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1.  Hypomethylation of Serum Blood Clot DNA, but Not Plasma EDTA-Blood Cell Pellet DNA, from Vitamin B12-Deficient Subjects 
PLoS ONE  2013;8(6):e65241.
Vitamin B12, a co-factor in methyl-group transfer, is important in maintaining DNA (deoxycytidine) methylation. Using two independent assays we examined the effect of vitamin B12-deficiency (plasma vitamin B12<148 pmol/L) on DNA methylation in women of childbearing age. Coagulated blood clot DNA from vitamin B12-deficient women had significantly (p<0.001) lower percentage deoxycytidine methylation (3.23±0.66%; n = 248) and greater [3 H]methyl-acceptance (42,859±9,699 cpm; n = 17) than DNA from B12-replete women (4.44±0.18%; n = 128 and 26,049±2,814 cpm; n = 11) [correlation between assays: r = –0.8538; p<0.001; n = 28]. In contrast, uncoagulated EDTA-blood cell pellet DNA from vitamin B12-deficient and B12-replete women exhibited similar percentage methylation (4.45±0.15%; n = 77 vs. 4.47±0.15%; n = 47) and [3 H]methyl-acceptance (27,378±4,094 cpm; n = 17 vs. 26,610±2,292 cpm; n = 11). Therefore, in simultaneously collected paired blood samples, vitamin B12-deficiency was associated with decreased DNA methylation only in coagulated samples. These findings highlight the importance of sample collection methods in epigenetic studies, and the potential impact biological processes can have on DNA methylation during collection.
doi:10.1371/journal.pone.0065241
PMCID: PMC3681792  PMID: 23785415
2.  Medications Used to Treat Nausea and Vomiting of Pregnancy and the Risk of Selected Birth Defects 
Background
Nausea and vomiting of pregnancy (NVP) occurs in up to 80% of pregnant women, yet its association with birth outcomes is not clear. Several medications are used for the treatment of NVP; however, data are limited on their possible associations with birth defects.
Methods
Using data from the National Birth Defects Prevention Study (NBDPS), a multi-site population-based case-control study, we examined whether NVP or its treatment was associated with the most common non-cardiac defects in the NBDPS (non-syndromic cleft lip with or without cleft palate (CL/P), cleft palate alone (CP), neural tube defects (NTDs), and hypospadias) compared to randomly-selected non-malformed live births.
Results
Among the 4524 cases and 5859 controls included in this study, 67.1% reported first trimester NVP, and 15.4% of them reported using at least one agent for NVP. Nausea and vomiting of pregnancy was not associated with CP or NTDs, but modest risk reductions were observed for CL/P (aOR=0.87, 0.77–0.98), and hypospadias (OR=0.84, 0.72–0.98). In regards to treatments for NVP in the first trimester, the following adjusted associations were observed with an increased risk: proton pump inhibitors and hypospadias (aOR=4.36, 1.21–15.81), steroids and hypospadias (aOR=2.87, 1.03–7.97), and ondansetron and CP (aOR=2.37, 1.18–4.76), while antacids were associated with a reduced risk for CL/P (aOR=0.58, 0.38–0.89).
Conclusions
Nausea and vomiting of pregnancy was not observed to be associated with an increased risk of birth defects, but possible risks related to three treatments (i.e. proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation.
doi:10.1002/bdra.22865
PMCID: PMC3299087  PMID: 22102545
hypospadias; medications; National Birth Defects Prevention Study; nausea and vomiting of pregnancy; neural tube defects; orofacial clefts
3.  Conference Proceedings: “Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks” 
Molecular genetics and metabolism  2011;104(1-2):13-22.
A December 2010 meeting, “Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks,” was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole.
doi:10.1016/j.ymgme.2011.07.005
PMCID: PMC3171614  PMID: 21835664
Down syndrome; registry; database; biobank; trisomy 21
4.  Genomic DNA Methylation Changes in Response to Folic Acid Supplementation in a Population-Based Intervention Study among Women of Reproductive Age 
PLoS ONE  2011;6(12):e28144.
Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 µg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 µg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (−14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.
doi:10.1371/journal.pone.0028144
PMCID: PMC3233549  PMID: 22163281
5.  Craniosynostosis and Nutrient Intake during Pregnancy 
OBJECTIVE
To examine the association of craniosynostosis with maternal intake of folic acid–containing supplements and dietary nutrients.
METHODS
The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic infants with craniosynostosis (n = 815) were compared to nonmalformed, population-based liveborn control infants (n = 6789), by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included mother’s age, parity, race-ethnicity, education, body mass index, smoking, alcohol, fertility treatments, plurality, and study center. We compared quartiles of intake and specified nutrients as continuous.
