In utero exposure to endocrine disrupting chemicals, micro-RNA profiles, and fetal growth: a pilot study protocol.

Background: The developing fetus is particularly vulnerable to the effects of endocrine disrupting chemicals (EDCs). Molecular fingerprints of EDCs can be identified via microRNA (miRNA) expression profiles and may be etiologically implicated in the developmental origin of disease (DOHaD). Methods/design: This pilot study includes pregnant women at high risk (smoking at conception), and low risk (non-smoking at conception) for SGA birth (birthweight<10th percentile for gestational age). We have randomly selected 12 mothers (3 high-risk SGA birth, 3 low-risk SGA birth, 3 high-risk non-SGA birth, 3 low-risk non-SGA birth), with EDC measurements from gestational week 17. All offspring are female. We aim to test the stability of our samples (maternal serum, cord blood, placenta tissue), observe the differential expression of miRNA profiles over time (gestational weeks 17, 25, 33, 37, birth), and study the consistency between maternal EDC measures and miRNA expression profiles across our repeated measures. Expected impact of the study for Public Health: Results from this pilot study will inform the development of a larger cohort wide analysis, and will impact the current state of knowledge in the fields of public health, epigenetics, and the DOHaD.

Maternal serum retinol, 25(OH)D and 1,25(OH)2D concentrations during pregnancy and peak bone mass and trabecular bone score in adult offspring at 26-year follow-up.

BACKGROUND: Vitamin A and D deficiency is prevalent in pregnant women worldwide. Both vitamins are involved in fetal skeletal development. A positive association between maternal vitamin D levels and offspring bone mineral density (BMD) at adulthood has been observed. The impact of maternal vitamin A status in pregnancy on offspring peak bone mass remains unclear. METHOD AND FINDINGS: Forty-one mother-child pairs were recruited from a population-based prospective cohort study in Trondheim, Norway, where pregnant women were followed from gestational week 17. Their term-born infants were followed from birth (1986-88). Regression analyses were performed for vitamin A (retinol), 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in maternal serum (gestational weeks 17, 33, 37) and cord blood. Offspring BMD and spine trabecular bone score (TBS), a measure of bone quality, were analyzed by dual x-ray absorptiometry at 26 years. Average levels during pregnancy of retinol, 25(OH)D and 1,25(OH)2D were 1.66 (0.32) µmol/L, 59.0 (20.6) nmol/L, and 251.3 (62.4) pmol/L, respectively. 1,25(OH)2D levels were similar in those with 25(OH)D levels <30 and >75 nmol/L. After adjustment for maternal age, BMI, smoking, and education, and offspring birth weight, maternal serum retinol was positively associated with offspring spine BMD [mean change 30.8 (CI 7.6, 54.0) mg/cm2 per 0.2 µmol/L retinol], and with offspring TBS, although non-significant (p = 0.08). No associations were found between maternal 25(OH)D and 1,25(OH)2D levels and offspring bone parameters. Vitamin levels in cord blood were not associated with offspring BMD or TBS. CONCLUSIONS: This is the first study to show an association between maternal vitamin A status and offspring peak bone mass. Our findings may imply increase future risk for osteoporotic fracture in offspring of mothers with suboptimal vitamin A level. No associations were observed between 25(OH)D and 1,25(OH)2D and offspring BMD.

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

A systematic review of maternal smoking during pregnancy and fetal measurements with meta-analysis.

