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1.  Uric Acid as a Pathogenic Factor in Preeclampsia 
Placenta  2008;29(Suppl A):S67-S72.
Hyperuricemia is a common finding in preeclamptic pregnancies evident from early pregnancy. Despite the fact that elevated uric acid often pre-dates the onset of clinical manifestations of preeclampsia, hyperuricemia is usually considered secondary to altered kidney function. Increased serum uric acid is associated with hypertension, renal disease and adverse cardiovascular events in the non-pregnant population and with adverse fetal outcomes in hypertensive pregnancies. We hypothesize that an elevated concentration of uric acid in preeclamptic women is not simply a marker of disease severity but rather contributes directly to the pathogenesis of the disorder. Using epidemiological and experimental evidence, gained largely outside of pregnancy, we will propose pathogenic roles for uric acid in preeclamptic pregnancies. Uric acid's ability to promote inflammation, oxidative stress and endothelial dysfunction will be highlighted with discussions of the potential impact on placental development and function and maternal vascular health.
doi:10.1016/j.placenta.2007.11.001
PMCID: PMC3319018  PMID: 18093648
2.  Elevated first-trimester uric acid concentrations are associated with the development of gestational diabetes 
Objective:
To demonstrate that elevated first trimester uric acid is associated with development of gestational diabetes mellitus (GDM).
Study Design:
Uric acid was measured in 1570 plasma samples collected at mean gestational age of 8.9 ± 2.5 weeks. The primary outcome was GDM, diagnosed by three hour glucose tolerance test using Carpenter and Coustan criteria or by a one hour value of ≥ 200 mg/dl. Logistic regression was performed, adjusting for relevant covariates.
Results:
Almost half (46.6%) of the women with GDM had first trimester uric acid concentrations in the highest quartile (>3.57-8.30 mg/dl). Women with uric acid in the highest quartile had a 3.25-fold increased risk (95%CI: 1.35, 7.83) of developing GDM after adjustment for BMI and age. This effect was concentration dependent as risk increased with increasing uric acid quartiles (p=0.003).
Conclusion:
First trimester hyperuricemia is associated with an increased risk of developing GDM, independent of BMI.
doi:10.1016/j.ajog.2009.06.065
PMCID: PMC2774120  PMID: 19788971
gestational diabetes; hyperuricemia; uric acid
3.  First Trimester Exposure to Ambient Air Pollution, Pregnancy Complications and Adverse Birth Outcomes in Allegheny County, PA 
Maternal and child health journal  2013;17(3):545-555.
Despite numerous studies of air pollution and adverse birth outcomes, few studies have investigated preeclampsia and gestational hypertension, two pregnancy disorders with serious consequences for both mother and infant. Relying on hospital birth records, we conducted a cohort study identifying 34,705 singleton births delivered at Magee-Women’s Hospital in Pittsburgh, PA between 1997 and 2002. Particle (<10 μm-PM10; <2.5 μm-PM2.5) and ozone (O3) exposure concentrations in the first trimester of pregnancy were estimated using the space–time ordinary Kriging interpolation method. We employed multiple logistic regression estimate associations between first trimester exposures and preeclampsia, gestational hypertension, preterm delivery, and small for gestational age (SGA) infants. PM2.5 and O3 exposures were associated with preeclampsia (adjusted OR = 1.15, 95 % CI = 0.96–1.39 per 4.0 μg/m3 increase in PM2.5; adjusted OR = 1.12, 95 % CI = 0.89–1.42 per 16.8 ppb increase in O3), gestational hypertension (for PM2.5 OR = 1.11, 95 % CI = 1.00–1.23; for O3 OR = 1.12, 95 % CI = 0.97–1.29), and preterm delivery (for PM2.5 ORs = 1.10, 95 % CI = 1.01–1.20; for O3 ORs = 1.23, 95 % CI = 1.01–1.50). Smaller 5–8 % increases in risk were also observed for PM10 with gestational hypertension and SGA, but not preeclampsia. Our data suggest that first trimester exposure to particles, mostly PM2.5, and ozone, may increase the risk of developing preeclampsia and gestational hypertension, as well as preterm delivery and SGA.
doi:10.1007/s10995-012-1028-5
PMCID: PMC3636771  PMID: 22544506
Air pollution; Particulate; Preeclampsia; Gestational hypertension; Preterm; Small for gestational; age (SGA)
4.  Uric acid concentrations are associated with insulin resistance and birthweight in normotensive pregnant women 
OBJECTIVE
To investigate whether uric acid concentrations are increased in pregnant women with insulin resistance and to correlate both with fetal growth.
STUDY DESIGN
Uric acid, glucose and insulin were measured in plasma at 20.4 (± 2.0) weeks gestation in 263 women. The association between uric acid and insulin resistance as estimated using the homeostasis model assessment (HOMA) was analyzed and related to birthweights.
RESULTS
In 212 (80.6%) women who remained normotensive throughout pregnancy, HOMA increased 1.23 units per 1 mg/dl increase in uric acid [(95%CI: 1.07,1.42), p=0.003]. Infants born to normotensive women in the upper quartile of uric acid and lowest HOMA quartile weighed 435.6 grams less than infants of women with highest uric acid and HOMA quartiles (p < 0.005).
