Robert W. Powers

Redefining Preeclampsia Using Placenta-Derived Biomarkers

Preeclampsia affects 3% to 8% of all pregnancies.1 Acute maternal complications include eclampsia, stroke, placental abruption, disseminated intravascular coagulation, HELLP (hemolysis, elevated liver enzymes, low platelets), liver hemorrhage or rupture, pulmonary edema, adult respiratory distress syndrome, acute renal failure, and death.2 Preeclampsia complications account for more than 50 000 maternal deaths annually.2,3 In developing countries, where lack of access to appropriate maternal care is a major problem, maternal death rates are as high as 15% as compared with 0% to 1.8% in industrialized countries.2 Perinatal consequences include stillbirth, preterm delivery, fetal growth restriction (FGR), neonatal complications, and later sequelae.4 Long-term maternal risks include chronic hypertension, diabetes mellitus, coronary artery disease,5 neurological deficit, and premature death.2 Here, we argue that the classic definitions of preeclampsia, based on concepts that are now more than 50 years old, have become outdated and that the definition could be modernized to take account of our current understanding of disease pathophysiology. We propose a first step that incorporates the placental biomarker placenta growth factor (PlGF), but we allow for the possibility that the definition may need to be expanded to include other factors, such as the antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFLT1) or soluble endoglin (sENG),6 in due course. This is intended as an exploratory rather than a final development. Diseases may be defined and classified by cause, pathogenesis, or by clinical findings. Clear definitions and classification are difficult when pathogenesis is unknown. As a result, diagnostic labels may reflect only a set of symptoms and signs, defining a syndrome. Syndromes are never precise, because the features are multiple, nonspecific, and therefore may have diverse causes. Preeclampsia is a syndrome of new onset hypertension and proteinuria in the second half of pregnancy, that was defined …

Uric Acid Is as Important as Proteinuria in Identifying Fetal Risk in Women With Gestational Hypertension

Gestational hypertension is differentiated into higher and lower risk by the presence or absence of proteinuria. We asked if hyperuricemia, a common finding in pregnancy hypertension, might also be an indicator of increased risk. We examined fetal outcome data from 972 pregnancies collected from 1997 to 2002 in a nested case-control study. Participants were nulliparous with no known medical complications. The frequency of preterm birth, the duration of pregnancy, frequency of small-for-gestational-age infants, and birth weight centile were determined for pregnancies assigned to 8 categories by the presence or absence of combinations of hypertension, hyperuricemia, and proteinuria. In women with gestational hypertension, hyperuricemia was associated with shorter gestations and smaller birth weight centiles and increased risk of preterm birth and small-for-gestational-age infants. Hyperuricemia increased the risk of these outcomes in the presence or absence of proteinuria. Risk was also increased in a small group of women with hyperuricemia and proteinuria without hypertension. Women with only hypertension and hyperuricemia have similar or greater risk as women with only hypertension and proteinuria. Those with hypertension, proteinuria, and hyperuricemia have greater risk than those with hypertension and proteinuria alone. The risk of these outcomes increased with increasing uric acid. Hyperuricemia is at least as effective as proteinuria at identifying gestational hypertensive pregnancies at increased risk. Uric acid should be reexamined for clinical and research utility.

Methylenetetrahydrofolate Reductase Polymorphism, Folate, and Susceptibility to Preeclampsia

Objectives: To test the hypothesis that the common missense mutation of 5,10-methylenetetrahydrofolate reductase (MTHFR) (677 C to T, ala to val) is more prevalent among nulliparous preeclamptic women compared with control and transient hypertension of pregnancy patients. The correlation of the METHFR T677/T677 genotype in mothers and fetuses was also investigated to test for possible maternal-fetal interactions. Lastly, possible differences in serum folate concentrations between control and preeclampsia patients and the possibility of a correlation between serum folate and MTHFR genotype were investigated as well. Methods: The MTHFR genotype was determined for 114 control subjects, 99 preeclamptic patients, and 24 patients with transient hypertension of pregnancy by a polymerase chain reaction/restriction fragment length polymorphism (PCR) method. To ensure homogeneity of ethnic background, only samples from white women were analyzed. Results were analyzed with a χ2 test for homogeneity. Serum folate was determined by radioimmunoassay (RIA). Results: The prevalence of the MTHFR T677/T677 genotype was not significantly different between the populations studied. There was no significant difference in the prevalence of the MTHFR T677/T677 genotype between the infants of preeclamptic and control mothers. Furthermore, there was no difference in serum folate concentrations between control and preeclampsia patients, and there was no correlation between serum folate and MTHFR genotype. Conclusion: These data suggest that contrary to previous published reports, the C677T missense mutation of MTHFR is not a risk factor for preeclampsia in this nulliparous patient population. Furthermore, this mutation is not related to serum folate status in late pregnancy.

