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1.  Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2012;7(8):e43508.
Background
The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.
Methods
We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1st 1979 through December 31st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.
Results
We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).
Conclusions
Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.
doi:10.1371/journal.pone.0043508
PMCID: PMC3429491  PMID: 22952698
2.  Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight 
PLoS ONE  2010;5(7):e11896.
Background
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
Methodology/Principal Findings
We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).
Conclusions/Significance
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
doi:10.1371/journal.pone.0011896
PMCID: PMC2912844  PMID: 20689593
3.  Prenatal Stress and Risk of Febrile Seizures in Children: A Nationwide Longitudinal Study in Denmark 
We aimed to examine whether exposure to prenatal stress following maternal bereavement is associated with an increased risk of febrile seizures. In a longitudinal population-based cohort study, we followed 1,431,175 children born in Denmark. A total of 34,777 children were born to women who lost a close relative during pregnancy or within 1 year before the pregnancy and they were included in the exposed group. The exposed children had a risk of febrile seizures similar to that of the unexposed children (hazard ratio (HR) 1.00, 95% CI 0.94–1.06). The HRs did not differ according to the nature or timing of bereavement. Our data do not suggest any causal link between exposure to prenatal stress and febrile seizures in childhood.
doi:10.1007/s10803-009-0717-4
PMCID: PMC2694316  PMID: 19291382
Prenatal stress; Bereavement; Febrile seizures; Fetal programming; Longitudinal study
4.  Long-Term Health Outcomes in Children Born to Mothers with Diabetes: A Population-Based Cohort Study 
PLoS ONE  2012;7(5):e36727.
Background
To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring.
Methods/Principal Findings
We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations.
Conclusions
This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
doi:10.1371/journal.pone.0036727
PMCID: PMC3359312  PMID: 22649497
5.  Preconception Predictors of Birth Outcomes: Prospective Findings from the Central Pennsylvania Women's Health Study 
Maternal and child health journal  2009;15(7):829-835.
Objective
To examine maternal pre-pregnancy (preconception) predictors of birthweight and fetal growth for singleton live births occurring over a 2-year period in a prospective study.
Methods
Data are from a population-based cohort study of 1,420 women who were interviewed at baseline and 2-years later; self-report data and birth records were obtained for incident live births during the followup period. The analytic sample includes 116 singleton births. Baseline preconception maternal health status and health-related behaviors were examined as predictors of birthweight and fetal growth, controlling for prenatal and sociodemographic variables, using multiple regression analysis.
Results
Preconception BMI (overweight or obese) and vegetable consumption (at least one serving per day) had statistically significant independent and positive effects on birthweight and fetal growth. Maternal weight gain during pregnancy, a prenatal variable, was an additional independent predictor of birthweight and fetal growth. Sociodemographic variables were not significant predictors after controlling for preconception and prenatal maternal characteristics.
Conclusions
Findings confirm that preconception maternal health status and health-related behaviors can affect birthweight and fetal growth independent of prenatal and socioeconomic variables. Implications for preconception care are discussed.
doi:10.1007/s10995-009-0473-2
PMCID: PMC2939188  PMID: 19472041
Preconception health; Birthweight; Body mass index; Nutrition; Cohort study
6.  Preconception care for women with type 1 diabetes. 
Canadian Family Physician  2003;49:769-773.
OBJECTIVE: To emphasize preconception care of women with type 1 diabetes and the role of primary care physicians in evaluating and counseling them. QUALITY OF EVIDENCE: Substantial level II evidence indicates that tight glycemic control before conception and early in pregnancy reduces the rate of congenital malformations. Most evidence concerning maternal and fetal risks during pregnancy in patients with type 1 diabetes is level III or IV. Little is published on the role of family physicians in providing preconception counseling or care. MAIN MESSAGE: Preconception care is effective in improving glycemic control early in pregnancy and in reducing the rate of congenital malformations. Preconception evaluation of type 1 diabetic patients involves assessment of prepregnancy glycemic control and diabetic complications. Preconception counseling includes discussing the rate of transmission of diabetes, the effects of pregnancy on maternal and fetal complications, and the use of contraception until optimal glycemic control can be attained. CONCLUSION: Primary care physicians often have frequent and early contact with women of reproductive age; they are ideal candidates for providing type 1 diabetic women with preconception evaluation and counseling.
