February 2010: Volume 36, Number 2
Prediction, Diagnosis, and Management Beyond Proteinuria and Hypertension
By Darci R. Block, PhD, and Amy K. Saenger, PhD
Preeclampsia is a multisystem disorder of pregnancy characterized by the presence of hypertension and proteinuria after 20 weeks gestation. While estimated to affect only 3%–5% of all pregnancies in the U.S., the disorder is responsible for 15% of premature deliveries and up to 18% of maternal deaths. In fact, complications from hypertension in pregnancy are the third leading cause of maternal death, surpassed only by embolism and hemorrhage. Other risks associated with preeclampsia include placental abruption, liver or renal failure, disseminated intravascular coagulopathy, cardiovascular complications, and seizures or other neurological manifestations (eclampsia).
The incidence of preterm birth is also higher in preeclamptic women, primarily because obstetricians attempt to minimize the risks to both the mother and fetus by delivering the fetus early. However, preterm infants are at risk of complications as well. They have a greater probability of developing respiratory distress syndrome, intraventricular hemorrhage, cerebral palsy, and other neurological and developmental delays. In women whose preeclampsia is caused by placental anomalies, severe intrauterine fetal growth restriction may occur, leading to higher prevalence of intrauterine asphyxia and placental abruption.
Despite being well recognized as a complication of pregnancy, many unknowns still surround prediction, diagnosis, and pathophysiology of preeclampsia, earning it the common name, “disease of theories.” Efforts to lessen the risks associated with preeclampsia have been focused on accurate and earlier diagnosis of the disorder. New biomarkers for predicting and possibly preventing preeclampsia promise to give the laboratory a major role in the care of at-risk pregnant women. Here we describe the current understanding of the etiology of preeclampsia, the lab’s current role in monitoring at-risk women, as well as how new biomarkers on the horizon may lead to greater involvement of the lab in earlier prediction of the condition.
Risk Factors for Preeclampsia
Epidemiological and clinical risk factors for preeclampsia are classified as maternal, paternal, and/or pregnancy-specific (Table 1, below). One hypothesis concerning the etiology of preeclampsia is that it is an autoimmune disorder and may reflect the immaturity of the maternal immune system to properly respond to the pregnancy. This hypothesis originates from the fact that the frequency of preeclampsia is higher in nulliparous women, women who conceive with assisted reproductive techniques, and women with autoimmune conditions.
Preeclampsia Risk Factors
- Age < 20 or 35–40 years
- Black race
- Prior or family history of PE or cardiovascular disease
- Woman born small for gestational age
- Chronic hypertension
- Chronic renal disease
- Diabetes mellitus (insulin resistance, type 1, and gestational)
- Antiphospholipid antibody syndrome
- Connective tissue diseases
- Multiple gestation
- Oocyte donation
- Urinary tract infection
- Congenital conditions affecting the fetus
- Hydatidiform mole
- Hydrops fetalis
- Structural anomalies
Limited sperm exposure
- Barrier contraception
- First-time father
- Donor insemination
Partner who fathered a preeclamptic pregnancy in another woman
Adapted from reference 2 and Dekker G, Sibai B. Primary, secondary, and tertiary prevention of preeclampsia. Lancet 2001;357:209–15.
In addition, pre-existing metabolic, renal, or vascular conditions increase the risk of preeclampsia due to the physiological stress of pregnancy combined with widespread endothelial dysfunction. Obese (BMI ≥30 Kg/m2) females are at very high risk for preeclampsia compared to lean women (odds ratio = 3.3), as well as women who have hypercholesterolemia or hypertriglyceridemia. On the other hand, smoking actually decreases a woman’s risk of preeclampsia.
Use of low-dose aspirin in women with these risk factors has been shown to slightly reduce the risk of preeclampsia (OR 0.86, 95% CI: 0.76–0.96) and perinatal mortality, but it failed to reduce placental abruption or delivery of low-birth-weight babies (1). Researchers have also studied vitamins C and E and calcium supplements in both low- and high-risk populations but found no evidence that these nutritional supplements reduced the prevalence of preeclampsia, hypertension, or eclampsia. Furthermore, preventive preeclampsia trials so far have produced disappointing results, perhaps due to an overall lack of understanding of the causal mechanisms of preeclampsia.