The Role of Obesity in Preeclampsia

The incidence of obesity is increasing at an alarming rate. There is compelling evidence that obesity increases the risk of preeclampsia about 3-fold, and in developed countries is the leading attributable risk for the disorder. In this presentation we explore this relationship and propose targets for future studies guided by the much more extensively studied relationship of obesity to cardiovascular disease. We further address the hypothesis that asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be one convergence point for the mechanism by which obesity increases the risk of preeclampsia. We conclude with consideration of the clinical implications of this information.

An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype.

RATIONALE Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (Fe(NO)). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. OBJECTIVES To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function. METHODS Cross-sectional study of participants from the Severe Asthma Research Program, across early- (<12 yr) and late- (>12 yr) onset asthma phenotypes. MEASUREMENTS AND MAIN RESULTS Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 μM, [interquartile range (IQR), 0.35-0.7] compared with early onset, 0.37 μM [IQR, 0.29-0.59], P = 0.01) and lower median plasma l-arginine (late onset, 52.3 [IQR, 43-61] compared with early onset, 51 μM [IQR 39-66]; P = 0.02). The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late- (r = -0.4, P = 0.0006) in contrast to the early-onset phenotype (r = -0.2, P = 0.07). Although Fe(NO) was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. CONCLUSIONS In late-onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to Fe(NO). In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.

Cigarette Smoke Exposure and Angiogenic Factors in Pregnancy and Preeclampsia

BACKGROUND Cigarette smoking during pregnancy is paradoxically associated with a reduced risk of developing preeclampsia. Both smoking and preeclampsia are associated with alterations in circulating angiogenic factors. The objective of this study was to investigate the relationship between cigarette smoking and the angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in pregnant women with and without preeclampsia. METHODS Plasma sFlt-1, PlGF, and cotinine were measured using enzyme-linked immunosorbent assay in 125 women with uncomplicated pregnancies (controls) and 58 women with preeclampsia. RESULTS In uncomplicated pregnancies, maternal sFlt-1 concentrations were lower in smokers compared to nonsmokers (779.6 (487.5-1,140.8) vs. 1,116.5 (793.6-1,905.2) pg/ml, P < 0.005). Preeclamptic women who smoked also demonstrated a trend toward lower concentrations of sFlt-1 compared to nonsmokers (3,423.0 (2,183.4-5,689.0) vs. 5,504.9 (3,418.0-6,361.3) pg/ml, P = 0.07). Maternal PlGF concentrations were higher in smokers with uncomplicated pregnancies (398.4 (165.2-621.7) vs. 191.4 (104.6-446.8) pg/ml); however, this was not a statistically significant difference (P = 0.07). PlGF concentrations were not different in preeclamptic smokers compared to nonsmokers. The sFlt/PlGF ratio was significantly lower in smokers with uncomplicated pregnancies, but not in smokers with preeclampsia compared to nonsmokers. CONCLUSIONS Cigarette smoking is associated with lower maternal sFlt-1 concentrations during pregnancy and preeclampsia. On the basis of these data, cigarette smoke exposure may decrease the risk of preeclampsia in part by moderating the anti-angiogenic phenotype observed in the syndrome.

Cardiovascular System During the Postpartum State in Women With a History of Preeclampsia

In subjects with previous preeclampsia, differences in cardiovascular and/or blood biochemical parameters are present in the nonpregnant state, and a simultaneous assessment of multiple derived indices better differentiates between women with or without previous preeclampsia. We examined 18 previous preeclamptic and 50 previous uncomplicated pregnancies, ≈16 months postpartum. Cardiovascular assessment included the following: (1) systemic hemodynamics and mechanics (Doppler echocardiography, tonometry, and oscillometric sphygmomanometry); (2) endothelial function (plethysmography); (3) left ventricular properties (echocardiography); and (4) blood biochemical analyses. Compared to women with previous uncomplicated pregnancies, previous preeclamptics had higher mean (80±1 versus 86±3 mm Hg; P=0.04) and diastolic (64±1 versus 68±2 mm Hg; P=0.04) pressures and total vascular resistance (1562±37 versus 1784±114 dyne · s/cm5; P=0.03). Systolic blood pressure, arterial compliance, and left ventricular properties were not different. Although heart-to-femoral pulse wave velocity was not different, heart-to-brachial pulse wave velocity tended to be faster in previous preeclamptics (374±8 versus 404±20 cm/s; P=0.06). Stress-induced increase in forearm blood flow was less in previous preeclamptics (245%±21% versus 136%±22%; P=0.01), indicating impaired endothelial function. No significant differences were observed in markers of endothelial activation, dyslipidemia, or oxidative stress; previous preeclamptics tended to have higher glucose level (58.7±1.9 versus 95±5.2 mg/dL; P=0.06). Logistic regression analysis indicated that a simultaneous evaluation of multiple derived indices better discriminated between the 2 groups. The differences in the previous preeclamptic group are in directions known to be associated with greater cardiovascular disease risk later in life.