CONCLUSION
Increasing uric acid concentrations were associated with insulin resistance in mid-pregnancy. Hyperuricemia was associated with lower birthweight in normotensive women, and this effect was attenuated by insulin resistance.
doi:10.1016/j.ajog.2009.06.043
PMCID: PMC2789906  PMID: 19729142
uric acid; hyperuricemia; insulin resistance; birthweight
5.  Association of Second and Third Trimester Weight Gain in Pregnancy with Maternal and Fetal Outcomes 
PLoS ONE  2013;8(1):e54704.
Objective
To investigate the association between weekly weight gain, during the second and third trimesters, classified according to the 2009 Institute of Medicine (IOM/NRC) recommendations, and maternal and fetal outcomes.
Methods
Gestational weight gain was evaluated in 2,244 pregnant women of the Brazilian Study of Gestational Diabetes (Estudo Brasileiro do Diabetes Gestacional – EBDG). Outcomes were cesarean delivery, preterm birth and small or large for gestational age birth (SGA, LGA). Associations between inadequate weight gain and outcomes were estimated using robust Poisson regression adjusting for pre-pregnancy body mass index, trimester-specific weight gain, age, height, skin color, parity, education, smoking, alcohol consumption, gestational diabetes and hypertensive disorders in pregnancy.
Results
In fully adjusted models, in the second trimester, insufficient weight gain was associated with SGA (relative risk [RR] 1.72, 95% confidence interval [CI] 1.26–2.33), and excessive weight gain with LGA (RR 1.64, 95% CI 1.16–2.31); in third trimester, excessive weight gain with preterm birth (RR 1.70, 95% CI 1.08–2.70) and cesarean delivery (RR 1.21, 95% CI 1.03–1.44). Women with less than recommended gestational weight gain in the 2nd trimester had a lesser risk of cesarean deliveries (RR 0.82, 95% CI 0.71–0.96) than women with adequate gestational weight gain in this trimester.
Conclusion
Though insufficient weight gain in the 3rd trimester was not associated with adverse outcomes, other deviations from recommended weight gain during second and third trimester were associated with adverse pregnancy outcomes. These findings support, in part, the 2009 IOM/NRC recommendations for nutritional monitoring during pregnancy.
doi:10.1371/journal.pone.0054704
PMCID: PMC3559868  PMID: 23382944
6.  Uric Acid Induces Trophoblast Il-1β Production Via The Inflammasome: Implications For The Pathogenesis Of Preeclampsia 
Problem
Preeclampsia is associated with hyperuricemia, which correlates with the disease severity. Levels of circulating uric acid increase before the clinical manifestations, suggesting they may be causally related. Uric acid, or monosodium urate (MSU), activates the Nod-like receptor, Nalp3, leading to inflammasome activation and IL-1β processing. Since preeclampsia is associated with placental immune/inflammatory dysregulation, we sought to determine in the trophoblast, the presence of the Nalp3 inflammasome, and the effect of MSU on its activation.
Method of Study
Isolated first and third trimester trophoblast were assessed for expression of the inflammasome components, Nalp1, Nalp3 and ASC. First trimester trophoblast cells were incubated with or without MSU, after which, IL-1β secretion and processing and caspase-1 activation was determined.
Results
Trophoblast cells expressed Nalp1, Nalp3 and ASC under basal conditions. Following incubation with MSU, first trimester trophoblast IL-1β secretion was upregulated. This correlated with increased expression levels of active IL-1β and active caspase-1. ASC knockdown reduced MSU-induced IL-1β secretion.
Conclusion
These findings demonstrate that uric acid activates the inflammasome in the trophoblast, leading to IL-1β production. This may provide a novel mechanism for the induction of inflammation at the maternal-fetal interface leading to placental dysfunction and adverse pregnancy outcome, including preeclampsia.
doi:10.1111/j.1600-0897.2010.00960.x
PMCID: PMC3114103  PMID: 21352397
Inflammasome; Nod-like receptor; placenta; preeclampsia; trophoblast; uric acid
7.  Diet During Pregnancy and Risk of Preeclampsia or Gestational Hypertension 
Annals of epidemiology  2007;17(9):663-668.
PURPOSE:
We sought to examine associations of first-trimester intake of calcium, n-3 and n-6 fatty acids, trans fatty acids, magnesium, folate, and vitamins C, D, and E with preeclampsia (PE) and gestational hypertension (GH).
METHODS:
We studied associations of diet with PE or GH among 1718 women in the prospective cohort study Project Viva, using logistic regression and adjusting for maternal age, prepregnancy body mass index, first trimester systolic blood pressure, race/ethnicity, education, and parity. We assessed first-trimester diet using a validated semiquantitative food frequency questionnaire.
RESULTS:
A total of 59 (3%) women developed PE, and 119 developed (7%) GH. We found a somewhat-lower risk of PE associated with higher intake of the elongated n-3 fatty acids docosahexaenoic and eicosapentaenoic acids (odds ratio [OR] 0.84, 95% confidence interval [95% CI]: 0.69–1.03 per 100 mg/day), fish (OR 0.91, 95% CI 0.75–1.09 per serving/day), and the ratio of docosahexaenoic + eicosapentaenoic to arachadonic acid (OR 0.82, 95% CI 0.66–1.01). We did not observe a lower risk of GH or PE with a greater intake of calcium; vitamin C, D, or E; milk; magnesium; folate; or with lower intake of n-6 or trans fatty acids.
