohort studies <16,17,21> (II-2); expert opinion <1,6,19,20> (III)

RECOMMENDATION
There is fair evidence to recommend screening for preeclampsia in the periodic examination of all pregnant women (B) There is insufficient evidence to recommend for or against low-dose aspirin in women with/without risk factors of preeclampsia (C)

Low-dose (60-150 mg per day) aspirin in nulliparous women with/without risk factors of preeclampsia

Low-dose aspirin reduces incidence of preeclampsia and intra-uterine growth retardation but has been associated with increased risks of complications in some studies without impact on neonatal mortality and morbidity.

Randomized controlled trials<7-9,15> (I)

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