Pathophysiology of Preeclampsia
Current concepts and theories of the pathophysiology of preeclampsia revolve around the common theme of endothelial cell dysfunction, primarily placental in origin, but extending to other organs such as the brain, liver, and kidneys. This longstanding hypothesis focuses on placental implantation and trophoblast invasion and originated after observations that delivery of the placenta quickly reversed the clinical manifestations of preeclampsia and eclampsia in a majority of patients. Immune maladaptation between the mother and fetus is also likely a factor in the development of preeclampsia, but the exact mechanisms are still unknown.
In normal pregnancy, the maternal-fetal interface and blood flow are established very early after conception. Proper placental implantation allows for adequate circulation between the mother and fetus and occurs when the placenta cytotrophoblast cells invade the maternal spiral arteries, causing them to lose their smooth muscle and enabling expansion of vascular capacity and angiogenesis. In preeclamptic patients the implantation of the placenta may be dysfunctional, such that the spiral arteries are poorly remodeled, resulting in inadequate circulation between the placenta and the uterus and ultimately a shallow placental implantation. This lack of perfusion or ischemia is thought to induce a majority of the endothelial dysfunction and lead to development of widespread organ alterations and detectable alterations in the cardio-renal system. Therefore, even though the localized endothelial changes originate from the placenta, the consequences of decreased perfusion extend to all other organs. Blood flow is further compromised by activation of the coagulation cascade and formation of microthrombi.
The severity of symptoms has also provided clues as to the pathophysiology of the disorder. Preeclampsia diagnosed early in pregnancy, before 34 weeks, has a higher probability of placental abnormalities and represents the most severe cases of preeclampsia and intrauterine growth restrictions in the baby. However, a majority of preeclampsia cases are late onset, diagnosed after 34 weeks, and notably lack placental anomalies and major adverse complications.
Diagnosis and Laboratory Testing
Obstetricians typically diagnose preeclampsia after 20 weeks gestation. Maternal presentation of new onset hypertension, proteinuria, and often edema trigger the diagnosis. Severe preeclampsia is recognized by a greater magnitude of increased blood pressure and a greater degree of proteinuria. Other clinical manifestations of severe preeclampsia include oliguria, cerebral or visual disturbances, and pulmonary edema. While the presence of hypertension is often the first sign of preeclampsia, hypertension alone does not define the disorder. The pathogenic evolution and progression of preeclampsia likely originates shortly after conception, and hypertension becomes apparent later in the pregnancy.
The American College of Obstetricians and Gynecologists recognizes four major classifications of hypertension-related disorders in pregnancy (2). These disorders include chronic hypertension, preeclampsia/eclampsia, preeclampsia superimposed on chronic hypertension, and gestational hypertension (Figure 1, below).
Classification of Preeclampsia and Pregnancy Related Hypertension
Adapted from reference 2 and Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1–22.
Click here for enlarged figure.
Chronic hypertension is unrelated to the pregnancy itself and is diagnosed if there is a documented pre-existing condition prior to 20 weeks gestation or if the hypertension persists at 12 weeks postpartum. Pre-eclampsia is defined as hypertension and proteinuria after 20 weeks gestation, while eclampsia is a severe progression and complication of preeclampsia and is indicated by new onset of seizures in previous pre-eclamptic women. Full eclampsia is relatively rare and estimated to occur in only 1% of preeclamptic patients.
Preeclampsia superimposed on chronic hypertension is characterized by new-onset proteinuria or by a marked increase in protein concentration if already present, an acute increase in hypertension, or development of HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Women may also have gestational hypertension. This condition is diagnosed when there is documented maternal hypertension without the presence of proteinuria, and the hypertension ceases by 12 weeks postpartum. However, approximately 25% of women with gestational hypertension develop proteinuria and progress to preeclampsia.
Currently, diagnosis and therapeutic monitoring of the progression of preeclampsia does not involve specific or sensitive blood biomarkers (Table 2, below). Therefore, involvement of the laboratory in the diagnosis has been minimal. However, the search for novel diagnostic markers for preeclampsia is an active focus of research, and there are several promising new biomarkers on the horizon that have the potential to give the lab a greater role.
Laboratory Tests for Preeclampsia and Eclampsia
Assessment for High Risk of Developing Preeclampsia
Goal: Establish baseline levels early in pregnancy and monitor for progression to HELLP or severe preeclampsia.
