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Objective: Small studies suggest that fetal sex alters maternal inflammation. We examined the association between fetal sex, preeclampsia and circulating maternal immune markers., Methods: This was a secondary data analysis within a nested case-control study of 216 preeclamptic women and 432 randomly selected normotensive controls from the Collaborative Perinatal Project. All women had singleton, primiparous pregnancies without chronic health conditions. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between female fetal sex and preeclampsia. Outcomes included preeclampsia, preterm preeclampsia (<37 and <34 weeks), and normotensive preterm birth <37 weeks. Associations between female fetal sex and immune markers [interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, and transforming growth factor-beta] were examined using a statistical method developed for large proportions of censored biomarker data. Models were adjusted for maternal age, race, body mass index, and smoking., Results: Women with early preterm preeclampsia (<34 weeks) had higher odds of having a female fetus (OR adj. 3.2, 95% CI 1.1-9.6) and women with normotensive preterm birth had lower odds (OR adj. 0.5, 95% CI 0.3-0.9). Female fetal sex was associated with lower first trimester pro-inflammatory IFNγ and IL-12 but higher second trimester pro-inflammatory IL1β and TNFβ, anti-inflammatory IL4r, and regulatory cytokines IL5 and IL10. Female fetal sex was associated with higher postpartum IL10 in preeclamptic women only., Conclusions: We identified sexual dimorphism in maternal inflammation. Longitudinal studies are needed to determine if fetal sex impacts the maternal immune milieu across pregnancy., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: Circulating immune markers may be associated with preeclampsia but further investigations in early pregnancy and among preeclampsia subtypes are warranted. We examined immune markers in 208 preeclamptic women and 411 normotensive controls., Methods: Our study was nested within the Collaborative Perinatal Project. A total of 242 women had first trimester serum samples and 392 had second trimester serum samples. Preeclampsia was defined as hypertension >20weeks of gestation with proteinuria or pulmonary edema, oliguria, or convulsions. Preterm preeclampsia was defined as preeclampsia with delivery less than 37weeks of gestation. Associations between immune markers RANTES, interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and beta, transforming growth factor (TGF)-beta and preeclampsia were explored using a modified version of cox regression developed to address data with non-detectable levels. Models were adjusted for body mass index, gestational age of blood sampling, fetal sex, smoking, socioeconomic status and maternal age., Results: In first trimester samples, IL-12 was associated with preeclampsia (p=0.0255). IFN-gamma (p=0.0063), IL1-beta (p=0.0006), IL5 (p=0.0422) and TNFr (p=0.0460) were associated with preterm preeclampsia only. In second trimester samples, IL1-beta was associated with preeclampsia (p=0.0180) and term preeclampsia (p=0.0454). After correction for multiple comparisons, only IL1-beta remained associated with preterm preeclampsia in the first trimester (p=0.0288)., Discussion: Elevated first trimester IL1-beta appears to be associated with preterm preeclampsia. However, few associations were observed in the second trimester. Systemic immune markers alone may not be useful for preeclampsia prediction., Competing Interests: No conflicts of interest to disclose, (Copyright © 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: To determine if mid-pregnancy circulating immune biomarkers are associated with preeclampsia., Study Design: Nested case-control study of 410 preeclamptic women and 297 normotensive controls with primiparous singleton pregnancies enrolled in the Danish National Birth Cohort. The mean gestational age in our cohort is 16 weeks (range 9-26)., Main Outcome Measures: Preeclampsia was defined by blood pressure ⩾140/90 mmHg and proteinuria ⩾3 g/24 h. Serum immune biomarkers included interleukin (IL)-6, IL-6 receptor, IL-4, IL-4 receptor, IL-5, IL-12, IL-2, TNF-α, TNF-β, TNF-receptor, IL-1β, IL-1α, IL-8, IL-10, IFN-γ, IL-18, macrophage migration inhibitory factor, macrophage inflammatory protein, transforming growth factor-beta (TGF-β), and RANTES. Associations with preeclampsia, term preeclampsia and preterm preeclampsia were determined using two logistic regression models; (1) biomarkers were dichotomized by the limit of detection (LOD); (2) on the continuous scale, non-detectable values were imputed by LOD/2 and transformed (base 2). All models were adjusted for body mass index and smoking., Results: IL1β was significantly associated with a decrease in the log odds of preeclampsia (p=0.0065), term preeclampsia (p=0.0230) and preterm preeclampsia (p=0.0068). Results were similar for IL4r and preeclampsia (p=0.0383). In the dichotomized models, detectable TNF-β was significantly associated with preeclampsia (ORadj 1.6, 95% CI 1.1-2.3) and term preeclampsia (OR 1.7, 95% CI 1.1-2.5) but not preterm preeclampsia. Detectable IL6 was significantly with term preeclampsia only (OR 1.5, 95% CI 1.1-2.2)., Conclusion: Mid-pregnancy circulating IL1β, IL4r, IL6, and TNFβ were associated with preeclampsia. However, results were not consistent across statistical models. As the relationship is complex, future studies should explore cytokine clusters in preeclampsia risk., (Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Leptin, an adipocyte-derived hormone, plays an important role in reproduction and angiogenesis. Studies examining leptin in preeclampsia are inconsistent, possibly because of small sample sizes and variability in sampling and outcome. We conducted a nested case-control study to examine associations between serum leptin (measured: 9-26 weeks gestation) and preeclampsia among 430 primiparous preeclamptic women and 316 primiparous normotensive controls from the Danish National Birth Cohort. Median (interquartile range) leptin concentrations were calculated. Associations between leptin and preeclampsia (blood pressure ≥140/90 mm Hg), term preeclampsia (preeclampsia and delivery ≥37 weeks gestation), or preterm preeclampsia (preeclampsia and delivery <37 weeks gestation) were examined using generalized linear models adjusting for body mass index, gestational age at blood draw, maternal age, smoking, and socio-occupational status. As leptin is increased in obese women and the risk of preeclampsia increases with body mass index, we used the Sobel test to examine whether leptin is a mediator of this relationship. After adjustments, leptin concentrations were significantly higher in women with preeclampsia (30.5 [24.6]; P=0.0117) and term preeclampsia (30.4 [24.9]; P=0.0228) compared with controls (20.9 [28.3]). There was no significant difference between preterm preeclampsia (30.6 [23.4]; P=0.2210) and controls. Leptin is a possible mediator of the association between body mass index and preeclampsia (P=0.0276). Leptin concentrations are higher in women with preeclampsia compared with normotensive controls and may mediate some of the relationship between body mass index and preeclampsia., (© 2014 American Heart Association, Inc.)

