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1.  Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia 
Scientific Reports  2013;3:2407.
We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach.
doi:10.1038/srep02407
PMCID: PMC3757356  PMID: 23989136
2.  Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta 
Mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), genes involved in nucleotide excision repair and transcription, can cause several disorders including trichothiodystrophy (TTD) and xeroderma pigmentosum (XP). In this study, we tested the hypothesis that mutations in the XPD gene affect placental development in a phenotype-specific manner. To test our hypothesis and decipher potential biologic mechanisms, we compared all XPD-associated TTD (n=43) and XP (n=37) cases reported in the literature with respect to frequencies of gestational complications. Our genetic epidemiologic investigations of TTD and XP revealed that the exact genetic abnormality was relevant to the mechanism leading to gestational complications such as preeclampsia. Through structural mapping, we localized the preeclampsia-associated mutations to a C-terminal motif and the helicase surfaces of XPD, most likely affecting XPD's binding to cdk-activating kinase (CAK) and p44 subunits of transcription factor (TF) IIH. Our results suggested a link between TTD- but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta. Our findings highlight the importance of the fetal genotype in development of gestational complications, such as preeclampsia. Therefore, future studies of genetic associations of preeclampsia and other placental vascular complications may benefit from focusing on genetic variants within the fetal DNA.
doi:10.1038/ejhg.2011.249
PMCID: PMC3355251  PMID: 22234153
trichothiodystrophy; xeroderma pigmentosum; XPD; TFIIH; human fetal development
3.  Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects 
BMC Medical Genetics  2012;13:62.
Background
Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
Methods
A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
Results
Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
Conclusions
To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
doi:10.1186/1471-2350-13-62
PMCID: PMC3458983  PMID: 22856873
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene
4.  U.S. Primary Care Physicians’ Diet, Physical Activity, and Weight-Related Care of Adult Patients 
Background
Overweight and obesity are substantial problems in the U.S., but few national studies exist on primary care physicians’ (PCPs) clinical practices regarding overweight and obesity.
Purpose
To profile diet, physical activity and weight control practice patterns of PCPs who treat adults.
Methods
A nationally representative survey of 1,211 PCPs sampled from the American Medical Association’s Masterfile was conducted in 2008 and analyzed in 2010. Outcomes included: PCPs’ assessment, counseling, referral, and follow-up of diet, physical activity and weight control in adult patients with and without chronic disease; PCPs’ use of pharmacologic treatments and surgical referrals for overweight and obesity.
Results
The survey response rate was 64.5%. Half of PCPs (49%) reported recording BMI regularly. Fewer than 50% reported always providing specific guidance on diet, physical activity, or weight control. Regardless of patients’ chronic disease status, <10% of PCPs always referred patients for further evaluation/management, and <22% reported always systematically tracking patients over time concerning weight or weight-related behaviors. Overall, PCPs were more likely to counsel on physical activity than on diet or weight control (ps<0.05). More than 70% of PCPs reported ever using pharmacologic treatments to treat overweight and 86% had referred for obesity-related surgery.
Conclusions
PCPs’ assessment and behavioral management of overweight and obesity in adults is at a low level relative to the magnitude of the problem in the U.S.
doi:10.1016/j.amepre.2011.03.017
PMCID: PMC3142674  PMID: 21665061
7.  Antenatal Testing – A Reevaluation 
Obstetrics and gynecology  2009;113(3):687-701.
In August 2007, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Office of Rare Diseases, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics cosponsored a 2-day workshop to reassess the body of evidence supporting antepartum assessment of fetal well-being, identify key gaps in the evidence, and formulate recommendations for further research. Participants included experts in obstetrics and fetal physiology, and representatives from relevant stakeholder groups and organizations. This article is a summary of the discussions at the workshop, including synopses of oral presentations on the epidemiology of stillbirth and fetal neurological injury, fetal physiology, techniques for antenatal monitoring, and maternal and fetal indications for monitoring. Finally, a synthesis of recommendations for further research compiled from three breakout workgroups is presented.
doi:10.1097/AOG.0b013e318197bd8a
PMCID: PMC2771454  PMID: 19300336
8.  MARKERS OF OXIDATIVE STRESS AND SYSTEMIC VASOCONSTRICTION IN PREGNANT WOMEN DRINKING ≥ 48 GRAMS OF ALCOHOL PER DAY 
Background
The precise pathway by which alcohol causes the characteristic features of fetal alcohol spectrum disorders (FASD) is unknown. Proposed mechanisms for fetal injury from maternal alcohol use include cellular damage from oxidative stress and impaired fetal oxygenation related to maternal systemic vasoconstriction. Our objective was to compare levels of urinary markers of oxidative stress and systemic vasoconstriction between women consuming large amounts of alcohol during pregnancy and women who did not drink alcohol during pregnancy.
Methods
Pregnant women consuming ≥ 48g alcohol/day (n=29) on average and pregnant women who abstained from alcohol use (n=39) were identified using detailed interviews and home visits. Random maternal urine specimens were collected. Urinary levels of the oxidative stress marker, 8-isoprostane F2α, and of the vasoactive prostaglandin metabolites, 2,3-dinor-6-keto-prostaglandin F1α (a vasodilator) and 11-dehydro-thromboxane B2 (a vasoconstrictor), were measured using mass spectrometric methods. All analyte levels were corrected for urinary creatinine.