CONCLUSIONS:
Our results support a potential benefit for elongated n-3 fatty acids in preventing preeclampsia.
doi:10.1016/j.annepidem.2007.03.003
PMCID: PMC2532559  PMID: 17521921
Antioxidants; Calcium; Diet; Hypertension—Pregnancy-Induced; n-3 Fatty Acids; Nutrition; Preeclampsia; Pregnancy
8.  First-trimester prediction of Preeclampsia using metabolomic biomarkers: a discovery phase study 
Prenatal diagnosis  2011;31(10):990-994.
Objective
We tested the hypothesis that first-trimester metabolic biomarkers offered a unique profile in women with preeclampsia (PE) in the second half of pregnancy, compared to controls.
Method
We conducted a nested-case control study within a prospective cohort of pregnant women followed from the first-trimester to delivery. Cases were those who developed PEat any gestational age and these were compared with a control group without adverse pregnancy outcome, matched for gestational age within three days. We analyzed maternal blood obtained at 11–14 weeks’ gestation for 40 acylcarnitine species (C2-C18 saturated, unsaturated, and hydroxylated) and 32 amino acids by LC tandem mass spectrometry. Logistic regression modeling estimated the association of each metabolite with development ofPE.
Results
We compared 41 cases with preeclampsia with 41 controls, and found four metabolites (Hydroxyhexanoylcarnitine, alanine, phenylalanine, and glutamate) that were significantly higher in the cases withPE. The area under the curve (AUC) using these metabolites individually to predict PE varied from 0.77–0.80; and when combined, the AUC improved to 0.82(95% CI 0.80–0.85) for all cases of PEand 0.85 (95% CI 0.76–0.91) for early onsetPE.
Conclusion
Our findings suggest a potential role for first-trimester metabolomics in screening for PE.
doi:10.1002/pd.2822
PMCID: PMC3713070  PMID: 21744367
9.  Mid-Trimester Maternal Serum hCG and Alpha Fetal Protein Levels: Clinical Significance and Prediction of Adverse Pregnancy Outcome 
Context
Maternal serum human Chorionic Gonadotropin (hCG) and Alpha Fetal Protein (AFP) were originally introduced to detect trisomy 21 and neural tube defects. However, in the absence of aneuploidy or neural tube defects, mid-trimester maternal serum hCG and/or maternal serum AFP associated with adverse pregnancy outcomes. Pregnancies with unexplained mid-trimester elevation in maternal serum hCG and/or maternal serum AFP, are at increased risk for pregnancy complications resulting from placental insufficiency.
Evidence Acquisition
Mid-trimester maternal serum hCG>2.5 MoM associated with an increased risk for pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, intrauterine growth restriction (IUGR), preterm delivery and intrauterine fetal death(IUFD). Mid-trimester maternal serum AFP levels >2.5 MoM are thought to reflect a defect in placentation and associated with an increased risk for pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, IUGR, preterm delivery and IUFD.
Results
Combined mid-trimester elevation in maternal serum hCG and AFP levels suggest a more complex type of placental pathology. They have stronger association with pregnancy complications including: late fetal loss, gestational hypertension, preeclampsia, IUGR, preterm delivery and IUFD.
Conclusions
Mid-trimester maternal serum hCG or AFP levels alone cannot detect all pregnant women with increased risk to develop pregnancy complications. Multiparameter testing of placental function in mid-trimester (maternal serum hCG and AFP screening, uterine artery Doppler and placental morphology) may allow us to identify women with increased risk to develop severe placental insufficiency and pregnancy complications. However, future prospective studies are needed to confirm the prognostic significance of multiparameter testing of placental function in mid-trimester.
doi:10.5812/ijem.5014
PMCID: PMC3693663  PMID: 23825981
Maternal Serum Screening Tests; Chorionic Gonadotropin; AFP; Adverse Pregnancy Outcome
10.  Serum uric acid and appropriate cutoff value for prediction of metabolic syndrome among Chinese adults 
The relation between serum uric acid and metabolic syndrome is observed not only with frank hyperuricemia but also with serum uric acid levels within the normal range. The current “normal” range set for hyperuricemia often fails to identify patients with potential metabolic disorders. We investigate the association between serum uric acid within the normal range and incident metabolic syndrome risk, and further to determine the optimal cut-off value of serum uric acid for the diagnosis or prediction of metabolic syndrome. A total of 7399 Chinese adults (2957 men and 4442 women; ≥20 years) free of metabolic syndrome were followed for 3 years. During the 3-year follow-up, 1190 normouricemic individuals developed metabolic syndrome (16.1%). After adjusting the associated variables, the top quartile of serum uric acid levels was associated with higher metabolic syndrome development compared with the bottom quartile in men (hazard ratio (HR), 1.29; p<0.05) and women (HR, 1.62; p<0.05). ROC curve analysis indicated that the optimal cut-off values for serum uric acid to identify metabolic syndrome were 6.3 mg/dl in men and 4.9 mg/dl in women. Our results suggested that high baseline serum uric acid levels within the normal range predict future development of metabolic syndrome after 3 y of follow-up.