Objective: Eclampsia has been found to be a strong risk factor for epilepsy in the offspring, but it is unclear whether the risk also applies to the preceding condition, preeclampsia., Methods: We conducted a population-based cohort study of 1537860 singletons born in Denmark (1978-2004). Information on preeclampsia (mild, severe, and unspecified), eclampsia, and epilepsy was obtained from the Danish National Hospital Register. Information on gestational age, birth weight, and Apgar score was obtained from the Danish Medical Birth Registry. We used Cox proportional hazard models to estimate the incidence rate ratio of epilepsy for children who were exposed to preeclampsia or eclampsia in prenatal life., Results: We identified 45288 (2.9%) children who were exposed to preeclampsia (34823 to mild, 7043 to severe, and 3422 to unspecified preeclampsia) and 654 (0.04%) to eclampsia during their prenatal life. We identified 20260 people who received a diagnosis of epilepsy during up to 27 years of follow-up in the entire cohort. Prenatal exposure to preeclampsia was associated with an increased risk for epilepsy among children with a gestational age at birth of at least 37 weeks. For mild preeclampsia, the incidence rate ratios were 1.16 among children born at term and 1.68 for children born postterm; for severe preeclampsia, the incidence rate ratios were 1.41 among children born at term and 2.57 among children born postterm. No associations between preeclampsia and epilepsy were found among children who were born preterm. Eclampsia was associated with epilepsy with an incidence rate ratio of 1.29 for children born at term and 5.03 for children born postterm., Conclusions: Prenatal exposure to both preeclampsia and eclampsia was associated with an increased risk of epilepsy in children born after 37 weeks of gestation.

Introduction: Genetic variants of the angiotensinogen gene have been linked to both hypertension and preeclampsia. The M235T polymorphism is more common in hypertension and preeclampsia in some populations. A polymorphism in the angiotensinogen basal promoter region of AGT -217 is more common in African Americans with hypertension. The authors investigated the frequency of M235T and AGT -217 in Caucasian and African American women with and without preeclampsia., Methods: The study was a nested case-control study of primiparous women with singleton pregnancies. Genomic DNA from preeclamptic and control subjects underwent polymerase chain reaction amplification and restriction digestion., Results: The M235T and AGT -217 polymorphisms were both more common in African American women; however, the variants were not more common in preeclampsia., Conclusion: The frequency of angiotensinogen polymorphisms M235T and AGT -217 is different by race; however, these polymorphisms are not associated with an increased risk of preeclampsia.

Cigarette smoking protects against preeclampsia but increases the risk of small-for-gestational-age birth (SGA). Regarding body weight, the converse is true: obesity elevates rates of preeclampsia but reduces rates of SGA. The authors assessed the combined effects of smoking and weight among US women developing preeclampsia or SGA, studying 7,757 healthy, primigravid women with singleton pregnancies in 1959-1965. Smoking (never, light, heavy), stratified by prepregnancy body mass index (BMI (weight (kg)/height (m)(2)); underweight, overweight, obese), was examined in relation to preeclampsia and SGA. Among underweight (BMI <18.5) and normal-weight (BMI 18.5-24.9) women, smoking decreased the risk of preeclampsia (for heavy smoking, light smoking, nonsmoking, test for trend p = 0.002 for underweight and p = 0.009 for normal weight) after adjustment for age, race, and socioeconomic status. However, among overweight/obese women (BMI >or=25), this trend was not apparent (p = 0.4). Among both underweight and overweight women, smoking significantly increased SGA risk (trend p < 0.001 for underweight and p = 0.02 for overweight/obese). Obesity eliminated the inverse association between smoking and preeclampsia but did not substantially alter the positive association between smoking and SGA. A possible unifying biologic explanation is discussed in this paper.

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.

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.