PMCID: PMC2214237  PMID: 12836865
7.  Diagnostic X-ray and ultrasound exposure and risk of childhood cancer. 
British Journal of Cancer  1994;70(3):531-536.
In a population-based case-control study of 642 childhood cancer cases and the same number of matched controls in Shanghai, China, we evaluated the relationship between diagnostic X-ray (preconception, pre- and post-natal) and antenatal ultrasound exposure and the subsequent risk of developing three major types of childhood cancer (acute leukaemia, lymphoma and brain tumours) and all childhood neoplasms combined. Consistent with previous studies, prenatal X-ray exposure was found to be associated with an 80% increased risk of childhood cancers, although the estimation was based on 4% and 2% exposed cases and controls and was only marginally statistically significant (P = 0.08). Post-natal X-ray exposure was also linked with a small elevation in the risk of all cancers and the major categories of malignancies in children. Little evidence, however, was found to relate parental preconception X-ray exposure with the subsequent cancer risk in offspring, regardless of the exposure window and the anatomical site of X-ray exposures. This study adds further to the growing literature indicating that antenatal ultrasound exposure is probably not associated with an increased risk of childhood cancer.
PMCID: PMC2033354  PMID: 8080742
8.  Preventive Health Examinations Part I 
Canadian Family Physician  1988;34:1119-1123.
The family physician may conduct preventive screening of children yet unborn, beginning with assessing the rubella-immunity status of 12-year-old females and continuing through the preconception period, the prenatal period, and the process of birth. Knowledge of both parents and their family history allows family physicians to deal effectively with the very sensitive issues of risks of congenital disorders and the effects of teratogenic drugs during pregnancy. Prenatal monitoring for various disorders and risks and assessing the growth curve of pregnancy will help to improve fetal outcomes. Proper use of suctioning, oxygen, and application of the Apgar score to monitor and detect evidence of asphyxia at birth can result in healthier babies.
PMCID: PMC2219068  PMID: 21253174
preventive health examinations; prenatal management
9.  Prenatal p,p´-DDE Exposure and Neurodevelopment among Children 3.5–5 Years of Age 
Environmental Health Perspectives  2012;121(2):263-268.
Background: The results of previous studies suggest that prenatal exposure to bis[p-chlorophenyl]-1,1,1-trichloroethane (DDT) and to its main metabolite, 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), impairs psychomotor development during the first year of life. However, information about the persistence of this association at later ages is limited.
Objectives: We assessed the association of prenatal DDE exposure with child neurodevelopment at 42–60 months of age.
Methods: Since 2001 we have been monitoring the neurodevelopment in children who were recruited at birth into a perinatal cohort exposed to DDT, in the state of Morelos, Mexico. We report McCarthy Scales of Children’s Abilities for 203 children at 42, 48, 54, and 60 months of age. Maternal DDE serum levels were available for at least one trimester of pregnancy. The Home Observation for Measurement of the Environment scale and other covariables of interest were also available.
Results: After adjustment, a doubling of DDE during the third trimester of pregnancy was associated with statistically significant reductions of –1.37, –0.88, –0.84, and –0.80 points in the general cognitive index, quantitative, verbal, and memory components respectively. The association between prenatal DDE and the quantitative component was weaker at 42 months than at older ages. No significant statistical interactions with sex or breastfeeding were observed.
Conclusions: These findings support the hypothesis that prenatal DDE impairs early child neurodevelopment; the potential for adverse effects on development should be considered when using DDT for malaria control.
doi:10.1289/ehp.1205034
PMCID: PMC3569679  PMID: 23151722
McCarthy scale; Mexico; neurodevelopment; organochlorines compounds; prenatal exposure; prospective cohort
10.  The Effects of Prenatal Cocaine Exposure and Gender on Inhibitory Control and Attention 
Neurotoxicology and teratology  2011;33(1):61-68.