BACKGROUND: Maternal smoking during pregnancy is linked to reduced birth weight but the gestation at onset of this relationship is not certain. We present a systematic review of the literature describing associations between maternal smoking during pregnancy and ultrasound measurements of fetal size, together with an accompanying meta-analysis. METHODS: Studies were selected from electronic databases (OVID, EMBASE and Google Scholar) that examined associations between maternal smoking or smoke exposure and antenatal fetal ultrasound measurements. Outcome measures were first, second or third trimester fetal measurements. RESULTS: There were 284 abstracts identified, 16 papers were included in the review and the meta-analysis included data from eight populations. Maternal smoking was associated with reduced second trimester head size (mean reduction 0.09 standard deviation (SD) [95% CI 0.01, 0.16]) and femur length (0.06 [0.01, 0.10]) and reduced third trimester head size (0.18 SD [0.13, 0.23]), femur length (0.27 SD [0.21, 0.32]) and estimated fetal weight (0.18 SD [0.11, 0.24]). Higher maternal cigarette consumption was associated with a lower z score for head size in the second (mean difference 0.09 SD [0, 0.19]) and third (0.15 SD [0.03, 0.26]) trimesters compared to lower consumption. Fetal measurements were not reduced for those whose mothers quit before or after becoming pregnant compared to mothers who had never smoked. CONCLUSIONS: Maternal smoking during pregnancy is associated with reduced fetal measurements after the first trimester, particularly reduced head size and femur length. These effects may be attenuated if mothers quit or reduce cigarette consumption during pregnancy.

Factors Associated with Maternal Serum Levels of Perfluoroalkyl Substances and Organochlorines: A Descriptive Study of Parous Women in Norway and Sweden.

INTRODUCTION: Perfluoroalkyl substances (PFASs) and organochlorines (OCs) are ubiquitous and persistent in the environment and proposed endocrine disrupting chemicals (EDCs). They can be transferred across the placenta during pregnancy, and studies suggest that the prenatal period may be particularly sensitive for influences on fetal growth and development. Several studies have investigated socio-demographic and pregnancy related factors associated with maternal serum PFAS and OC levels, but few studies have been conducted in time periods with increasing emissions of PFASs and recent emissions of OCs. METHODS: Serum from 424 pregnant women participating in the NICHD Scandinavian Successive Small-for-gestational Age (SGA) births study was collected in 1986-1988, and analyses of two PFASs and six OCs were conducted. Associations between EDCs and geographic, time dependent, socio-demographic and pregnancy related variables were evaluated by using multivariable linear regression models. RESULTS: Previous breastfeeding duration, time since last breastfeeding period, sampling date and country of residence were important factors associated with serum levels of PFOS and PFOA. Smoking status and pre-pregnancy BMI were negatively associated with PFOS, and maternal height was borderline negatively associated with PFOS and PFOA. Glomerular filtration rate (GFR) was negatively associated with PFOS in a sub-sample. Maternal serum levels of OCs were positively associated with maternal age, and negatively associated with previous breastfeeding duration and sampling date. Smoking had a consistently negative association with PCB 118 in a dose-dependent manner. Education level, pre-pregnancy BMI and alcohol consumption varied in importance according to the compound under study. CONCLUSIONS: Several maternal factors, including potentially modifiable factors, markers of pregnancy physiology and factors also related to perinatal outcomes were associated with EDC levels. Results from this study are relevant to populations with still high PFAS and OC levels, i.e. developing countries. Moreover, we can use this knowledge about associated factors on emerging EDCs with similar properties.

Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults.

OBJECTIVE: To examine the effect on adult cognitive function of being born small for gestational age (SGA), and to evaluate whether cognitive function is related to intrauterine growth restriction (IUGR). STUDY DESIGN: Fifty-nine SGA subjects (birth weight <10th percentile) and 81 controls (birth weight ≥10th percentile) born at term underwent cognitive assessment with the Wechsler Adult Intelligence Scale-Third Edition at age 19-20 years. Repeated ultrasound measures of fetal growth were available for weeks 25, 33, and 37 in a subgroup of 29 SGA subjects and 75 control subjects, and these were data used to dichotomize the 29 SGA subjects into those with IUGR and those without IUGR. IUGR was defined as growth deviating more than -2 SD from the mean value of the control group. The effect of maternal smoking during pregnancy was considered as well. Group differences were analyzed using a general linear model, controlling for sex and socioeconomic status. RESULTS: The SGA group had lower full IQ scores than the control group (mean difference, -6.3; 95% CI, -2.8 to -9.7; P = .001), including lower scores on 6 of the Wechsler Adult Intelligence Scale-Third Edition subtests. In the SGA subgroup with repeated ultrasound measures, 6 of 29 subjects (21%) had IUGR, and these subjects also had a lower IQ compared with controls (mean difference, -14.0; 95% CI: -4.8 to -23.3; P = .003). Maternal smoking during pregnancy was related to lower IQ in the control group but not in the SGA group, independent of IUGR or non-IUGR status. CONCLUSION: IQ scores were lower in young adults born SGA compared with controls. Our analysis suggest that this outcome is related to IUGR.

