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Prevention of preeclampsia
Prevention of Preeclampsia Farid Mattar and Baha M. Sibai
Preeclampsia is a multisystem disorder of unknown cause. Efforts to prevent the disease or reduce its incidence have utilized pharmacological intervention as well as dietary supplementation. Recent, large, randomized trials have not shown a benefit from the use o f aspirin. Calcium supplementation has also been studied extensively and found to be similarly ineffective in reducing the incidence or severity o f preeclampsia in healthy women. The studies regarding the use of magnesium, zinc, and fish oils for the prevention o f preeclampsia are fewer in number, but have also found minimal to no benefit. In the same respect, numerous randomized trials have been performed using antihypertensive agents, diuretics, and low-salt diet. Results of these studies have not shown any beneficial effect. Prevention of preeclampsia is unlikely as long as the underlying origin remains unknown. Copyright 9 1999 by W.B. Saunders Company
I reeclampsia is a multisystem disorder unique to h u m a n pregnancy. It complicates 5% to 10% of pregnancies, an incidence that varies d e p e n d i n g on the population, region, or country examined. 1 T h e cause of preeclampsia is unknown. Many theories have b e e n p r o p o s e d and challenged, whereas others r e m a i n the subj e c t of o n g o i n g research. T h e r e is e n o u g h evid e n c e in the c u r r e n t literature to say that the primary defect in pregnancies complicated by p r e e c l a m p s i a starts early in the first trimester in the f o r m of an a b n o r m a l vascular response to placentation. In n o r m a l pregnancies, trophoblastic invasion transforms the uteroplacental circulation into a high-capacitance, low-resistance system that exhibits relative resistance to vasopressor agents. This process occurs in two stages, whereby the decidual segments o f the spiral arterioles are affected by the first wave of trophoblastic invasion followed by a second wave in the second trimester e x t e n d i n g into the inner third of the m y o m e t r i u m , z In preeclamptic pregnancies there is failure of the second wave of trophoblastic invasion, resulting in a state of arteriolar vasoconstriction, abnormally increased sensitivity to vasopressor peptides and amines, a n d r e d u c e d uteroplacental b l o o d f l o w / O u r limited u n d e r s t a n d i n g of the cause of p r e e c l a m p s i a has dramatically influenced our
F
From the Department of Obstetricsand Gynecology, The University of Tennessee, Memphis, Memphis, TN. Address reprint requests to Baha M. Sibai, MY), Department of Obstetrics and Gynecology, University of Tennessee, Memphis, 853 Jefferson Ave, Room El02, Memphis, TN 38103. Copyright 9 1999 by W.B. Saunders Company O146-0005/99/2301-0007510. 00/0
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efforts at finding effective means of prediction and prevention of the disease. A variety of clinical, biochemical, and biophysical tests have b e e n studied in an a t t e m p t to predict the future d e v e l o p m e n t of preeclampsia. Most of these tests have p o o r sensitivity and positive predictive value and are not practical for use in routine clinical settings. 4 As a result, all studies on prevention have used patients with various risk factors for preeclampsia. N u m e r o u s clinical trials have b e e n carried out in an a t t e m p t to prevent or reduce the severity of preeclampsia. These studies used various a p p r o a c h e s ranging f r o m adequate prenatal care to dietary and pharmacological treatment. Although earlier studies r e p o r t e d beneficial results, the recent literature could not show a significant i m p r o v e m e n t in preeclampsia prevention with any of these interventions. T h e following discussion summarizes the data f r o m these studies and presents a conclusion for their controversial findings.
Antithrombotie Agents Preeclampsia is associated with arteriolar vasospasm and increased peripheral vascular resistance, e n h a n c e d platelet aggregation, activation of the coagulation system, a n d endothelial cell dysfunction. N o r m a l p r e g n a n c y is characterized by a relative resistance to vasopressor agents such as angiotensin II, a physiological mechanism that is absent in patients with preeclampsia. It has b e e n established that in preeclamptic pregnancies, there is an alteration in prostaglandin metabolism that favors an increased throm-
Seminars in Perinatology, Vol 23, No 1 (February), 1999: pp 58-64
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Table 1. Randomized Trials of Low-Dose Aspirin to Prevent Preeclampsia
Study
Risk Factors
Enrollment Gestational Age (wk)
Hauth et aP s Sibai et al is Italian study 12. CLASPTM ECPPA ~5 Golding 19 Caritis et a116 BLASP17
Nulliparas Nulliparas Obstetrical history Obstetrical history Obstetrical history Nulliparas High risk None
24 13-26 16-32 12-32 12-32 12-32 13-26 12-32
No. of Patients
Preeclampsia (%)
Aspirin
Placebo
Aspirin
Placebo
302 1,485 565 4,659 476 3,022 1,254 1,819
302 1,500 477t 4,650 494 3,024 1,249 1,822
1.7 4.6 2.9 6.7 6.7 7.1 18.4 2.2
5.6* 6.3 2.7 7.6 6.1 6.3 20.3 2.5
* No treatment. t P = .009. boxane A 2 (TxA2) to prostacyclin (PGI2) ratio. 5 These two eicosanoids p r o d u c e opposite effects on the circulating platelets and vascular endothelium. T x A 2 is a potent vasoconstrictor and p r o m o t e r of platelet aggregation, whereas PGI 2 causes vasodilatation and inhibits platelet aggregation. Nitric oxide (NO) p r o d u c e d and secreted by the vascular endothelium also plays an important role in decreasing vascular tone and preventing platelet aggregation and adhesion. 6.7 Based on the above, various antithrombotic agents were studied in an attempt to find a way to prevent preeclampsia. O f these agents, aspirin was the most widely studied, and perhaps the most controversial. Aspirin induces a long-lasting, irreversible inhibition of platelet cyclooxygenase and TxA 2 production, with minimal effects on vascular PGI~ p r o d u c t i o n - - t h u s producing a PGI 2 to TxA 2 ratio similar to that found in normal pregnancy, a Aspirin also blunts the e n h a n c e d responsiveness to angiotensin II demonstrated in preeclamptic women. 9 In all the clinical studies, low-dose aspirin was used, ranging from 50 to 150 mg. T h e first report on the effectiveness of aspirin in reducing the incidence of preeclampsia came from a retrospective study c o n d u c t e d by Crandon and Isherwood in 1979. l~ This was followed-up by a series of prospective, randomized trials that c o m p a r e d aspirin (alone or in combination with other antithrombotic agents) with no treatment or placebo in patients at high risk for preeclampsia. The criteria for patient selection varied from one study to the other, and included p o o r obstetric history, previous preeclampsia, chronic hypertension, positive angio-