Children exposed prenatally to cocaine show deficits in emotion regulation and inhibitory control. While controlling for the measures of medical complication in the perinatal period, environmental risk, and prenatal polydrug exposure (alcohol, tobacco, and marijuana), we examined the effects of prenatal cocaine exposure and gender on attention and inhibitory control in 203 children at ages 6, 9, and 11. Cocaine exposure affected the performance of males, but not females. Heavily exposed males showed deficits in the attention and the inhibition tasks. In addition, a significantly greater proportion of heavily exposed males (21%) than unexposed males (7%) or heavily exposed females (7%) failed to complete the task (p < .01). Even without those poorest performing subjects, the overall accuracy for heavily exposed males (81%) was significantly reduced (p < .05) compared to lightly exposed males (87%) and unexposed males (89%). The findings highlight the importance of considering gender specificity in cocaine exposure effects. Processes by which cocaine effects may be specific to males are discussed.
doi:10.1016/j.ntt.2010.07.004
PMCID: PMC3052746  PMID: 21256425
attention; inhibitory control; prenatal cocaine exposure
11.  Statistical and Practical Issues in the Design of a National Probability Sample of Births for the Vanguard Study of the National Children's Study 
Statistics in medicine  2010;29(13):1368-1376.
Summary
The National Children's Study is a national household probability sample designed to identify 100,000 children at birth and follow the sampled children for 21 years. Data from the study will support examining numerous hypotheses concerning genetic and environmental effects on the health and development of children. The goals of the study present substantial challenges. For example, the need for preconception, prenatal, and postnatal data require identifying women in the early stages of pregnancy, the collection of many types of data, and the retention of the children over time. In this paper, we give an overview of the sample design used in a pilot study called the Vanguard Study, and highlight the approaches used to address these challenges. We will also describe the rationale for the sampling choices made at each stage, the unique organizational structure of the NCS and issues we expect to face during implementation.
doi:10.1002/sim.3891
PMCID: PMC2894610  PMID: 20527010
Multistage sample; area probability sample; primary sampling unit; segment; listing
12.  Maternal Bereavement and Childhood Asthma—Analyses in Two Large Samples of Swedish Children 
PLoS ONE  2011;6(11):e27202.
Background
Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma.
Methodology and Principal Findings
We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1–4 (n = 426 334) and 7–12 (n = 493 813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1–4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7–12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1–4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7–12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant.
Conclusions/Significance
Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls.
doi:10.1371/journal.pone.0027202
PMCID: PMC3210147  PMID: 22087265
13.  Children’s Exposure to Diagnostic Medical Radiation and Cancer Risk: Epidemiologic and Dosimetric Considerations 
Pediatric radiology  2008;39(Suppl 1):S4.
While the etiology of most childhood cancers is largely unknown, epidemiologic studies have consistently found an association between exposure to medical radiation during pregnancy and risk of childhood cancer in offspring. The relation between early life diagnostic radiation exposure and occurrence of pediatric cancer risks is less clear. This review summarizes current and historical estimated doses for common diagnostic radiologic procedures as well as the epidemiologic literature on the role of maternal prenatal, children’s postnatal and parental preconception diagnostic radiologic procedures on subsequent risk of childhood malignancies Risk estimates are presented according to factors such as the year of birth of the child, trimester and medical indication for the procedure, and the number of films taken. The paper also discusses limitations of the methods employed in epidemiologic studies to assess pediatric cancer risks, the effects on clinical practice of the results reported from the epidemiologic studies, and clinical and public health policy implications of the findings. Gaps in understanding and additional research needs are identified. Important research priorities include nationwide surveys to estimate fetal and childhood radiation doses from common diagnostic procedures, and epidemiologic studies to quantify pediatric and lifetime cancer risks from prenatal and early childhood exposures to diagnostic radiography, computed tomography, and fluoroscopically-guided procedures.
doi:10.1007/s00247-008-1026-3
PMCID: PMC2814780  PMID: 19083224
ionizing radiation; pediatric neoplasms; cancer risks; diagnostic radiography; CT
14.  Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models. 
Environmental Health Perspectives  2000;108(Suppl 3):573-594.
In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal. Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive. In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.
Images
PMCID: PMC1637809  PMID: 10852857
15.  Variants in the SIRT1 Gene May Affect Diabetes Risk in Interaction With Prenatal Exposure to Famine 
Diabetes Care  2012;35(2):424-426.
OBJECTIVE
To investigate whether SIRT1, a nutrient-sensing histone deacetylase, influences fetal programming during malnutrition.
