COMMENTARY

December 2004: The Year in Review -- Ob/Gyn & Women's Health

Ursula Snyder, PhD

Disclosures

January 24, 2005

Pregnancy - Preeclampsia

Preeclampsia, a multisystem disorder unique to human pregnancy,[117] remains a leading cause of maternal and fetal morbidity and mortality, particularly in developing countries. Prevalence for the condition has been variously cited as occurring in a range of 2% to 10% of pregnancies. Most recently, Villar and colleagues[118] cite incidence rates of 1.3% to 6.7% in developing countries and 0.4% to 2.8% in industrialized countries.

Fisher[119] has noted that many researchers consider preeclampsia an end-stage disease. Recent data also suggest that it is not one disease but a heterogeneous syndrome.[120,121] The condition is marked by the sudden onset of maternal hypertension, proteinuria, edema, excessive weight gain, and increased vascular resistance. The fetus is also affected, with risk of growth restriction, intrauterine death, and premature delivery. An abnormal interaction of maternal and fetal tissue occurs at the uteroplacental interface. Although the detailed etiology of the condition is still unknown, it has become apparent that the cytotrophoblast differentiation pathway that leads to uterine invasion is defective. Fisher explains:

The placenta is a remarkable organ. In normal pregnancy its specialized cells (termed cytotrophoblasts) differentiate into various specialized subpopulations that play pivotal roles in governing fetal growth and development. One cytotrophoblast subset acquires tumor-like properties that allow the cells to invade the decidua and myometrium, a process that attaches the placenta to the uterus. The same subset also adopts a vascular phenotype that allows these fetal cells to breach and subsequently line uterine blood vessels, a process that channels maternal blood to the rest of the placenta. In the pregnancy complication preeclampsia...cytotrophoblast invasion is shallow and vascular transformation incomplete. These findings, together with very recent evidence from animal models, suggest that preeclampsia is associated with abnormal placental production of vasculogenic/angiogenic substances that reach the maternal circulation with the potential to produce at least a subset of the clinical signs of this syndrome. The current challenge is to build on this knowledge to design clinically useful tests for predicting, diagnosing and treating this dangerous disorder.

Aspects of the etiology currently under active investigation include the following[117,122]:

  • Defective placental vascular remodeling (secondary to impaired cytotrophoblast invasion)

  • Abnormal genetic polymorphisms

  • Rejection of the placenta by the maternal immune system

  • Vascular endothelial cell activation

  • Oxidative stress (as a result of inadequate placental perfusion, which is thought to result from rudimentary endovascular invasion by the cytotrophoblasts)

  • Exaggeration of a systemic inflammatory process

Increased risk of preeclampsia has been associated with the following:

  • Nulliparity

  • Advanced maternal age

  • Multiple pregnancies

  • Past history of diabetes, hypertension, kidney disease

  • Past history of preeclampsia

  • Changed paternity (?)[123,124]

In the past year, much of the research published has highlighted the many factors that have been found to be associated with preeclampsia, which are summarized here:

  • Genetic factors[125,126]

  • Family history of hypertension, heart disease and stroke[127]

  • High maternal weight/obesity [128,129,130,131,132]

  • Increased insulin resistance[133,134]

  • History of asthma[135]

  • History of rheumatologic disease[136]

  • Early pregnancy dyslipidemia[137]

  • Increased fetal DNA in the maternal circulation in early pregnancy[138,139]

  • Elevated homocysteine[140,141,142]

  • Elevated leptin[128,143]

  • Elevated C-reactive protein[144]

  • Elevated serum inhibin A[145]

  • Elevated fms-like tyrosine kinase 1[146,147]

  • Depressed levels of sex hormone binding globulin (SHBG) and placental growth factor (PlGF)[133,146]

  • Elevated soluble vascular endothelial growth factor receptor (sVEGFR-1)[148,149]

  • Elevated plasma carnitine[150]

  • Elevated levels of endothelial microparticles[151]

  • Factor V Leiden (1691G-A) single nucleotide polymorphism[120]

  • Low plasma volume (for recurrent preeclampsia)[152]

  • Increased oxidative stress[122]

  • Low plasma levels of oxidized low-density lipoprotein[153]

  • Low pregnancy-associated plasma protein A levels in the first trimester[154]

  • Conception in summer months[155]

  • Short stature in multiparas (severe preeclampsia)[156]

  • Decreased brachial artery reactivity in singleton pregnancies[157]

  • Social disadvantage (poverty, low education, immigrant or refugee status) and limited access to healthcare services[131,158,159]

  • In the United States, black women[160] and Hispanic women[161] have a higher risk for preeclampsia than non-Hispanic white women.

