Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Is systemic lupus erythematosus different in urban versus rural living environment? Data from the Cretan Lupus Epidemiology and Surveillance Registry.

BACKGROUND: Examining urban-rural differences can provide insights into susceptibility or modifying factors of complex diseases, yet limited data exist on systemic lupus erythematosus (SLE). OBJECTIVE: To study SLE risk, manifestations and severity in relation to urban versus rural residence. METHODOLOGY: Cross-sectional analysis of the Crete Lupus Registry. Demographics, residency history and clinical data were obtained from interviews and medical records ( N=399 patients). Patients with exclusively urban, rural or mixed urban/rural residence up to enrolment were compared. RESULTS: The risk of SLE in urban versus rural areas was 2.08 (95% confidence interval: 1.66-2.61). Compared with rural, urban residence was associated with earlier (by almost seven years) disease diagnosis - despite comparable diagnostic delay - and lower female predominance (6.8:1 versus 15:1). Rural patients had fewer years of education and lower employment rates. Smoking was more frequent among urban, whereas pesticide use was increased among rural patients. A pattern of malar rash, photosensitivity, oral ulcers and arthritis was more prevalent in rural patients. Residence was not associated with organ damage although moderate/severe disease occurred more frequently among rural-living patients (multivariable adjusted odds ratio: 2.17, p=0.011). CONCLUSION: Our data suggest that the living environment may influence the risk, gender bias and phenotype of SLE, not fully accounted for by sociodemographic factors.

Low maternal vitamin D status in pregnancy increases the risk of childhood obesity.

BACKGROUND: Vitamin D may modulate adipogenesis. However, limited studies have investigated the effect of maternal vitamin D during pregnancy on offspring adiposity or cardiometabolic parameters with inconclusive results. OBJECTIVES: The objective of this study is to examine the association of maternal 25(OH)-vitamin D [25(OH)D] status with offspring obesity and cardiometabolic characteristics in 532 mother-child pairs from the prospective pregnancy cohort Rhea in Crete, Greece. METHODS: Maternal 25(OH)D concentrations were measured at the first prenatal visit (mean: 14 weeks, SD: 4). Child outcomes included body mass index standard deviation score, waist circumference, skin-fold thickness, blood pressure and serum lipids at ages 4 and 6 years. Body fat percentage was also measured at 6 years. Body mass index growth trajectories from birth to 6 years were estimated by mixed effects models with fractional polynomials of age. Adjusted associations were obtained via multivariable linear regression analyses. RESULTS: About two-thirds of participating mothers had 25(OH)D concentrations <50 nmol L-1 . Offspring of women in the low 25(OH)D tertile (<37.7 nmol L-1 ) had higher body mass index standard deviation score (ß 0.20, 95% CI: 0.03, 0.37), and waist circumference (ß 0.87 95% CI: 0.12, 1.63) at preschool age, compared with the offspring of women with higher 25(OH)D measurements (≥37.7 nmol L-1 ), on covariate-adjusted analyses. The observed relationships persisted at age 6 years. We found no association between maternal 25(OH)D concentrations and offspring blood pressure or serum lipids at both time points. CONCLUSIONS: Exposure to very low 25(OH)D concentrations in utero may increase childhood adiposity indices. Given that vitamin D is a modifiable risk factor, our findings may have important public health implications.

Air pollution, weight loss and metabolic benefits of bariatric surgery: a potential model for study of metabolic effects of environmental exposures.

