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ObjectiveTo assess the adequacy of periconceptional intake of key micronutrients for perinatal health in relation to regular cereal consumption of pregnant women.Design, setting and subjectsLow-income pregnant women (n596) in Pittsburgh, Pennsylvania, USA, who enrolled in a cohort study at ResultsAbout 31 % of the women regularly consumed cereal. After adjusting for energy intake, race/ethnicity, marital status, breakfast consumption and supplement use, cereal eaters had significantly higher intakes of folate, Fe, Zn, Ca, fibre and vitamins A, C, D and E (allP< 0·01) and were approximately two to six times more likely to have intakes in the highest third of the distribution for folate, Fe, Zn, Ca, vitamins A and D, and fibre (allP< 0·01) than cereal non-eaters. Cereal consumption was also associated with reductions of 65–90 % in the risk of nutrient inadequacies compared with non-consumption (allP< 0·01).ConclusionsEncouraging cereal consumption may be a simple, safe and inexpensive nutrition intervention that could optimize periconceptional intake for successful placental and fetal development.

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.

The authors compared postpartum adiponectin levels among women with prior pregnancy-induced disturbances and assessed their association with homeostasis model assessment for insulin resistance (HOMA-IR), the metabolic syndrome (MS), and the Framingham risk score (FRS). Women delivering in 1998 through 2001 and who had gestational diabetes mellitus (n=22), gestational hypertension (n=32), or preeclampsia (n=34) were examined 1 to 2 years after delivery and were grouped-matched to controls (n=29) by age and prepregnancy body mass index. HOMA-IR was increased, adiponectin values were decreased, and there was a higher MS prevalence in women with prior gestational diabetes mellitus (all P

We hypothesized that TNF-alpha would be higher in obese versus lean women with preeclampsia.Total plasma TNF-alpha was measured in a nested case-control study of 123 nulliparous lean and obese control women and women with preeclampsia.Adjusted mean TNF-alpha concentrations were 0.97 +/- 0.11 (pg/mL +/- SEM) in lean controls, 1.01 +/- 0.10 in obese controls, 1.43 +/- 0.11 in lean women with preeclampsia and 1.16 +/- 0.11 in obese women with preeclampsia. Pregnancy outcome was the single predictor of TNF-alpha concentration in the general linear regression model (p = 0.04).TNF-alpha concentration was higher in preeclampsia compared with control subjects. Obesity was not associated with higher TNF-alpha concentrations in either preeclampsia or control subjects.

Biomarkers of exposure & early effects: field studiesBiomarker: mutation frequency of glycophorin AExposure/effect represented: cigarette smoke/ DNA damageStudy design: cross-sectionalStudy size: 2405 pregnant womenAnalytical technique: The GPA somatic cell mutation assayTissue/biological material/sample size: peripheral bloodImpact on outcome (including dose-response): active smoker/non-smoker a positive significant overall association of smoking with a newborn Ψ/N Vf was observed by generalized linear model analysis (P=0.023)Quality control: reliability of maternal self-reported cigarette smoking was verified by measuring cotinine levels in maternal blood samples in a separate analysisBiomarkers of individual susceptibility: field studiesBiomarker (including alleles if genetic): CYP1A1*2A, CYP1A1*3, CYP2E1*5B, NAT2*5, *6A, *7A and *14A, GSTM1 and GSTT1Effect studied (phenotype/pathology): DNA damageMethod of analysis: RFLP-PCRImpact on outcome (including dose-response): CYP1A1* 2A or CYP1A1*3, 33.6%; CYP2E1*5B, 6.9%; GSTM1 null, 46.8%; GSTT1 null, 24.1%; and NAT2 slow, 43.1%. KEYWORDS CLASSIFICATION: Adolescent;Adult;Alleles;biomarkers of exposure & effect: field studies;biomarkers of individual susceptibility: field studies;blood;Female;Fetal Blood;genetics;Genotype;Glycophorin;Humans;Infant,Newborn;metabolism;methods;Maternal-Fetal Exchange;Mothers;Mutation;Pharmacogenetics;Polymorphism,Genetic;Pregnancy;Research;Smoking. Prenatal exposure to carcinogens results in newborn DNA damage which in turn is associated with impaired health conditions in both childhood and adulthood. The present study aimed to evaluate whether phase I and II biotransformation enzyme genetic polymorphisms in combination with environmental exposures during pregnancy result in elevated levels of newborn DNA damage. Maternal peripheral and umbilical cord blood samples from 406 mother/newborn pairs were genotyped for a panel of phase I/II metabolic enzymes (CYP1A1, CYP2E1, GSTM1, GSTT1 and NAT2) responsible for the metabolism of tobacco and lifestyle-related mutagens and carcinogens. DNA damage was measured by somatic cell mutation frequency at the glycophorin A (GPA) locus in newborns. No association with elevated somatic cell mutation frequency was observed between the combination of maternal/newborn genotypes and cigarette smoke or lifestyle exposures. The observed variation in newborn GPA frequency might be due to either environmental factors not assessed in this study or inter-individual differences in alternative metabolic or DNA repair pathways.

