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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.
Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy.
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.
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.
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. ( number, NCT00014989.)
PMCID: PMC2803083  PMID: 18753646
2.  Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy 
Oncotarget  2015;5(24):12704-12714.
As a cell cycle inhibitor and tumor suppressor, p27 is frequently misregulated in human cancers. Increased degradation is the most common mechanism of misregulation, however in some cancers, p27 is mislocalized from its cell cycle inhibitory location in the nucleus, to the cytoplasm. In normal cells cytoplasmic p27 has functions that are distinct from its cell cycle-regulatory nuclear functions. Therefore, an important question is whether localization of p27 to the cytoplasm in tumor cells is primarily a mechanism for cancelling its inhibitory effect on cell proliferation, or whether cytoplasmic p27 has more direct oncogenic actions. To study p27 mislocalization in human cancers we screened a panel of common breast cancer cell lines. We observed that p27 accumulated in the cytoplasm exclusively in cell lines that are Her2+. To address the significance of p27 mislocalization in Her2+ breast cancer cells we interrogated the cellular response to the dual-Her2/EGFR kinase inhibitor, lapatinib. Knockdown of p27 using shRNA sensitized Her2+ cells to lapatinib-induced apoptosis. Moreover, expression of a constitutively cytoplasmic form of p27 (p27ΔNLS) reversed the lapatinib-induced apoptosis, suggesting that cytoplasmic p27 contributed to lapatinib resistance in Her2+ breast cancer cells by suppressing apoptosis. Our results suggest that p27 localization may be useful as a predictive biomarker of therapeutic response in patients with Her2+ breast cancers.
PMCID: PMC4350358  PMID: 25587029
p27Kip1 (p27); cell proliferation; cytoplasmic localization; Her2+ breast cancer cells; lapatinib; drug sensitivity
3.  If we know so much about preeclampsia, why haven't we cured the disease? 
Preeclampsia has been recognized for at least 100 years. In the last 20 years, the consideration of the disorder as more than simply hypertension in pregnancy has led to an explosion in knowledge about preeclampsia pathophysiology. It is now evident that for most cases of preeclampsia, the root cause is the placenta. Relatively reduced placental perfusion leads to inflammation, oxidative stress, and endoplasmic reticulum stress, which converge to modify maternal physiology, with endothelium an important target. Although preeclampsia is characteristically diagnosed in the last third of pregnancy, it is evident that many of these pathophysiological changes can be detected long before clinically evident disease. Furthermore, it is evident that the “maternal constitution,” including genetic, behavioral, and metabolic factors, influences the maternal response to the abnormal placentation of preeclampsia. These insights would seem to provide a guide for the prediction of the disorder in early pregnancy, along with targets for intervention. However, this has not been the case. Predictive tests guided by this knowledge do not predict well and several interventions guided by the expanded understanding of pathophysiology do not prevent the disease. We propose that these failures are secondary to the fact that preeclampsia is more than one disorder. Further, we suggest that future progress toward prediction and prevention will require research guided by this concept.
PMCID: PMC4066309  PMID: 23890710
Preeclampsia; Pathophysiology; Prediction; Prevention; Translation
4.  Maternal vitamin D status and the risk of mild and severe preeclampsia 
Epidemiology (Cambridge, Mass.)  2014;25(2):207-214.
We sought to determine the association between maternal vitamin D status at ≤26 weeks gestation and the risk of preeclampsia separately by clinical subtype.
We conducted a case-cohort study among women enrolled at 12 U.S. sites from 1959 to 1966 in the Collaborative Perinatal Project. In 717 women who later developed preeclampsia (560 mild and 157 severe cases) and in 2986 mothers without preeclampsia, we measured serum 25-hydroxyvitamin D at ≤26 weeks gestation (median 20.9 weeks) over 40 years later using liquid-chromatography-tandem mass spectrometry.
Half of women in the subcohort had 25(OH)D <50 nmol/L. Maternal 25(OH)D 50–<75 nmol/L was associated with a reduction in the absolute and relative risk of preeclampsia and mild preeclampsia compared with 25(OH)D <30 nmol/L, but the effects were no longer present after adjustment for confounders including race, prepregnancy body mass index, and parity. For severe preeclampsia, 25(OH)D ≥50 nmol/L was associated with a reduction of 3 cases per 1,000 pregnancies (adjusted RD −.003, 95% CI: −.005, .0002) and a 40% reduction in risk (adjusted RR .65, 95% CI .43, .98) compared with 25(OH)D <50 nmol/L. The conclusions were the same after restricting to women with 25(OH)D measured at <22 weeks gestation and after formal sensitivity analyses for unmeasured confounding.