doi:10.3164/jcbn.12-65
PMCID: PMC3541417  PMID: 23341696
serum uric acid; cutoff value; metabolic syndrome; follow-up
11.  REACTIONS OF PEROXYNITRITE WITH URIC ACID: FORMATION OF REACTIVE INTERMEDIATES, ALKYLATED PRODUCTS AND TRIURET, AND IN VIVO PRODUCTION OF TRIURET UNDER CONDITIONS OF OXIDATIVE STRESS 
Hyperuricemia is associated with hypertension, metabolic syndrome, preeclampsia, cardiovascular disease and renal disease, all conditions associated with oxidative stress. We hypothesized that uric acid, a known antioxidant, might become prooxidative following its reaction with oxidants; and, thereby contribute to the pathogenesis of these diseases. Uric acid and 1,3-15N2-uric acid were reacted with peroxynitrite in different buffers and in the presence of alcohols, antioxidants and in human plasma. The reaction products were identified using liquid chromatography-mass spectrometry (LC-MS) analyses. The reactions generate reactive intermediates that yielded triuret as their final product. We also found that the antioxidant, ascorbate, could partially prevent this reaction. Whereas triuret was preferentially generated by the reactions in aqueous buffers, when uric acid or 1,3-15N2-uric acid was reacted with peroxynitrite in the presence of alcohols, it yielded alkylated alcohols as the final product. By extension, this reaction can alkylate other biomolecules containing OH groups and others containing labile hydrogens. Triuret was also found to be elevated in the urine of subjects with preeclampsia, a pregnancy-specific hypertensive syndrome that is associated with oxidative stress, whereas very little triuret is produced in normal healthy volunteers. We conclude that under conditions of oxidative stress, uric acid can form reactive intermediates, including potential alkylating species, by reacting with peroxynitrite. These reactive intermediates could possibly explain how uric acid contributes to the pathogenesis of diseases such as the metabolic syndrome and hypertension.
doi:10.1080/15257770902736400
PMCID: PMC2742358  PMID: 19219741
Uric acid; methyluric acid; peroxynitrite; cardiovascular disease; endothelial dysfunction; triuret; ascorbate; alkylation; preeclampsia; hypertension; oxidative stress; reactive intermediates
12.  Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease 
Background
Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD).
Methods
Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit.
Results
Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6–8.9; P < 0.001) and 2.9 (1.6–5.3; P < 0.001)].
Conclusions
Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.
doi:10.1093/ndt/gfs417
PMCID: PMC3616764  PMID: 23222419
autosomal-dominant polycystic kidney disease; end-stage renal disease; hypertension; kidney volume; uric acid
13.  Urinary nephrin: A new predictive marker for pregnancies with preeclampsia and small-for-gestational age infants 
Objective
The objective of this study was to determine the differences in urinary nephrin among controls, gravidas with preeclampsia (PE), and small-for-gestational age (SGA) infants. We also determined whether or not maternal urinary concentrations of nephrin are associated with the subsequent development of PE and SGA infants.
Methods
We analyzed maternal urinary levels of nephrin in women who were normal controls (n=50), women who were delivered SGA infants (n=40), and gravidas with PE (n=33) in the first, second and third trimesters. Urinary nephrin concentrations were measured with nephrin enzyme-linked immunosorbent assay kits.
Results
The levels of urinary nephrin were higher in gravida developing preeclampsia or SGA than in controls after adjusting serum creatinine (P<0.05 for both). Maternal urine concentrations of nephrin were higher in pregnancies complicated by SGA and PE in the third trimester (P<0.05), and also higher in pregnancies complicated by SGA in the first trimester (P<0.05). The sensitivity and specificity of nephrin in predicting SGA from normal pregnancies were 67% and 89% in the first trimester, 60% and 79% in the second trimester, and 80% and 84% in the third trimester, respectively. The sensitivity and specificity of nephrin in predicting PE from normal pregnancies were 67% and 83% in the first trimester and 73% and 79% in the third trimester, respectively.
Conclusion
We suggest that urinary nephrin can be used as an early marker in pregnancies at risk for developing PE and SGA infants.
doi:10.5468/OGS.2013.56.1.22
PMCID: PMC3784106  PMID: 24327976
Nephrin; Small-for-gestational age; Preeclampsia; Urine; Early marker
14.  Does decreasing serum uric acid level prevent hypertension? – a nested RCT in cohort study: rationale, methods, and baseline characteristics of study cohort 
BMC Public Health  2013;13:1069.
Background
Previous epidemiologic studies have demonstrated an association between uric acid and hypertension. Our objective was to conduct a prospective cohort study with a nested randomised controlled trial (RCT in cohort) that aims to identify the association of hyperuricemia with the development of hypertension and to examine the efficacy of dietary intervention in lowering uric acid level and prevention of hypertension.
Methods/Design
Participants were considered eligible to enrol for this cohort study if they were not diagnosed with hypertension until their last routine health examination. The characteristics of the eligible participants were analyzed. After enrolment, participants with prehypertension and hyperuricemia simultaneously were randomly distributed to either the intervention group or the control group. An education package of dietary intervention for lowering uric acid was delivered to the intervention group. The primary evaluation criterion was the first manifestation of hypertension.