Plasma levels of inflammatory markers neopterin, sialic acid, and C-reactive protein in pregnancy and preeclampsia.

BACKGROUND To determine whether the cellular inflammatory marker of activated macrophages and monocytes, neopterin (NEO), and the acute-phase inflammatory markers sialic acid (SA) and C-reactive protein (CRP) are elevated in pregnancy and further elevated in the pregnancy syndrome preeclampsia. METHODS Maternal plasma concentrations of NEO, SA, and CRP were measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA) or high-performance liquid chromatography in 20 nonpregnant women, 40 women with uncomplicated pregnancies, 50 women with transient hypertension of pregnancy alone, 49 women with small for gestational age (SGA) infants without preeclampsia, and 47 women with preeclampsia. RESULTS The mean concentration of plasma NEO, SA, and CRP were all significantly elevated in all groups of pregnant women compared to nonpregnant women (P < 0.001 for all). In addition, maternal plasma NEO concentrations were further elevated in women with preeclampsia compared to the other groups of pregnant women (P < 0.01). As expected, the acute-phase inflammatory markers CRP and SA correlated positively with each other. However, CRP was also correlated with the activated macrophage and monocyte marker NEO in women with transient hypertension of pregnancy and with preeclampsia (P < 0.05). CONCLUSIONS The inflammatory markers NEO, SA, and CRP are all elevated during pregnancy. However, only NEO, a marker of macrophage and monocyte activation, was further elevated in women with preeclampsia. These data suggest that there is a striking increase in inflammation during pregnancy, and cellular immune activation is further elevated during preeclampsia.

C-Reactive Protein Is Elevated 30 Years After Eclamptic Pregnancy

Women with a history of preeclampsia or eclampsia (seizure during preeclamptic pregnancy) are at increased risk for cardiovascular disease after pregnancy for reasons that remain unclear. Prospective studies during pregnancy suggest that inflammation, dyslipidemia, and insulin resistance are associated with increased risk of preeclampsia. Elevated serum C-reactive protein (CRP >3 mg/L) is an indicator of inflammation and cardiovascular risk. We hypothesized that Icelandic postmenopausal women with a history of eclampsia would manifest higher concentrations of serum CRP than Icelandic postmenopausal controls with a history of uncomplicated pregnancies. We also asked whether elevated CRP is associated with the dyslipidemia and insulin resistance previously identified in this cohort. CRP, measured by high-sensitivity enzyme-linked immunoassay, was higher in women with prior eclampsia (n=25) than controls (n=28) (median mg/L [interquartile range]: 9.0 [0.9 to 13.2] versus 2.0 [0.3 to 5.1]; P<0.03). This difference remained significant after adjustment for body mass index, smoking, hormone replacement, and current age. Women with prior eclampsia clustered into either high CRP (range 8.97 to 40.6 mg/L, n=13) or lower CRP (median 1.0, range 0.05 to 3.77, n=12) subsets. The prior eclampsia/high CRP subset displayed significantly elevated systolic blood pressures, lower high-density lipoprotein (HDL) cholesterol, higher apolipoprotein B, and higher fasting insulin and homeostasis model of insulin resistance (HOMA) values compared to controls, whereas the prior eclampsia/low CRP subset differed from controls only by marginally increased apolipoprotein B. The triad of inflammation, low HDL, and insulin resistance may elevate risk for both preeclampsia/eclampsia and cardiovascular disease in later life.

Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants.

OBJECTIVE The purpose of this study was to investigate maternal plasma concentrations of asymmetric dimethylarginine (ADMA) in mid pregnancy and at the time of disease in women who experience preeclampsia, compared with women with uncomplicated pregnancies and women with small-for-gestational-age infants. STUDY DESIGN Plasma samples were collected at mid-pregnancy and at the time of delivery from 31 women with uncomplicated pregnancies, from 12 women with small-for-gestational-age infants, and from 15 women with preeclampsia. ADMA and L-arginine concentrations were measured using high-pressure liquid chromatography. RESULTS Maternal ADMA concentrations were elevated at mid pregnancy and remained elevated at delivery in women who later experienced preeclampsia (0.45 +/- 0.09 micromol/L) compared with women with uncomplicated pregnancies (0.34 +/- 0.08 micromol/L; P < .01) and with women with small-for-gestational-age infants (0.33 +/- 0.06 micromol/L; P < .01). CONCLUSION Maternal ADMA concentrations are higher in mid pregnancy in women who experience preeclampsia, compared with women with uncomplicated pregnancies and small-for-gestational-age infants. Elevated ADMA concentration before clinical onset of preeclampsia suggests a role of this nitric oxide synthase inhibitor in the pathophysiologic condition of preeclampsia.