Maternal vitamin D deficiency may be a risk factor for severe preeclampsia, but it is not associated with preeclampsia overall or its mild subtypes. Contemporary cohorts with large numbers of severe preeclampsia cases are needed to confirm or refute these findings.
PMCID: PMC4053531  PMID: 24457526
5.  Particulate Air Pollution Exposure and C-reactive Protein During Early Pregnancy 
Epidemiology (Cambridge, Mass.)  2011;22(4):524-531.
It is not well understood how air pollution leads to adverse pregnancy outcomes. One pathway may be through C-reactive protein, a biomarker of systemic inflammation that has been reported to increase the risk of preterm delivery. We examined whether air pollution influences serum concentrations of C-reactive protein in early pregnancy.
We studied 1696 pregnant women in Allegheny County, PA, from 1997 through 2001. C-reactive protein concentrations were assayed in blood collected before the 22nd week of gestation. We estimated levels of particles of less than 10 μm (PM10) and less than 2.5 μm diameter (PM2.5), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone at the maternal zip code using Kriging interpolation for measurements obtained from ambient stations. Associations between air pollution and high C-reactive protein concentrations (≥8 ng/mL) were evaluated using logistic regression.
Among nonsmokers, an observed 9.2 μg/m3 increase in PM10 (averaged over 28 days prior to the blood sample) was associated with an odds ratios of 1.41 for high C-reactive protein concentrations (95% confidence interval = 0.99–2.00). Similarly, a 4.6 μg/m3 increase in PM2.5 was associated with an odds ratio of 1.47 (1.05–2.06). The odds ratio was 1.49 (0.75–2.96) per 7.9 ppb increase in ozone during summer. There were no associations in smokers or for other air pollutants, and there was no evidence for effect-measure modification by obesity.
PM10, PM2.5, and ozone exposures were associated with increased C-reactive protein concentrations in early pregnancy, suggesting that these air pollutants contribute to inflammation and thereby possibly to adverse pregnancy outcomes.
PMCID: PMC4325994  PMID: 21516040
6.  Prenatal Chlamydia trachomatis infection increases the risk of preeclampsia 
Pregnancy hypertension  2013;3(3):151-154.
The relationship between Chlamydia trachomatis (CT) and preeclampsia was examined longitudinally among 205 cases and 423 normotensive controls nested within the Collaborative Perinatal Project. Antibodies were analyzed at a first prenatal visit (mean 14.2 weeks) and at delivery. Prenatal infections were identified as IgG/IgM seroconversion or a four-fold rise in IgG antibody titers. Although serological evidence of incident prenatal CT infection was uncommon (n=9, 1.4%) in this general pregnant population, infected women were more likely to develop preeclampsia, after adjustment for maternal age, body mass index, smoking status, race and time between blood draws (ORadj 7.2, 95% CI 1.3 – 39.7).
PMCID: PMC3775369  PMID: 24058897
Chlamydia trachomatis; Chlamydia pneumoniae; cytomegalovirus; herpes simplex virus; preeclampsia
7.  Maternal Vitamin D Deficiency Increases the Risk of Preeclampsia 
Vitamin D has direct influence on molecular pathways proposed to be important in the pathogenesis of preeclampsia, yet the vitamin D-preeclampsia relation has not been studied.
We aimed to assess the effect of maternal 25-hydroxyvitamin D [25(OH)D] concentration on the risk of preeclampsia and to assess the vitamin D status of newborns of preeclamptic mothers.
Design and Setting
We conducted a nested case-control study of pregnant women followed from less than 16 wk gestation to delivery (1997–2001) at prenatal clinics and private practices.
Patients included nulliparous pregnant women with singleton pregnancies who developed preeclampsia (n = 55) or did not develop preeclampsia (n = 219). Women’s banked sera were newly measured for 25(OH)D.
Main Outcome Measure
The main outcome measure was preeclampsia (new-onset gestational hypertension and proteinuria for the first time after 20 wk gestation). Our hypotheses were formulated before data collection.