BACKGROUND: Emerging experimental evidence suggests that air pollution may contribute to development of obesity and diabetes, but studies of children are limited. OBJECTIVES: We hypothesized that pollution effects would be magnified after bariatric surgery for treatment of obesity, reducing benefits of surgery. METHODS: In 75 obese adolescents, excess weight loss (EWL), high-density lipoprotein (HDL) cholesterol, triglycerides, alkaline phosphatase (ALP) and hemoglobin A1c (HbA1c ) were measured prospectively at baseline and following laparoscopic adjustable gastric banding (LAGB). Residential distances to major roads and the average two-year follow-up exposure to particulate matter <2.5 µm (PM2.5 ), nitrogen dioxide (NO2 ) and ozone were estimated. Associations of exposure with change in outcome and with attained outcome two years post-surgery were examined. RESULTS: Major-roadway proximity was associated with reduced EWL and less improvement in lipid profile and ALP after surgery. NO2 was associated with less improvement in HbA1c and lower attained HDL levels and change in triglycerides over two years post-surgery. PM2.5 was associated with reduced EWL and reduced beneficial change or attained levels for all outcomes except HbA1c . CONCLUSIONS: Near-roadway, PM2.5 and NO2 exposures at levels common in developed countries were associated with reduced EWL and metabolic benefits of LAGB. This novel approach provides a model for investigating metabolic effects of other exposures.

Pregnancy, perinatal and postpartum complications as determinants of postpartum depression: the Rhea mother-child cohort in Crete, Greece.

AIMS: Few epidemiological studies evaluated associations between perinatal complications and maternal mood at the early postpartum period and the findings are inconsistent. We aimed at investigating a wide range of complications during pregnancy, at delivery, and at the early postpartum period as determinants of postpartum depression (PPD) at 8 weeks postpartum. METHODS: A total of 1037 women who enrolled in the Rhea mother-child cohort in Crete, Greece participated in the present study. Information on pregnancy, perinatal and postpartum complications was obtained from clinical records or by questionnaires. Postpartum depressive symptoms were assessed at 8 weeks postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multivariable linear and logistic regression models were fit to estimate the association between pregnancy, perinatal and postpartum complications and maternal depressive symptoms, adjusting also for potential confounders. RESULTS: The prevalence of women with probable depression (EPDS score ≥ 13) was 13.6% at 8 weeks postpartum. Gestational hypertension and/or preeclampsia (ß coefficient 1.86, 95% CI: 0.32, 3.41) and breastfeeding difficulties (ß coefficient 0.77, 95% CI: 0.02, 1.53) were significantly associated with higher PPD symptoms. Sleep patterns during pregnancy, such as sleep deprivation (OR = 3.57, 95% CI: 1.91, 6.67) and snoring (OR = 1.81, 95% CI: 1.11, 2.93), and breastfeeding duration less than 2 months (OR = 1.77, 95% CI: 1.19, 2.64) were significantly associated with increase in the odds for PPD. Some other complications, such as unplanned pregnancy and hospitalisation during pregnancy were also associated with EPDS score, but these associations were explained by socio-demographic characteristics of the mother. CONCLUSIONS: We found that several pregnancy, perinatal and postpartum complications may have an adverse effect on maternal mood at the early postpartum period. These findings have considerable implications for developing effective prevention and early psychoeducational intervention strategies for women at risk of developing PPD.

Polyunsaturated fatty acid levels at birth and child-to-adult growth: Results from the MEFAB cohort.

BACKGROUND: Prenatal exposure to polyunsaturated fatty acids (PUFAs) may influence childhood growth. However, available evidence mostly derived from short-term studies is inconsistent. OBJECTIVE: To assess whether fetal PUFA exposure is associated with height and body mass index (BMI), a common measure of adiposity, from 6 months to 23 years of age. METHODS: In the MEFAB cohort, we assessed cord blood phospholipid n-3 and n-6 PUFA levels, reflecting fetal exposure in late pregnancy. For 250 (45.2% females) participants, we collected a total of 1770 (n= 802 for females) repeated growth measurements from infancy to young adulthood. We examined sex-specific associations of PUFAs with height and BMI at different developmental ages (infant: 6 months; toddler: 2 years; pre-schooler: 4 years; school-aged child: 7 years; adolescent: 12 years; and young adult: 23 years) using fractional polynomial mixed models adjusted for important covariates. RESULTS: Higher n-3 PUFA levels were associated with higher infant length in males (ß= 0.44cm [95% CI: 0.07, 0.82] per SD increase), whereas, for females, higher n-6 PUFA concentrations were associated with lower length in infancy (ß= -0.69cm [95% CI: -1.08, -0.30] per SD increase). A higher ratio of n-3 to n-6 PUFAs was associated with higher infant length in both sexes (ß= 0.40cm [95% CI: 0.01, 0.78] and 0.42cm [95% CI: 0.05, 0.79] per unit increase for males and females, respectively). These associations were not detectable later in childhood and young adulthood. No associations with BMI were found at any time point examined. CONCLUSIONS: Our findings suggest a small sex-specific influence of PUFA status at birth on length in infancy, but this does not persist in later life up to young adulthood. PUFA status at birth does not seem to affect BMI from infancy till young adulthood.