Results
In crude analyses, there was no significant difference in 8-isoprostane F2α between pregnant drinkers and nondrinkers (2.16 vs. 2.08 ng/mg creatinine respectively, P=.87). There were no significant differences between the drinking and non-drinking groups in levels of 2,3-dinor-6-keto-prostaglandin F1α (1.03 vs. 1.17 ng/mg creatinine repectively, P=.50), 11-dehydro-thromboxane B2 (0.72 vs. 0.59 ng/mg creatinine respectively, P=.21), or the ratio of vasodilatory metabolite to vasoconstrictive metabolite (1.73 vs. 2.72 respectively, P=.14). Adjusting for maternal age, marital status, smoking, and gestational age at sampling did not substantially alter the results.
Conclusion
Our results show no difference in levels of urinary eicosanoid markers of oxidative stress and systemic vasoconstriction between pregnant women who drink heavily and pregnant women who abstain. These findings speak against a role for maternal oxidative stress or systemic vasoconstriction in the pathogenesis of alcohol damage to the fetus.
doi:10.1111/j.1530-0277.2008.00773.x
PMCID: PMC2615682  PMID: 18715278
Alcohol; Pregnancy; Isoprostanes; Prostacyclin; Thromboxane; Fetal Alcohol Spectrum Disorders
9.  CIRCULATING SOLUBLE ENDOGLIN AND PLACENTAL ABRUPTION 
Prenatal diagnosis  2008;28(9):852-858.
Objective
Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption.
Methods
In a nested case control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (<20 weeks), mid- (21–32 weeks), and late (≥33 weeks) pregnancy.
Results
There was no significant difference in sEng between abruption cases and controls in early pregnancy. sEng was significantly elevated among abruption cases at 21–32 weeks (10.7 versus 5.9 ng/mL, P<0.01). Subgroup analyses revealed no differences in sEng concentrations at any gestational age interval between cases with abruption without hypertension and healthy controls. Among women who developed hypertension and placental abruption, sEng was not significantly increased in early pregnancy, but was in mid-pregnancy (19.3 versus 5.5 ng/mL, P=0.002) and in late pregnancy (15.6 versus 9.5 ng/mL, P=0.04).
Conclusion
Serum levels of the anti-angiogenic factor sEng are elevated prior to the development of hypertension and placental abruption. These elevations are not apparent until the late second trimester (26 – 27 weeks, on average), but they persist from this time in gestation onward. sEng may be useful for identifying pregnant women at risk for abruption and hypertension.
doi:10.1002/pd.2065
PMCID: PMC2574843  PMID: 18702104
Abruptio placentae; preeclampsia; gestational hypertension; endoglin; angiogenic factors
10.  Neonatal Morbidity and Mortality After Elective Cesarean Delivery 
Clinics in perinatology  2008;35(2):361-vi.
As overall cesarean delivery rates have continued to rise, there has been growing interest in the rates of elective cesarean delivery (ECD), and its relative benefits and harms for the mother and neonate. This article explores the effects of elective cesarean delivery at term on neonatal morbidity and mortality. Available data are subject to a number of limitations, and do not provide conclusive evidence regarding the safety of planned elective cesarean versus planned vaginal delivery. Nevertheless, some data suggest an association between ECD and increased neonatal respiratory morbidity and lacerations, and possibly decreased central and peripheral nervous system injury. Potentially increased risks of neonatal mortality with ECD at term may be counterbalanced by risks of fetal demise in ongoing pregnancies. Patients and physicians considering ECD should carefully review competing risks and benefits; further research is needed to inform these discussions.
doi:10.1016/j.clp.2008.03.009
PMCID: PMC2475575  PMID: 18456074
cesarean delivery; elective; neonatal; morbidity; mortality; respiratory morbidity; injury
11.  Choline concentrations in human maternal and cord blood and intelligence at 5 y of age2 
Background
Animal studies indicate that maternal prenatal choline supplementation leads to permanent enhancement of attention and spatial memory abilities in offspring, whereas dietary choline restriction during pregnancy impairs cognitive function in offspring. The association between gestational choline concentrations and neurodevelopmental outcome in humans has not been studied.
Objective
Our objective was to assess the relation between maternal and cord blood choline concentrations and child intelligence quotient (IQ) scores at 5 y of age.
Design
With data and samples from a prospective study (n = 404 maternal-child pairs), serum concentrations of free and total choline were measured in maternal serum at 4 gestational age intervals (16–18 wk, 24–26 wk, 30–32 wk, and 36–38 wk) and in cord blood. Child IQ at 5 y of age was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised. Multiple regression techniques were used to estimate the relation between choline concentrations and Full Scale IQ, Verbal and Performance IQ, and subscales that assess spatial relation and memory ability while adjusting for other factors that affect IQ.
Results
There was no effect at gestational ages 16–18 wk, 24–26 wk, 30–32 wk, and 36–38 wk or in cord blood of serum concentrations of free or total choline on Full Scale child IQ or on selected scales related to visuospatial processing and memory.
Conclusion
Gestational and newborn choline concentrations in the physiologic range showed no correlation with childhood intelligence.
PMCID: PMC2423009  PMID: 18400712

Results 1-11 (11)