On the other hand, not surprisingly, a reduced risk of preeclampsia has been associated with regular physical activity.[162,163] Weisberger and colleagues[164] propose that the protective effect of exercise may be mediated through the following mechanisms:

  • Stimulation of placental growth and vascularity

  • Reduction of oxidative stress

  • Exercise-induced reversal of maternal endothelial dysfunction

Perhaps more surprisingly, a reduced risk is also associated with cigarette smoking.[165] Bainbridge and colleagues [165] propose that cigarette smoke reduces the risk of developing preeclampsia through direct placental effects, including upregulation of antioxidant systems within the placenta. Of note is that the NIH will be conducting a large trial (10,000 subjects) to investigate whether antioxidants can prevent preeclampsia.[122]

In addition, research published in 2004 suggests that preeclampsia may be a risk factor for future disease, including cancer (specifically of the stomach, breast, ovary, lung, and larynx).[166] (See Medscape Medical News story The study by Paltiel and colleagues conducted in West Jerusalem is notable because it contradicts earlier research done in North America and Europe that had suggested that preeclampsia actually reduced the risk of cancer. An editorial by Taylor[167] asks whether it may be that only certain populations (eg, women from the Middle East) are at increased risk for cancer after preeclampsia -- a question that requires more population-based studies with long follow-up. Preeclampsia is also now thought to be associated with an increased risk of future CVD.[168,169,170,171,172,173,174] The work by Freeman and colleagues[168]suggests that changes in inflammatory marker levels that occur during preeclampsia persist. In their study, the IL-6 to IL-10 ratio 20 years after the index pregnancy was nearly twice as high in women who had had preeclampia compared with those who had a normal pregnancy. Recent studies have also shown that women with a history of severe preeclampsia had elevated total homocysteine levels and higher oxidized homocysteine levels in whole blood[169]; that women with a history of preeclampsia manifested impaired endothelial function up to 1 year postpartum[170]; and that women with a history of preeclampsia demonstrate altered expression of angiogenesis-related proteins and an increased value for the homeostasis model of insulin resistance > 1 year postpartum.[171] Rodie and colleagues[172] suggest that preeclampsia with the possible sequelae of intrauterine growth restriction and premature delivery constitute a "metabolic syndrome of pregnancy," with a 7-fold additive risk of future CVD.

Currently, the World Health Organization is coordinating systematic reviews that will focus on the etiology and the best strategies for the screening, prevention, and treatment of preeclampsia.[118] Unfortunately, as Conde-Agudelo and colleagues[175] point out in their systematic review of screening tests, "as of early 2004, there is no clinically useful screening test to predict preeclampsia in either high- or low-risk populations." Some of the research published this year, especially with molecular markers, such as soluble fms-like tyrosine kinase 1 and placental growth factor[133,145] and fetal DNA, seems promising, although Solomon and Seely[176] caution that prior experience with markers has found that ultimately they lacked sufficient predictive value. (For a review of some potential markers, see Tjoa and colleagues.[177])

Cotter and colleagues[138] have found that the presence of fetal DNA in the maternal circulation in early pregnancy is associated with an 8-fold increased risk of developing preeclampsia and that there seems to be a correlation between the quantity of fetal DNA and the risk of developing preeclampsia. Levine and colleagues[139] have further found that increase in fetal DNA occurs in 2 stages and suggest that measurement of fetal DNA may be useful as a screening and diagnostic marker. Inhibin A has also been proposed as potential early risk marker. In the study by Salomon and colleagues,[145] the first-trimester inhibin A levels were significantly higher in women who went on to develop preeclampsia relative to those who did not, and the authors calculated an odds ratio of nearly 5 for severe preeclampsia in women with high inhibin A concentrations compared with women with normal levels.