Male reproductive proteins (MRPs), associated with sperm and semen, are the moieties responsible for carrying male genes into the next generation. Evolutionary biologists have focused on their capacity to control conception. Immunologists have shown that MRPs cause female genital tract inflammation as preparatory for embryo implantation and placentation. These observations argue that MRPs are critically important to reproductive success. Yet the impact of male reproductive proteins on obstetrical outcomes in women is largely unstudied. Epidemiologic and clinical observations suggest that shorter-duration exposure to MRPs prior to conception may elevate the risk for preeclampsia. A limited literature has also linked sexual behavior to bacterial vaginosis and preterm birth. We offer a clinical opinion that MRPs may have broad implications for successful reproduction, potentially involved in the composition of vaginal microflora, risks of preterm birth and preeclampsia, and success of assisted reproduction.

Background: Preeclampsia (PE), especially severe or early PE, is a leading cause of morbidity and mortality among mothers and infants. We estimated the population attributable fractions of severe or early PE associated with pre-existing conditions among nulliparous and multiparous women., Methods: Among 70 924 women in the Danish National Birth Cohort, we used hospital discharge data to identify 2117 cases of PE, of which 449 were early (<37 weeks), 426 were severe (clinically diagnosed) and 228 were both early and severe. Prospective interview data were supplemented with hospital registry data to identify women with pre-existing conditions. Generalized estimating equations were utilized to estimate adjusted relative risks, and population attributable fractions were calculated with 95% CI., Results: Pre-existing hypertension, diabetes, obesity or multiple gestation were associated with 22.3% (19.8-24.9) of all PE cases among nulliparous women. These conditions, or a prior preeclamptic pregnancy, were associated with 52.2% (46.4-57.9) of PE among multiparous women. Early PE was preceded by these pre-existing conditions among 34% (28.3-40.0) of affected nulliparous women and among 50% (37.5-63.4) of multiparous women. The fraction of severe PE associated with these conditions was 23% among nulliparas and 59% among multiparas. Being obese or overweight was associated with 15-17% of the population risk of early PE among nulliparous and multiparous women., Conclusions: Pre-existing maternal and obstetric conditions are associated with a high proportion of severe or early cases of PE. Obesity and overweight contributed independently to the risk of pre-term PE, a finding with potentially profound public health implications.

Leptin concentrations were measured in African American women in order to assess leptin's role in the increased frequency and severity of preeclampsia. In addition, leptin concentrations were measured in women who delivered small-for-gestational-age (SGA) infants. A case-control study of African American and Caucasian women with normal pregnancies, preeclampsia, or SGA infants was done. Plasma leptin was quantitated by radio-immunoassay. The previously recognized pattern of increased leptin concentrations in preeclampsia was replicated. Leptin concentrations did not differ by race in any diagnostic category, and concentrations in women with SGA infants were not higher than those in healthy women. Differences in the frequency and severity of preeclampsia in African Americans cannot be explained by higher leptin concentrations.

The objective was to assess the independent effect of regular periconceptional multivitamin use on the risk of preeclampsia. Pregnant women (n=1,835) enrolled in the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh, Pennsylvania, 1997-2001) at less than 16 weeks' gestation were asked whether they regularly used multivitamins or prenatal vitamins in the past 6 months. Women were classified as users or nonusers. The unadjusted prevalence of preeclampsia was 4.4% in nonusers and 3.8% in users. After adjustment for race/ethnicity, marital status, parity, prepregnancy physical activity, and income in a multiple logistic regression model, regular use of multivitamins was associated with a 45% reduction in preeclampsia risk compared with nonuse (odds ratio (OR)=0.55, 95% confidence interval (CI): 0.32, 0.95). Prepregnancy overweight modified this effect. After confounder adjustment, lean multivitamin users had a 71% reduction in preeclampsia risk compared with lean nonusers (OR=0.29, 95% CI: 0.12, 0.65). In contrast, there was no relation between multivitamin use and preeclampsia among overweight women (OR=1.08, 95% CI: 0.52, 2.25). A sensitivity analysis for unmeasured confounding by fruit and vegetable intake supported these conclusions. If confirmed by others, these results suggest that regular use of a multivitamin supplement in the periconceptional period may help to prevent preeclampsia, particularly among lean women.

Intrauterine growth restriction (IUGR) and preeclampsia differ in their association with maternal disease but share a similar placental pathology. Moreover, mothers who have had pregnancies complicated by preeclampsia or IUGR are at elevated later-life cardiovascular risk. Why, then, do some women develop IUGR and others develop preeclampsia? In this clinical opinion, based on a review of the literature, we hypothesize that both women experiencing preeclampsia and IUGR enter pregnancy with some degree of endothelial dysfunction, a lesion that predisposes to shallow placentation. In our opinion, preeclampsia develops when abnormal placentation, through the mediator of elevated circulating cytokines, interacts with maternal metabolic syndrome, comprised of adiposity, insulin resistance/hyperglycemia, hyperlipidemia, and coagulopathy. IUGR develops in the absence of antenatal metabolic syndrome. Among these women, the baby is affected by shallow placentation but the mother does not develop clinically apparent disease. This conceptualization provides a testable framework for future etiologic studies of preeclampsia and IUGR.

