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1.  A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy 
The New England journal of medicine  2008;359(9):895-905.
BACKGROUND
Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy.
METHODS
In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo. The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age.
RESULTS
A total of 2241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event.
CONCLUSIONS
Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors. (ClinicalTrials.gov number, NCT00014989.)
doi:10.1056/NEJMoa0801187
PMCID: PMC2803083  PMID: 18753646
2.  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)
3.  Psychometric Evaluation of the Epworth Sleepiness Scale in an Obstetric Population 
Sleep medicine  2012;14(1):116-121.
The Epworth Sleepiness Scale (ESS) was initially developed to measure daytime sleep propensity in patients affected by a variety of sleep disorders. Obstetrical research has measured sleepiness in pregnant women with the ESS, although a psychometric analysis and dimensionality evaluations have never been conducted with this population.
Objective
to perform a psychometric evaluation of the ESS in an obstetric population.
Design
secondary data analysis of subjects enrolled in the Prenatal Exposures and Preeclampsia Prevention III (PEPP) study.
Setting
subjects who received prenatal care at Magee-Women’s Hospital UPMC in Pittsburgh, Pennsylvania.
Participants
337 pregnant women in their first trimester who completed the ESS.
Methods
principal components analysis and confirmatory factor analysis were performed using SPSS and M-Plus. Additionally, reliability was assessed and construct validity was measured using the Life Orientation Test (LOT). Lastly, a relationship between daytime sleepiness and snoring was investigated using Item 5e from the Pittsburgh Sleep Quality Index (PSQI).
Results
PCA with varimax rotation yielded two factors that explained approximately 50% of the variance. CFA results verified the two-factor solution. An overall Cronbach’s alpha (0.751) revealed moderate reliability (Factor 1α = .754 ; Factor 2α = .524 ). Both convergent and discriminant validity were established.
Conclusion
The ESS is appropriate for use in an obstetric population to measure daytime sleepiness. Future work should include additional evaluations of the ESS in a diverse group of pregnant women.
doi:10.1016/j.sleep.2012.10.007
PMCID: PMC3693185  PMID: 23218535
Epworth Sleepiness Scale; pregnancy; psychometrics; sleepiness; sleep; Confirmatory Factor Analysis; Exploratory Factor Analysis
4.  The placenta in preeclampsia 
Pregnancy hypertension  2012;2(2):72-83.
The root cause of preeclampsia is the placenta. Preeclampsia begins to abate with the delivery of the placenta and can occur in the absence of a fetus but with the presence of trophoblast tissue with hydatidiform moles. In view of this, study of the placenta should provide insight into the pathophysiology of preeclampsia. In this presentation we examine placental pathological and pathophysiological changes with preeclampsia and fetal growth restriction (FGR). It would seem that this comparison should be illuminating as both conditions are associated with similarly abnormal placentation yet only in preeclampsia is there a maternal pathophysiological syndrome. Similar insights about early and late onset preeclampsia should also be provided by such information.
We report that the placental abnormalities in preeclampsia are what would be predicted in a setting of reduced perfusion and oxidative stress. However, the differences from FGR are inconsistent. The most striking differences between the two conditions are found in areas that have been the least studied. There are differences between the placental findings in early and late onset preeclampsia but whether these are qualitative, indicating different diseases, or simply quantitative differences within the same disease is difficult to determine.
We attempt to decipher the true differences, seek an explanation for the disparate results and provide recommendations that we hope may help resolve these issues in future studies.
doi:10.1016/j.preghy.2012.01.001
PMCID: PMC3381433  PMID: 22745921
Preeclampsia; Fetal Growth Restriction; Placenta; Pathology; Morphology; Pathophysiology
5.  The Utility of Uterine Artery Doppler Velocimetry in Prediction of Preeclampsia in a Low-Risk Population 
Obstetrics and gynecology  2012;120(4):815-822.
Objective
The underlying pathophysiology of preeclampsia is thought to be abnormal trophoblast invasion of the spiral arteries, leading to maldevelopment of uteroplacental perfusion. We estimated whether uterine artery Doppler measurements made in the early second trimester would predict the subsequent development of preeclampsia.
Methods
Uterine artery Doppler measurements prior to 21 weeks of gestation (median 16.6 weeks) were correlated with subsequent development of preeclampsia in a cohort of 2,188 low-risk nulliparous women in a randomized control trial of antioxidant supplementation for prevention of preeclampsia. Preeclampsia developed in 165 (7.5%) women.