- Platelet count
- Urine protein (12 or 24 hour)
- Serum creatinine
- Serum uric acid
Diagnosis of HELLP Syndrome
- Bilirubin >1.2 mg/dL
- Peripheral blood smear abnormal
- Lactate dehydrogenase >600 U/L
- Liver function tests
- Platelet count <100 x109/L
Diagnosed Preeclampsia (Therapeutic Monitoring)
- All of the above
- Coagulation testing
Adapted from Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S1–22.
Emerging Biomarkers for Preeclampsia
Research has shown that endothelial dysfunction produces an imbalance of pro- and anti-angiogenic factors, making factors involved with the angiogenesis process of placental formation and implantation good candidate biomarkers for preeclampsia. Several circulating factors have been identified that are involved in this process. Pro-angiogenic factors include vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), while anti-angiogenic factors include soluble fms-like tyrosine kinase 1 receptor (sFlt-1) and soluble endoglin (sEng).
Expressed by the placenta, VEGF and PlGF promote angiogensis by interacting with the VEGF receptor. PlGF serum concentrations in pregnancy increase significantly and to a much greater extent than VEGF levels. Several studies have shown that PlGF and VEGF concentrations both decrease prior to the onset of clinical preeclampsia symptoms, although the magnitude of difference from normal pregnancy values is greater for PlGF than VEGF. In particular, researchers have found that women who later developed preeclampsia had reductions in serum PlGF in the second trimester.
In addition to placental growth factors recruited for the purposes of angiogenesis and placental implantation, researchers have identified proteins that counteract the effect of PlGF and VEGF. sFlt-1, also known as soluble VEGF receptor 1, circulates in the blood and is capable of binding VEGF and PlGF to further inhibit receptor binding and angiogenic effects. Studies have shown that sFlt-1 is elevated in women with preeclampsia compared to controls, correlates to disease severity, and subsequently decreases following delivery (3, 4). Moreover, the ratio of sFlt-1 to PlGF is useful as an index of anti-angiogenic activity, reflecting both increased sFlt-1 and decreased PlGF in women who develop preeclampsia.
Studies have also indicated that the sFlt-1:PlGF ratio predicts preeclampsia up to 5 weeks earlier than clinical diagnosis made with current markers or either protein alone. Interestingly, sFlt-1 given exogenously in pregnant rats triggered development of hypertension, proteinuria, and glomeruloendotheliosis (5).
Another factor involved in angiogenesis of the placenta is soluble endoglin (sEng). This protein is a circulating form of endoglin that is expressed on the vascular endothelium and trophoblast cells and functions as a modulator of transforming growth factor (TGF-β) signaling. sEng competes directly with TGF-β and acts as a negative regulator of angiogenesis. Similar to sFlt-1, soluble endoglin concentrations correlate to the occurrence and severity of preeclampsia and resolve following delivery. Furthermore, sEng levels have been shown to be significantly higher 3 months prior to the development of proteinuria or hypertension, whereas the sFlt1:PlGF ratio increases closer to disease onset (3, 4).
Pregnancies in which there is intrauterine growth restriction unrelated to preeclampsia also demonstrate elevated levels of sEng, suggesting this marker may not be specific for preeclampsia but rather for a dysfunctional placenta. Animal model studies demonstrate that induction of the hepatic and renal complications that occur with HELLP syndrome transpire after administration of sEng and sFlt-1, suggesting that the two proteins may have a synergistic effect responsible for the more severe cases of PE (6).
Although PlGF, VEGF, sFlt-1, and sEng all appear to be important in the pathogenesis of preeclampsia, they do not have sufficiently high positive-predictive value when used alone. Based on the overall findings, it seems likely that a combination of these markers will improve their utility as predictors or preeclampsia.
There are several other biomarkers that also show promise in the prediction to management of preeclampsia. These include: placental protein 13 (PP-13); asymmetric dimethylarginine (ADMA); cell-free DNA; pregnancy-associated plasma protein A (PAPP-A); autoantibodies against the angiotensin II type 1 (AT1) receptor; inhibin A; and activin A. Larger longitudinal, case-controlled trials are needed to validate the clinical and analytical characteristics of these markers.
Treatment of Preeclampsia
Delivery of the baby is the only cure for preeclampsia. Prenatal treatment options are limited due to the potential risks to the fetus; therefore, patients with preeclampsia are simply monitored for signs and symptoms of distress. Obstetricians monitor blood pressure and lab tests results in women with mild preeclampsia twice weekly to indicate progression to HELLP or eclampsia with liver and kidney involvement. Women with severe preeclampsia are put on mandatory bed rest and monitored in a similar manner to prevent seizures and lower their blood pressure.