tensin II sensitivity test result, positive rollover test result, or abnormal uterine artery Doppler study findings. In 1993, Dekker and SibaP 1 published a review of the first seven low-dose aspirin studies in women at high risk for preeclampsia. They found that low-dose aspirin reduced the incidence o f gestational hypertension, preeclampsia, and fetal growth retardation. ~1 These results generated considerable excitem e n t and research with the h o p e that aspirin might be the w o n d e r drug for preeclampsia prevention. Eight prospective, randomized trials have been published since 1993 involving more than 27,000 patients from all over the world. 12-19 T h e results of these trials are summarized in Table 1.2o Only one o f these trials showed a significant reduction in preeclampsia in the aspirin group. This was a single-center study and had the smallest n u m b e r o f patients a m o n g the studies examined. TM These disappointing results are in complete disagreement with those o f the earlier studies. The discrepancy is related, to a great extent, to the nature and m e t h o d o l o g y o f each of these clinical trials. First, the earlier studies were limited by the small sample size. Second, a n u m b e r o f earlier similarly small trials were probably never published because they failed to show encouraging results. Third, the recent large, randomized trials suffered from the inclusion of low-risk and high-risk patients in the same patient population. T h e latter is evident by the fact that in seven of the eight large trials, the incidence o f preeclampsia was 2.7% to 7.6% in the placebo groups. Only one study included women at high risk for preeclampsia, as d e m o n strated by the 20.3% incidence in the placebo
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group. 16 In addition, these studies used different risk factors to identify high-risk patients, as well as different diagnostic criteria for preeclampsia. In this respect, some of these trials failed to m e n t i o n how preeclampsia was diagnosed. O t h e r studies relied on urine dipstick to define proteinuria, knowing that it has been shown that urinary dipstick protein correlates poorly with the m o r e accurate 24-hour urine protein measurement. 21 Finally, results of the studies that showed aspirin to be effective in preventing preeclampsia did not show any improvement in either maternal or perinatal outcome. Low-dose aspirin has also been studied in combination with o t h e r anfithrombotic agents such as dipyridamole, heparin, and (most recently) ketanserin, a selective serotonin-2-receptor antagonist. 22-25 In one study, the addition of ketanserin to aspirin was associated with a decrease in the incidence of preeclampsia and severe hypertension, and with an improvement in pregnancy o u t c o m e a m o n g patients with mild to m o d e r a t e midtrimester hypertension. 24 T h e investigators c o n c l u d e d that further studies were n e e d e d to confirm their results. In a study involving patients with severe renal disease, the combination o f heparin and aspirin resulted in a reduction in the prevalence ofpreeclampsia and an i m p r o v e m e n t in fetal outcome. 23 Low-dose aspirin is safe for use in pregnancy. Several studies have shown that aspirin selectively inhibits maternal platelet cyclooxygenase without affecting fetal PGI 2 synthesis or platelet function, with only a slight decrease in fetal platelet TxA2.25,26Similarly, fetal urine output, cardiac function, and overall neonatal outcome did not suffer any adverse effect. 14,27,28 Epidural anesthesia is not contraindicated in pregnant women taking low-dose aspirin. 29
Calcium Over the past decade, there has been a growing interest in the role of calcium in the hypertensive disorders of pregnancy. Epidemiological studies have r e p o r t e d an inverse relationship between calcium intake and the development of high blood pressure and preeclampsia i n pregnancy, s~ This hypothesis was based on the observation that populations with a low calcium intake (such as the Thai and Japanese populations) had a high incidence of preeclampsia, whereas
populations with a high calcium intake (such as the Ethiopian and Guatemalan populations) had a low incidence of preeclampsia, sl Additional support for this hypothesis came from two studies that r e p o r t e d an association between preeclampsia and hypocalciuria at the time of diagnosis and several weeks before the onset of the disease. 32,ss Although the exact causal relationship between calcium deficiency and preeclampsia has not yet b e e n established, it has b e e n postulated that low calcium intake may stimulate either parathyroid h o r m o n e or renin release and increase renal calcium reabsorption, thus decreasing urinary calcium excretion, s~ T h e increase in serum parathyroid h o r m o n e levels drives calcium into the vascular smooth-muscle cells, thereby increasing vascular tone and responsiveness to pressor agents. High concentrations of intracellular calcium were also f o u n d in the erythrocytes and platelets of women with preeclampsia.Z4, s5 The effect of dietary calcium supplementation on d e v e l o p m e n t of hypertension and preeclampsia during pregnancy has b e e n the subject of at least twelve clinical trials. These studies differed in their patient populations, study designs, gestational age at entry, sample size, and dose of calcium (156 to 200 mg) as well as in their definition of hypertension and preeclampsia. Table 2 summarizes the results of seven randomized, double-blind, placebo-controlled studies reported so far. s6-42The remaining trials were not included either because they were not placebo controlled, failed to report the incidence of preeclampsia, or used calcium in combination with o t h e r agents. 2~ Two of the trials that demonstrated significant reductions in the incidence of preeclampsia in the treatment group also r e p o r t e d a high incidence o f preeclampsia in healthy nulliparous women (23.5%), and in one of these studies, all the w o m e n with hypertension also had preeclampsia, s6,s7 We, therefore, d o u b t the accuracy of their results. Two more studies similarly showed beneficial effects, but they had a limited sample size. sS,s9 T h e findings of the remaining three trials show that calcium supplementation does not reduce the incidence o f preeclampsia in healthy nulliparous women.
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Table 2. Randomized Trials of Calcium Supplementation to Prevent Preeclampsia
Study
Risk Factors
Lopez-Jaramillo et al a6 Lopez-Jaramillo et al a7 Villar and Repke a9 Belizan et al4~ Sanchez-Ramos et alas Levine et a142 Lopez-Jaramillo et a 1 4 1
Enrollment Gestational Age
Nulliparas + ROT Nulliparas (85%) Nulliparas + ROT and Ang II Nulliparas Nulliparas
24 24-32 24 20 24-28 13-21 20
No. of Patients Calcium
55 22 90 579 29 2,295 125
Preeclampsia (%)
Placebo
Calcium
Placebo
51 34 88 588 34 2,294 135
3.6 0.0 0.0 2.6 13.8 6.9 3.2
23.5* 23.5* 3.4 3.9 44.1" 7.3 15.5
NOTE. Only double-blind placebo trials are included. Abbreviations: ROT, roll over test; Ang II, angiotensin sensitivity test. *P < .05.