Results
Development of preeclampsia overall was associated with increased resistance index (RI), pulsatility index (PI), a PI or RI multiples of the median (MoM) at or above the 75th %ile, but not the presence of a notch or a bilateral notch prior to 21 weeks. The sensitivity was 43% (95% CI 35–51) and specificity 67% (95% CI 65–69) for prediction of preeclampsia overall. The presence of a notch or bilateral notch, RI and PI MoM were significantly associated with early onset (before 34 weeks of gestation) vs late onset or no preeclampsia (OR = 6.9 (95% CI 2.3–20.9), sensitivity 78% (95% CI 52–94), specificity 66% (95% CI 64–68)). The presence of a notch or RI MoM at or above the 75%ile increased the odds of developing severe vs mild or no preeclampsia (OR=2.2 (95% CI 1.4–3.7), sensitivity 53% (95% CI 40–65), specificity 66% (95% CI 64–68)).
Conclusion
Our data show poor sensitivity of second-trimester Doppler ultrasound measurements for prediction of preeclampsia overall in a well-characterized, low-risk, nulliparous population. The technique has utility in identifying poor trophoblast invasion of spiral arteries of a magnitude that severely compromises uteroplacental blood flow and gives early-onset disease.
doi:10.1097/AOG.0b013e31826af7fb
PMCID: PMC3449210  PMID: 22996099
6.  Excessive Early Gestational Weight Gain And Risk of Gestational Diabetes Mellitus in Nulliparous Women 
Obstetrics and Gynecology  2012;119(6):1227-1233.
Objective
To estimate whether there is an association between excessive early gestational weight gain and the development of gestational diabetes mellitus (GDM) and excessive fetal growth.
Methods
This is a secondary analysis of a randomized controlled trial of vitamins C and E in nulliparous low-risk women. Maternal weight gain from prepregnancy (self-reported) to 15–18 weeks of gestation was measured, and expected gestational weight gain was determined using the Institute of Medicine (IOM) 2009 guidelines for each prepregnancy body mass index (BMI) category. Excessive early gestational weight gain was defined as gestational weight gain greater than the upper range of the IOM guidelines. Rates of GDM, birth weight greater than 4000g, and large for gestational age ([LGA], birth weight 90th percentile or higher) were calculated and compared between women with excessive early gestational weight gain and early nonexcessive gestational weight gain (within or below IOM guidelines).
Results
A total of 7,985 women were studied. Excessive early gestational weight gain occurred in 47.5% of women. Ninety-three percent of women with excessive early gestational weight gain had total gestational weight gain greater than IOM guidelines. In contrast, only 55% of women with nonexcessive early gestational weight gain had total gestational weight gain greater than IOM guidelines (p<0.001). Rates of GDM, LGA, and birth weight greater than 4000 grams were higher in women with excessive early gestational weight gain.
Conclusions
In our population, excessive early gestational weight gain occurred in 93% of women who had total gestational weight gain greater than the IOM guidelines. In low-risk nulliparous women, excessive early gestational weight gain is associated with the development of GDM and excessive fetal growth.
doi:10.1097/AOG.0b013e318256cf1a
PMCID: PMC3360415  PMID: 22617588
7.  Variations in Discovery-based Preeclampsia Candidate Genes 
Preeclampsia is a common and potentially lethal pregnancy disorder with lifelong increased risk of cardiovascular disease in survivors. Our prior global gene expression microarray analysis led to a novel set of 36 candidates in first trimester placentas of women who subsequently developed preeclampsia. In this report, we present preliminary studies demonstrating biomarkers of genotype and methylation variations in a subset of these candidate genes in maternal leukocyte and fetoplacental DNA of 28 case and 27 control dyads. We tested 84 single nucleotide polymorphisms (SNPs) using MassArray iPLEX and 50 CpG sites using EpiTYPER assays. Promising prediction modeling was identified with 25 SNPs selected using Fisher's exact tests (p≤0.05) and 20 CpG sites selected on fold change. Genotype Distribution Analysis identified SNP variations that differed between 9 paired cases versus paired controls. The findings validate the examined candidate genes and support feasibility of methods for further biomarker development. The integrative approach that was implemented begins to translate the 36 candidates toward clinical utility as a screening modality for preeclampsia.
doi:10.1111/j.1752-8062.2012.00413.x
PMCID: PMC3419489  PMID: 22883611
8.  Ambient air pollution exposure and blood pressure changes during pregnancy 
Environmental research  2012;117:46-53.