Magnesium sulfate has been used to decrease the incidence of seizures and may also have the added benefit of decreasing placental abruption. Patients receiving this therapy must be monitored closely for magnesium toxicity, especially for decreased liver and kidney function. Antihypertensive drugs may also be used for the treatment of acute maternal symptoms, and the fetus may be given corticosteroids to assist with lung maturity as a precaution for impending delivery.
Other treatment options are also being explored. Administrating a VEGF variant to an sFlt-1 overexpressing rat model was found to reverse the preeclamptic phenotype without apparent harm to the fetus (7). This and other ongoing studies are aimed at elucidating the etiology of disease, as well as restoring angiogenic balance.
Although preeclampsia is a disorder of pregnancy, the higher relative concentrations of anti-angiogenic factors are thought to trigger widespread vascular endothelial cell injuries, as well as induce an altered cardiovascular state during the affected pregnancy and beyond. The risk factors for cardiovascular disease and preeclampsia are remarkably similar and include: obesity, hypertension, hyperglycemia, insulin resistance, diabetes, and dyslipidemia (Table 1, above).
Several epidemiological studies have provided convincing evidence that cardiovascular risk is increased in women with a history of preeclampsia compared with normal control subjects, particularly if they deliver a preterm, low-birth weight baby. One contributing factor may be the occurrence of microalbuminuria 3–5 years postpartum, which occurs in up to 50% of women with a history of preeclampsia compared to women with no history of the disorder. It is uncertain how long this condition persists, but there is a significant link to increased cardiovascular risk and microalbuminuria in menopausal women (8).
Authors of a recent meta-analysis also reported several associations between pre-eclampsia and cardiovascular morbidity and mortality. In women diagnosed with preeclampsia, there is approximately a four-fold risk of future hypertension and an approximate two-fold risk of ischemic heart disease, venous thromboembolism, and stroke (9). In addition, if preeclampsia is diagnosed in a subsequent pregnancy, the risk of future hypertension and cardiovascular events increases even further.
On the Horizon: Preeclampsia Biomarkers
Preeclampsia is clearly a complex disorder that involves a delicate balance between the maternal immune system, fetus, and placenta. Readily accessible screening tests for preeclampsia would ideally reduce the incidence of maternal and neonatal complications.
Several preeclampsia biomarkers are in development and being evaluated on auto-mated immunoassay platforms. If these markers prove to have adequate sensitivity and positive-predictive value in screening for preeclampsia, labs will have the opportunity to help improve the quality of care for outcomes of obstetrical patients. With new biomarkers, earlier prediction of preeclampsia in high-risk pregnancies will allow obstetricians to treat women earlier and hopefully improve outcomes for both the mother and the fetus.
- Coomarasamy A, Honest H, Papaioannou S, Gee H, et al. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol 2003;101:1319–32.
- Gilstrap L, Ramin S. ACOG Committee on Practice Bulletins: Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin Clinical Management Guidelines for Obstetrician-Gynecologists 2002;33:1–9.
- Carty DM, Delles C, Dominiczak AF. Nov-el biomarkers for predicting preeclampsia. Trends Cardiovasc Med 2008;18:186–94.
- Levine RJ, Lam C, Qian C, Yu KF, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006;355:992–1005.
- Maynard SE, Min JY, Merchan J, Lim KH, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649–58.
- Venkatesha S, Toporsian M, Lam C, Hanai J, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12:642–9.
- Steinberg G, Khankin EV, Karumanchi SA. Angiogenic factors and preeclampsia. ThrombRes 2009;123:S93–9.
- Davison JM, Homuth V, Jeyabalen A, Conrad KP, et al. New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol 2004;15:2440–8.
- Bellamy L, Casas J, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974–85.
Darci S. Block, PhD, is a clinical chemistry fellow in the Department of Laboratory Medicine and Pathology at the Mayo Clinic, Rochester, Minn.
Amy K. Saenger, PhD, is the director of the Central Clinical Laboratory and an assistant professor in the Department of Laboratory Medicine and Pathology at the Mayo Clinic, Rochester, Minn.
Disclosure: Dr. Saenger has received grant/research support from Roche.