RESEARCH DESIGN AND METHODS
In 793 individuals of the Dutch Famine Birth Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms (SNPs) and prenatal exposure to famine on type 2 diabetes risk.
RESULTS
In the total population (exposed and unexposed), SIRT1 variants were not associated with type 2 diabetes. A significant interaction was found between two SIRT1 SNPs and exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2 diabetes only in individuals who had been exposed to famine prenatally (odds ratio for rs7895833 0.50 [95% CI 0.24–1.03], P = 0.06; for rs1467568 0.48 [0.25–0.91], P = 0.02).
CONCLUSIONS
SIRT1 may be an important genetic factor involved in fetal programming during malnutrition, influencing type 2 diabetes risk later in life.
doi:10.2337/dc11-1203
PMCID: PMC3263901  PMID: 22228742
16.  Hypoglycemia in Type 1 Diabetic Pregnancy 
Diabetes Care  2009;33(3):473-477.
OBJECTIVE
A recent randomized trial compared prandial insulin aspart (IAsp) with human insulin in type 1 diabetic pregnancy. The aim of this exploratory analysis was to investigate the incidence of severe hypoglycemia during pregnancy and compare women enrolled preconception with women enrolled during early pregnancy.
RESEARCH DESIGN AND METHODS
IAsp administered immediately before each meal was compared with human insulin administered 30 min before each meal in 99 subjects (44 to IAsp and 55 to human insulin) randomly assigned preconception and in 223 subjects (113 for IAsp and 110 for human insulin) randomly assigned in early pregnancy (<10 weeks). NPH insulin was the basal insulin. Severe hypoglycemia (requiring third-party assistance) was recorded prospectively preconception (where possible), during pregnancy, and postpartum. Relative risk (RR) of severe hypoglycemia was evaluated with a gamma frailty model.
RESULTS
Of the patients, 23% experienced severe hypoglycemia during pregnancy with the peak incidence in early pregnancy. In the first half of pregnancy, the RR of severe hypoglycemia in women randomly assigned in early pregnancy/preconception was 1.70 (95% CI 0.91–3.18, P = 0.097); the RR in the second half of pregnancy was 1.35 (0.38–4.77, P = 0.640). In women randomly assigned preconception, severe hypoglycemia rates occurring before and during the first and second halves of pregnancy and postpartum for IAsp versus human insulin were 0.9 versus 2.4, 0.9 versus 2.4, 0.3 versus 1.2, and 0.2 versus 2.2 episodes per patient per year, respectively (NS).
CONCLUSIONS
These data suggest that initiation of insulin analog treatment preconception rather than during early pregnancy may result in a lower risk of severe hypoglycemia in women with type 1 diabetes.
doi:10.2337/dc09-1605
PMCID: PMC2827491  PMID: 20007944
17.  Impact of a Preconception Counseling Program for Teens With Type 1 Diabetes (READY-Girls) on Patient-Provider Interaction, Resource Utilization, and Cost 
Diabetes Care  2010;33(4):701-705.
OBJECTIVE
To evaluate the impact of a preconception counseling program tailored for teens with type 1 diabetes on cognitive, psychosocial, and behavioral outcomes and to assess its cost-effectiveness.
RESEARCH DESIGN AND METHODS
A total of 88 teens with type 1 diabetes from two sites were randomized into the READY-Girls (Reproductive-health Education and Awareness of Diabetes in Youth for Girls) intervention (IG) (n = 43) or standard care (SC) (n = 45) groups. During three diabetes clinic visits, IG subjects viewed a two-part CD-ROM, read a book, and met with a nurse. Program effectiveness was measured by knowledge, attitudes, intentions, and behaviors regarding diabetes, pregnancy, sexuality, and preconception counseling. Assessments occurred at baseline, before and after viewing program materials, and at 9 months. Economic analyses included an assessment of resource utilization, direct medical costs, and a break-even cost analysis.