Magnesium Several studies have linked preeclampsia to dietary magnesium deficiency and low intracellular magnesium concentrations during pregnancy. One observational study from the early 1980s reported a reduction in the frequency of fetal growth retardation and preeclampsia in association with magnesium supplementation. 4s Two subsequent double-blind, placebo-controlled trials showed no reduction in the incidence o f preeclampsia in the magnesium-supp l e m e n t e d group (Table 3)44.45 Zinc
Several studies have reported decreased plasma, leukocyte, and placental zinc levels in patients with pregnancy-induced hypertension compared to those with normotensive pregnancies. "~ Two randomized, double-blinded, placebo-controlled studies followed. 47,48 H u n t et a147 reported a significant reduction in the incidence of pregnancy-induced hypertension in patients treated with a mineral supplement containing 20 mg of zinc compared with a matched group Table 3. Prevention of Preeclampsia with Magnesium Supplementation Preeclampsia
Study
Magnesium (%)
Placebo or No Treatment (%)
Conradt et al4s Spatling and Spatling44 Sibai et al 6a
0/882
97/4023 (2)
2/278 (1) 32/187 (17.3)
2/290 (1) 35/190 (18.5)
o f women receiving placebo (2% v 16%). In a later study, M a h o m e d et al 4s showed n o such beneficial effect. This disparity can be attributed to differences in baseline zinc levels between the two study populations or differences in definitions o f preeclampsia. Both studies had limited sample size.
Fish Oil The first report on the beneficial effects of fish oil on the incidence of preeclampsia dates back to 1942. 49 Over 5,000 women were enrolled to assess the effects of a dietary supplement consisting of vitamins, minerals, and halibut liver oil. Although the supplemented group had fewer women with preeclampsia, the quality of the study was questionable, and it was not until the last decade that the interest in fish oil was revived. T h e beneficial effect o f fish oil seems to be related mainly to its long-chain n-3 polyunsaturated fatty acids, eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosahexoenoic (DHA) acids. These acids inhibit platelet TxA~ p r o d u c t i o n without affecting endothelial PGIe production, leading to a state of r e d u c e d platelet aggregation and increased vasodilatation. 5~ Moreover, one study provided evidence that n-3 fatty acid supplementation is associated with a change in angiotensin II sensitivity. 5' Recent data from five randomized trials showed no reduction in the incidence o f preeclampsia in the fish-oil group (Table 4).52-54 These findings were confirmed by a large, European, multicenter trial comparing fish oil with olive oil in women at high risk for preeclampsia (Gus Dekker, MD, personal communication, D e c e m b e r 1998).
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Table 4. Fish-Oil for the Prevention of Hypertension or Preeclampsia
Study
Conclusion
Hypertension Preeclampsza Only (%) (%)
Bulstra-Ramakers et a152. Fish oil (n = 32) Placebo (n = 31) Onwude et aP 3. Fish oil (n -- 113) Placebo (n = 119) Salvig et a154t Fish oil (n = 266) No oil (n = 131)
7 (21.9) 4 (12.9)
5 (15.6) 3 (9.7)
38 (33.6) 35 (30.0)
15 (13.4) 18 (15.2)
8 (3.0) 2 (1.5)
0 (0) 1 (0.7)
* Women at risk for hypertension or fetal growth retardation. t Healthy women.
Antihypertensive Drugs C h r o n i c h y p e r t e n s i o n is a m a j o r risk factor for preeclampsia. 55 T o date, six r a n d o m i z e d trials (only o n e o f which was p l a c e b o controlled) have e x a m i n e d the beneficial effect o f m e t h y l d o p a , labetalol, o r atenolol o n patients with c h r o n i c h y p e r t e n s i o n (Table 5). I n a critical analysis o f these trials, Sibai 56 f o u n d n o r e d u c t i o n in the incidence of superimposed preeclampsia among the treated patients. Moreover, n o n e o f these trials h a d an a d e q u a t e s a m p l e size to d e m o n strate such a benefit.
Diuretics and Low-Salt Diet A meta-analysis o f n i n e r a n d o m i z e d trials c o m prising m o r e t h a n 7,000 subjects r e g a r d i n g the use o f prophylactic diuretics in p r e g n a n c y s h o w e d n o decrease in the i n c i d e n c e o f pree c l a m p s i a - - a l t h o u g h a r e d u c t i o n in the incid e n c e s o f e d e m a a n d h y p e r t e n s i o n was noted. 57 T h e use o f low-salt diet d u r i n g p r e g n a n c y , a l o n g - s t a n d i n g practice o f m a n y obstetricians a n d midwives worldwide, derives f r o m the old conc e p t that salt is intimately associated with hypertensive disorders ( i n c l u d i n g preeclampsia). In a large review covering m o s t o f the past century, Steegers et al 5s did n o t find e n o u g h evidence to s u p p o r t the t h e o r y that salt restriction d u r i n g p r e g n a n c y prevents o r r e d u c e s the i n c i d e n c e o f preeclampsia. T h e r e are two r e c e n t r a n d o m i z e d trials o f low-salt d i e t in p r e g n a n c y , a n d n e i t h e r c o u l d d e m o n s t r a t e a r e d u c t i o n in t h e incid e n c e o f g e s t a t i o n a l h y p e r t e n s i o n in t h e study groups.59, 60
P r e e c l a m p s i a is a m a j o r c o n t r i b u t o r to m a t e r n a l a n d fetal mortality a n d morbidity. Dietary supp l e m e n t a t i o n a n d p h a r m a c o l o g i c a l intervention, as evident in the r e c e n t literature, does n o t p r e v e n t p r e e c l a m p s i a o r r e d u c e its severity. Alt h o u g h results o f a few studies showed a reduction in the i n c i d e n c e o f p r e e c l a m p s i a in the treated populationS, they failed to d e m o n s t r a t e any i m p r o v e m e n t in m a t e r n a l o r n e o n a t a l outc o m e . T h e disparity b e t w e e n the earlier studies a n d the m o r e r e c e n t r a n d o m i z e d trials is partly s e c o n d a r y to differences in study design, such as patient selection, sample size, r a n d o m i z a t i o n , a n d definition o f the disease process. Equally i m p o r t a n t is the a b s e n c e o f effective m e a n s for the early p r e d i c t i o n o f preeclampsia. P r e e c l a m p sia is a s y n d r o m e o f u n c e r t a i n etiology. It may develop u n d e r the influence o f i m m u n o l o g i c , genetic, o r dietary factors, o r u n d e r l y i n g medical disease, o r a c o m b i n a t i o n thereof. W e t h i n k that f u t u r e research s h o u l d be targeted at b e t t e r u n d e r s t a n d i n g the causes a n d p a t h o p h y s i o l o g y o f this clinical entitv. Until then, it will be unlikely to r e a c h the m e a n s by which p r e e c l a m p s i a can be u n d i s p u t a b l y prevented.