Objective: We investigated changes in serum uric acid across pregnancy in women with gestational hyperuricemia at delivery, with and without preeclampsia, compared with normal pregnant and women with preeclampsia without gestational hyperuricemia., Study Design: This was a nested case-control study of 116 controls, 27 women with preeclampsia with predelivery hyperuricemia, 37 women with preeclampsia without predelivery hyperuricemia, and 35 women with gestational hypertension with hyperuricemia at delivery but without proteinuria. Serum uric acid and creatinine was measured across pregnancy., Results: Women with predelivery hyperuricemia, with and without preeclampsia, had increased uric acid concentrations across pregnancy compared with controls, after 25 weeks' gestation compared with women with preeclampsia without predelivery hyperuricemia. Adjusting for differences in glomerular filtration by serum creatinine accounted for part but not all of the increase in serum uric acid among women with preeclampsia and predelivery hyperuricemia., Conclusions: Among women with hyperuricemia at delivery, elevations in uric acid occur early. Multiple mechanisms may contribute to increased uric acid including changes in renal function.

The objective of this study was to quantify the mediating role of inflammation and triglycerides in the association between prepregnancy body mass index (weight (kg)/height (m)2) and preeclampsia. The authors conducted a nested case-control study of 55 preeclamptic women and 165 pregnant controls from the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh, Pennsylvania, 1997-2001). Serum samples collected at < or = 20 weeks' gestation were analyzed for levels of C-reactive protein and triglycerides. The adjusted odds ratio (AOR) from a multivariable conditional logistic regression model assessing the total effect of body mass index on preeclampsia risk was compared with the AOR from the same model after results were controlled for C-reactive protein, triglycerides, and confounding factors (direct-effects model). The percentage of the total effect that was mediated through inflammation and triglycerides was calculated as 100 - [ln(direct-effects AOR)/ln(total-effects AOR)]. In the total-effects model, 4- and 8-unit increases in body mass index were associated with 1.7-fold (95% confidence interval (CI): 1.3, 2.3) and 2.9-fold (95% CI: 1.6, 5.2) increases in preeclampsia risk, whereas in the direct-effects model, these AORs were 1.4 (95% CI: 1.0, 1.9) and 2.0 (95% CI: 1.0, 3.8), respectively. Inflammation was a more important mediator than triglycerides. These findings suggest that approximately one third of the total effect of body mass index on preeclampsia risk is mediated through inflammation and triglyceride levels.

Purpose: A predisposition to coronary artery disease (CAD) may put women at risk for preeclampsia. Morbid preeclampsia (early, severe, recurrent, and with neonatal morbidity) represents the subset of preeclampsia of greatest public health concern., Methods: We review here the published links between preeclampsia and CAD., Results: Many risk factors are common to both CAD and preeclampsia. These include obesity; elevated blood pressure; dyslipidemia; insulin resistance; and hyperglycemia, together termed "Syndrome X"; as well as endothelial dysfunction; hyperuricemia; hyperhomocysteinemia; and abnormalities of inflammation, thrombosis, and angiogenesis. After pregnancy, women with preeclampsia are more likely to experience later life CAD., Conclusions: Both the association between CAD risk factors and preeclampsia and the association between preeclampsia and later CAD appears to be more pronounced among the subset of women with morbid preeclampsia. Thus, women at elevated risk for CAD may be at particularly high risk for morbid preeclampsia and women with morbid preeclampsia may be those at highest risk for later life CAD.

Context: An excess of the soluble receptor, fms-like tyrosine kinase 1 (sFlt-1) may contribute to maternal vascular dysfunction in women with preeclampsia by binding and thereby reducing concentrations of free vascular endothelial growth factor and placental growth factor (PlGF) in the circulation. The putative stimulus for increased sFlt-1 during preeclampsia, placental hypoxia due to poor perfusion, is common to both preeclampsia and idiopathic intrauterine growth restriction. However, the latter condition occurs without maternal vascular disease., Objective: We asked whether, as with preeclampsia, sFlt-1 is increased and free PlGF is decreased in villous placenta and maternal serum of normotensive women with small-for-gestational-age (SGA) neonates., Study Design: This was a case-control study using banked samples. Groups of women with SGA neonates (birth weight centile < 10th) and women with preeclampsia were matched to separate sets of normal pregnancy controls based on gestational age at blood sampling (serum) or gestational age at delivery (placenta)., Results: sFlt-1 levels were higher in preeclamptics than controls (serum, P < 0.0001; placental protein, P = 0.03; placental mRNA, P = 0.007) but not increased in SGA pregnancies. PlGF was lower in both preeclampsia (serum, P < 0.0001; placental protein, P = 0.05) and SGA (serum, P = 0.0008; placental protein, P = 0.03) compared with their controls. PlGF in preeclampsia and SGA groups did not differ., Conclusions: These data are consistent with a role for sFlt-1 in the maternal manifestations of preeclampsia. In contrast to preeclampsia, sFlt-1 does not appear to contribute substantially to decreased circulating free PlGF in SGA pregnancies in the absence of a maternal syndrome.