RESULTS
Age range was 13.2–19.7 years (mean ± SD 16.7 ± 1.7 years); 6% (n = 5) were African American, and 24% (n = 21) were sexually active. Compared with baseline and SC subjects, IG subjects demonstrated a significant group-by-time interaction for benefit and knowledge of preconception counseling and reproductive health: increasing immediately after the first visit (P < 0.001) and being sustained for 9 months (P < 0.05 benefits; P < 0.001 knowledge). For IG subjects, preconception counseling barriers decreased over time (P < 0.001), and intention and initiation of preconception counseling and reproductive health discussions increased (P < 0.001). Costs of adverse reproductive outcomes are high. Direct medical costs of READY-Girls were low.
CONCLUSIONS
READY-Girls was beneficial and effects were sustained for at least 9 months. This low-cost self-instructional program can potentially empower young women with type 1 diabetes to make well-informed reproductive health choices, adding little time burden or cost to their diabetes management.
doi:10.2337/dc09-1821
PMCID: PMC2845009  PMID: 20067963
18.  MOTHER-INFANT INTERACTION AT 12 MONTHS IN PRENATALLY COCAINE-EXPOSED CHILDREN 
This study examined mother-infant interactions of 12-month-old African-American prenatally cocaine-exposed infants and their mothers. Videotaped observations were made during a free-play dyadic interaction, a brief separation, and a reunion period. Videotapes were coded for maternal and child behaviors during each phase of the procedure. Although there were few differences in interactive behaviors between prenatally cocaine-exposed and nonexposed children and their mothers, children who were prenatally exposed to cocaine ignored their mother’s departure (odds ratio [OR] = 3.0, p < .05) during separation significantly more often than nonexposed subjects. In addition, mothers who abused cocaine engaged in significantly more verbal behavior (F(2,104) = 7.00, p < .001) with their children than mothers of nonexposed children. These findings indicate that women who used cocaine during pregnancy may not differ from nonusers in their interactions with their 12-month-old infants.
PMCID: PMC1522055  PMID: 11417936
Mother-child interaction; Prenatal cocaine exposure
19.  Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e30850.
Background
Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.
Methodology/Principal Findings
To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.
Conclusions/Significance
Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.
doi:10.1371/journal.pone.0030850
PMCID: PMC3266299  PMID: 22295115
20.  Early Life Nutrition Modulates Muscle Stem Cell Number: Implications for Muscle Mass and Repair 
Stem Cells and Development  2011;20(10):1763-1769.
Suboptimal nutrition during prenatal and early postnatal development is associated with increased risk for type 2 diabetes during adult life. A hallmark of such diabetes risk is altered body composition, including reduced lean mass and increased adiposity. Since stem cell number and activity are important determinants of muscle mass, modulation of perinatal nutrition could alter stem cell number/function, potentially mediating developmentally programmed reductions in muscle mass. Skeletal muscle precursors (SMP) were purified from muscle of mice subjected to prenatal undernutrition and/or early postnatal high-fat diet (HFD)—experimental models that are both associated with obesity and diabetes risk. SMP number was determined by flow cytometry, proliferative capacity measured in vitro, and regenerative capacity of these cells determined in vivo after muscle freeze injury. Prenatally undernutrition (UN) mice showed significantly reduced SMP frequencies [Control (C) 4.8%±0.3% (% live cells) vs. UN 3.2%±0.4%, P=0.015] at 6 weeks; proliferative capacity was unaltered. Reduced SMP in UN was associated with 32% decrease in regeneration after injury (C 16%±3% of injured area vs. UN 11%±2%; P<0.0001). SMP frequency was also reduced in HFD-fed mice (chow 6.4%±0.6% vs. HFD 4.7%±0.4%, P=0.03), and associated with 44% decreased regeneration (chow 16%±2.7% vs. HFD 9%±2.2%; P<0.0001). Prenatal undernutrition was additive with postnatal HFD. Thus, both prenatal undernutrition and postnatal overnutrition reduce myogenic stem cell frequency and function, indicating that developmentally established differences in muscle-resident stem cell populations may provoke reductions in muscle mass and repair and contribute to diabetes risk.
doi:10.1089/scd.2010.0349
PMCID: PMC3182031  PMID: 21247245
21.  Preconception care of women with diabetes: a review of current guideline recommendations 
BMC Women's Health  2010;10:5.