Table 5. Randomized Trials of Antihypertensive Therapy in Pregnant Women With Mild Chronic Hypertension and the Subsequent Risk of Preeclampsia
Gestation at Entry (wk) Leather et a162 Control (n = 24) Treated (n = 23) Redman et a163 Control (n = 107) Treated (n = 101) Arias and Zamora 64 Control (n = 29) Treated (n = 29) Weitz et a165 Control (n = 12) Treated (n = 13) Butters et a166 Control (n = 15) Treated (n = 14) Sibai et a167 Control (n = 90) Treated (n = 173)
Preeclampsia
<24
? ?
20.6 +- 0.5 21.9 + 0.5
4,7 6,7
16.4 + 1.1 14.7 + 1.0
10.3 3.4
<34
33.3 38.4
12.0 -+ 24,0 12.0 • 24.0
? ?
11.3 -+ 0.2 1t,2 --- 0.2
15.6 17.3
NOTE. Preeclampsia defined as increased blood pressure plus proteinuria. Data are presented as mean _ SEM where available.
Prevention of Preeclampsia
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17. Rotchell YE, CruickshankJH, Phillips GM, et al: Barbados low-dose aspirin study in pregnancy (BLASP): A randomised trial for the prevention of pre-eclampsia and its complications. BrJ Obstet Gynaecol 105:286-292, 1998 18. HauthJC, Goldenberg RL, Parker CRJr, et al: Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol 168:1083-1093, 1993 19. Golding J: Low-dose aspirin for primiparae in pregnancy. The Jamaica Low-dose Aspirin Study Group. Br J Obstet Gynaecol 105:293-299, 1998 20. Sibai BM: Prevention of preeclampsia: A big disappointment! A m J Obstet Gynecol (in press) 21. Meyer NL, Mercer BM, Friedman SA, et al: Urinary dipstick protein: A poor predictor of absent or severe proteinuria: Am J Obstet Gynecol 170:137-41, 1994 22. Beaufils M, Uzan S, Donsimoni R, et al: Prevention of preeclampsia by early antiplatelet therapy. Lancet 1:840842, 1985 23. North RA, Ferrier C, Gamble G, et al: Prevention of preeclampsia with heparin and antiplatelet drugs in women with renal disease. Aus N Z J Obstet Gynaecol 35:357-362, 1995 24. Steyn DW, Odendaal HJ: Randomised controlled trial of ketanserin and aspirin in prevention of pre-eclampsia. Lancet 350:1267-1271, t997 25. Sibai BM, Mirro R, Chesney CM, et al: Low dose aspirin in pregnancy. Obstet Gynecol 74:551-557, 1989 26. Louden KA, Broughton Pipkin F, Heptinstall S, et al: Neonatal platelet reactivity and serum thromboxane B, production in whole blood: The effect of maternal low dose aspirin. BrJ Obstet Gynaecol 101:203-208, 1994 27. MaherJE, Owen J, Hauth J, et al: The effect of low-dose aspirin on fetal urine output and amniotic fluid volume. Am J Obstet Gynecol 169:885-888, 1993 28. DiSessa T, Moretti M, Khoury A, et al: Cardiac function profile in fetuses and newborns exposed to low-dose aspirin (ASA) during pregnancy. Am J Obstet Gynecol 171:892-900, 1994 29. Sibai B, Caritis S, Thorn S, et al: Low-dose aspirin in nulliparous women: Safety of epidural and correlation between bleeding time and maternal neonatal bleeding complications. Presented at the 14th Annual Meeting of the Society of Perinatal Obstetricians, Las Vegas, Nevada, January 24-29, 1994. Am J Obstet Gynecol 170:293, 1994 (abstr 61) 30. Belizan JM, VillarJ, Repke J: The relationship between calcium intake and pregnancy-induced hypertension: up-to-date evidence. Am J Obstet Gynecol 158:898-902, 1988 31. Ito M, Koyama H, Ohshige A, et al: Prevention of preeclampsia with calcium supplementation and vitamin D~ in an antenatal protocol. Int J Gynecol Ohstet 47:115120, 1994 32. Taufield PA, Ales KL, Resnick LM, et al: Hypocalciuria in preeclampsia. N EnglJ Med 316:715-718, 1987 33. Sanchez-Ramos L, Jones DC, Cullen MT: Urinary calcium as an early marker for preeclampsia. Obstet Gynecol 77:685-689, 1991 34. Sowers JR, Zemel MB, Bronsteen RA, et al: Erythrocyte cation metabolism in preeclampsia. Am J Obstet Gynecol 161:441-445, 1989
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35. Hailer H, Oeney T, Hauck U, et al: Increased intracellular free calcium and sensitivity to angiotensin II in platelets of preeclamptic women. A m J Hypertens 2:238243, 1989 36. Lopez-Jarmnillo P, Narvaez M, Weigel RM, e t al: Calcium supplementation reduces the risk of pregnancy-induced hypertension in an Andes population. BrJ Obstet Gynaecol 96:648-655, 1989 37. Lopez-Jaramillo P, Narvaez M, Felix C, et al: Dietary calcium supplementation and prevention of pregnancy hypertension. Lancet 335:293, 1990 (letter) 38. Sanchez-Ramos L, Briones DK, Kaunitz AM, et al: Prevention of pregnancy-induced hypertension by calcium supplementation in angiotensin I-sensitive patients. Obstet Gynecol 84:349-353, 1994 39. VillarJ, RepkeJ: Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations. Am J Obstet Gynecol 163:1124-1131, 1990 40. Belizan JM, Villar J, Gonzalez L, et al: Calcium supplementation to prevent hypertensive disorders of pregnancy. N E n g l J Med 35:1399-1405, 1991 41. Lopez-Jaramillo P, Delgado F, Jacome P, et al: Calcium supplementation and the risk of preeclampsia in Ecuadorian pregnant teenagers. Obstet Gynecol 90:162-167, 1997 42. Levine RJ, Hauth JC, Curet LB, et al and the MaternalFetal Medicine Units Network: Trial of calcium to prevent preeclampsia. N Engl J Med 337:69-76, 1997 43. Conradt A, Weidinger H, Algayer H: On the role of magnesium in fetal hypotrophy, pregnancy-induced hypertension and preeclampsia. Magnesium Bulletin 6:6876, 1984 44. Spatling L, Spatling G: Magnesium supplementation in pregnancy--A double-blind study. B r J Obstet Gynaecol 95:120-125, 1988 45. Sibai BM, Villar MA, Bray E: Magnesium supplementation during pregnancy: A double-blind randomized controlled clinical trial. Am J Obstet Gynecol 161:115-119, 1989 46. Adeniyi AAF: The implications of hypozincemia in pregnancy. Acta Obstet Gynecol Scand 66:679-685, 1987 47. Hunt IF, Murphy NJ, Cleaver AE, et al: Zinc supplementation during pregnancy: Effects on selected blood constituents and on progress and outcome of pregnancy in low-income women of Mexican descent. Am J Clin Nutr 40:508-521, 1984 48. Mahomed K, James DK, Golding J, et al: Zinc supplementation during pregnancy: A double-blind randomised controlled trial. BMJ 299:826-830, 1989 49. OIsen SF, Secher NJ: A possible preventive effect of low-dose fish oil on early delivery and preeclampsia: Indications from a 50-year-old controlled trial. BrJ Nutr 64:599-609, 1990 50. SorensenJD, Olsen SF, Pedersen AK, et al: Effects offish oil supplementation in the third trimester of pregnancy on prostacyclin and thromboxane production. A m J Obstet Gynecol 168:915-922, 1993 51. Adair CD, Sanchez-Ramos L, Briones DL, et al: The
52.