Discussion
Based on the results of their health examination in 2010, 19, 724 subjects met the inclusion criteria and this source population guaranteed the required minimum sample size for this study. The baseline characteristics of the study cohort showed that hyperuricemia was associated with prehypertension, and was independent of age, body mass index (BMI), and abdominal obesity in females; however, in males it was contrary.
The impact of lowering uric acid on the prevention of hypertension is still inconclusive. This RCT in cohort study provides important data on the prevention of hypertension, especially in patients with a high risk for hypertension development. Results are expected to be available in 2015.
Trial registration
The study is registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-12002925).
doi:10.1186/1471-2458-13-1069
PMCID: PMC3830560  PMID: 24219579
Randomised controlled trial; Cohort study; Pre-hypertension; Hyperuricemia
15.  Fetal Exposure to Altered Amniotic Fluid Glucose, Insulin, and Insulin-Like Growth Factor–Binding Protein 1 Occurs Before Screening for Gestational Diabetes Mellitus 
Diabetes Care  2010;34(1):139-144.
OBJECTIVE
We explored the possibility that perturbations in amniotic fluid glucose, insulin, and insulin-like growth factor–binding protein 1(IGFBP1) and/or metabolic acids exist before routine screening for GDM.
RESEARCH DESIGN AND METHODS
We selected consenting mother-infant pairs (n = 408) who met our inclusion criteria (singleton pregnancy, no genetic abnormalities, and no preexisting diabetes) and for whom sufficient amniotic fluid and appropriate medical information were available. We compared birth outcomes and second trimester amniotic fluid glucose, insulin, IGFBP1 concentrations, and amniotic fluid lactic, β-hydroxybutyric, and uric acids of mothers with gestational diabetes mellitus (GDM) (n = 52) with those of mothers with no diagnosis of GDM at >24 weeks (n = 356).
RESULTS
Higher amniotic fluid glucose, lactic acid, uric acid, and insulin and lower IGFBP1 concentrations were present by 15.1 ± 0.1 weeks in mothers in whom GDM was subsequently diagnosed. However, logistic regression showed that second trimester amniotic fluid glucose, but not insulin, IGFBP1, or metabolic acids was associated with an increased odds ratio (1.2 [95% CI 1.052–1.338]) for diagnosis of GDM at 24–28 weeks. In addition, probability contour maps that accounted for nonlinear relationships among the dynamically changing amniotic fluid constituents showed an increased risk for GDM with elevated second trimester amniotic fluid glucose in combination with either elevated amniotic fluid insulin or low amniotic fluid IGFBP1
CONCLUSIONS
Fetuses are exposed to increased amniotic fluid glucose before 15 weeks of gestation, suggesting that metabolic perturbations are underway before diagnosis and that earlier screening and intervention may be warranted.
doi:10.2337/dc10-0607
PMCID: PMC3005441  PMID: 20855548
16.  Uric Acid Inhibits Placental System A Amino Acid Uptake☆ 
Placenta  2008;30(2):195-200.
Hyperuricemia, a common clinical characteristic of preeclamptic pregnancies, has historically been considered a marker of reduced renal function in preeclamptic women. More recently it has been suggested that uric acid may directly contribute to pathological cell signaling events involved in disease progression as well as maternal and fetal pregnancy outcomes including fetal growth restriction. We hypothesize that the increased frequency of restricted fetal growth seen in relation to increasing uric acid concentrations in preeclamptic women is in part the result of uric acid-induced reductions in amino acid transport across the placenta. The objective of the current study was to examine the effects of uric acid on human placental System A amino acid transport using a primary placental villous explant model. Further, we examined the necessity of uric acid uptake and the role of redox signaling as a potential mechanism through which uric acid may attenuate System A activity. Placental uptake of a radiolabeled amino acid analogue, specific to the System A transporter, was reduced in a concentration-dependent fashion with increasing uric acid (0−7 mg/dL), corresponding to uric acid concentrations measured in healthy pregnant and preeclamptic women in the third trimester. Uric acid-induced reduction in System A activity was partially reversed by NADPH oxidase inhibition and completely eliminated by antioxidant treatment. This study demonstrates inhibition of placental System A amino acid transport with uric acid treatment, as a result of uric acid-induced stimulation of intracellular redox signaling cascades. These findings may be relevant to the increased frequency of fetal growth restriction observed in hyperuricemic preeclampsia. Additionally the results of this study, indicating a detrimental effect of hyperuricemia on amino acid transport in the placenta, at concentrations present in women with preeclampsia, also suggest a role for uric acid in the pathophysiology of preeclampsia.
doi:10.1016/j.placenta.2008.10.015
PMCID: PMC2677697  PMID: 19058847
Uric acid; Amino acid transport; System A; Antioxidants; Redox signaling; Placenta; Preeclampsia; Fetal growth restriction; Hyperuricemia; NADPH oxidase; Probenecid; Explants
17.  Altered Global Gene Expression in First Trimester Placentas of Women Destined to Develop Preeclampsia 
Placenta  2008;30(1):15-24.
Background
Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely-held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia.