Being born small for gestational age reduces white matter integrity in adulthood: a prospective cohort study.

BACKGROUND: Being born small for gestational age (SGA) (birth weight <10th percentile) is connected to decreased white matter (WM) integrity in newborns and increased prevalence of psychiatric symptoms in adulthood. The aims of this study were to investigate whether being born SGA at term affects WM integrity in young adulthood and to explore possible relationships between fractional anisotropy (FA) and pre- and perinatal factors and cognitive and psychiatric outcomes in adulthood in SGA and controls. METHODS: Diffusion tensor imaging and tract-based spatial statistics were conducted to test for voxelwise differences in FA in SGAs (n = 46) and controls (n = 57) at 18-22 y. RESULTS: As compared with controls SGAs had reduced FA in ventral association tracts and internal/external capsules. In the SGAs, no relationship was found between FA and intrauterine head growth in the third trimester, although total intelligence quotient was negatively correlated to FA. In controls, a positive correlation was found between FA and brain growth in the third trimester and maternal smoking. No relationship was found between FA and psychiatric measures in SGAs or controls. CONCLUSION: These results demonstrate that being born SGA leads to reduced WM integrity in adulthood, and suggest that different factors modulate the development of WM in SGA and control groups.

Birthweight and mortality in adulthood: a systematic review and meta-analysis.

BACKGROUND: Small birth size may be associated with increased risk of cardiovascular diseases (CVD), whereas large birth size may predict increased risk of obesity and some cancers. The net effect of birth size on long-term mortality has only been assessed in individual studies, with conflicting results. METHODS: The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines for conducting and reporting meta-analysis of observational studies were followed. We retrieved 22 studies that assessed the association between birthweight and adult mortality from all causes, CVD or cancer. The studies were systematically reviewed and those reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs) per kilogram (kg) increase in birthweight were included in generic inverse variance meta-analyses. RESULTS: For all-cause mortality, 36,834 deaths were included and the results showed a 6% lower risk (adjusted HR = 0.94, 95% CI: 0.92-0.97) per kg higher birthweight for men and women combined. For cardiovascular mortality, the corresponding inverse association was stronger (HR = 0.88, 95% CI: 0.85-0.91). For cancer mortality, HR per kg higher birthweight was 1.13 (95% CI: 1.07-1.19) for men and 1.04 (95% CI: 0.98-1.10) for women (P(interaction) = 0.03). Residual confounding could not be eliminated, but is unlikely to account for the main findings. CONCLUSION: These results show an inverse but moderate association of birthweight with adult mortality from all-causes and a stronger inverse association with cardiovascular mortality. For men, higher birthweight was strongly associated with increased risk of cancer deaths. The findings suggest that birthweight can be a useful indicator of processes that influence long-term health.

The role of entry screening in case finding of tuberculosis among asylum seekers in Norway.

BACKGROUND: Most new cases of active tuberculosis in Norway are presently caused by imported strains and not transmission within the country. Screening for tuberculosis with a Mantoux test of everybody and a chest X-ray of those above 15 years of age is compulsory on arrival for asylum seekers.We aimed to assess the effectiveness of entry screening of a cohort of asylum seekers. Cases detected by screening were compared with cases detected later. Further we have characterized cases with active tuberculosis. METHODS: All asylum seekers who arrived at the National Reception Centre between January 2005--June 2006 with an abnormal chest X-ray or a Mantoux test ≥ 6 mm were included in the study and followed through the health care system. They were matched with the National Tuberculosis Register by the end of May 2008.Cases reported within two months after arrival were defined as being detected by screening. RESULTS: Of 4643 eligible asylum seekers, 2237 were included in the study. Altogether 2077 persons had a Mantoux ≥ 6 mm and 314 had an abnormal chest X-ray. Of 28 cases with tuberculosis, 15 were detected by screening, and 13 at 4-27 months after arrival. Abnormal X-rays on arrival were more prevalent among those detected by screening. Female gender and Somalian origin increased the risk for active TB. CONCLUSION: In spite of an imperfect follow-up of screening results, a reasonable number of TB cases was identified by the programme, with a predominance of pulmonary TB.