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55. 56. 57. 58.
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60.
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64.
65.
66. 67.
effect of high dietary N-3 fatty acid supplementation on angiotensin II pressor response in h u m a n pregnancy. Am J Obstet Gynecol 76:688-691, 1996 Bulstra-Ramakers MTEW, Huisjes HJ, Visser GHA: The effects of 3 g eicosapentaenoic acid daily on recurrence of intrauterine growth retardation and pregnancy induced hypertension. Br J Obstet Gynaecol 102:123-126, 1994 Onwude JL, Lilford RJ, Hjartardottier H, et al: A randomised double-blind placebo-controlled trial of fish oil in high risk pregnancy. BrJ Obstet Gynaecol 109:95-100, 1995 SalvigJD, Olsen SF, Secher NJ: Effects offish oil supplementation in lage pregnancy on blood pressure: a randomised controlled trial. B r J Obstet Gynaecol 103:529533, 1996 Sibai BM: Diagnosis and management of chronic hypertension in pregnancy. Obstet Gynecol 78:451-461, 1991 Sibai BM: Treatment of hypertension in pregnant women. N EnglJ Med 335:257-265, 1996 Collins R, Yusuf S, Peto R: Overview of randomized trials of diuretics in pregnancy. BMJ 29:17-23, 1985 Steegers EAP, Eskes TKAB, Jongsma HW, et al: Dietary sodium restriction during pregnancy: A historical review. E u r J Obstet Gynecol Reprod Biol 40:83-90, 1991 Steegers EAP, van Lakwijk HPJM, Jongsma HW, et al: (Patho)physiological implications of chronic dietary sodium restriction during pregnancy: A longitudinal prospective randomised study. BrJ Obstet Gynaeco198:980987, 1991 Knuist M, Bonsel GJ, Zondervan HA, et al: Low sodium diet and pregnancy-induced hypertension: A multi-centre randomised controlled trial. Br J Obstet Gynaecol 105:430-434, 1998 Sibai BM, EI-Nazer A, Gonzalez-Ruiz AR: Severe preeclampsia-eclampsia in young primigravidas: Subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 155:1101-1116, 1986 Leather HM, Humphreys DM, Baker PB, et al: A controlled trial of hypertensive agents in hypertension in pregnancy. Lancet 1:488-489, 1968 Redman CWG, Beilin LJ, BonnerJ, et al: Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 2:753-756, 1976 Arias F, ZamoraJ: Antihypertensive treatment and pregnancy outcome in patients with mild chronic hypertension. Obstet Gynecol 53:489-494, 1979 Weitz C, Khouzami V, Maxwell K, et al: Treatment of hypertension in pregnancy with methyldopa, randomized double-blind study. I n t J Gynaecol Obstet 25:35-40, 1987 Butters L, Kennedy S, Rubin P: Atenolol in essential hypertension during pregnancy. BMJ 301:58%589, 1990 Sibai BM, Mabie WC, Shamsa F, et al: A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 162:960-967, 1990
Preeclampsia is a multisystem disorder of unknown cause. Efforts to prevent the disease or reduce its incidence have utilized pharmacological intervention as well as dietary supplementation. Recent, large, randomized trials have not shown a benefit from the use o f aspirin. Calcium supplementation has also been studied extensively and found to be similarly ineffective in reducing the incidence or severity o f preeclampsia in healthy women. The studies regarding the use of magnesium, zinc, and fish oils for the prevention o f preeclampsia are fewer in number, but have also found minimal to no benefit. In the same respect, numerous randomized trials have been performed using antihypertensive agents, diuretics, and low-salt diet. Results of these studies have not shown any beneficial effect. Prevention of preeclampsia is unlikely as long as the underlying origin remains unknown. Copyright 9 1999 by W.B. Saunders Company
I reeclampsia is a multisystem disorder unique to h u m a n pregnancy. It complicates 5% to 10% of pregnancies, an incidence that varies d e p e n d i n g on the population, region, or country examined. 1 T h e cause of preeclampsia is unknown. Many theories have b e e n p r o p o s e d and challenged, whereas others r e m a i n the subj e c t of o n g o i n g research. T h e r e is e n o u g h evid e n c e in the c u r r e n t literature to say that the primary defect in pregnancies complicated by p r e e c l a m p s i a starts early in the first trimester in the f o r m of an a b n o r m a l vascular response to placentation. In n o r m a l pregnancies, trophoblastic invasion transforms the uteroplacental circulation into a high-capacitance, low-resistance system that exhibits relative resistance to vasopressor agents. This process occurs in two stages, whereby the decidual segments o f the spiral arterioles are affected by the first wave of trophoblastic invasion followed by a second wave in the second trimester e x t e n d i n g into the inner third of the m y o m e t r i u m , z In preeclamptic pregnancies there is failure of the second wave of trophoblastic invasion, resulting in a state of arteriolar vasoconstriction, abnormally increased sensitivity to vasopressor peptides and amines, a n d r e d u c e d uteroplacental b l o o d f l o w / O u r limited u n d e r s t a n d i n g of the cause of p r e e c l a m p s i a has dramatically influenced our
F
From the Department of Obstetricsand Gynecology, The University of Tennessee, Memphis, Memphis, TN. Address reprint requests to Baha M. Sibai, MY), Department of Obstetrics and Gynecology, University of Tennessee, Memphis, 853 Jefferson Ave, Room El02, Memphis, TN 38103. Copyright 9 1999 by W.B. Saunders Company O146-0005/99/2301-0007510. 00/0
58
efforts at finding effective means of prediction and prevention of the disease. A variety of clinical, biochemical, and biophysical tests have b e e n studied in an a t t e m p t to predict the future d e v e l o p m e n t of preeclampsia. Most of these tests have p o o r sensitivity and positive predictive value and are not practical for use in routine clinical settings. 4 As a result, all studies on prevention have used patients with various risk factors for preeclampsia. N u m e r o u s clinical trials have b e e n carried out in an a t t e m p t to prevent or reduce the severity of preeclampsia. These studies used various a p p r o a c h e s ranging f r o m adequate prenatal care to dietary and pharmacological treatment. Although earlier studies r e p o r t e d beneficial results, the recent literature could not show a significant i m p r o v e m e n t in preeclampsia prevention with any of these interventions. T h e following discussion summarizes the data f r o m these studies and presents a conclusion for their controversial findings.