Purpose: To explore the dose-dependent relation between prepregnancy body mass index (BMI) and the risk of preeclampsia after adjusting for measured confounders., Methods: We studied 1179 primiparous women who enrolled at < 16 weeks' gestation into a prospective cohort study of the pathogenesis of preeclampsia. Multivariable logistic regression was used to quantify the independent effect of prepregnancy BMI on the risk of preeclampsia after adjusting for race and smoking status. BMI was specified as a restricted quadratic spline., Results: Preeclampsia risk rose strikingly from a BMI of 15 to 30 kg/m(2). Compared with women with a BMI of 21, the adjusted risk of preeclampsia doubled at a BMI of 26 (odds ratio 2.1 [95% confidence interval, 1.4, 3.4]), and nearly tripled at a BMI of 30 (2.9 [1.6, 5.3]). Women with a BMI of 17 had a 57% reduction in preeclampsia risk compared with women with a BMI of 21 (0.43 [0.25, 0.76]), and a BMI of 19 was associated with a 33% reduction in risk (0.66 [0.50, 0.87])., Conclusions: These results indicate that preeclampsia risk rises through most of the BMI distribution. The dramatic elevation in overweight prevalence in the United States may increase preeclampsia incidence in the future.

Objective: We measured maternal serum soluble fms-like tyrosine kinase 1 concentrations across pregnancy and immediately postpartum in women who developed preeclampsia and normal pregnant women., Study Design: This was a nested case control study of 113 normal pregnant women and 55 women with preeclampsia., Results: Serum soluble fms-like tyrosine kinase 1 concentrations increased similarly in early pregnancy in both groups. Mean serum soluble fms-like tyrosine kinase 1 concentrations were increased in women who developed preeclampsia, compared with normal pregnant women, and this increase was most pronounced in severe preeclampsia. However, many women with preeclampsia had soluble fms-like tyrosine kinase 1 concentrations similar to normal pregnant women. Lastly, soluble fms-like tyrosine kinase 1 decreased rapidly after delivery, but this decrease was significantly slower in women with severe preeclampsia., Conclusion: Increased soluble fms-like tyrosine kinase 1 is not an early-pregnancy event among women who later develop preeclampsia. Increased soluble fms-like tyrosine kinase 1 is more likely to be present in women with severe preeclampsia, but it is not present in all women with preeclampsia. Soluble fms-like tyrosine kinase 1 concentrations decrease more slowly after delivery in women with preeclampsia, consistent with a decreased rate of excretion or continued production.

Objective: The purpose of this study was to examine the relationship between cytokine genotypes and preeclampsia., Study Design: We conducted a case-control study that examined cytokine genotypes among 150 primiparous preeclamptic women and 661 primiparous, normotensive women. Analyses were adjusted for age, prepregnancy cigarette smoking, and education., Results: Preeclamptic white women were more likely than normotensive white women to carry the up-regulating tumor necrosis factor-alpha-308 A/A (odds ratio, 4.1; 95% CI, 1.1-15.3) genotype. Both black and white women with preeclampsia were more likely than normotensive control subjects to carry the interleukin-1alpha-producing-4845 G/G genotype (black odds ratio, 11.6; 95% CI, 1.5-89.3; white odds ratio, 1.7; 95% CI, 0.7-3.9), -889 C/C genotype (black odds ratio, 5.1; 95% CI, 0.6-41.6; white odds ratio, 1.9; 95% CI, 0.8-4.7), and the interleukin-1alpha-4845/interleukin-1alpha-889/interleukin-1beta-3957 GCC/GCC haplotype (black odds ratio, 3.4; 95% CI, 1.3-8.7; white odds ratio, 2.1; 95% CI, 1.4-3.2)., Conclusion: Cytokine genotypes were associated with preeclampsia and may identify women who are at high risk for preeclampsia.

Altered angiogenesis and insulin resistance are associated with preeclampsia and cardiovascular disease (CVD), and women with preeclampsia appear to be at increased risk of future CVD. We hypothesized that these factors are detectable in asymptomatic postpartum women with a history of preeclampsia and may represent pathophysiological mechanisms bridging preeclampsia and future CVD. We measured fasting insulin, glucose, vascular endothelial growth factor, and its circulating inhibitor, soluble fms-like tyrosine kinase (sFlt-1) in 29 normotensive women with a history of preeclampsia and 32 women with prior normotensive pregnancies at 18.0 +/- 9.7 months postpartum. The homeostasis model of insulin resistance (HOMA(IR)) [(insulin [microunits per milliliter] x glucose [millimoles per liter])/22.5] was calculated. Compared with women with normal pregnancies, women with prior preeclampsia had significantly increased levels of sFlt-1 (41.6 +/- 6.7 vs. 30.4 +/- 10.2; P < 0.01) and median HOMA(IR) (2.8 vs. 1.9; P = 0.04). Membership in the upper quartile of either sFlt-1 or HOMA(IR) was associated with prior preeclampsia (odds ratio 5.7; 95% confidence interval 1.7, 20.0; P < 0.01), and all five women in the upper quartiles of both sFlt-1 and HOMA(IR) had a history of preeclampsia. Women with a history of preeclampsia demonstrate altered expression of angiogenesis-related proteins and increased HOMA(IR) more than 1 yr postpartum. These factors may contribute to their risk of future CVD.