Adherence to the Mediterranean diet during pregnancy and offspring adiposity and cardiometabolic traits in childhood.

BACKGROUND: In adults, adherence to the Mediterranean diet has been inversely associated with cardiovascular risk, but the extent to which diet in pregnancy is associated with offspring adiposity is unclear. We aimed to investigate the association between adherence to Mediterranean diet in pregnancy and offspring cardiometabolic traits in two pregnancy cohorts. METHODS: We studied 997 mother-child pairs from Project Viva in Massachusetts, USA, and 569 pairs from the Rhea study in Crete, Greece. We estimated adherence to the Mediterranean diet with an a priori defined score (MDS) of nine foods and nutrients (0 to 9). We measured child weight, height, waist circumference, skin-fold thicknesses, blood pressure, and blood levels of lipids, c-reactive protein and adipokines in mid-childhood (median 7.7 years) in Viva, and in early childhood (median 4.2 years) in Rhea. We calculated cohort-specific effects and pooled effects estimates with random-effects models for cohort and child age. RESULTS: In Project Viva, the mean (SD, standard deviation) MDS was 2.7 (1.6); in Rhea it was 3.8 (1.7). In the pooled analysis, for each 3-point increment in the MDS, offspring BMI z-score was lower by 0.14 units (95% CI, -0.15 to -0.13), waist circumference by 0.39 cm (95% CI, -0.64 to -0.14), and the sum of skin-fold thicknesses by 0.63 mm (95% CI, -0.98 to -0.28). We also observed lower offspring systolic (-1.03 mmHg; 95% CI, -1.65 to -0.42) and diastolic blood pressure (-0.57 mmHg; 95% CI, -0.98 to -0.16). CONCLUSION: Greater adherence to Mediterranean diet during pregnancy may protect against excess offspring cardiometabolic risk.

The independent role of prenatal and postnatal exposure to active and passive smoking on the development of early wheeze in children.

Maternal smoking during pregnancy increases childhood asthma risk, but health effects in children of nonsmoking mothers passively exposed to tobacco smoke during pregnancy are unclear. We examined the association of maternal passive smoking during pregnancy and wheeze in children aged ≤2 years.Individual data of 27 993 mother-child pairs from 15 European birth cohorts were combined in pooled analyses taking into consideration potential confounders.Children with maternal exposure to passive smoking during pregnancy and no other smoking exposure were more likely to develop wheeze up to the age of 2 years (OR 1.11, 95% CI 1.03-1.20) compared with unexposed children. Risk of wheeze was further increased by children's postnatal passive smoke exposure in addition to their mothers' passive exposure during pregnancy (OR 1.29, 95% CI 1.19-1.40) and highest in children with both sources of passive exposure and mothers who smoked actively during pregnancy (OR 1.73, 95% CI 1.59-1.88). Risk of wheeze associated with tobacco smoke exposure was higher in children with an allergic versus nonallergic family history.Maternal passive smoking exposure during pregnancy is an independent risk factor for wheeze in children up to the age of 2 years. Pregnant females should avoid active and passive exposure to tobacco smoke for the benefit of their children's health.