Background
Maternal exposure to ambient air pollution has been associated with adverse birth outcomes such as preterm delivery. However, only one study to date has linked air pollution to blood pressure changes during pregnancy, a period of dramatic cardiovascular function changes.
Objectives
We examined whether maternal exposures to criteria air pollutants, including particles of less than 10 µm (PM10) or 2.5 µm diameter (PM2.5), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3), in each trimester of pregnancy are associated with magnitude of rise of blood pressure between the first 20 weeks of gestation and late pregnancy in a prospectively followed cohort of 1684 pregnant women in Allegheny County, PA.
Methods
Air pollution measures for maternal ZIP code areas were derived using Kriging interpolation. Using logistic regression analysis, we evaluated the associations between air pollution exposures and blood pressure changes between the first 20 weeks of gestation and late pregnancy.
Results
First trimester PM10 and ozone exposures were associated with blood pressure changes between the first 20 weeks of gestation and late pregnancy, most strongly in non-smokers. Per interquartile increases in first trimester PM10 and O3 concentrations were associated with mean increases in systolic blood pressure of 1.88 mmHg (95% CI = 0.84 to 2.93) and 1.84 (95% CI = 1.05 to 4.63), respectively, and in diastolic blood pressure of 0.63 mmHg (95% CI= −0.50 to 1.76) and 1.13 (95% CI= −0.46 to 2.71) in non-smokers.
Conclusions
Our novel finding suggests that first trimester PM10 and O3 air pollution exposures increase blood pressure in the later stages of pregnancy. These changes may play a role in mediating the relationships between air pollution and adverse birth outcomes.
doi:10.1016/j.envres.2012.05.011
PMCID: PMC3656658  PMID: 22835955
Ambient air pollution; Pregnancy; Blood pressure changes
9.  First-Trimester Prediction of Preeclampsia in Low-Risk Nulliparous Women 
Obstetrics and Gynecology  2012;119(6):1234-1242.
Objective
To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia.
Methods
We conducted a multicenter observational study in 2,434 low-risk nulliparous women to identify biomarkers that possibly predict preeclampsia. Clinical history, complete blood count, and biochemical markers were assessed in the first trimester. The trophoblast and angiogenesis markers ADAM-12 (a disintegrin and metalloprotease 12), pregnancy-associated plasma protein-A (PAPP-A), PP13, placental growth factor (PlGF), soluble fms-like tyrosine kinase-1, and endoglin were measured in a case-control subset of 174 women with preeclampsia and 509 controls.
Results
Univariable analysis revealed maternal age, race, marital status, years of education, source of medical payment, prenatal caregiver, body mass index (BMI), and systolic blood pressure at enrollment were significantly associated with preeclampsia. Mean platelet volume was greater at enrollment in women who later developed preeclampsia (median 9.4 vs 9.0fl, p=0.02). First-trimester concentrations (multiples of the median) of ADAM-12 (1.14 vs 1.04, p=0.003), PAPP-A (0.94 vs 0.98, p=0.04), and PlGF (0.83 vs 1.04, p<0.001) were significantly different in women who developed preeclampsia compared with controls. The optimal multivariable model included African American race, systolic blood pressure, BMI, education level, ADAM-12, PAPP-A and PlGF, and yielded an area under the curve of 0.73 (95% CI 0.69–0.77) and a sensitivity of 46.1% (95% CI 38.3–54.0) for 80% specificity.
Conclusion
A multivariable analysis of clinical data and biochemical markers in the first trimester did not identify a model that had clinical utility for predicting preeclampsia in a low-risk nulliparous population.
doi:10.1097/AOG.0b013e3182571669
PMCID: PMC3360523  PMID: 22617589
10.  Haptoglobin Phenotype, Angiogenic Factors and Preeclampsia Risk 
American Journal of Obstetrics and Gynecology  2012;206(4):358.e10-358.e18.
Objectives
To determine whether haptolgobin phenotype is related to preeclampsia risk, or to plasma concentrations of soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF).