Black women have an increased risk of preeclampsia compared with white women. Plasma homocysteine is increased in preeclampsia. Homocysteine concentrations are affected by nutritional deficiencies, particularly decreased folic acid and B12, leading to increased homocysteine. Previous studies have reported racial differences in nutritional intake including folic acid. Therefore, we investigated whether there were racial differences in plasma homocysteine, folic acid, and vitamin B12 among women with preeclampsia. We tested for an association between homocysteine and folic acid and B12, and we hypothesized an inverse relationship of homocysteine and folic acid in preeclampsia, more so in black women in whom preeclampsia developed. Black women with preeclampsia (n=26) had elevated homocysteine concentrations (8.7+/-1.4 micromol/L) compared with black women with normal pregnancy (n=52, 7.6+/-0.5 micromol/L), white women with preeclampsia (n=34, 7.5+/-0.6 micromol/L), and white women with normal pregnancy (n=48, 5.5+/-0.3 micromol/L). Folic acid concentrations were lower in black women (14.1+/-0.8 ng/mL) compared with white women (18.5+/-0.9 ng/mL, P<0.01). However, plasma homocysteine was inversely related to folic acid only among black women with preeclampsia (r=-0.23, P=0.01). These racial differences may have implications for the higher rates of preeclampsia in this group and may have long-term implications for future cardiovascular risk. Racial differences in diet, adherence to folic acid supplementation, or interactions of nutritional and maternal factors warrant further study by race and pregnancy status.

Preeclampsia is a disorder of pregnancy diagnosed by gestational hypertension and proteinuria. Epidemiological evidence suggests that women who experience preeclampsia are at a greater risk of hypertension and heart disease later in life compared with women who had normal pregnancies. Our objective was to determine whether endothelial function is impaired in postpartum women with a history of preeclampsia in their first pregnancy. We measured forearm blood flow (FBF) by venous occlusion plethysmography in 50 healthy women: 16 with prior preeclampsia, 14 with a prior normotensive pregnancy, and 20 never pregnant controls. The postpartum women participated 6-12 mo after delivery. Heart rate (HR) and blood pressure (BP) were concurrently monitored on the contralateral arm. Hemodynamic variables were assessed at baseline and during a mental stress test known to elicit endothelium-dependent vasodilatation. We found that baseline FBF, HR, systolic BP, and diastolic BP did not significantly differ among the groups, whereas mean arterial pressure in the preeclamptic group was greater than that of the normal pregnancy group (P = 0.03). Stress-induced FBF (percent change over baseline) was reduced in the preeclamptic group compared with both the normal pregnancy and never pregnant groups (P = 0.06) and was significantly attenuated compared with women with prior normal pregnancies (91% vs. 147%, P = 0.006). These data demonstrate that women with a history of preeclampsia exhibit impaired endothelial function up to 1 yr postpartum. This observation may explain their increased risk for hypertension and cardiovascular disease.

Background: The immune maladaptation theory suggests that tolerance to paternal antigens, resulting from prolonged exposure to sperm, protects against the development of preeclampsia. We tested whether barrier contraception and shorter sexual experience with the father of the pregnancy would increase the risk of preeclampsia., Methods: Of 2211 women delivering singleton births after enrollment in a pregnancy cohort study, 85 (3.8%) developed preeclampsia as defined by antepartum systolic blood pressure > or = 140 or diastolic blood pressure > or = 90 plus proteinuria. At a mean of 10.2 weeks of gestation, all women in the cohort were asked about preconception contraception and timing of first sexual intercourse with the father of the pregnancy. Odds ratios (OR) comparing cases with preeclampsia to the rest of the cohort were adjusted for age, smoking, parity, and body mass index (BMI)., Results: Women using barrier contraception prior to conception were no more likely than women not using barrier contraception to develop preeclampsia (adjusted OR 1.0, 95% CI 0.6-1.6). In unadjusted analyses, a prolonged time to conception was associated with preeclampsia (OR 1.9), however, after adjustment, the association was less prominent (OR 1.6) and after stratification by contraception method, the link between time to conception and preeclampsia was eliminated., Conclusion: These data do not support the immune maladaptation theory of preeclampsia.

The pathophysiology of pre-eclampsia is contested, but one hypothesis indicates that it is a heterogeneous condition in which only a subset of affected women bear small-for-gestational age (SGA) babies. In intrauterine growth-restricted (IUGR) infants, placental transport of amino acids is diminished and the resulting decrease in cord-blood amino acid concentrations is thought to contribute to their stunted growth. In contrast, the metabolic syndrome (dyslipidaemia, hyperinsulinaemia, hyperglycaemia, hypertension and obesity) which is associated with high amino acid concentrations is more prevalent in women with pre-eclampsia. The focus of this study was to compare maternal and fetal serum amino acid concentrations during normal pregnancy and pre-eclampsia and to evaluate the associations between the amino acid concentrations and fetal growth. The results indicate that maternal and cord-blood amino acid concentrations were significantly higher in women with pre-eclampsia compared with normal pregnant women and the concentrations were inversely associated with measures of infant growth. Maternal and cord-blood amino acid concentrations were also significantly higher in pre-eclamptic mothers with SGA infants compared with pre-eclamptic mothers whose babies were not SGA. These data indicate that, in contrast to IUGR, pre-eclampsia is associated with enhanced placental amino acid transport or reduced fetal amino acid utilization. Furthermore, the data are consistent with the hypothesis that pre-eclampsia is a heterogeneous disease associated with the metabolic syndrome.