Adjusted serum 25(OH)D concentrations in early pregnancy were lower in women who subsequently developed preeclampsia compared with controls [geometric mean, 45.4 nmol/liter, and 95% confidence interval (CI), 38.6 –53.4 nmol/liter, vs. 53.1 and 47.1–59.9 nmol/liter; P < 0.01]. There was a monotonic dose-response relation between serum 25(OH)D concentrations at less than 22 wk and risk of preeclampsia. After confounder adjustment, a 50-nmol/liter decline in 25(OH)D concentration doubled the risk of preeclampsia (adjusted odds ratio, 2.4; 95% CI, 1.1–5.4). Newborns of preeclamptic mothers were twice as likely as control newborns to have 25(OH)D less than 37.5 nmol/liter (adjusted odds ratio, 2.2; 95% CI, 1.2– 4.1).
Maternal vitamin D deficiency may be an independent risk factor for preeclampsia. Vitamin D supplementation in early pregnancy should be explored for preventing preeclampsia and promoting neonatal well-being.
PMCID: PMC4288954  PMID: 17535985
8.  High Prevalence of Vitamin D Insufficiency in Black and White Pregnant Women Residing in the Northern United States and Their Neonates1 
The Journal of nutrition  2007;137(2):447-452.
In utero or early-life vitamin D deficiency is associated with skeletal problems, type 1 diabetes, and schizophrenia, but the prevalence of vitamin D deficiency in U.S. pregnant women is unexplored. We sought to assess vitamin D status of pregnant women and their neonates residing in Pittsburgh by race and season. Serum 25-hydroxyvitamin D (25(OH)D) was measured at 4–21 wk gestation and predelivery in 200 white and 200 black pregnant women and in cord blood of their neonates. Over 90% of women used prenatal vitamins. Women and neonates were classified as vitamin D deficient [25(OH)D <37.5 nmol/L], insufficient [25(OH)D 37.5–80 nmol/L], or sufficient [25(OH)D >80 nmol/L]. At delivery, vitamin D deficiency and insufficiency occurred in 29.2% and 54.1% of black women and 45.6% and 46.8% black neonates, respectively. Five percent and 42.1% of white women and 9.7% and 56.4% of white neonates were vitamin D deficient and insufficient, respectively. Results were similar at <22 wk gestation. After adjustment for prepregnancy BMI and periconceptional multivitamin use, black women had a smaller mean increase in maternal 25(OH)D compared with white women from winter to summer (16.0 ± 3.3 nmol/L vs. 23.2 ± 3.7 nmol/L) and from spring to summer (13.2 ± 3.0 nmol/L vs. 27.6 ± 4.7 nmol/L) (P < 0.01). These results suggest that black and white pregnant women and neonates residing in the northern US are at high risk of vitamin D insufficiency, even when mothers are compliant with prenatal vitamins. Higher-dose supplementation is needed to improve maternal and neonatal vitamin D nutriture.
PMCID: PMC4288960  PMID: 17237325
9.  Pregnancy Outcomes With Weight Gain Above or Below the 2009 Institute of Medicine Guidelines 
Obstetrics and gynecology  2013;121(5):969-975.
To evaluate pregnancy outcomes according to 2009 Institute of Medicine (IOM) gestational weight gain guidelines.
This study is a secondary analysis of a preeclampsia prevention trial among nulliparas carrying singletons. Odds ratios and 95% confidence intervals (adjusted for maternal age, race, smoking, and treatment group) were calculated based on total weight gain below or above the IOM guidelines, stratified by prepregnancy body mass index (BMI). The referent group was weight gain within the guidelines.
Of 8,293 pregnancies, 9.5% had weight gain below, 17.5% within, and 73% above IOM guidelines. With excess weight gain, all BMI categories had an increased risk of hypertensive disorders; normal weight and overweight women also had increased risk of cesarean delivery and infant birth weight at or above the 90th centile but a decreased risk of weight below the10th centile. There were no consistent associations with insufficient weight gain and adverse outcomes.
Excess weight gain was prevalent and associated with an increased risk of hypertensive disorders, cesarean delivery and large for gestational age infants..
PMCID: PMC3971915  PMID: 23635732
10.  Prevalence of Sleep Deficiency in Early Gestation and its Associations with Stress and Depressive Symptoms 
Journal of Women's Health  2013;22(12):1028-1037.
Sleep deficiency is an emerging concept denoting a deficit in the quantity or quality of sleep. This may be particularly salient for pregnant women since they report considerable sleep complaints. Sleep deficiency is linked with morbidity, including degradations in psychosocial functioning, (e.g., depression and stress), which are recognized risk factors for adverse pregnancy outcomes. We sought to describe the frequency of sleep deficiency across early gestation (10–20 weeks) and whether sleep deficiency is associated with reports of more depressive symptoms and stress.