Antithrombotie Agents Preeclampsia is associated with arteriolar vasospasm and increased peripheral vascular resistance, e n h a n c e d platelet aggregation, activation of the coagulation system, a n d endothelial cell dysfunction. N o r m a l p r e g n a n c y is characterized by a relative resistance to vasopressor agents such as angiotensin II, a physiological mechanism that is absent in patients with preeclampsia. It has b e e n established that in preeclamptic pregnancies, there is an alteration in prostaglandin metabolism that favors an increased throm-
Seminars in Perinatology, Vol 23, No 1 (February), 1999: pp 58-64
Prevention of Preeclampsia
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Table 1. Randomized Trials of Low-Dose Aspirin to Prevent Preeclampsia
Study
Risk Factors
Enrollment Gestational Age (wk)
Hauth et aP s Sibai et al is Italian study 12. CLASPTM ECPPA ~5 Golding 19 Caritis et a116 BLASP17
Nulliparas Nulliparas Obstetrical history Obstetrical history Obstetrical history Nulliparas High risk None
24 13-26 16-32 12-32 12-32 12-32 13-26 12-32
No. of Patients
Preeclampsia (%)
Aspirin
Placebo
Aspirin
Placebo
302 1,485 565 4,659 476 3,022 1,254 1,819
302 1,500 477t 4,650 494 3,024 1,249 1,822
1.7 4.6 2.9 6.7 6.7 7.1 18.4 2.2
5.6* 6.3 2.7 7.6 6.1 6.3 20.3 2.5
* No treatment. t P = .009. boxane A 2 (TxA2) to prostacyclin (PGI2) ratio. 5 These two eicosanoids p r o d u c e opposite effects on the circulating platelets and vascular endothelium. T x A 2 is a potent vasoconstrictor and p r o m o t e r of platelet aggregation, whereas PGI 2 causes vasodilatation and inhibits platelet aggregation. Nitric oxide (NO) p r o d u c e d and secreted by the vascular endothelium also plays an important role in decreasing vascular tone and preventing platelet aggregation and adhesion. 6.7 Based on the above, various antithrombotic agents were studied in an attempt to find a way to prevent preeclampsia. O f these agents, aspirin was the most widely studied, and perhaps the most controversial. Aspirin induces a long-lasting, irreversible inhibition of platelet cyclooxygenase and TxA 2 production, with minimal effects on vascular PGI~ p r o d u c t i o n - - t h u s producing a PGI 2 to TxA 2 ratio similar to that found in normal pregnancy, a Aspirin also blunts the e n h a n c e d responsiveness to angiotensin II demonstrated in preeclamptic women. 9 In all the clinical studies, low-dose aspirin was used, ranging from 50 to 150 mg. T h e first report on the effectiveness of aspirin in reducing the incidence of preeclampsia came from a retrospective study c o n d u c t e d by Crandon and Isherwood in 1979. l~ This was followed-up by a series of prospective, randomized trials that c o m p a r e d aspirin (alone or in combination with other antithrombotic agents) with no treatment or placebo in patients at high risk for preeclampsia. The criteria for patient selection varied from one study to the other, and included p o o r obstetric history, previous preeclampsia, chronic hypertension, positive angio-
tensin II sensitivity test result, positive rollover test result, or abnormal uterine artery Doppler study findings. In 1993, Dekker and SibaP 1 published a review of the first seven low-dose aspirin studies in women at high risk for preeclampsia. They found that low-dose aspirin reduced the incidence o f gestational hypertension, preeclampsia, and fetal growth retardation. ~1 These results generated considerable excitem e n t and research with the h o p e that aspirin might be the w o n d e r drug for preeclampsia prevention. Eight prospective, randomized trials have been published since 1993 involving more than 27,000 patients from all over the world. 12-19 T h e results of these trials are summarized in Table 1.2o Only one o f these trials showed a significant reduction in preeclampsia in the aspirin group. This was a single-center study and had the smallest n u m b e r o f patients a m o n g the studies examined. TM These disappointing results are in complete disagreement with those o f the earlier studies. The discrepancy is related, to a great extent, to the nature and m e t h o d o l o g y o f each of these clinical trials. First, the earlier studies were limited by the small sample size. Second, a n u m b e r o f earlier similarly small trials were probably never published because they failed to show encouraging results. Third, the recent large, randomized trials suffered from the inclusion of low-risk and high-risk patients in the same patient population. T h e latter is evident by the fact that in seven of the eight large trials, the incidence o f preeclampsia was 2.7% to 7.6% in the placebo groups. Only one study included women at high risk for preeclampsia, as d e m o n strated by the 20.3% incidence in the placebo
60
Mattar and Sibai
group. 16 In addition, these studies used different risk factors to identify high-risk patients, as well as different diagnostic criteria for preeclampsia. In this respect, some of these trials failed to m e n t i o n how preeclampsia was diagnosed. O t h e r studies relied on urine dipstick to define proteinuria, knowing that it has been shown that urinary dipstick protein correlates poorly with the m o r e accurate 24-hour urine protein measurement. 21 Finally, results of the studies that showed aspirin to be effective in preventing preeclampsia did not show any improvement in either maternal or perinatal outcome. Low-dose aspirin has also been studied in combination with o t h e r anfithrombotic agents such as dipyridamole, heparin, and (most recently) ketanserin, a selective serotonin-2-receptor antagonist. 22-25 In one study, the addition of ketanserin to aspirin was associated with a decrease in the incidence of preeclampsia and severe hypertension, and with an improvement in pregnancy o u t c o m e a m o n g patients with mild to m o d e r a t e midtrimester hypertension. 24 T h e investigators c o n c l u d e d that further studies were n e e d e d to confirm their results. In a study involving patients with severe renal disease, the combination o f heparin and aspirin resulted in a reduction in the prevalence ofpreeclampsia and an i m p r o v e m e n t in fetal outcome. 23 Low-dose aspirin is safe for use in pregnancy. Several studies have shown that aspirin selectively inhibits maternal platelet cyclooxygenase without affecting fetal PGI 2 synthesis or platelet function, with only a slight decrease in fetal platelet TxA2.25,26Similarly, fetal urine output, cardiac function, and overall neonatal outcome did not suffer any adverse effect. 14,27,28 Epidural anesthesia is not contraindicated in pregnant women taking low-dose aspirin. 29
