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1.  Frequency of Prenatal Cytogenetic Diagnosis and Pregnancy Outcomes by Maternal Race–Ethnicity, and the Effect on the Prevalence of Trisomy 21, Metropolitan Atlanta, 1996–2005 
The prevalence of trisomy 21 has been reported to differ by race–ethnicity, however, the results are inconsistent and the cause of the differences is unknown. Using data from 1996 to 2005 from the Metropolitan Atlanta Congenital Defects Program (MACDP), we analyzed the use of prenatal cytogenetic testing and the subsequent use of elective termination among pregnancies affected with any MACDP-eligible birth defect and trisomy 21, by maternal race–ethnicity. We then examined whether these factors could explain the observed differences in the prevalence of trisomy 21 among race–ethnicity groups. Among all pregnancies with birth defects, prenatal cytogenetic testing as well as elective terminations after an abnormal prenatal cytogenetic test result were observed less frequently among Hispanic women than among non-Hispanic white women (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.56–0.78, respectively). In pregnancies affected by trisomy 21, both the Hispanic and the non-Hispanic black populations had more live births (89.5% and 77.8%, respectively) and fewer elective terminations (5.7% and 15.2%, respectively) compared to the non-Hispanic white population (63.0% live births, 32.3% elective terminations). After adjusting for elective terminations, non-Hispanic white mothers had a higher live birth prevalence of trisomy 21 compared to non-Hispanic black (OR 0.64, 95% CI 0.54–0.76) or Hispanic mothers (OR 0.69, 95% CI 0.55–0.86). Overall, our data suggest that factors associated with decisions made about the use of prenatal testing, and about pregnancy management after testing, might play a large role in the race–ethnicity differences observed in the live birth prevalence of trisomy 21.
doi:10.1002/ajmg.a.36247
PMCID: PMC4517177  PMID: 24273106
trisomy 21; Down syndrome; prenatal; cytogenetics; congenital defect; elective termination
2.  Cancer in Children with Nonchromosomal Birth Defects 
The Journal of pediatrics  2012;160(6):978-983.
Objective
To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies.
Study design
We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% Cls based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies.
Results
Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% Cl, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% Cl, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer(HR, 1.58;95% Cl, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors.
Conclusion
Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.
doi:10.1016/j.jpeds.2011.12.006
PMCID: PMC4490790  PMID: 22244463
3.  Human Teratogens Update 2011: Can We Ensure Safety during Pregnancy? 
Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer-generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is “safe” for use during pregnancy. In the absence of adequate, well-controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus.
doi:10.1002/bdra.22887
PMCID: PMC4490791  PMID: 22328359
4.  Social Conditions for People With Down Syndrome: A Register-Based Cohort Study in Denmark 
Today, most persons with Down syndrome (DS) survive into middle age, but information on their social conditions as adults is limited. We addressed this knowledge gap using data from national registers in Denmark. We identified a national cohort of 1,998 persons with DS who were born between 1968 and 2007 (1,852 with standard trisomy 21, 80 with Robertsonian translocations and 66 with mosaicism) using the Danish Cytogenetic Register. We followed this cohort from 1980 to 2007. Information on social conditions (education, employment, source of income, marital status, etc.) was obtained by linkages to national registers, including the Integrated Database for Longitudinal Labor Market Research. For those aged 18 and older, more than 80%of persons with DS attended 10 years of primary school, with about 2% completing secondary or post-secondary education. About 4% obtained a full-time job, whereas the remaining mainly received public support from the government. Only a few (1–2%) of persons with DS were married or had a child. No significant differences in these social conditions were seen between males and females. More persons with mosaic DS attended secondary or post-secondary education, had a full-time job, were married, or had a child (18%, 28%, 15%, and 7%, respectively), compared with persons with standard DS (1%, 2%, 1%, and 1%, respectively). These data may provide families with better insight into social conditions and society with a better understanding of the social support needed for persons with DS.
doi:10.1002/ajmg.a.36272
PMCID: PMC4490827  PMID: 24273114
Down syndrome; mosaic trisomy 21; social conditions; offspring
5.  The Association Between Reported Venlafaxine Use in Early Pregnancy and Birth Defects, National Birth Defects Prevention Study, 1997–2007 
Background
Few epidemiologic studies have investigated the use of venlafaxine (Effexor®), an antidepressant used to treat major depression and anxiety disorders in adults, during pregnancy. Our objective was to determine whether use of venlafaxine during pregnancy is associated with specific birth defects.