Background
The prevalence of type 2 diabetes mellitus (T2DM) continues to rise worldwide. More women from developing countries who are in the reproductive age group have diabetes resulting in more pregnancies complicated by T2DM, and placing both mother and foetus at higher risk. Management of these risks is best achieved through comprehensive preconception care and glycaemic control, both prior to, and during pregnancy. The aim of this review was to compare the quality and content of current guidelines concerned with the preconception care of women with diabetes and to develop a summary of recommendations to assist in the management of diabetic women contemplating pregnancy.
Methods
Relevant clinical guidelines were identified through a search of several databases (MEDLINE, SCOPUS and The Cochrane Library) and relevant websites. Five guidelines were identified. Each guideline was assessed for quality using the AGREE instrument. Guideline recommendations were extracted, compared and contrasted.
Results
All guidelines were assessed as being of high quality and strongly recommended for use in practice. All were consistent in counselling about the risk of congenital malformation related to uncontrolled blood sugar preconceptionally, ensuring adequate contraception until glycaemic control is achieved, use of HBA1C to monitor metabolic control, when to commence insulin and switching from ACE inhibitors to other antihypertensives. Major differences were in the targets recommended for optimal metabolic control and opinion regarding the usage of metformin as an adjunct or alternative treatment before or during pregnancy.
Conclusions
International guidelines for the care of women with diabetes who are contemplating pregnancy are consistent in their recommendations; however some are more comprehensive than others. Having established current standards for the preconception care of diabetic women, there is now a need to focus on guideline implementation through an examination of the barriers and enablers to successful implementation, and the applicability of the recommendations in the local setting.
doi:10.1186/1472-6874-10-5
PMCID: PMC2834595  PMID: 20113524
22.  Effect of conjugal bereavement on mortality of the bereaved spouse in participants of the Renfrew/Paisley Study 
Objectives
To investigate how loss of a spouse affects mortality risk in the bereaved partner.
Design and setting
Prospective cohort study in Renfrew and Paisley in Scotland.
Participants
4395 married couples aged 45–64 years when the study was carried out between 1972 and 1976.
Methods
The date of bereavement for the bereaved spouse was the date of death of his or her spouse. Bereavement could occur at any time during the follow‐up period, so it was considered as a time‐dependent exposure variable and the Cox proportional hazards model for time‐dependent variables was used. The relative rate (RR) of mortality was calculated for bereaved versus non‐bereaved spouses and adjusted for confounding variables.
Main outcome measures
Causes of death to 31 March 2004.
Results
Bereaved participants were at higher risk than non‐bereaved participants of dying from any cause (RR 1.27; 95% CI 1.2 to 1.35). These risks remained but were attenuated after adjustment for confounding variables. There were raised RRs for bereaved participants dying of cardiovascular disease, coronary heart disease, stroke, all cancer, lung cancer, smoking‐related cancer, and accidents or violence. After adjustment for confounding variables, RRs remained higher for bereaved participants for all these causes except for mortality from lung cancer. There was no strong statistical evidence that the increased risks of death associated with bereavement changed with time after bereavement.
Conclusions
Conjugal bereavement, in addition to existing risk factors, is related to mortality risk for major causes of death.
doi:10.1136/jech.2006.052043
PMCID: PMC2465697  PMID: 17435215
23.  ENVIRONMENTAL FACTORS ASSOCIATED WITH CHILDHOOD-ONSET TYPE I DIABETES: AN EXPLORATION OF THE HYGIENE AND OVERLOAD HYPOTHESES 
Objective
To assess the relationship between selected maternal and infant characteristics and risk of Type 1 diabetes, specifically characteristics identified from birth records that may pertain to the “Hygiene” or “Overload” hypotheses.
Design
Population-based case-control study.
Setting
Washington State from 1987–2005.
Participants
All children <19 years hospitalized for Type 1 diabetes (ICD-9 250.x1, 250.x3) identified (N=1852) from hospital discharge data and linked with their birth certificates. Controls (N=7408) were randomly selected from birth records, frequency matched on year of birth.
Main Exposures
Maternal factors included age, race, educational attainment, marital status, use of Medicaid insurance, body mass index, prepregnancy weight, prior births, timing and adequacy of prenatal care, and caesarian delivery. Infant factors included birthweight, size for gestational age, and gestational age.