RESULTS
Intake of folic acid–containing supplements was not associated with craniosynostosis (AORs were close to 1). Analyses of dietary nutrients were restricted to mothers who took supplements during the first trimester (i.e., most women). Based on continuous specifications of nutrients, sagittal synostosis risk was significantly lower among women with higher intake of riboflavin and vitamins B6, E, and C; metopic synostosis risk was significantly higher among women with higher intakes of choline and vitamin B12; and coronal synostosis risk was significantly lower among women with higher intake of methionine and vitamin C. As examples, AORs for sagittal synostosis among women with intakes of vitamin B6 and riboflavin in the highest versus lowest quartiles were 0.4 (95% CI, 0.2–0.6) and 0.5 (95% CI, 0.3–0.7), respectively.
CONCLUSION
This analysis suggests that dietary intake of certain nutrients may be associated with craniosynostosis, and results may vary by suture type.
doi:10.1002/bdra.20717
PMCID: PMC3136510  PMID: 20842649
craniosynostosis; nutrition; folic acid; diet
6.  Orofacial Clefts in the National Birth Defects Prevention Study, 1997-2004 
Orofacial clefts are among the most common types of birth defects, but their clinical presentation has not been well described in a geographically diverse US population. To describe the birth prevalence and phenotype of nonsyndromic clefts, we used data from the National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study aimed at identifying genetic and environmental risk factors for birth defects. Included in the study were infants born during 1997-2004 with a cleft lip (CL), cleft lip with cleft palate (CLP), or cleft palate (CP). Infants with clefts associated with recognized single-gene disorders, chromosome abnormalities, holoprosencephaly, or amniotic band sequence were excluded. A total of 3,344 infants with nonsyndromic orofacial clefts were identified, including 751 with CL, 1,399 with CLP, and 1,194 with CP, giving birth prevalence estimates of 0.3, 0.5, and 0.4/1,000 live births, respectively. Among infants with CLP where cleft laterality was specified, about twice as many had unilateral vs. bilateral involvement, while for CL there were over 10 times as many with unilateral vs. bilateral involvement. Involvement was most often left-sided. About one-quarter of infants with CP had Pierre Robin sequence. Over 80% of infants had an isolated orofacial cleft. Among infants with CL or CLP, heart, limb, and musculoskeletal defects were most commonly observed, while heart, limb, and central nervous system defects were most common among infants with CP. Better understanding of the birth prevalence and phenotype may help guide clinical care as well as contribute to an improved understanding of pathogenesis.
doi:10.1002/ajmg.a.32854
PMCID: PMC3111146  PMID: 19441124
cleft lip; cleft palate; congenital abnormalities; prevalence; birth defects
7.  Fetal Constraint as a Potential Risk Factor for Craniosynostosis 
Non-syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, were used to evaluate associations between 4 selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight > 4000 g), post-term gestational age (≥42 weeks), and nulliparity (no previous live births). Case infants (n=675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single-gene conditions or chromosomal abnormalities were excluded. Control infants (n=5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these 4 factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a two fold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these 4 constraint-related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint-related factors.
doi:10.1002/ajmg.a.33246
PMCID: PMC2815148  PMID: 20101684
Craniosynostosis; Fetal Constraint; Plurality; Twinning; Macrosomia; Prolonged Gestation; Low Birth Weight; Calvarial Morphogenesis; Skull deformation; Sagittal Synostosis; Metopic Synostosis
8.  Assessment of risk factors for infantile cataracts using a case-control study, National Birth Defects Prevention Study, 2000–2004 
Ophthalmology  2010;117(8):1500-1505.
Objective
To identify risk factors for infantile cataracts of unknown etiology.
Design
Case-control study
Participants
Case-infants (N=152) and control-infants (N=4205) enrolled in the National Birth Defects Prevention Study for birth years 2000–2004.
Methods
Multivariate analysis was performed exploring associations for risk factors for bilateral and unilateral infantile cataracts of unknown etiology.
Main Outcome Measures
Infantile cataracts of unknown etiology
Results
Maternal interviews were completed for 43 case-infants with bilateral and 109 with unilateral infantile cataracts of unknown etiology. Very low birth weight (<1500g) was associated with both unilateral (adjusted odds ratio [OR]=6.0; 95% confidence interval [CI]=2.2–16.3) and bilateral (OR=13.2; 95% CI=4.2–41.1) cataracts, while low birth weight (1500–2499g) was only associated with bilateral cataracts (OR=3.3; 95% CI=1.3–8.1). Infants with unilateral cataracts were more likely to be born to primigravid women (OR=1.6; 95% CI=1.0–2.7) than women with two or more previous pregnancies, although this was of borderline significance. While not statistically significant, effect estimates were elevated suggesting a possible association between unilateral cataracts and maternal substance abuse during pregnancy, and between bilateral cataracts and urinary tract infection during pregnancy and aspirin use during pregnancy.