Calcium Over the past decade, there has been a growing interest in the role of calcium in the hypertensive disorders of pregnancy. Epidemiological studies have r e p o r t e d an inverse relationship between calcium intake and the development of high blood pressure and preeclampsia i n pregnancy, s~ This hypothesis was based on the observation that populations with a low calcium intake (such as the Thai and Japanese populations) had a high incidence of preeclampsia, whereas
populations with a high calcium intake (such as the Ethiopian and Guatemalan populations) had a low incidence of preeclampsia, sl Additional support for this hypothesis came from two studies that r e p o r t e d an association between preeclampsia and hypocalciuria at the time of diagnosis and several weeks before the onset of the disease. 32,ss Although the exact causal relationship between calcium deficiency and preeclampsia has not yet b e e n established, it has b e e n postulated that low calcium intake may stimulate either parathyroid h o r m o n e or renin release and increase renal calcium reabsorption, thus decreasing urinary calcium excretion, s~ T h e increase in serum parathyroid h o r m o n e levels drives calcium into the vascular smooth-muscle cells, thereby increasing vascular tone and responsiveness to pressor agents. High concentrations of intracellular calcium were also f o u n d in the erythrocytes and platelets of women with preeclampsia.Z4, s5 The effect of dietary calcium supplementation on d e v e l o p m e n t of hypertension and preeclampsia during pregnancy has b e e n the subject of at least twelve clinical trials. These studies differed in their patient populations, study designs, gestational age at entry, sample size, and dose of calcium (156 to 200 mg) as well as in their definition of hypertension and preeclampsia. Table 2 summarizes the results of seven randomized, double-blind, placebo-controlled studies reported so far. s6-42The remaining trials were not included either because they were not placebo controlled, failed to report the incidence of preeclampsia, or used calcium in combination with o t h e r agents. 2~ Two of the trials that demonstrated significant reductions in the incidence of preeclampsia in the treatment group also r e p o r t e d a high incidence o f preeclampsia in healthy nulliparous women (23.5%), and in one of these studies, all the w o m e n with hypertension also had preeclampsia, s6,s7 We, therefore, d o u b t the accuracy of their results. Two more studies similarly showed beneficial effects, but they had a limited sample size. sS,s9 T h e findings of the remaining three trials show that calcium supplementation does not reduce the incidence o f preeclampsia in healthy nulliparous women.
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61
Table 2. Randomized Trials of Calcium Supplementation to Prevent Preeclampsia
Study
Risk Factors
Lopez-Jaramillo et al a6 Lopez-Jaramillo et al a7 Villar and Repke a9 Belizan et al4~ Sanchez-Ramos et alas Levine et a142 Lopez-Jaramillo et a 1 4 1
Enrollment Gestational Age
Nulliparas + ROT Nulliparas (85%) Nulliparas + ROT and Ang II Nulliparas Nulliparas
24 24-32 24 20 24-28 13-21 20
No. of Patients Calcium
55 22 90 579 29 2,295 125
Preeclampsia (%)
Placebo
Calcium
Placebo
51 34 88 588 34 2,294 135
3.6 0.0 0.0 2.6 13.8 6.9 3.2
23.5* 23.5* 3.4 3.9 44.1" 7.3 15.5
NOTE. Only double-blind placebo trials are included. Abbreviations: ROT, roll over test; Ang II, angiotensin sensitivity test. *P < .05.
Magnesium Several studies have linked preeclampsia to dietary magnesium deficiency and low intracellular magnesium concentrations during pregnancy. One observational study from the early 1980s reported a reduction in the frequency of fetal growth retardation and preeclampsia in association with magnesium supplementation. 4s Two subsequent double-blind, placebo-controlled trials showed no reduction in the incidence o f preeclampsia in the magnesium-supp l e m e n t e d group (Table 3)44.45 Zinc
Several studies have reported decreased plasma, leukocyte, and placental zinc levels in patients with pregnancy-induced hypertension compared to those with normotensive pregnancies. "~ Two randomized, double-blinded, placebo-controlled studies followed. 47,48 H u n t et a147 reported a significant reduction in the incidence of pregnancy-induced hypertension in patients treated with a mineral supplement containing 20 mg of zinc compared with a matched group Table 3. Prevention of Preeclampsia with Magnesium Supplementation Preeclampsia
Study
Magnesium (%)
Placebo or No Treatment (%)
Conradt et al4s Spatling and Spatling44 Sibai et al 6a
0/882
97/4023 (2)
2/278 (1) 32/187 (17.3)
2/290 (1) 35/190 (18.5)
o f women receiving placebo (2% v 16%). In a later study, M a h o m e d et al 4s showed n o such beneficial effect. This disparity can be attributed to differences in baseline zinc levels between the two study populations or differences in definitions o f preeclampsia. Both studies had limited sample size.