Study Design
Haptoglobin phenotype was retrospectively determined in primiparous women with uncomplicated pregnancies (n=309), gestational hypertension (n=215) and preeclampsia (n=249). Phenotype was assessed by peroxidase staining following native polyacrylamide gel electrophoresis of hemoglobin-supplemented serum.
Results
Compared to haptoglobin 1-1, haptoglobin 2-1 was associated with a significantly increased risk of preeclampsia (odds ratio (95% confidence interval) 2.11 (1.07, 4.18)) and term preeclampsia (2.45 (1.07, 5.83)) in Caucasian women. Haptoglobin phenotype was not associated with preeclampsia risk in African Americans. Preeclamptic women had higher plasma sEng and sFlt-1, and lower PlGF, than controls. sEng, sFlt-1 and PlGF did not differ among women of different haptoglobin phenotypes.
Conclusion
Haptoglobin 2-1 is associated with higher preeclampsia risk in primiparous Caucasian women.
doi:10.1016/j.ajog.2012.01.009
PMCID: PMC3319170  PMID: 22340942
Haptoglobin phenotype; angiogenesis; preeclampsia; gestational hypertension
11.  Variation in endoglin pathway genes is associated with preeclampsia: a case–control candidate gene association study 
Background
Preeclampsia is a hypertensive, multi-system pregnancy disorder whose pathophysiology remains unclear. Elevations in circulating soluble endoglin (sENG) and placental/blood ENG mRNA expression antedate the clinical onset of preeclampsia. This study investigated if endoglin (ENG) pathway genetic variation was also associated with the development of preeclampsia.
Methods
We used a case–control candidate gene association design. Data from 355 white (181 preeclampsia cases/174 controls) and 60 black (30 preeclampsia cases/30 controls) women matched on ancestry, age, and parity were analyzed. Tagging single nucleotide polymorphisms (tSNPs) and potentially functional SNPs in ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2 were genotyped with iPLEX® and TaqMan®. Chi-square or Fisher’s exact tests were used to conduct allele/genotype/haplotype tests in white/black subgroups separately. Odds ratios were computed with binary logistic regression for tSNPs with significant genotype tests.
Results
Of the 49 SNPs evaluated, variation in two ENG tSNPs (rs11792480, rs10121110) and one TGFβR2 tSNP (rs6550005) was associated with preeclampsia in white women (P <0.05, each). In black women, variation in two TGFβ1 tSNPs (rs4803455, rs4803457), one TGFβR1 tSNP (rs10739778), and three TGFβR2 tSNPs (rs6550005, rs1346907, rs877572) was associated with preeclampsia (P <0.05, each). Further evaluation of ENG tSNP rs10121110 revealed that white women inheriting the AA genotype were 2.29 times more likely to develop preeclampsia compared to the GG genotype (P = 0.008, [99% CI: 1.02 to 5.13]). For black women, similar evaluation of TGFβ1 tSNP rs4803457 revealed women inheriting the CT genotype were 7.44 times more likely to develop preeclampsia than those with the CC genotype (P = 0.005, [99% CI: 1.19 to 46.41]).
Conclusions
ENG pathway genetic variation is associated with preeclampsia. Different ENG pathway genes may be involved in preeclampsia development among white and black women. Additional studies are needed to validate these findings and to determine if genetic variation in ENG pathway genes impacts ENG and sENG levels in preeclampsia.
doi:10.1186/1471-2393-13-82
PMCID: PMC3651360  PMID: 23548068
Endoglin; Genetic association study; Preeclampsia; SNP
12.  LOW PGF ACROSS PREGNANCY IDENTIFIES A SUBSET OF WOMEN WITH PRETERM PREECLAMPSIA; TYPE 1 vs. TYPE 2 PREECLAMPSIA? 
Hypertension  2012;60(1):239-246.