Screening and treatment of latent tuberculosis in a cohort of asylum seekers in Norway.

AIMS: Asylum seekers are screened for tuberculosis at entry to Norway. We aimed to assess follow-up of screening results at different healthcare levels in relation to demographics, screening results and organizational factors, and how this influenced treatment of latent tuberculosis. METHODS: All asylum seekers >or=18 years with a Mantoux test >or=6 mm or positive x-ray findings who arrived at the National Reception Centre from January 2005 to June 2006, were included. Data were collected from public health authorities in the municipality where the asylum seekers had moved, and from internists in case they had been referred to a specialist. Specialists are responsible for treating latent tuberculosis. Individual subjects were matched with the National Tuberculosis Register to which everybody who had started treatment for latent tuberculosis was reported. RESULTS: Of 4,643 asylum seekers, 2,237 fulfilled the inclusion criteria. By May 2008, 30 persons had started treatment for latent TB, a median of 17 months (range 3-36) after arrival. A Mantoux test >or=15 mm on arrival was significantly associated with treatment. Demographic factors influenced follow-up in primary healthcare while screening results did not. Referral to specialist was related to screening results. Several specialists were reluctant to diagnose and treat latent tuberculosis and to treat persons without a permanent visa in particular. CONCLUSIONS: Just 1% of the study group received treatment for latent tuberculosis and with a long time delay. The reason for this may be organizational factors affecting follow-up and referral and specialists not following current guidelines.

Tuberculosis screening and follow-up of asylum seekers in Norway: a cohort study.

BACKGROUND: About 80% of new tuberculosis cases in Norway occur among immigrants from high incidence countries. On arrival to the country all asylum seekers are screened with Mantoux test and chest x-ray aimed to identify cases of active tuberculosis and, in the case of latent tuberculosis, to offer follow-up or prophylactic treatment.We assessed a national programme for screening, treatment and follow-up of tuberculosis infection and disease in a cohort of asylum seekers. METHODS: Asylum seekers >or= 18 years who arrived at the National Reception Centre from January 2005 to June 2006, were included as the total cohort. Those with a Mantoux test >or= 6 mm or positive x-ray findings were included in a study group for follow-up.Data were collected from public health authorities in the municipality to where the asylum seekers had moved, and from hospital based internists in case they had been referred to specialist care.Individual subjects included in the study group were matched with the Norwegian National Tuberculosis Register which receive reports of everybody diagnosed with active tuberculosis, or who had started treatment for latent tuberculosis. RESULTS: The total cohort included 4643 adult asylum seekers and 97.5% had a valid Mantoux test. At least one inclusion criterion was fulfilled by 2237 persons. By end 2007 municipal public health authorities had assessed 758 (34%) of them. Altogether 328 persons had been seen by an internist. Of 314 individuals with positive x-rays, 194 (62%) had seen an internist, while 86 of 568 with Mantoux >or= 15, but negative x-rays (16%) were also seen by an internist. By December 31st 2006, 23 patients were diagnosed with tuberculosis (prevalence 1028/100 000) and another 11 were treated for latent infection. CONCLUSION: The coverage of screening was satisfactory, but fewer subjects than could have been expected from the national guidelines were followed up in the community and referred to an internist. To improve follow-up of screening results, a simplification of organisation and guidelines, introduction of quality assurance systems, and better coordination between authorities and between different levels of health care are all required.