Measurement of endothelial microparticles has been proposed as a possible diagnostic tool for preeclampsia by Gonzalez-Quintero and colleagues,[151] who found that levels of plasma endothelial microparticles are higher in women with preeclampsia than in women with gestational hypertension or the women who served as controls.

Early dyslipidemia that occurs in women who go on to develop preeclampsia may also serve as a diagnostic marker. Specifically, Enquobahrie and colleagues[137] found that at 13 weeks' gestation, women who later developed preeclampsia had significantly higher levels of LDL cholesterol, triglycerides, and LDL/HDL ratios and significantly lower HDL levels than control women. In their study, there was a linear increase in preeclampsia risk with increasing tertiles of LDL cholesterol, triglyceride concentrations, and LDL/HDL ratio.

As mentioned, oxidative stress is thought to play a role in preeclampsia, and Moretti and colleagues[178] reported that a breath test revealed greater oxidative stress in women with preeclampsia than in uncomplicated pregnancy and nonpregnant control subjects. Their results suggest the test could be useful to predict preeclampsia and that further studies are required. A research group from Turkey has also shown that a novel automated colorimetric assay can assess antioxidant status, and they suggest that it could be used as a routine test to evaluate and follow up the levels of oxidative stress in preeclampsia.[179] Oxidized LDL may be another potential marker, as a new study has shown that women with preeclampsia had lower plasma levels of oxidized LDL compared with gestational age-matched controls.[153]

August and colleagues[180] have developed a model to predict preeclampsia in women with chronic hypertension during pregnancy. They found that " women with high systolic blood pressure (> 140 mm Hg), elevated uric acid (>3.6 mg/dL), and low plasma renin activity (< 4 ng/mL/hr) had an 86% probability of having superimposed preeclampsia. Women with 2 risk factors had a 62% probability of superimposed preeclampsia, and women with only 1 risk factor had a 30% to 40% probability of superimposed preeclampsia." Perhaps also worth noting is a study by Phelan and colleagues,[181] who assessed the accuracy of dipstick testing for proteinuria using automated urinalysis. They found that accepting a diagnosis of preeclampsia on the basis of de novo hypertension and dipstick testing alone was accurate less often when > 1 + was used as a discriminant value than when > 2 + was used. They suggest that accepting ≥ 2 + dipstick proteinuria will improve overall diagnostic accuracy for preeclampsia, although the false-negative rate will be higher. They also conclude that their study emphasizes the need to confirm dipstick proteinuria with a further test in all hypertensive pregnant women.

No doubt a healthy lifestyle, with proper nutrition, regular physical activity, and weight control, is important for prevention of preeclampsia. The social conditions that encourage such a lifestyle thus are important. A recent Cochrane review found that low-dose aspirin has a small-to-moderate benefit for prevention of preeclampsia, but that it remains to be established which women are most likely to benefit, when treatment is best started, and at what dose.[182] Merviel[183] suggests treatment should begin before 13 weeks' gestation and at a dose of at least 100 g/day.

The current standard approach to treatment is expectant management, with close monitoring of maternal and fetal health, bed rest, antihypertensive therapy, and seizure prophylaxis with magnesium sulfate. A recent study from France concluded that expectant management of severe preeclampsia at 24 to 33 weeks in a tertiary care center is associated with good perinatal outcome with a minimal risk for the mother.[184] A recent survey of Canadian doctors indicates there is consensus that women with preeclampsia should be delivered for uncontrolled hypertension, end-organ dysfunction, or fetal compromise.[185] There is less consensus for delivery for preeclampsia at > 34 weeks, mild asymptomatic HELLP syndrome, hyperreflexia, and absent end-diastolic flow by umbilical artery Doppler velocimetry. A recent review of magnesium sulfate prophylaxis concluded that although current evidence confirms its efficacy for moderate to severe preeclampsia, there is not sufficient evidence to support its routine use in mild preeclampsia.[186] Finally, "delivery is not the only cure for preeclampsia," according to Heyborne and Porreco, who showed that in the case of twin pregnancies in which second-trimester preeclampsia was associated with a lethal condition in 1 twin, selective fetocide resolved the preeclampsia.[187]

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