Objective: Preeclampsia shares many risk factors and pathophysiologic features with coronary heart disease. We studied whether, like atherosclerosis, preeclampsia is related to seroprevalence of immunoglobulin (Ig) G antibodies to Chlamydia pneumoniae., Methods: Cross-sectional comparisons were made for 37 women with preeclampsia and 37 women with normal pregnancies at term. In these two groups, antibody titers for IgG, IgM, and IgA seroprevalence to C pneumoniae and IgG to Chlamydia trachomatis and Chlamydia psittaci were compared., Results: Immunoglobulin G antibodies to C pneumoniae at a titer of at least 1:16 were more common in women with preeclampsia (25 of 37) than in women without (15 of 37) (odds ratio 3.1; 95% confidence interval 1.2, 7.9). There were no significant differences in the seroprevalence of IgA or IgM antibodies to C pneumoniae. Women with preeclampsia were also no more likely to have IgG antibodies to C trachomatis or C psittaci., Conclusion: Women with preeclampsia had an increased IgG seroprevalence to C pneumoniae but not to C trachomatis or C psittaci. These preliminary data suggest a specific association between infection with C pneumoniae and preeclampsia.

Objective: To test the hypothesis that enhanced oxidative stress during pregnancies complicated by preeclampsia is associated with improper copper (Cu) binding by plasma albumin, resulting in enhanced Cu redox-cycling activity and that altered Cu binding, in turn, is caused by interactions of excessive amounts of free fatty acids with albumin., Study Design: We studied binding and redox-cycling activity of Cu in 17 normal pregnancy and 17 preeclampsia plasma samples. Binding of exogenous Cu in plasma samples was quantified indirectly using spectrophotometric measurements of its complex with a specific chelator of Cu(I), bathocuproine disulfonate. Redox-cycling activity of Cu in plasma samples was estimated by electron paramagnetic resonance (EPR) spectroscopy of ascorbate radicals formed during one-electron oxidation of ascorbate by redox-active catalytic Cu. Formation of Cu/albumin complexes in model systems in the presence and absence of fatty acids was studied using EPR spectroscopy of Cu(II)/albumin., Results: We found that preeclampsia plasma (as compared to normal pregnancy plasma) (1) displays elevated endogenous ascorbate redox-cycling that is normalized by a Cu(II) chelator, cuprizone I, (2) has lowered capacity to bind and redox-regulate exogenously added Cu, and (3) responds to treatment with fatty-acid-free albumin by diminished ascorbate oxidizing activity. Conversely, addition of free fatty acid (oleic acid) to normal pregnancy plasma sample yields increased ascorbate redox-cycling activity. Our model experiments showed that Cu-dependent redox-cycling activity of purified human serum albumin is significantly increased by excess free fatty acids., Conclusion: Mishandling of Cu by albumin contributes to oxidative stress in preeclampsia. Cu chelators may represent promising mechanism-based antioxidants to attenuate oxidative stress in preeclampsia.

Objective: The objective of this study was to confirm that endothelial dysfunction is present in preeclampsia and absent in transient hypertension of pregnancy, and to determine whether the cardiovascular risk factor homocysteine is associated with the degree of endothelial dysfunction., Methods: We measured cellular fibronectin (as a marker of endothelial injury) and total plasma homocysteine in samples collected at the time of admittance to labor and delivery in 17 women with preeclampsia (increased blood pressure, proteinuria, and hyperuricemia), 16 women with transient hypertension of pregnancy (only increased blood pressure), and 34 normal pregnant women. Each subject with preeclampsia was matched by prepregnancy body mass index, race, and gestational age at delivery to one subject with transient hypertension of pregnancy and two controls., Results: Cellular fibronectin was found to be significantly increased in women with preeclampsia compared to subjects with transient hypertension of pregnancy or normal pregnant women (22.9 +/- 14.1 microg/mL versus 10.9 +/- 5.4 and 10.1 +/- 6.2 microg/mL, respectively, p<0.0001). Similarly, total plasma homocysteine was also significantly increased in the women with preeclampsia compared to subjects with transient hypertension of pregnancy or normal pregnant women (8.3 +/- 2.5 microM versus <5.5 +/- 2.2 and 5.4 +/- 3.4 microM respectively, p<0.01). However, contrary to our hypothesis, there was no apparent association between cellular fibronectin and homocysteine., Conclusions: The increased concentrations of homocysteine observed in preeclampsia are not a general feature of all hypertensive complications of pregnancy. Furthermore, endothelial dysfunction is present in preeclampsia and is not evident in transient hypertension of pregnancy. However, the apparent endothelial dysfunction in preeclampsia is not explained by the increase in homocysteine concentrations observed.