Fish Oil The first report on the beneficial effects of fish oil on the incidence of preeclampsia dates back to 1942. 49 Over 5,000 women were enrolled to assess the effects of a dietary supplement consisting of vitamins, minerals, and halibut liver oil. Although the supplemented group had fewer women with preeclampsia, the quality of the study was questionable, and it was not until the last decade that the interest in fish oil was revived. T h e beneficial effect o f fish oil seems to be related mainly to its long-chain n-3 polyunsaturated fatty acids, eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosahexoenoic (DHA) acids. These acids inhibit platelet TxA~ p r o d u c t i o n without affecting endothelial PGIe production, leading to a state of r e d u c e d platelet aggregation and increased vasodilatation. 5~ Moreover, one study provided evidence that n-3 fatty acid supplementation is associated with a change in angiotensin II sensitivity. 5' Recent data from five randomized trials showed no reduction in the incidence o f preeclampsia in the fish-oil group (Table 4).52-54 These findings were confirmed by a large, European, multicenter trial comparing fish oil with olive oil in women at high risk for preeclampsia (Gus Dekker, MD, personal communication, D e c e m b e r 1998).
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Table 4. Fish-Oil for the Prevention of Hypertension or Preeclampsia
Study
Conclusion
Hypertension Preeclampsza Only (%) (%)
Bulstra-Ramakers et a152. Fish oil (n = 32) Placebo (n = 31) Onwude et aP 3. Fish oil (n -- 113) Placebo (n = 119) Salvig et a154t Fish oil (n = 266) No oil (n = 131)
7 (21.9) 4 (12.9)
5 (15.6) 3 (9.7)
38 (33.6) 35 (30.0)
15 (13.4) 18 (15.2)
8 (3.0) 2 (1.5)
0 (0) 1 (0.7)
* Women at risk for hypertension or fetal growth retardation. t Healthy women.
Antihypertensive Drugs C h r o n i c h y p e r t e n s i o n is a m a j o r risk factor for preeclampsia. 55 T o date, six r a n d o m i z e d trials (only o n e o f which was p l a c e b o controlled) have e x a m i n e d the beneficial effect o f m e t h y l d o p a , labetalol, o r atenolol o n patients with c h r o n i c h y p e r t e n s i o n (Table 5). I n a critical analysis o f these trials, Sibai 56 f o u n d n o r e d u c t i o n in the incidence of superimposed preeclampsia among the treated patients. Moreover, n o n e o f these trials h a d an a d e q u a t e s a m p l e size to d e m o n strate such a benefit.
Diuretics and Low-Salt Diet A meta-analysis o f n i n e r a n d o m i z e d trials c o m prising m o r e t h a n 7,000 subjects r e g a r d i n g the use o f prophylactic diuretics in p r e g n a n c y s h o w e d n o decrease in the i n c i d e n c e o f pree c l a m p s i a - - a l t h o u g h a r e d u c t i o n in the incid e n c e s o f e d e m a a n d h y p e r t e n s i o n was noted. 57 T h e use o f low-salt diet d u r i n g p r e g n a n c y , a l o n g - s t a n d i n g practice o f m a n y obstetricians a n d midwives worldwide, derives f r o m the old conc e p t that salt is intimately associated with hypertensive disorders ( i n c l u d i n g preeclampsia). In a large review covering m o s t o f the past century, Steegers et al 5s did n o t find e n o u g h evidence to s u p p o r t the t h e o r y that salt restriction d u r i n g p r e g n a n c y prevents o r r e d u c e s the i n c i d e n c e o f preeclampsia. T h e r e are two r e c e n t r a n d o m i z e d trials o f low-salt d i e t in p r e g n a n c y , a n d n e i t h e r c o u l d d e m o n s t r a t e a r e d u c t i o n in t h e incid e n c e o f g e s t a t i o n a l h y p e r t e n s i o n in t h e study groups.59, 60
P r e e c l a m p s i a is a m a j o r c o n t r i b u t o r to m a t e r n a l a n d fetal mortality a n d morbidity. Dietary supp l e m e n t a t i o n a n d p h a r m a c o l o g i c a l intervention, as evident in the r e c e n t literature, does n o t p r e v e n t p r e e c l a m p s i a o r r e d u c e its severity. Alt h o u g h results o f a few studies showed a reduction in the i n c i d e n c e o f p r e e c l a m p s i a in the treated populationS, they failed to d e m o n s t r a t e any i m p r o v e m e n t in m a t e r n a l o r n e o n a t a l outc o m e . T h e disparity b e t w e e n the earlier studies a n d the m o r e r e c e n t r a n d o m i z e d trials is partly s e c o n d a r y to differences in study design, such as patient selection, sample size, r a n d o m i z a t i o n , a n d definition o f the disease process. Equally i m p o r t a n t is the a b s e n c e o f effective m e a n s for the early p r e d i c t i o n o f preeclampsia. P r e e c l a m p sia is a s y n d r o m e o f u n c e r t a i n etiology. It may develop u n d e r the influence o f i m m u n o l o g i c , genetic, o r dietary factors, o r u n d e r l y i n g medical disease, o r a c o m b i n a t i o n thereof. W e t h i n k that f u t u r e research s h o u l d be targeted at b e t t e r u n d e r s t a n d i n g the causes a n d p a t h o p h y s i o l o g y o f this clinical entitv. Until then, it will be unlikely to r e a c h the m e a n s by which p r e e c l a m p s i a can be u n d i s p u t a b l y prevented.
Table 5. Randomized Trials of Antihypertensive Therapy in Pregnant Women With Mild Chronic Hypertension and the Subsequent Risk of Preeclampsia
Gestation at Entry (wk) Leather et a162 Control (n = 24) Treated (n = 23) Redman et a163 Control (n = 107) Treated (n = 101) Arias and Zamora 64 Control (n = 29) Treated (n = 29) Weitz et a165 Control (n = 12) Treated (n = 13) Butters et a166 Control (n = 15) Treated (n = 14) Sibai et a167 Control (n = 90) Treated (n = 173)
Preeclampsia
<24
? ?
20.6 +- 0.5 21.9 + 0.5
4,7 6,7
16.4 + 1.1 14.7 + 1.0
10.3 3.4
<34
33.3 38.4
12.0 -+ 24,0 12.0 • 24.0
? ?
11.3 -+ 0.2 1t,2 --- 0.2
15.6 17.3
NOTE. Preeclampsia defined as increased blood pressure plus proteinuria. Data are presented as mean _ SEM where available.
Prevention of Preeclampsia
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