Methods
Surplus chorionic villus sampling (CVS) tissues were collected at 10–12 weeks gestation in 160 patients with singleton fetuses. Four patients developed preeclampsia, and their banked CVS specimens were matched to 8 control samples from patients with unaffected pregnancies. Affymetrix HG-U133 Plus 2.0 GeneChips were utilized for microarray analysis. Naïve Bayes prediction modeling and pathway analysis were conducted. qRT-PCR examined three of the dysregulated genes.
Results
Thirty-six differentially expressed genes were identified in the preeclampsia placentas. qRT-PCR verified the microarray analysis. Thirty-one genes were down-regulated. Many were related to inflammation/immunoregulation and cell motility. Decidual gene dysregulation was prominent. No evidence was found for alterations in hypoxia and oxidative stress regulated genes.
Conclusions
To our knowledge, this is the first study to show dysregulation of gene expression in the early placentas of women ~6 months before developing preeclampsia, thereby reinforcing a placental origin of the disorder. We hypothesize that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization, or both, thereby impairing trophoblast invasion. Several of the genes provide potential targets for the development of clinical biomarkers in maternal blood during the first trimester. Supplementary materials are available for this article via the publisher’s online edition.
doi:10.1016/j.placenta.2008.09.015
PMCID: PMC2667803  PMID: 19027158
Oligonucleotide; microarray; chorionic villus sampling; maternal-fetal interface; immune regulation; decidualization; cell motility; hypoxia inducible factor; oxidative stress
18.  Lack of association between dietary fructose and hyperuricemia risk in adults 
Background
High serum uric acid concentration (hyperuricemia) has been studied for its relationship with multiple adverse health outcomes, such as metabolic syndrome. Intervention studies have produced inconsistent outcomes for the relationship between fructose intake and serum uric acid concentration.
Methods
The association of dietary fructose intake with hyperuricemia risk in adults was examined using logistic regression and U.S. NHANES 1999-2004 databases. A total of 9,384 subjects, between the ages 20 and 80 years, without diabetes, cancer, or heart disease, were included.
Results
The highest added or total fructose intake (quartiles by grams or % energy) was not associated with an increase of hyperuricemia risk compared to the lowest intake with or without adjustment (odds ratios = 0.515-0.992). The associations of alcohol and fiber intakes with the risk were also determined. Compared to the lowest intake, the highest alcohol intake was associated with increased mean serum uric acid concentration (up to 16%, P < 0.001) and hyperuricemia risk (odds ratios = 1.658-1.829, P = 0.057- < 0.001); the highest fiber intake was correlated with decreases of uric acid concentration (up to 7.5%, P < 0.002) and lower risk (odds ratios = 0.448-0.478, P = 0.001- < 0.001). Adults who were over 50 y old, male, or obese had significantly greater risk.
Conclusions
The data show that increased dietary fructose intake was not associated with increased hyperuricemia risk; while increased dietary alcohol intake was significantly associated with increased hyperuricemia risk; and increased fiber intake was significantly associated with decreased hyperuricemia risk. These data further suggest a potential effect of fructose consumption in an ordinary diet on serum uric acid differs from results found in some short-term studies using atypical exposure and/or levels of fructose administration.
doi:10.1186/1743-7075-7-16
PMCID: PMC2842271  PMID: 20193069
19.  Association of Renal Manifestations with Serum Uric Acid in Korean Adults with Normal Uric Acid Levels 
Journal of Korean Medical Science  2010;25(12):1766-1770.
Several studies have reported that hyperuricemia is associated with the development of hypertension and cardiovascular disease. Increasing evidences also suggest that hyperuricemia may have a pathogenic role in the progression of renal disease. Paradoxically, uric acid is also widely accepted to have antioxidant activity in experimental studies. We aimed to investigate the association between glomerular filtration rate (GFR) and uric acid in healthy individuals with a normal serum level of uric acid. We examined renal function determined by GFR and uric acid in 3,376 subjects (1,896 men; 1,480 women; aged 20-80 yr) who underwent medical examinations at Gangnam Severance Hospital from November 2006 to June 2007. Determinants for renal function and uric acid levels were also investigated. In both men and women, GFR was negatively correlated with systolic and diastolic blood pressures, fasting plasma glucose, total cholesterol, uric acid, log transformed C reactive protein, and log transformed triglycerides. In multivariate regression analysis, total uric acid was found to be an independent factor associated with estimated GFR in both men and women. This result suggests that uric acid appears to contribute to renal impairment in subjects with normal serum level of uric acid.
doi:10.3346/jkms.2010.25.12.1766
PMCID: PMC2995231  PMID: 21165292
Glomerular Filtration Rate; Uric Acid; Antioxidants
20.  THE CHANGE IN CONCENTRATIONS OF ANGIOGENIC AND ANTI-ANGIOGENIC FACTORS IN MATERNAL PLASMA BETWEEN THE FIRST AND SECOND TRIMESTERS IN RISK ASSESSMENT FOR THE SUBSEQUENT DEVELOPMENT OF PREECLAMPSIA AND SGA 
Introduction
An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascual endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of preeclampsia and/or delivery of an SGA neonate.