Pregnant women (N=160) with no self-reported sleep or psychological disorder provided sleep data collected via diary and actigraphy during early pregnancy: 10–12, 14–16, and 18–20 weeks' gestation. Sleep deficiency was defined as short sleep duration, insufficient sleep, or insomnia. Symptoms of depression and stress were collected at the same three time points. Linear mixed effects models were used to analyze the data.
Approximately 28%–38% met criteria for sleep deficiency for at least one time point in early gestation. Women who were sleep deficient across all time points reported more perceived stress than those who were not sleep deficient (p<0.01). Depressive symptoms were higher among women with diary-defined sleep deficiency across all time points (p=0.02).
Sleep deficiency is a useful concept to describe sleep recognized to be disturbed in pregnancy. Women with persistent sleep deficiency appear to be at greater risk for impairments in psychosocial functioning during early gestation. These associations are important since psychosocial functioning is a recognized correlate of adverse pregnancy outcomes. Sleep deficiency may be another important risk factor for adverse pregnancy outcomes.
PMCID: PMC3852611  PMID: 24117003
11.  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.
PMCID: PMC3381433  PMID: 22745921
Preeclampsia; Fetal Growth Restriction; Placenta; Pathology; Morphology; Pathophysiology
12.  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.
PMCID: PMC3318579  PMID: 22331465
13.  Haptoglobin Phenotype, Preeclampsia and Response to Vitamin C and E Supplementation in Pregnant Women with Type 1 Diabetes 
The phenotype of the anti-oxidant and pro-angiogenic protein haptoglobin (Hp) predicts cardiovascular disease risk and treatment response to antioxidant vitamins in individuals with diabetes. Our objective was to determine whether the Hp phenotype influences preeclampsia risk, or the efficacy of vitamins C and E in preventing preeclampsia, in women with Type 1 diabetes.
This is a secondary analysis of a randomized controlled trial in which women with diabetes received daily vitamins C and E, or placebo, from 8–22 weeks gestation until delivery.
25 antenatal metabolic clinics across the UK (northwest England, Scotland, and Northern Ireland).
Pregnant women with Type 1 diabetes.
Hp phenotype was determined in white women who completed the study, and had plasma samples available (n=685). \
Main Outcome Measures
Compared to Hp 2-1, Hp 1-1 (odds ratio: 0.59 (95% confidence interval: 0.30–1.16)) and Hp 2-2 (0.93 (0.60–1.45)) were not associated with significantly decreased preeclampsia risk after adjusting for treatment group and HbA1c at randomization. Our study was not powered to detect an interaction between Hp phenotype and treatment response. However, our preliminary analysis suggests that vitamins C and E did not prevent preeclampsia in women of any Hp phenotype (Hp 1-1: 0.77 (0.22–2.71); Hp 2-1: 0.81 (0.46–1.43); Hp 2-2: 0.67 (0.34–1.33)) after adjusting for HbA1c at randomization.
Hp phenotype did not significantly affect preeclampsia risk in women with Type 1 diabetes.
PMCID: PMC3860176  PMID: 23718253
pregnancy; preeclampsia; Type 1 diabetes; haptoglobin phenotype; vitamin C; vitamin E
14.  Variability in Cerebral Oxygen Delivery Is Reduced in Premature Neonates Exposed to Chorioamnionitis 
Pediatric research  2006;59(2):299-304.
Premature infants exposed to chorioamnionitis are at increased risk for periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH), lesions that may result from inflammation and/or fluctuations in cerebral blood flow. The effect of chorioamnionitis on near-infrared spectroscopy (NIRS) measures of cerebral oxygen delivery has not been evaluated previously. Forty-nine infants born at 25–31 6/7 wk gestation underwent NIRS examination on d 1, 2, 3, and 7 of life. Variability in NIRS tracings was analyzed by partitioning each tracing into three components: long-term, intermediate, and short-term variability; the latter two components were analyzed. Chorioamnionitis-exposed infants manifest reduced intermediate variability in cerebral oxygenated and deoxygenated Hb but not total Hb. Infants with severe IVH/PVL had the lowest intermediate variability on d 1. Short-term variability was similar between chorioamnionitis-exposed and unexposed infants, and between infants with versus without severe IVH or PVL. We conclude that intermediate-term variability in NIRS cerebral oxygen delivery is reduced in chorioamnionitis-exposed infants. We speculate that intermediate variability represents the important time frame for evaluating the pathogenesis of perinatal brain injury. Further studies are needed to determine how these findings relate to cerebral blood flow autoregulation and oxygen utilization in premature infants.