Preeclampsia is a heterogeneous syndrome affecting 3–5% of all pregnancies. An imbalance of the anti and pro-angiogenic factors, soluble receptor fms-like tyrosine kinase 1 (sFLT1) and placental growth factor (PGF), are thought to contribute to the pathophysiology of preeclampsia. Maternal plasma PGF and sFLT1 were quantified by specific immunoassays in cross-sectional samples from 130 preeclamptic subjects and 342 normotensive controls at delivery, and longitudinally in samples from 50 women who developed preeclampsia and 250 normotensive controls. Among women who developed preeclampsia, 46% (n=23) evidenced a pattern of consistently low maternal PGF across pregnancy below the lower 95%CI of controls from 15 weeks gestation to term. In contrast, the remaining 54% (n=27) women who developed preeclampsia had maternal PGF concentrations similar to or above (n=7) those of normotensive controls. Subjects with low PGF across pregnancy who developed preeclampsia evidenced significantly higher blood pressure in early pregnancy (p<0.05), and after diagnosis, earlier gestational age at delivery (p<0.05), and more preterm birth (p<0.05) compared to preeclamptic patients with high PGF. A significant subset of women who develop preeclampsia evidence consistently low PGF across pregnancy. Low PGF with preeclampsia was associated with preterm delivery compared to preeclamptic patients with high PGF. Identifying women with consistently low plasma PGF during pregnancy may provide a greater understanding of preeclampsia pathophysiology, and may provide more focused research and clinical activities.
doi:10.1161/HYPERTENSIONAHA.112.191213
PMCID: PMC3578235  PMID: 22647886
pregnancy; preeclampsia; preterm birth; placental growth factor; soluble vascular endothelial growth factor receptor-1
13.  Loss of Cyclin-Dependent Kinase 2 (CDK2) Inhibitory Phosphorylation in a CDK2AF Knock-In Mouse Causes Misregulation of DNA Replication and Centrosome Duplication 
Molecular and Cellular Biology  2012;32(8):1421-1432.
Cyclin-dependent kinase 1 (CDK1) inhibitory phosphorylation controls the onset of mitosis and is essential for the checkpoint pathways that prevent the G2- to M-phase transition in cells with unreplicated or damaged DNA. To address whether CDK2 inhibitory phosphorylation plays a similar role in cell cycle regulation and checkpoint responses at the start of the S phase, we constructed a mouse strain in which the two CDK2 inhibitory phosphorylation sites, threonine 14 and tyrosine 15, were changed to alanine and phenylalanine, respectively (CDK2AF). This approach showed that inhibitory phosphorylation of CDK2 had a major role in controlling cyclin E-associated kinase activity and thus both determined the timing of DNA replication in a normal cell cycle and regulated centrosome duplication. Further, DNA damage in G1 CDK2AF cells did not downregulate cyclin E-CDK2 activity when the CDK inhibitor p21 was also knocked down. We were surprised to find that this was insufficient to cause cells to bypass the checkpoint and enter the S phase. This led to the discovery of two previously unrecognized pathways that control the activity of cyclin A at the G1 DNA damage checkpoint and may thereby prevent S-phase entry even when cyclin E-CDK2 activity is deregulated.
doi:10.1128/MCB.06721-11
PMCID: PMC3318579  PMID: 22331465
14.  The Two Stage Model of Preeclampsia: Variations on the Theme 
Placenta  2008;30(Suppl A):S32-S37.
The Two Stage Model of preeclampsia proposes that a poorly perfused placenta (Stage 1) produces factor(s) leading to the clinical manifestations of preeclampsia (Stage2). Stage 1 is not sufficient to cause the maternal syndrome but interacts with maternal constitutional factors (genetic, behavioral or environmental) to result in Stage 2. Recent information indicates the necessity for modifications of this model. It is apparent that changes relevant to preeclampsia and other implantation disorders can be detected in the first trimester, long before the failed vascular remodeling necessary to reduce placental perfusion. In addition, although the factor(s) released from the placenta has usually been considered a toxin, we suggest that what is released may also be an appropriate signal from the fetal/placental unit to overcome reduced nutrient availability that cannot by tolerated by some women who develop preeclampsia. Further, it is evident that linkage is not likely to be by one factor but several, different for different women. Also although the initial model limited the role of maternal constitutional factors to the genesis of Stage 2, this does not appear to be the case. It is evident that the factors increasing risk for preeclampsia are also associated with abnormal implantation. These several modifications have important implications. An earlier origin for Stage 1, which appears to be recognizable by altered concentrations of placental products, could allow earlier intervention. The possibility of a fetal placental factor increasing nutrient availability could provide novel therapeutic options. Different linkages and preeclampsia subtypes could direct specific preventive treatments for different women while the role of maternal constitutional factors to affect placentation provides targets for prepregnancy therapy. The modified Two Stage Model provides a useful guide towards investigating pathophysiology and guiding therapy.
doi:10.1016/j.placenta.2008.11.009
PMCID: PMC2680383  PMID: 19070896
15.  Cardiovascular System during the Post Partum State in Women with a History of Preeclampsia 
Hypertension  2011;58(1):57-62.