Methods
This longitudinal case-control study included 402 singleton pregnancies in the following groups: 1) normal pregnancies with appropiate for gestational age (AGA) neonates (n=201); 2) patients who delivered an SGA neonate (n=145); and 3) patients who developed PE (n=56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: 1) first sample obtained between 6 and 15 weeks of gestation (“first trimester” sample); and 2) second sample obtained between 20 and 25 weeks of gestation (“second trimester” sample). Plasma concentrations of s-Eng, sVEGFR-1 and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity and body mass index (BMI). General linear models and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and product to the subsequent development of delivery of an SGA neonate.
Results
1) An increase in the maternal plasma concentration of s-Eng between the first and second trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0, and OR 2.9, 95% CI 1.5-5.6, respectively); 2) An increase in the maternal plasma concentration of sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE (OR 3.9, 95% CI 1.2-12.6); 3) A subnormal increase in maternal plasma PlGF concentration between the first and the second trimester was a risk factor for the subsequent development of preterm and term PE (OR 4.3, 95% CI 1.2-15.5, and OR 2.7, 95% CI 1.2-5.9, respectively); 4) In addition, the combination of the three analytes into a pro-angiogenic versus anti-angiogenic ratio [PlGF/(sEng x VEGFR-1)] conferred risk for the subsequent development of preterm preeclampsia (OR 3.7, 95% CI 1.1-12.1); 5) Importantly, patients with a high change in the s-Eng x sVEGFR-1 product had an OR of 10.38 (95% CI 3.18-33.84) for the development of preterm PE and 1.62 (95% CI 1.01-2.60) for the development of SGA.
Conclusion
Changes in the maternal plasma concentrations of s-Eng, sVEGFR-1, PlGF or their ratios between the first and second trimesters of pregnancy confer an increased risk to deliver a SGA neonate and/or develop PE.
doi:10.1080/14767050802034545
PMCID: PMC2846114  PMID: 18446652
SGA; longitudinal; PlGF; endoglin; sVEGFR-1
21.  First Trimester Maternal Serum PP13 in the Risk Assessment for Preeclampsia 
American journal of obstetrics and gynecology  2008;199(2):122.e1-122.e11.
Objective
To determine whether first trimester maternal serum Placental Protein 13 (PP13) concentrations can be used in the risk assessment for preeclampsia.
Study Design
This case-control study included 50 patients with preeclampsia and 250 patients with normal pregnancies. Samples were collected between 8-13 weeks of gestation. Serum PP13 concentrations were measured by ELISA and expressed as medians and multiples of the median (MoM) for gestational age. Sensitivity and specificity were derived from receiver operating characteristic curve analysis.
Results
1) Serum PP13 concentration in the first trimester was significantly lower in patients who developed preterm and early-onset preeclampsia than in those with normal pregnancies; and 2) At 80% specificity, a cutoff of 0.39 MoM had a sensitivity of 100% for early-onset preeclampsia and 85% for preterm preeclampsia.
Conclusion
Maternal serum first trimester PP13 appears to be a reasonable marker for risk assessment, but a weak marker for severe preeclampsia at term, and ineffective for identifying mild preeclampsia at term.
doi:10.1016/j.ajog.2008.01.013
PMCID: PMC2784814  PMID: 18539259
Risk assessment; screening; maternal serum biochemistry; high-risk pregnancy; prenatal care
22.  Fibroids Are Not A Risk Factor For Adverse Outcomes in Twin Pregnancies 
Objective
Uterine fibroids have been associated with adverse outcomes in singleton pregnancies. We aimed to estimate risk for adverse obstetric outcomes associated with fibroids in twin pregnancies.
Study Design
A retrospective cohort study of twin pregnancies with ≥ 1 fibroid on second trimester ultrasound. Outcomes included small for gestational age (SGA) fetal growth, preterm delivery, preterm rupture of membranes, abruption, preeclampsia, and intrauterine fetal death. Univariable and multivariable analyses were used to evaluate the impact of fibroids on outcomes in twin pregnancies compared to twin pregnancies without fibroids.
Results
Of 2,378 nonanomalous twin pregnancies, 2.3% had fibroids. Twin pregnancies with fibroids were no more likely to have SGA growth (40.0% vs. 36.0%, aOR 1.1, 95%CI 0.7-2.0) or preterm delivery < 34 weeks (25.0% vs. 24.0%, aOR 1.0, 95%CI 0.5-1.9) than twin pregnancies without fibroids. Other adverse outcomes were no more likely to occur in twin pregnancies with fibroids than twin pregnancies without fibroids. Post hoc power calculations suggested greater than 97% power to detect 2-fold differences in small for gestational age and preterm delivery <34 weeks.