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.

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–α–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-1α–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-1α–4845/interleukin-1α–889/interleukin-1β–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.

We tested the hypothesis that twin pregnancies would lead to increased maternal plasma homocysteine. We further hypothesized that twin pregnancies complicated by preeclampsia would have increased plasma homocysteine compared to twin pregnancies without preeclampsia and normal singleton pregnancies.Plasma was collected at delivery from 127 nulliparous subjects: 57 women with normal singleton pregnancies, 39 women with singleton and preeclampsia, 17 women with uncomplicated twin pregnancies, and 14 women with twins and preeclampsia. Subjects were group matched for prepregnancy body mass index (BMI) and race. Plasma homocysteine was analyzed by high pressure liquid chromatography (HPLC) with fluorescence detection, and plasma folic acid was measured by radio immunoassay (RIA).The mean plasma concentration of homocysteine was significantly increased in all women with preeclampsia (7.4+/-2.9 microM) compared to all normal pregnant women (5.9+/-2.1 microM, p=0.002). However, homocysteine was not significantly increased in all women with twins (6.7+/-2.1 microM) compared to all women with singleton pregnancies (6.5+/-2.7 microM, p=0.61). In addition, women with twins and preeclampsia did not have increased homocysteine (6.8+/-2.1 microM) compared to women with twins and normal pregnancy (6.7+/-2.1 microM, p=0.72). As expected, because of extra supplementation, plasma folic acid was significantly increased in women with twins (27.9+/-11.6 ng/mL) compared to women with singleton pregnancies (20.8+/-8.5 ng/mL, p=0.0003). However, folic acid was not different between preeclamptics and controls (23.5+/-10.8 vs. 21.9+/-9.2 ng/mL respectively, p=0.36). Lastly, there was a significant inverse correlation between homocysteine and folic acid among all the subjects (r2=- 0.053, p0.01), and this correlation persisted in the women with singleton pregnancies (r2=- 0.078, p0.01), but was lost in the twins (r2=- 0.073, p=0.14).With contemporary management including increased folic acid supplementation, plasma homocysteine is not increased in twin pregnancies with or without preeclampsia.

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.Of 2211 women delivering singleton births after enrollment in a pregnancy cohort study, 85 (3.8%) developed preeclampsia as defined by antepartum systolic blood pressureor = 140 or diastolic blood pressureor = 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).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.These data do not support the immune maladaptation theory of preeclampsia.

Objective A single-base polymorphism within the promoter of the gene for tumor necrosis factor α at position -308 relative to the transcriptional start site of the gene is correlated with differences in production of tumor necrosis factor α. There are two allelic forms: TNFA1 and TNFA2. The TNFA2 allele is associated with increased production of tumor necrosis factor α. The purpose of this study is to assess the relationship between carriage of the TNFA2 allele and clinical chorioamnionitis. Methods In this retrospective cohort study, previously banked deoxyribonucleic acid from 149 women who had spontaneous labor from 37 to 42 weeks’ gestation was used. Polymerase chain reaction was used for polymorphism assay. Demographic and clinical information was obtained from the medical record. Clinical chorioamnionitis was defined as at least one temperature elevation above 38C combined with at least two of the following signs: maternal or fetal tachycardia, uterine tenderness greater than expected, foul-smelling vaginal discharge, and white blood cell count more than 18,000. Results Chorioamnionitis was present in 18 women (12.1%). Among women who did not carry TNFA2, the chorioamnionitis rate was 7.4%. Among women who carried TNFA2, the chorioamnionitis rate was 24.4%. The relative risk for chorioamnionitis with carriage of TNFA2 was 3.3 (95% confidence interval 1.3, 7.1). This increased risk was not altered after adjustment for race, type of rupture of membranes, intrauterine pressure catheter use, smoking, and prolonged rupture of membranes. Conclusion Carriage of the TNFA2 allele is associated with a more than three-fold increased risk of clinical chorioamnionitis, even when accounting for important clinical and microbiologic risk factors.