PMCID: PMC4074908  PMID: 16439596
15.  Excessive Early Gestational Weight Gain And Risk of Gestational Diabetes Mellitus in Nulliparous Women 
Obstetrics and Gynecology  2012;119(6):1227-1233.
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.
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).
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.
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.
PMCID: PMC3360415  PMID: 22617588
16.  Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming 
Preeclampsia is a pregnancy-specific syndrome, defined by such clinical hallmarks as the onset of maternal hypertension and proteinuria after 20 weeks of gestation. The syndrome is also characterized by impaired blood flow through the utero-placental circulation and relative placental ischemia, which in turn, may generate feto-placental endothelial dysfunction. Endothelial dysfunction in offspring born from preeclamptic pregnancies has been associated with an increased risk of cardiovascular disease, including hypertension, later in life. Interestingly, diminished endothelial function, manifested by low angiogenic capacity, leads to hypertension in animal studies. Recently, we have shown that the adenosine receptor A2A/nitric oxide/vascular endothelial growth factor axis is reduced in human umbilical vein endothelial cells derived from preeclamptic pregnancies, an effect correlated with gestational age at onset of preeclampsia. We and others suggested that impaired vascular function might be associated with high cardiovascular risk in offspring exposed to pregnancy diseases. However, we are not aware of any studies that examine impaired adenosine-mediated angiogenesis as a possible link to hypertension in offspring born from preeclamptic pregnancies. In this review, we present evidence supporting the hypothesis that reduced adenosine-mediated angiogenesis during preeclamptic pregnancies might be associated with development of hypertension in the offspring.
PMCID: PMC4046493  PMID: 24926270
adenosine receptors; angiogenesis; placenta; preeclampsia; programming
17.  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.
PMCID: PMC3636771  PMID: 22544506
Air pollution; Particulate; Preeclampsia; Gestational hypertension; Preterm; Small for gestational; age (SGA)
18.  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.
to perform a psychometric evaluation of the ESS in an obstetric population.
secondary data analysis of subjects enrolled in the Prenatal Exposures and Preeclampsia Prevention III (PEPP) study.
subjects who received prenatal care at Magee-Women’s Hospital UPMC in Pittsburgh, Pennsylvania.
337 pregnant women in their first trimester who completed the ESS.
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).
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.
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.
PMCID: PMC3693185  PMID: 23218535
Epworth Sleepiness Scale; pregnancy; psychometrics; sleepiness; sleep; Confirmatory Factor Analysis; Exploratory Factor Analysis
19.  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.
PMCID: PMC2680383  PMID: 19070896
20.  The Utility of Uterine Artery Doppler Velocimetry in Prediction of Preeclampsia in a Low-Risk Population 
Obstetrics and gynecology  2012;120(4):815-822.
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.
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.
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)).
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.
PMCID: PMC3449210  PMID: 22996099
21.  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.
PMCID: PMC3419489  PMID: 22883611
22.  Ambient air pollution exposure and blood pressure changes during pregnancy 
Environmental research  2012;117:46-53.
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.
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.
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.
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.
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.
PMCID: PMC3656658  PMID: 22835955
Ambient air pollution; Pregnancy; Blood pressure changes
23.  First-Trimester Prediction of Preeclampsia in Low-Risk Nulliparous Women 
Obstetrics and Gynecology  2012;119(6):1234-1242.
To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia.
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.
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.
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.
PMCID: PMC3360523  PMID: 22617589
24.  Haptoglobin Phenotype, Angiogenic Factors and Preeclampsia Risk 
American Journal of Obstetrics and Gynecology  2012;206(4):358.e10-358.e18.
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.
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.
Haptoglobin 2-1 is associated with higher preeclampsia risk in primiparous Caucasian women.
PMCID: PMC3319170  PMID: 22340942
Haptoglobin phenotype; angiogenesis; preeclampsia; gestational hypertension
25.  Variation in endoglin pathway genes is associated with preeclampsia: a case–control candidate gene association study 
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.
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.
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]).
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.
PMCID: PMC3651360  PMID: 23548068
Endoglin; Genetic association study; Preeclampsia; SNP

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