Hypothesis
In subjects with previous preeclampsia, differences in cardiovascular and/or blood biochemical parameters are present in the non-pregnant state and that a simultaneous assessment of multiple derived indices better differentiates between women with or without prior preeclampsia.
We examined 18 prior preeclamptic and 50 prior uncomplicated pregnancies, ~16 months post partum. Cardiovascular assessment included: (1) systemic hemodynamics and mechanics (Doppler echocardiography, tonometry, oscillometric sphygmomanometry) (2) endothelial function (plethysmography) (3) left ventricular properties (echocardiography), and (4) blood biochemical analyses.
Compared to women with prior uncomplicated pregnancies, prior preeclamptics had higher mean (80±1 vs. 86±3 mmHg, P=0.04) and diastolic (64±1 vs. 68±2 mmHg; P=0.04) pressures and total vascular resistance (1562±37 vs. 1784±114 dyne•s/cm5; P=0.03). Systolic blood pressure, arterial compliance, and left ventricular properties were not different. While heart-to-femoral pulse wave velocity was not different, heart-to-brachial pulse wave velocity tended to be faster in prior preeclamptics (374±8 vs. 404±20 cm/s; P=0.06). Stress-induced increase in forearm blood flow was less in prior preeclamptics (245±21% vs. 136±22%; P=0.01), indicating impaired endothelial function. No significant differences were observed in markers of endothelial activation, dyslipidemia, or oxidative stress; prior preeclamptics tended to have higher glucose level (58.7±1.9 vs. 95±5.2 mg/dl; P=0.06). Logistic regression analysis indicated that a simultaneous evaluation of multiple derived indices better discriminated between the two groups. The differences in the prior preeclamptic group are in directions known to be associated with greater cardiovascular disease risk later in life.
doi:10.1161/HYPERTENSIONAHA.111.173278
PMCID: PMC3139979  PMID: 21606389
preeclampsia; cardiac function; blood pressure; plethysmography; vascular resistance; compliance; endothelial function
16.  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
17.  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
18.  Maternal Insulin Resistance and Preeclampsia 
Objective
To determine whether midtrimester insulin resistance (IR) is associated with subsequent preeclampsia.
Study Design
This is a secondary analysis of 10,154 nulliparas administered vitamin C and E or placebo daily from 9-16 weeks' gestation until delivery. Of these, 1,187 women had fasting plasma glucose and insulin tested between 22 and 26 weeks' gestation. IR was calculated by the homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI).
Results
Obese women were twice as likely to have a HOMA-IR ≥ 75th percentile. Hispanic and African-American women had a higher percentage ≥ 75th percentile for HOMA-IR than Caucasians (42.2, 27.2 and 16.9%, respectively, p<0.001). HOMA-IR ≥ 75th percentile was higher among the 85 nulliparas who subsequently developed preeclampsia compared with women who remained normotensive (40.5% vs. 24.8%; adjusted odds ratio 1.9, 95% confidence interval [1.1-3.2]). QUICKI results were similar to HOMA-IR.
Conclusion
Midtrimester maternal IR is associated with subsequent preeclampsia.
doi:10.1016/j.ajog.2011.02.024
PMCID: PMC3127262  PMID: 21458622
Insulin resistance; low risk nulliparas; risk for preeclampsia
19.  Prior Preterm or Small-for-Gestational-Age Birth Related to Maternal Metabolic Syndrome 
Obstetrics and gynecology  2011;117(2 Pt 1):225-232.
OBJECTIVE
To estimate whether women who deliver small babies due to preterm birth or growth restriction have excess risk for cardiovascular disease and diabetes later in life.
METHODS
Eight years after pregnancy, we estimated the prevalence of metabolic syndrome and its components in a cohort study of women with prior preterm (preterm birth before 37 weeks, n=181) or small for gestational age ([SGA], less than the tenth percentile, n=192) births, compared with women with term births (37 or more weeks, n=306). Women delivered at Magee-Womens Hospital in Pittsburgh, Pennsylvania, and those with preeclampsia or prepregnancy diabetes or hypertension were excluded. Women underwent a structured interview and fasting blood sampling.