We measured bound and free leptin levels in preeclamptic and matched normal pregnant and never-pregnant women to determine whether the free component of leptin is increased during pregnancy and further increased in preeclampsia. Two milliliters of serum was obtained from 18 normal and 18 preeclamptic patients matched by pre-pregnancy body mass index (BMI), and from 18 never-pregnant women matched by BMI with the pregnant groups. The sample was subjected to gel filtration using Sephadex G-100. Radioimmunoassay (RIA) was performed on all fractions, and the proportions of bound and free leptin were determined by analyzing the areas under the curve of the chromatographic profile. The total maternal serum leptin concentration was significantly higher in normal pregnancy compared with the nonpregnant state and was further increased in preeclampsia (33.8 +/- 4.1 v 15.2 +/- 1.8 ng/mL, P = .002, and 48.1 +/- 5.6 ng/mL, P = .02, respectively). Free leptin was increased in normal pregnant compared with never-pregnant women (25.9 +/- 4.1 v 11.0 +/- 2.0 ng/mL, respectively, P = .01), while the increase of total leptin in preeclampsia was exclusively in the free fraction that was significantly higher versus the normal pregnant group (41.8 +/- 5.6 v25.9 +/- 4.1 ng/mL, respectively, P = .01). The bound leptin fraction, by contrast, was significantly increased in the normal pregnant group compared with the preeclamptic group and the never-pregnant group (7.9 +/- 0.56 v 6.2 +/- 0.36 and 4.1 +/- 0.36 ng/mL, respectively, P = .009 and P = <.0001). In conclusion, the free leptin concentration increases in normal pregnancy and is further increased in preeclampsia. This supports the hypothesis that biologically active leptin is elevated in normal pregnancy and is increased more in women with preeclampsia.

Objective: We assessed tobacco exposure in nulliparous women with preeclampsia compared with that in control subjects by measuring urinary cotinine to confirm the reduced risk of preeclampsia associated with tobacco exposure during pregnancy., Study Design: A case-control study group of 50 women with preeclampsia after 35 weeks of gestation and a group of 50 control subjects matched for gestational age, date of delivery, and body mass index were selected from the project database. Urine obtained on admission was assayed for cotinine. Self-reported smoking information was blinded during patient selection and laboratory assay., Results: Thirty-five patients had detectable urinary cotinine levels, 11 (22%) with preeclampsia and 24 (48%) control women. Mean cotinine concentrations among exposed women were 331 ng/mL for those with preeclampsia and 540 ng/mL for control subjects. The odds ratio of preeclampsia developing in an exposed woman was 0.31 (95% confidence interval, 0.12-0.79)., Conclusion: These findings, obtained by using laboratory assay, confirm the reduced risk of developing preeclampsia with tobacco exposure.

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 MTHFR 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 chi 2 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.

Objective: We tested the hypothesis that the independent risk factor for atherosclerosis of increased plasma homocysteine concentration is associated with the pregnancy syndrome of preeclampsia. We further hypothesized that increased plasma homocysteine concentration during pregnancy may advance endothelial dysfunction in preeclampsia by promoting oxidative stress., Study Design: Antepartum blood samples were collected >/=6 hours after the last meal from 33 women with normal, uncomplicated pregnancies and from 21 women with preeclampsia. These plasma samples were analyzed for concentrations of total homocysteine; folate; triglycerides; creatinine; a marker of endothelial activation, cellular fibronectin; and a marker of oxidative stress, malondialdehyde., Results: The mean value of total plasma homocysteine in preeclampsia was significantly higher than that observed in normal pregnancy (P <. 04). Similarly, plasma malondialdehyde (P <.001), triglyceride (P <. 001), and cellular fibronectin (P <.006) concentrations were also greater in women with preeclampsia than in control subjects. However, no differences were observed between women with preeclampsia and control subjects in folate (P =.97) or creatinine (P =.28) concentrations. Homocysteine concentration did not correlate with plasma creatinine (P =.61), malondialdehyde (P =.32), or triglyceride (P =.89) concentrations. However, cellular fibronectin concentration correlated positively with homocysteine concentration in both women with preeclampsia and control subjects (r = 0.87, P <. 0001, and r = 0.50, P <.004, respectively), and folate concentrations were weakly but negatively correlated with homocysteine values (P =.03, r = 0.32)., Conclusions: Total plasma homocysteine concentration is increased in preeclampsia and is significantly correlated with cellular fibronectin concentration, suggesting that homocysteine plays a role in promoting endothelial dysfunction in preeclampsia. Furthermore, despite the use of pregnancy multivitamins and no indications of overt folate deficiency in this subject population, homocysteine concentration weakly and negatively correlates with plasma folate concentration.

The cause of preeclampsia remains elusive in spite of many attempts to understand its biologic characteristics and to characterize its predictors. We suggest that there are distinct origins of preeclampsia, each with its own pathologic characteristics and natural history. One genesis is the result of reduced placental perfusion, which we will call placental, and another results from maternal disorders preexisting (but sometimes not evident before) pregnancy. These preexisting maternal disorders comprise predisposing factors for cardiovascular disease such as hypertension, renal disease, overweight, and diabetes. A critical review of the epidemiologic and pathologic literature is presented, which supports the hypothesis that preeclampsia is the result of heterogeneous causes. The implications of this hypothesis are discussed, particularly its impact on the development of rules to predict the occurrence of preeclampsia.