Methods
We used data from the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study in the United States. Our analysis included mothers with pregnancies affected by one of 30 selected birth defects (cases) and babies without birth defects (controls) with estimated dates of delivery between 1997–2007. Exposure was any reported use of venlafaxine from one month preconception through the third month of pregnancy. We calculated adjusted odds ratios (aORs) and 95% Fisher’s Exact confidence intervals (CIs) for 24 birth defect groups for which at least 400 case mothers were interviewed. Our adjusted analyses controlled for maternal age and race-ethnicity.
Results
Among the 27,045 NBDPS participants who met inclusion criteria, 0.17% (14/8,002) of control mothers and 0.40% (77/19,043) of case mothers reported any use of venlafaxine from one month preconception through the third month of pregnancy. Statistically significant associations were found for anencephaly, atrial septal defect (ASD) secundum or ASD not otherwise specified, coarctation of the aorta, cleft palate, and gastroschisis.
Conclusions
Our data suggest associations between periconceptional use of venlafaxine and some birth defects. However, sample sizes were small, confidence intervals were wide, and additional studies are needed to confirm these results.
doi:10.1002/bdra.23096
PMCID: PMC4484721  PMID: 23281074
Venlafaxine; Birth Defects; Pregnancy; Antidepressants; Epidemiology
6.  Factors affecting maternal participation in the genetic component of the National Birth Defects Prevention Study—United States, 1997–2007 
Purpose
As epidemiological studies expand to examine gene–environment interaction effects, it is important to identify factors associated with participation in genetic studies. The National Birth Defects Prevention Study is a multisite case–control study designed to investigate environmental and genetic risk factors for major birth defects. The National Birth Defects Prevention Study includes maternal telephone interviews and mailed buccal cell self-collection kits. Because subjects can participate in the interview, independent of buccal cell collection, detailed analysis of factors associated with participation in buccal cell collection was possible.
Methods
Multivariable logistic regression models were used to identify the factors associated with participation in the genetic component of the study.
Results
Buccal cell participation rates varied by race/ethnicity (non-Hispanic whites, 66.9%; Hispanics, 60.4%; and non-Hispanic blacks, 47.3%) and study site (50.2–74.2%). Additional monetary incentive following return of buccal cell kit and shorter interval between infant’s estimated date of delivery and interview were associated with increased participation across all racial/ethnic groups. Higher education and delivering an infant with a birth defect were associated with increased participation among non-Hispanic whites and Hispanics.
Conclusion
Factors associated with participation varied by race/ethnicity. Improved understanding of factors associated with participation may facilitate strategies to increase participation, thereby improving generalizability of study findings.
doi:10.1038/gim.2013.143
PMCID: PMC4471475  PMID: 24071796
birth defects; data collection; epidemiologic methods; ethnic groups; risk factors
7.  Current Estimate of Down Syndrome Population Prevalence in the United States 
The Journal of pediatrics  2013;163(4):1163-1168.
Objective
To calculate a reliable estimate of the population prevalence of Down syndrome in the US.
Study design
The annual number of births of infants with Down syndrome were estimated by applying published birth prevalence rates of Down syndrome by maternal age to US data from the Centers for Disease Control and Prevention for the years for which births by maternal age were available (1940–2008). Death certificate data for persons with Down syndrome were available for the years 1968–2007. We estimated the number of people with Down syndrome on January 1, 2008, using a life table approach based on proportions of deaths by age. Monte Carlo sampling was used to create 90% uncertainty intervals (UIs) for our estimates.
Results
We estimated the January 1, 2008, population prevalence of Down syndrome as approximately 250 700 (90% UI, 185 900–321 700) based on proportions of deaths by age from the most recent 2 years (2006–2007) of death certificate data. This estimate corresponds to a prevalence of 8.27 people with Down syndrome per 10 000 population (90% UI, 6.14–10.62).
Conclusion
Our estimate of Down syndrome prevalence is roughly 25%–40% lower than estimates based solely on current birth prevalence. The results presented here can be considered a starting point for facilitating policy and services planning for persons with Down syndrome.
doi:10.1016/j.jpeds.2013.06.013
PMCID: PMC4445685  PMID: 23885965
8.  Hospitalizations among persons with Down syndrome: a national cohort study in Denmark 
Summary
Background
Most persons with Down syndrome (DS) now survive to adulthood, but their health care needs beyond childhood are not well described. We examined hospitalizations among persons with DS in Denmark.