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.

Pre-eclamptic (PE) placentae overexpress hypoxia inducible transcription factors-1alpha and -2alpha proteins (Biol. Repro. 64: 499-506, 2001; Ibid 1019-1020). Possible explanations include (a) impaired oxygen-dependent reduction, and/or (b) enhanced sensitivity to reduced oxygen. After 18 h equilibration under 21 per cent O(2) atmosphere, we subjected villous explants prepared from placentae of normal pregnant (NP) and pre-eclamptic (PE) women (n=8 each) to 4h of hypoxia (2 per cent oxygen), and then studied the disappearance of HIF-1alpha and -2alpha proteins during subsequent oxygenation over 90 min (21 per cent oxygen). The disappearance of these HIF proteins as assessed by Western analysis was significantly impaired in the pre-eclamptic tissues. Even after 18h equilibration under a 21 per cent O(2) atmosphere, and then a further 4h at 21 per cent O(2), HIF-1alpha and -2alpha protein expression remained increased in villous explants from PE women (both P< 0.04 vs NP). To address whether chronic hypoxia per se (which is believed to exist in the pre-eclamptic placenta) might contribute to these findings, we subjected villous explants from normal placentae (n=6) to 18 h preincubation under 2 per cent or 21 per cent oxygen prior to subsequent incubation for 4h at 2 per cent oxygen and then 90 min at 21 per cent oxygen. The time course of disappearance of HIF proteins during oxygenation was similar irrespective of the 2 per cent or 21 per cent preconditioning. To evaluate oxygen sensitivity, we exposed villous explants from NP and PE women (n=6 each) to different oxygen atmospheres for 4h and measured HIF protein induction. Although the data showed a significant inverse relationship between HIF expression and oxygen concentration, there was no significant difference between the slopes of this relationship for the two groups of women. We conclude that villous explants from PE placentae fail to adequately downregulate HIF protein expression upon oxygenation. This abnormality may contribute to their overexpression in vivo.

Objective: To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the fetal morbidity of those infections. Methods: We obtained demographic and occupational information about pregnant women exposed to sources of B19 and about the nature and duration of the exposures. We performed serologic testing 10–14 days after exposure using an indirect capture enzyme-linked immunosorbent assay. Women with immunoglobulin (Ig) M were examined with weekly ultrasound until 12 weeks after exposure, and the outcome of the pregnancy was ascertained from interviews with patients and their obstetricians. Logistic regression analysis was used to determine risk factors for maternal immunity and infection by B19. Results: Of 618 pregnant women exposed, 307 (49.7%) were immune to B19, 259 remained susceptible after exposure, and 52 (16.7% of all susceptibles) contracted B19 infection. None of the 52 fetuses of infected women developed nonimmune hydrops, and there were no fetal deaths attributable to B19 in this group. The relative risk of maternal B19 infection was 2.8 if the source was a related child living in the household (95% confidence interval 1.7,4.6; P < .001). No significant differences were found for maternal B19 infection in eight categories of maternal occupation. Maternal symptoms of polyarthralgia (46%), fever (19%), and nonspecific rash (38%) were significantly more common (P < .001) in IgM-positive patients than in noninfected women (4.1%, 2.8%, and 5.7%, respectively). Only 17 (33%) of the IgM-positive women were entirely asymptomatic. Conclusion: The risk of maternal B19 infection in pregnancy could not be predicted by a gravida's occupation, but it was significantly higher when the source of exposure was her own child. The fetal risk of nonimmune hydrops after maternal B19 infection must be very low. As a consequence, exclusion of pregnant women from the workplace during endemic periods with seasonal clusters of cases is not justified. Weekly fetal ultrasound evaluation in these cases carries a low yield.

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans. The average maternal age was 24.9+/-5.8 (mean+/-S.D.) years. Thirty-nine percent of the Caucasian Americans and 45.4% of the African Americans self-reported that they were active smokers during the index pregnancy. The average number of cigarettes smoked per day was 2.65+/-5.75 and 1.37+/-3.17 for Caucasian and African American mothers, respectively. Peripheral blood lymphocytes from the mother and from the fetal side of the placenta were evaluated for chromosome aberrations by whole chromosome painting. Aliquots from the same blood samples were also used to assess genetic susceptibility with an in vitro bleomycin challenge assay. Spontaneous translocation frequencies in both maternal and newborn lymphocytes were not associated with cigarette smoking, socioeconomic status, or education. The absence of a smoking effect may be attributable to the low level of cigarette usage in these subjects. The average bleomycin-induced damage in the maternal and newborn populations was 0.37+/-0.27 and 0.15+/-0.14 breaks per cell, respectively, a difference that was highly significant (p