Main Outcome Measure
The main outcome was first hospitalization for Type 1 diabetes mellitus; adjusted odds ratios were estimated for the association of selected maternal and infant characteristics with Type 1 diabetes.
Results
Consistent with the hygiene hypothesis, Type 1 diabetes was negatively associated with having older siblings (for 3+ siblings, OR=0.56, 95% CI 0.45–0.70), and with indicators of lower economic status or care access, such as an unmarried mother (OR=0.79, 95% CI 0.69–0.91), inadequate prenatal care (OR=0.53, 95% CI 0.40,–0.71), or Medicaid insurance (OR=0.67, 95% CI 0.58–0.77). Related to the overload hypothesis, maternal BMI >30 (OR=1.29, 95% CI 1.01–1.64) was associated with increased risk of diabetes.
Conclusions
Environmental factors related to decreased antigenic stimulation in early life and maternal obesity may be associated with Type 1 diabetes.
doi:10.1001/archpediatrics.2010.115
PMCID: PMC3064074  PMID: 20679164
24.  Prevalence of Risk Factors for Adverse Pregnancy Outcomes During Pregnancy and the Preconception Period—United States, 2002–2004 
Maternal and Child Health Journal  2006;10(Suppl 1):101-106.
Objectives: To assess the prevalence of risk factors for adverse pregnancy outcome during the preconception stage and during pregnancy, and to assess differences between women in preconception and pregnancy. Methods: Data from the 2002 and 2004 Behavioral Risk Factor Surveillance System, United States, were used to estimate the prevalence of selected risk factors among women 18–44 in the preconception period (women who wanted a baby in the next 12 months, and were not using contraception, not sterile and not already pregnant) with women who reported that they were pregnant at the time of interview. Results: Major health risks were reported by substantial proportions of women in the preconceptional period and were also reported by many pregnant women, although pregnant women tended to report lower levels of risk than preconception women. For example, 54.5% of preconception women reported one or more of 3 risk factors (frequent drinking, current smoking, and absence of an HIV test), compared with 32.0% of pregnant women (p < .05). The difference in the prevalence of these three risk factors between preconception and pregnancy was significant for women with health insurance (52.5% in preconception vs. 29.4% in pregnancy, p < .05), but not for women without insurance (63.4% vs. 52.7%, p > .05). Conclusions: Women appear to be responding to messages regarding behaviors that directly affect pregnancy such as smoking, alcohol consumption and taking folic acid, but many remain unaware of the benefits of available interventions to prevent HIV transmission and birth defects. Although it appears that some women reduce their risk for adverse pregnancy outcomes after learning of their pregnancy, the data suggest that a substantial proportion of women do not. Furthermore, if such change occurs it is often too late to affect outcomes, such as birth defects resulting from alcohol consumption during the periconception period. Preconception interventions are recommended to achieve a more significant reduction in risk and further improvement in perinatal outcomes.
doi:10.1007/s10995-006-0093-z
PMCID: PMC1592157  PMID: 16710762
Pregnancy; Riskfactors; Preconception
25.  Preconception Counseling in Women With Diabetes 
Diabetes Care  2009;33(3):586-588.
OBJECTIVE
To investigate the association of preconception counseling with markers of care and maternal characteristics in women with pregestational diabetes.
RESEARCH DESIGN AND METHODS
The study includes data from a regional multi-center survey on 588 women with pregestational diabetes who delivered a singleton pregnancy between 2001 and 2004. Logistic regression was used to obtain crude and adjusted estimates of association.
RESULTS
Preconception counseling was associated with better glycemic control 3 months preconception (odds ratio 1.91, 95% CI 1.10–3.04) and in the first trimester (2.05, 1.39–3.03), higher preconception folic acid intake (4.88, 3.26–7.30), and reduced risk of adverse pregnancy outcome (P = 0.027). Uptake of preconception counseling was positively associated with type 1 diabetes (1.87, 1.14–3.07) and White British ethnicity (2.56, 1.17–5.6) and negatively with deprivation score (0.78, 0.70–0.87).
CONCLUSIONS
Efforts are needed to improve preconception counseling rates. Uptake is associated with maternal sociodemographic characteristics.
doi:10.2337/dc09-1585
PMCID: PMC2827513  PMID: 20040652

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