Conclusions
In contrast to data suggesting an increased risk for adverse outcomes in singleton pregnancies with fibroids, twin pregnancies with fibroids do not appear to be at increased risk for complications compared to those without fibroids.
doi:10.1016/j.ajog.2012.10.879
PMCID: PMC3612957  PMID: 23103343
Fibroids; twin pregnancies; preterm birth
23.  Placental Protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm preeclampsia and HELLP syndrome 
Placental Protein 13 (PP13) is a galectin expressed by the syncytiotrophoblast. Women who subsequently develop preterm preeclampsia have low first trimester maternal serum PP13 concentrations. This study revealed that third trimester maternal serum PP13 concentration increased with gestational age in normal pregnancies (p<0.0001), and it was significantly higher in women presenting with preterm preeclampsia (p=0.02) and HELLP syndrome (p=0.01) than in preterm controls. Conversely, placental PP13 mRNA (p=0.03) and protein, as well as cytoplasmic PP13 staining of the syncytiotrophoblast (p<0.05) was decreased in these pathological pregnancies compared to controls. No differences in placental expression and serum concentrations of PP13 were found at term between patients with preeclampsia and control women. In contrast, the immunoreactivity of the syncytiotrophoblast microvillous membrane was stronger in both term and preterm preeclampsia and HELLP syndrome than in controls. Moreover, large syncytial cytoplasm protrusions, membrane blebs and shed microparticles strongly stained for PP13 in preeclampsia and HELLP syndrome. In conclusion, parallel to its decreased placental expression, an augmented membrane shedding of PP13 contributes to the increased third trimester maternal serum PP13 concentrations in women with preterm preeclampsia and HELLP syndrome.
doi:10.1007/s00428-008-0658-x
PMCID: PMC2775473  PMID: 18791734
Brush border membrane; galectin; syncytiotrophoblast microparticle; trafficking; virtual microscopy
24.  Perfluoroalkyl chemicals and elevated serum uric acid in US adults 
Clinical Epidemiology  2011;3:251-258.
Background:
Perfluoroalkyl chemicals, including perfluorooctanoic acid and perfluorooctane sulfonate, are man-made chemicals that have been detected in the blood of over 98% of the US population. Serum uric acid is a novel biomarker, even mild elevations of which has been implicated in the development of hypertension, diabetes mellitus, cardiovascular disease, and chronic kidney disease. We examined the relationship of serum perfluoroalkyl chemicals, including perfluorooctanoic acid and perfluorooctane sulfonate, and elevated uric acid levels in a representative sample of US adults.
Methods:
We examined 3883 participants from the 1999–2000 and 2003–2006 National Health and Nutritional Examination Surveys, a representative, multiethnic population-based survey of noninstitutionalized US adults. Serum perfluorooctanoic acid and perfluorooctane sulfonate were analyzed as quartiles. The main outcome was hyperuricemia.
Results:
We found that serum levels of perfluoroalkyl chemicals, including perfluorooctanoic acid and perfluorooctane sulfonate, were positively associated with hyperuricemia. This association appeared to be independent of confounders such as age, gender, race-ethnicity, body mass index, diabetes, hypertension, and serum cholesterol. Compared with subjects in quartile 1 (referent), the multivariate odds ratio for hyperuricemia among subjects in quartile 4 was 1.97 (95% confidence interval 1.44–2.70, P < 0.0001) for perfluorooctanoic acid and 1.48% (95% confidence interval 0.99–2.22, P = 0.0433) for perfluorooctane sulfonate. This observed association persisted in subgroup analysis by gender and body mass index.
Conclusion:
Our results demonstrate that elevated levels of perfluoroalkyl chemicals are associated with hyperuricemia even at low perfluoroalkyl chemical exposure levels as seen in the US general population.
doi:10.2147/CLEP.S21677
PMCID: PMC3191115  PMID: 22003309
perfluoroalkyl chemicals; perfluorooctanoic acid; perfluorooctane sulfonate; uric acid
25.  Should Bilateral Uterine Artery Notching be used in the Risk Assessment for Preeclampsia, Small-for-Gestational-Age, and Gestational Hypertension? 
Objective
To determine the value of bilateral uterine artery notching in the second trimester in the risk assessment for preeclampsia, gestational hypertension, and small-for-gestational age (SGA) without preeclampsia.
Methods
This prospective cohort study included 4,190 singleton pregnancies that underwent ultrasound examination between 23-25 weeks of gestation. The 95th percentile of the mean pulsatility index (PI) and resistance index (RI) of both uterine arteries were calculated. Multivariable logistic regression analyses were performed to determine if bilateral uterine artery notching is an independent explanatory variable for the occurrence of preeclampsia, early-onset preeclampsia (≤34 weeks), late-onset preeclampsia (>34 weeks), gestational hypertension and delivery of an SGA without preeclampsia, while controlling for confounding factors.
Results
1) The prevalence of preeclampsia, early-onset preeclampsia, late-onset preeclampsia, SGA and gestational hypertension were 3.4%, 0.5%, 2.9%, 10%, and 7.9%, respectively; 2) 7.2% of the study population had bilateral uterine artery notching; 3) bilateral uterine artery notching was an independent explanatory variable for the development of preeclampsia [odds ratio (OR) 2.1; 95% confidence interval (CI):1.28-3.36], early-onset preeclampsia (OR: 4.47; 95%CI: 1.50-13.35), and gestational hypertension (OR: 1.50; 95%CI: 1.02-2.26), but not for late-onset preeclampsia or SGA.
Conclusions
Bilateral uterine notching between 23-25 weeks of gestation is an independent risk factor for the development of early-onset preeclampsia and gestational hypertension. Thus, bilateral uterine artery notching should be considered in the assessment of risk for the development of these pregnancy complications.
PMCID: PMC3020574  PMID: 20587434
Small for gestational age; uterine artery Doppler velocimetry; pulsatility index; pregnancy; prediction; early-onset preeclampsia; uteroplacental ischemia

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