Myeloperoxidase (MPO) is a hemoprotein normally released from activated monocytes and neutrophils. Traditionally viewed as a microbicidal enzyme, MPO also induces low-density lipoprotein oxidation, activates metalloproteinases, and oxidatively consumes endothelium-derived NO. The elevated plasma MPO level is a risk factor for myocardial events in patients with coronary artery disease. Patients with preeclampsia display evidence of the inflammation and endothelial dysfunction associated with oxidative stress in the circulation, vasculature, and placenta. We hypothesized that MPO levels in the circulation and placental extracts from women with preeclampsia would be greater than levels in women with normal pregnancies. Placental extracts were prepared from placental villous biopsies from preeclamptic (n=27) and control (n=43) placentas. EDTA plasma samples were obtained from gestationally age-matched preeclamptic and control normal pregnancies. MPO concentrations were measured by ELISA. Immunohistochemistry was used to determine MPO localization in the placenta. MPO levels in placental extracts from women with preeclampsia were significantly higher than the levels in normal control subjects (546±62 versus 347±32 ng/mL;P=0.025). MPO was found in the floating villi and basal plate of placentas with a greater staining in the basal plates from preeclampsia placentas compared with normal pregnancies. Plasma MPO levels were 3-fold higher in patients with preeclampsia compared with normal control subjects (36.6±7.6 versus 11.0±3.1 ng/mL;P=0.003). In conclusion, MPO levels are significantly increased in the circulation and placenta of women with preeclampsia. We speculate that MPO may contribute to the oxidative damage reported in the endothelium and placenta of women with preeclampsia.

We hypothesized that women with small-for-gestational-age (SGA) neonates would have lower concentrations of leptin compared to women with appropriately grown infants (AGA).This is a nested case-control study of normotensive nulliparous women. Cases (n = 28) delivered SGA10 percentile and controls (n = 77) delivered AGA. Maternal plasma leptin concentrations were compared at 18, 28, and 40 weeks' gestation via repeated measures.Maternal leptin concentrations at 18 weeks were correlated with prepregnancy BMI (r = 0.69, P.0001) and early pregnancy waist circumference (r = 0.59, P.0001). After adjustment for maternal body composition, leptin was lower across pregnancy in women with SGA compared to AGA neonates (13.6 vs 15.2 ng/mL at 18 weeks; 13.6 vs 17.3 ng/mL at 28 weeks; 16.6 vs 20.7 ng/mL at 40 weeks; P = .04).Maternal leptin was correlated with maternal adiposity; however, after adjustment for body composition, leptin was lower across pregnancy in women with SGA.

S -nitrosoalbumin (SNO-Alb) is a major reservoir of releasable nitric oxide (NO) in plasma. In preeclampsia, a pregnancy-specific disorder associated with endothelial dysfunction, we previously found significant elevations in plasma SNO-Alb concentrations and decreased plasma ascorbate (Asc) levels. This increased SNO-Alb may result from low-plasma Asc if Asc, along with transition metals (eg, copper [Cu]) are necessary for release of NO from S -nitrosothiols. We propose that vasodilator effects of SNO-Alb, mediated by release of NO, are fully realized only when Asc/Cu availability is sufficient. Relaxation responses to SNO-Alb or the control reduced human serum albumin (SH-Alb), and responses to pooled plasma from normal or preeclamptic pregnancies were examined in isolated mouse arteries. Arteries preconstricted with phenylephrine were exposed to SNO-Alb or SH-Alb at physiologically relevant concentrations. When free Cu was added in excess (10 μmol/L), NO release was not dependent on Asc. However, when Cu was added at lower (physiological) levels, NO release was dependent on Asc. The addition of Asc and Cu to SNO-Alb stimulated vasodilatory responses in isolated arteries >90%, whereas no change in the SH-Alb (5%) response was observed. Preeclampsia plasma with higher levels of SNO-Alb caused arteries to relax 44.1±4.7%, whereas normal pregnancy plasma caused 11.9±4.2% relaxation ( P =0.007). These data indicate that SNO-Alb alone or in plasma can act as a potent vasodilator, and that sufficient Asc/Cu promotes this action. We suggest that the higher circulating levels of SNO-Alb, in women with preeclampsia, reflect a deficiency in Asc/Cu-mediated release of NO from SNO-Alb.