Conclusions
Very low birth weight is associated with both bilateral and unilateral cataracts, while low birth weight is associated with bilateral cataracts and primigravidity with unilateral cataracts. Other associations, while not of statistical significance, suggest risk factors that merit further research.
doi:10.1016/j.ophtha.2009.12.026
PMCID: PMC2994269  PMID: 20363508
9.  Emerging and Zoonotic Infections in Women 
Synopsis
Emerging infections, many of them zoonotic, are caused by a wide variety of pathogens with global distribution. Their impact on women is similarly diverse. Pathogens that were previously rare are emerging in recent years to cause disease in new populations, and global travel facilitates their rapid spread across continents. Finally, human encroachment on previously remote areas has brought people into contact with zoonotic diseases and vectors never before characterized. Although systematic study of rare outbreaks can be challenging, our knowledge of emerging pathogens and their differential effects on women, including those who are pregnant, has started to accumulate. We discuss the effects on women of lymphocytic choriomeningitis virus, West Nile virus, SARS coronavirus, avian influenza A (H5N1), virus, and the viral hemorrhagic fevers. We also explore the spirochetal illnesses and Chagas disease as they pertain to the pregnant patient. Finally, we review the potential impact of candidate bioterror agents on the female population, and address related issues of prophylaxis and therapy.
doi:10.1016/j.idc.2008.05.007
PMCID: PMC2650502  PMID: 18954762
10.  Pandemic Influenza and Pregnant Women 
Emerging Infectious Diseases  2008;14(1):95-100.
Planning for a future influenza pandemic should include considerations specific to pregnant women. First, pregnant women are at increased risk for influenza-associated illness and death. The effects on the fetus of maternal influenza infection, associated fever, and agents used for prophylaxis and treatment should be taken into account. Pregnant women might be reluctant to comply with public health recommendations during a pandemic because of concerns regarding effects of vaccines or medications on the fetus. Guidelines regarding nonpharmaceutical interventions (e.g., voluntary quarantine) also might present special challenges because of conflicting recommendations about routine prenatal care and delivery. Finally, healthcare facilities need to develop plans to minimize exposure of pregnant women to ill persons, while ensuring that women receive necessary care.
doi:10.3201/eid1401.070667
PMCID: PMC2600164  PMID: 18258087
pregnancy; women; influenza; H5N1; avian influenza; pandemic influenza; antiviral medications; influenza vaccine; perspective
11.  Emerging Infections and Pregnancy 
Emerging Infectious Diseases  2006;12(11):1638-1643.
Immunologic changes of pregnancy may increase susceptibility to certain intracellular pathogens.
A key component of the response to emerging infections is consideration of special populations, including pregnant women. Successful pregnancy depends on adaptation of the woman's immune system to tolerate a genetically foreign fetus. Although the immune system changes are not well understood, a shift from cell-mediated immunity toward humoral immunity is believed to occur. These immunologic changes may alter susceptibility to and severity of infectious diseases in pregnant women. For example, pregnancy may increase susceptibility to toxoplasmosis and listeriosis and may increase severity of illness and increase mortality rates from influenza and varicella. Compared with information about more conventional disease threats, information about emerging infectious diseases is quite limited. Pregnant women's altered response to infectious diseases should be considered when planning a response to emerging infectious disease threats.
doi:10.3201/eid1211.060152
PMCID: PMC3372330  PMID: 17283611
emerging infectious diseases; pregnancy; immunology; synopsis
12.  Prophylaxis and Treatment of Pregnant Women for Emerging Infections and Bioterrorism Emergencies 
Emerging Infectious Diseases  2006;12(11):1631-1637.
Infectious disease emergency preparedness planners should consider the special medical issues of pregnant women.
Emerging infectious disease outbreaks and bioterrorism attacks warrant urgent public health and medical responses. Response plans for these events may include use of medications and vaccines for which the effects on pregnant women and fetuses are unknown. Healthcare providers must be able to discuss the benefits and risks of these interventions with their pregnant patients. Recent experiences with outbreaks of severe acute respiratory syndrome, monkeypox, and anthrax, as well as response planning for bioterrorism and pandemic influenza, illustrate the challenges of making recommendations about treatment and prophylaxis for pregnant women. Understanding the physiology of pregnancy, the factors that influence the teratogenic potential of medications and vaccines, and the infection control measures that may stop an outbreak will aid planners in making recommendations for care of pregnant women during large-scale infectious disease emergencies.
doi:10.3201/eid1211.060618
PMCID: PMC3372351  PMID: 17283610
Pregnancy; bioterrorism; communicable diseases; vaccines; synopsis
13.  Infectious Etiologies of Chronic Diseases: Focus on Women1 
Emerging Infectious Diseases  2004;10(11):2028-2029.
doi:10.3201/eid1011.040623_07
PMCID: PMC3329021  PMID: 16010733
Infectious etiologies of chronic disease; chronic disease; infection; women; autoimmune; neurodevelopmental disorder

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