RESULTS
Women were, on average, 8 years postpartum and 39 years old at evaluation. Women with a prior preterm birth had higher blood pressure, triglycerides, and LDL-cholesterol compared with those in a term control group. Women with prior SGA births were leaner and more likely to smoke compared with those with term births. Women with prior preterm birth had elevated risk of metabolic syndrome, adjusted for demographic, smoking and body size factors (23% preterm compared with 17% control group; odds ratio [OR] 1.76 [1.06, 2.80]). In women with a prior preterm birth, low HDL (11% preterm compared with 5% control group; OR 2.6 [1.2, 5.2]), hypertriglyceridemia (22% compared with 14%; OR 1.9 [1.2, 2.9]), and elevated glucose (24% compared with 19%; OR 1.5 [1.0, 2.3]) accounted for this excess metabolic syndrome. In women with SGA, the only element of metabolic syndrome that was aberrant was glucose metabolism.
CONCLUSION
Eight years after pregnancy, women with prior preterm or SGA births had evidence of metabolic syndrome compared with women with term births. Screening and intervention in these women after pregnancy may delay or prevent disease.
doi:10.1097/AOG.0b013e3182075626
PMCID: PMC3074407  PMID: 21252733
20.  p27Kip1 controls cytokinesis via the regulation of citron kinase activation  
p27Kip1 (p27) acts as a tumor suppressor by inhibiting cyclin–cyclin-dependent kinase (cyclin-CDK) activity. However, mice expressing a form of p27 that is unable to bind or inhibit cyclin-CDK complexes (p27CK–) have increased incidence of tumor development as compared with wild-type and p27–/– mice, revealing an oncogenic role for p27. Here, we identified a phenotype of multinucleation and polyploidy in p27CK– mice not present in p27–/– animals, suggesting a role for p27 in G2/M that is independent of cyclin-CDK regulation. Further analysis revealed that p27CK– expression caused a cytokinesis and abscission defect in mouse embryonic fibroblasts. We identified the Rho effector citron kinase (citron-K) as a p27-interacting protein in vitro and in vivo and found that p27 and citron-K colocalized at the contractile ring and mid-body during telophase and cytokinesis. Moreover, overexpression of the minimal p27-binding domain of citron-K was sufficient to rescue the phenotype caused by p27CK–. Conversely, expression of a mutant p27CK– unable to bind citron-K did not induce multinucleation. Finally, by binding to citron-K, p27 prevented the interaction of citron-K with its activator RhoA. Taken together, these data suggest a role for p27 during cytokinesis via the regulation of citron-K activity.
doi:10.1172/JCI60376
PMCID: PMC3287231  PMID: 22293177
21.  Is There Evidence of Separate Inflammatory or Metabolic Forms of Preeclampsia? 
Objectives
To examine whether high insulin resistance versus high inflammation identifies subtypes of preeclampsia.
Methods
A cytokine panel, glucose and insulin were measured in 37 preeclampsia plasma samples. Wilcoxon rank sum assessed median concentration of HOMAIR by pro-inflammatory: anti-inflammatory ratio. Regression stratifying by BMI and preterm birth was conducted.
Results
There was no difference in median HOMAIR by the pro-inflammatory: anti-inflammatory ratio (p = 0.16). No subsets scatterplot clusters emerged. A positive correlation between HOMAlog and the ratio was significant (p = 0.04).
Conclusions
No dichotomous subsets of preeclampsia by inflammation versus insulin resistance were detected. Contrary to our hypothesis, insulin resistance was higher as inflammation increased in preeclampsia.
doi:10.3109/10641950903322907
PMCID: PMC3066632  PMID: 20462373
Multi-plex cytokines; Subtypes; Systems biology; Pregnancy complication
22.  The Role of Obesity in Preeclampsia 
Pregnancy hypertension  2011;1(1):6-16.
The incidence of obesity is increasing at an alarming rate. There is compelling evidence that obesity increases the risk of preeclampsia about 3-fold, and in developed countries is the leading attributable risk for the disorder. In this presentation we explore this relationship and propose targets for future studies guided by the much more extensively studied relationship of obesity to cardiovascular disease. We further address the hypothesis that asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be one convergence point for the mechanism by which obesity increases the risk of preeclampsia. We conclude with consideration of the clinical implications of this information.
doi:10.1016/j.preghy.2010.10.013
PMCID: PMC3082136  PMID: 21532964
23.  Caffeine and insulin resistance in pregnancy 
American journal of perinatology  2011;28(7):571-578.