Racial disparities in health are largely unexplained. Because many diseases causing premature mortality among African Americans are mediated by the immune system, the authors explored the race-specific distribution of allelic variants in cytokine genes known to stimulate inflammation. The authors studied women seeking prenatal care and delivering singletons in uncomplicated first births at a US hospital in 1997-2001. A total of 179 African-American women and 396 White women were evaluated for functionally relevant allelic variants in cytokine genes. African-American women were significantly more likely to carry allelic variants known to up-regulate proinflammatory cytokines; odds ratios increased with allele dose. Odds ratios for African Americans versus Whites in genotypes up-regulating proinflammatory interleukin (IL) 1 (IL1A-4845G/G, IL1A-889T/T, IL1B-3957C/C, and IL1B-511A/A) ranged from 2.1 to 4.9. The proinflammatory cytokine interleukin-6 IL6-174 G/G genotype was 36.5 times (95% confidence interval (CI): 8.8, 151.9) more common among African Americans. Genotypes known to down-regulate the antiinflammatory interleukin-10 (IL10-819 T/T and IL10-1082 A/A) were elevated 3.5-fold (95% CI: 1.8, 6.6) and 2.8-fold (95% CI: 1.6, 4.9) in African Americans. Cytokine genotypes found to be more common in African-American women were consistently those that up-regulate inflammation.

The soluble VEGF receptor, sFlt-1 (otherwise referred to as sVEGFR-1), has been implicated in the pathogenesis of preeclampsia. The preeclamptic placenta has been previously demonstrated to produce high levels of the soluble VEGF receptor. Here we tested the hypothesis that peripheral blood mononuclear cells (PBMCs) may also represent an additional source for circulating sFlt-1 during normal and preeclamptic pregnancies. We first demonstrate that preeclamptic placentae show five-fold increased Flt-1 and sFlt-1 mRNA levels. We also show that the Flt-1 and sFlt-1 levels are eight-fold higher in preeclamptic placentae if we collect biopsies without rinsing them in saline to remove excess blood. Cultured villous explants from women with preeclampsia failed to show the increased amount of Flt-1 and sFlt-1 mRNA that was observed in the placental biopsies of normal pregnancy and preeclampsia. Under normoxic conditions the Flt-1 and sFlt-1 mRNA levels in the explants were 3.11+/-0.6 fold in normal pregnancy and 3.6+/-0.4 fold in women with preeclampsia (p = NS by ANOVA). However, the same villous explants showed hypoxic induction of Flt-1 mRNA (NP 3.96+/-0.4 fold, p = NS and PE 5.24+/-0.6 fold, p < 0.05 by ANOVA). We analyzed Flt-1 and sFlt-1 protein levels in the peripheral blood mononuclear cells (PBMCs) to analyze the possibility of an extra-placental sFlt-1 source. Our results indicate that PBMCs of pregnant women are capable of expressing variable amounts of Flt-1 proteins. PBMCs from pregnant women exposed to hypoxia show up-regulation of HIF-1alpha and Flt-1 proteins. PBMCs obtained from women with preeclampsia (n = 9) produced significantly higher amounts of sFlt-1 under normal tissue culture conditions (104.6+/-14.3 pg/ml vs. 46.23+/-5.03 pg/ml, p < 0.05 by ANOVA) and much higher concentrations under hypoxia (196.74+/-26.3pg/ml vs. 83.3+/-13.6pg/ml, p < 0.05 by ANOVA) than PBMCs from normal pregnant women (n = 11). Moreover, analysis of PBMCs from a different group of women with a history of preeclampsia showed persistent abnormality of Flt-1 women one year post-partum. The present study indicates that Flt-1 dysregulation in PBMCs of pregnant women resulting in over-expression of sFlt-1 could be an additional (extra-placental) source of sFlt-1 that contributes to the pathogenesis of preeclampsia.