Methods
We followed 3,212 persons with DS (1910-2007), identified from the Danish Cytogenetic Register, and a random sample of persons without DS from the general population (as comparison group), through the National Hospital Register from January 1, 1977, to May 31, 2008. Poisson regression was used to calculate rate ratios for numbers of overnight hospital admissions and hospital days.
Findings
During this time period, persons with DS had more than twice the rate of hospital admissions and nearly three times as many bed-days as the population as whole. Malformations, diseases of the respiratory system, and diseases of the nervous system or sensory organs were the principal indications for hospital admissions. The higher rate ratios for hospital admissions were mainly seen among persons less than 20 years of age, and hospitalization for neoplasms or for diseases of the musculoskeletal system or connective tissue was much less frequent than expected among adults with DS. Persons with DS who had congenital heart defects were far more likely to be hospitalized than those without.
Interpretation
Persons with DS in Denmark are hospitalized more frequently and for more days than persons without DS; however, hospitalization usage differs by age (with a higher burden at younger ages) and by presence of a congenital heart defect. As survival among persons with DS continues to improve, these data are helpful for health care planning, although results may be different within other health care systems.
doi:10.1002/ajmg.a.35711
PMCID: PMC4415492  PMID: 23404922
Down syndrome; hospitalization; comorbidity; congenital heart defects
9.  Maternal Smoking, Xenobiotic Metabolizing Enzyme Gene Variants, and Gastroschisis Risk 
Maternal smoking during pregnancy is one proposed risk factor for gastroschisis, but reported associations have been modest, suggesting that differences in genetic susceptibility might play a role. We included 108 non-Hispanic white and 62 Hispanic families who had infants with gastroschisis, and 1147 non-Hispanic white and 337 Hispanic families who had liveborn infants with no major structural birth defects (controls) in these analyses. DNA was extracted from buccal cells collected from infants and mothers, and information on periconceptional smoking history was obtained from maternal interviews, as part of the National Birth Defects Prevention Study. We analyzed five polymorphisms in three genes that code for enzymes involved in metabolism of some cigarette smoke constituents (CYP1A1, CYP1A2, and NAT2). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) independently for maternal smoking and maternal and infant gene variants, and to assess joint associations of maternal smoking and maternal or infant gene variants with gastroschisis. In analyses adjusted for maternal age at delivery and stratified by maternal race-ethnicity, we identified three suggestive associations among 30 potential associations with sufficient numbers to calculate ORs: CYP1A1*2A for non-Hispanic white mothers who smoked periconceptionally (aOR=0.38, 95% CI 0.15-0.98), and NAT2*6 for Hispanic non-smoking mothers (aOR=2.17, 95% CI 1.12-4.19) and their infants (aOR=2.11, 95% CI 1.00-4.48). This analysis does not support the occurrence of effect modification between periconceptional maternal smoking and most of the xenobiotic metabolizing enzyme gene variants assessed.
doi:10.1002/ajmg.a.36478
PMCID: PMC4382863  PMID: 24668907
maternal smoking; CYP; NAT; genetic epidemiology; risk factors; gastroschisis
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  Corticosteroid use and risk of orofacial clefts 
Background
Maternal use of corticosteroids during early pregnancy has been inconsistently associated with orofacial clefts in the offspring. A previous report from the National Birth Defect Prevention Study (NBDPS), using data from 1997 to 2002, found an association with cleft lip and palate (odds ratio, 1.7; 95% confidence interval [CI], 1.1–2.6), but not cleft palate only (odds ratio, 0.5, 95%CI, 0.2–1.3). From 2003 to 2009, the study population more than doubled in size, and our objective was to assess this association in the more recent data.
Methods
The NBDPS is an ongoing multi-state population-based case-control study of birth defects, with ascertainment of cases and controls born since 1997. We assessed the association of corticosteroids and orofacial clefts using data from 2372 cleft cases and 5922 controls born from 2003 to 2009. Maternal corticosteroid exposure was based on telephone interviews.
Results
The overall association of corticosteroids and cleft lip and palate in the new data was 1.0 (95% CI, 0.7–1.4). There was little evidence of associations between specific corticosteroid components or timing and clefts.
Conclusion
In contrast to the 1997 to 2002 data from the NBDPS, the 2003 to 2009 data show no association between maternal corticosteroid use and cleft lip and palate in the offspring. Birth Defects Research (Part A) 100:499–506, 2014. © 2014 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.
doi:10.1002/bdra.23248
PMCID: PMC4283705  PMID: 24777675
orofacial clefts; cleft lip and palate; corticosteroids; birth defects; pregnancy

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