Outside pregnancy, acute caffeine consumption is associated with insulin resistance. We investigated if during pregnancy plasma concentrations of caffeine and its metabolite, paraxanthine, were associated with insulin resistance. Caffeine, paraxanthine, glucose and insulin were measured and insulin resistance estimated by homeostasis model assessment (HOMA) in banked samples from 251 fasting subjects at mean gestational age of 20.3 ± 2.0 weeks. Analysis of covariance and adjusted logistic regression were performed. Most (96.4%) women had caffeine and/or paraxanthine present. Caffeine concentrations in the upper two quartiles (> 266 ng/ml) were associated with 3-fold higher odds of having higher insulin resistance estimated by log HOMA ≥ 75th percentile (3rd quartile OR, 3.02; 95% CI: 1.21 – 7.54 and 4th quartile OR, 2.95; 95% CI: 1.19 – 7.31). Paraxanthine concentrations in the upper quartile (> 392 ng/ml) were also associated with 3-fold higher odds of having higher insulin resistance (OR, 3.04; 95% CI: 1.28 – 7.25). Adjusted mean HOMA in the 1st caffeine to paraxanthine ratio quartile was 1.5 ± 2.2 versus 1.3 ± 2.3 in the 4th quartile (P < .01). Both high caffeine and paraxanthine concentrations were associated with insulin resistance, but slow versus fast metabolism did not make an important difference.
doi:10.1055/s-0031-1274511
PMCID: PMC3116064  PMID: 21380987
caffeine; insulin resistance; paraxanthine
24.  Cyclin A Promotes S-Phase Entry via Interaction with the Replication Licensing Factor Mcm7 ▿ †  
Molecular and Cellular Biology  2010;31(2):248-255.
Cyclin A is known to promote S-phase entry in mammals, but its critical targets in this process have not been defined. We derived a novel human cyclin A mutant (CycA-C1), which can activate cyclin-dependent kinase but cannot promote S-phase entry, and isolated replication licensing factor Mcm7 as a factor that interacts with the wild-type cyclin A but not with the mutant. We demonstrated that human cyclin A and Mcm7 interact in the chromatin fraction. To address the physiological significance of the cyclin A-Mcm7 interaction, we isolated an Mcm7 mutant (Mcm7-3) that is capable of association with CycA-C1 and found that it can also suppress the deficiency of CycA-C1 in promoting S-phase entry. Finally, RNA interference experiments showed that the CycA-C1 mutant is defective for the endogenous cyclin A function in S-phase entry and that this defect can be suppressed by the Mcm7-3 mutant. Our findings demonstrate that interaction with Mcm7 is essential for the function of cyclin A in promoting S-phase entry.
doi:10.1128/MCB.00630-10
PMCID: PMC3019979  PMID: 21078875
25.  Who is teaching and supervising our junior residents' central venous catheterizations? 
BMC Medical Education  2011;11:16.
Background
The extent to which medical residents are involved in the teaching and supervision of medical procedures is unknown. This study aims to evaluate the teaching and supervision of junior residents in central venous catheterization (CVC) by resident-teachers.
Methods
All PGY-1 internal medicine residents at two Canadian academic institutions were invited to complete a survey on their CVC experience, teaching, and supervision prior to their enrolment in a simulator CVC training curriculum.
Results
Of the 69 eligible PGY-1 residents, 32 (46%) consenting participants were included in the study. There were no significant baseline differences between participants from the two institutions in terms of sex, number of ICU months completed, previous CVC training received, number of CVCs observed and performed. Only 16 participants (50%) received any CVC training at baseline. Of those who received any training, 63% were taught only by senior resident-teachers. A total of 81 CVCs were placed by 17 participants. Thirty-two CVCs (45%) were supervised by resident-teachers.
Conclusions
Resident-teachers play a significant role both in the teaching and supervision of CVCs placed by junior residents. Educational efforts should focus on preparing residents for their role in teaching and supervision of procedures.
doi:10.1186/1472-6920-11-16
PMCID: PMC3098212  PMID: 21513575

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