Three to five percent of pregnancies are complicated by preeclampsia, a multisystemic disorder characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. Although widespread inflammation and endothelial dysfunction appear to be central maternal abnormalities in preeclampsia, the pathogenesis of the syndrome remains poorly understood (1). The intracellular iron storage protein ferritin can hold up to 4000 iron atoms. Low concentrations of ferritin are found in normal serum because of active secretion from reticuloendothelial or parencymal cells (2)(3). During normal pregnancy, serum ferritin concentrations decrease with advancing gestation to reach a nadir at the third trimester (4). The metabolism of the serum iron and iron-binding proteins, ferritin and transferrin, is abnormal in women with preeclampsia (5)(6)(7)(8). Median serum ferritin concentrations are approximately fivefold higher during preeclampsia than in normal pregnancy (6)(8)(9). The lowest quartile of ferritin concentrations at 28–30 weeks of gestation is associated with decreased risk of preeclampsia, premature rupture of membranes, and infant admission to the neonatal unit (4). The reasons for the increased serum ferritin with preeclampsia remain unclear. Serum ferritin is a reliable indicator of total body iron status in nondiseased individuals, with low concentrations diagnostic of iron deficiency. However, a high ferritin does not always signify iron excess. Unlike intracellular ferritin, which is nonglycosylated and high in iron, normal serum ferritin is 60–80% glycosylated and very low in iron, suggesting active secretion rather than nonspecific leakage from cells (2)(10). Blood concentrations of ferritin increase with inflammation or infection as a result of augmented intracellular synthesis (2)(11). In such cases, the proportion of glycosylated serum ferritin is basically unchanged, and the serum ferritin is iron-poor, reflecting the fact that the normal mechanisms of ferritin production remain operative …

Reductions in breast cancer risk observed in daughters of pre-eclamptic pregnancies are hypothesized to be mediated by lower in utero estrogen concentrations. Whereas maternal urinary estriol excretion is generally lower in pre-eclamptic women, results for maternal blood concentrations are equivocal, and little is known about estrogen concentrations in the cord of pre-eclamptic pregnancies. Unconjugated estrogen and androgen concentrations were measured in mixed umbilical cord sera from 86 pre-eclamptic and 86 uncomplicated, singleton pregnancies, matched on length of gestation, maternal age, parity, and type of delivery. Pre-eclamptic and uncomplicated pregnancies were similar in maternal age, prepregnancy weight, maternal height, type of delivery, use and type of anesthesia, and sex of offspring. Estriol, estradiol, estrone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, and testosterone concentrations measured in cord sera were not significantly different in pre-eclamptics compared with uncomplicated pregnancies. Estriol was 9% lower (P = 0.43), and all of the other hormones were actually higher in pre-eclamptics with testosterone and estradiol approaching statistical significance (P = 0.06 and P = 0.12, respectively). These data do not support the hypothesis that the lower breast cancer risk in daughters of pre-eclamptic pregnancies is explained by lower in utero estrogen exposure.

Evidence suggests that adult cancer risk of hormonally related tumors may be influenced by the in utero environment, and most speculation on the biological mechanism has focused on the hormonal component. Epidemiological studies investigating the biological nature of pregnancy and maternal factors associated with offspring's cancer risk have relied on maternal hormone measurements. The degree to which maternal hormone levels represent the fetal environment, however, is not widely known. Pregnancy estrogen, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate concentrations were measured in maternal and mixed umbilical cord sera from 86 singleton pregnancies. Spearman correlations between maternal and cord hormone levels generally ranged between 0.2 and 0.3. The correlation was 0.26 for estriol, the estrogen of highest concentration in pregnancy, and 0.27 for estradiol, the most biologically active estrogen. The correlations between mother and offspring for the estrogens and DHEA appeared similar for males and females, whereas there was a suggestion that the maternal-umbilical cord correlations for other androgens varied in magnitude by fetal sex, and all correlations appeared higher in pregnancies lasting38 weeks compared with longer gestational lengths, although these stratified findings may have been attributable to chance. These data show a moderate degree of correlation in hormone concentrations between the maternal and fetal circulation. Studies using maternal hormone concentrations as a proxy for the fetal environment should consider the misclassification resulting with the use of this marker.

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.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.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).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.

Women who deliver preterm infants may be at increased risk for cardiovascular disease, perhaps related to dyslipidemia.In a nested case control study of women with spontaneous preterm birth, cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were evaluated. Lipid concentrations and gestational changes, as well as risk for preterm birth, were evaluated in women who delivered34 (n = 23),or=34-37 (n = 67), andor=37 weeks (n = 199).High cholesterol or triglyceridesor=15 weeks were associated with a 2.8-fold (1.0-7.9) and 2.0-fold (1.0-3.9) increased risk for preterm birth34 weeks andor=34-37 weeks, respectively. Overweight women who delivered34 weeks had particularly elevated early pregnancy concentrations of cholesterol and low-density lipoprotein; lean women with moderate preterm birth had elevated triglycerides. There was a reduced triglyceride response in the first half of pregnancy among women who delivered34 weeks.Our results indicate the presence of dyslipidemia in women with spontaneous preterm birth.