Leptin, acylcarnitine metabolites and development of adiposity in the Rhea mother-child cohort in Crete, Greece.

OBJECTIVE: This study aims to investigate relations of serum leptin at age 4 with development of adiposity and linear growth during 3 years of follow-up among 75 Greek children and to identify serum metabolites associated with leptin at age 4 and to characterize their associations with adiposity gain and linear growth. METHODS: Linear regression models that accounted for maternal age, education and gestational weight gain and child's age and sex were used to examine associations of leptin and leptin-associated metabolites measured at age 4 with indicators of adiposity and linear growth at age 7. RESULTS: Each 1-unit increment in natural log-(ln)-transformed leptin corresponded with 0.33 (95% CI: 0.10, 0.55) units greater body mass index-for-age z-score gain during follow-up. Likewise, higher levels of the leptin-associated metabolites methylmalonyl-carnitine and glutaconyl-carnitine corresponded with 0.14 (95% CI: 0.01, 0.27) and 0.07 (95% CI: -0.01, 0.16) units higher body mass index-for-age z-score gain, respectively. These relationships did not differ by sex or baseline weight status and were independent of linear growth. CONCLUSIONS: These findings suggest that leptin, methylmalonyl-carnitine and possibly glutaconyl-carnitine are associated with weight gain during early childhood. Future studies are warranted to confirm these findings in other populations.

Early life determinants of dietary patterns in preschool children: Rhea mother-child cohort, Crete, Greece.

BACKGROUND/OBJECTIVES: The determination of dietary patterns in children examines the effects of the overall diet at early ages, instead of looking at individual foods or energy providing nutrients. The present analysis aims to identify the dietary patterns of preschool children and to examine their associations with multiple socio-economic and lifestyle characteristics. SUBJECTS/METHODS: Dietary data were collected for 1081 children participating in the Rhea mother-child cohort in Crete, Greece. Diet was assessed using a validated food frequency questionnaire, and dietary patterns were identified with principal component analysis. Multivariable linear regression models were used to examine factors associated with each dietary pattern. RESULTS: Three dietary patterns were identified explaining 45.8% of the total diet variation. The 'Mediterranean' pattern was based on pulses, olive oil, vegetables, fish and fruits; the 'Snacky' pattern included potatoes and other starchy roots, salty snacks, sugar products and eggs; the 'Western' pattern contained cereals, cheese, added lipids, beverages and meat. Preschool attendance and increased time spent with the mother (⩾2 h/day) were positively associated with the 'Mediterranean' pattern, whereas watching TV was inversely associated with this pattern. Lower parental education, maternal age and earlier introduction to solid foods were positively associated with the 'Snacky' pattern. Higher scores on the 'Western' type diet were associated with exposure to passive smoking and watching TV. No variation in energy providing nutrient intake was observed across tertiles of the identified dietary patterns. CONCLUSIONS: The results from this analysis indicate the important role of socio-demographic factors on children's dietary preferences in early age.

Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.

Effect of maternal n-3 long-chain polyunsaturated fatty acid supplementation during pregnancy and/or lactation on adiposity in childhood: a systematic review and meta-analysis of randomized controlled trials.

It is hypothesized that prenatal and early postnatal exposure to n-3 long-chain polyunsaturated fatty acids (LCPUFAs) is negatively associated with adiposity later in life. We conducted a systematic review and meta-analysis to evaluate whether maternal n-3 LCPUFA supplementation in pregnancy and/or lactation exerts a beneficial effect on adiposity status in childhood. We searched six electronic databases till 20 May 2014 for randomized controlled trials (RCTs) of n-3 LCPUFA supplementation to pregnant and/or lactating women that reported data on body mass index (BMI), waist circumference, sum of skinfold thicknesses or body fat mass in children. Adiposity measures were grouped into three age categories: preschool children (<5 years), school-aged children (6-12 years), and adolescents (>13 years). Trial quality was assessed. We conducted fixed-effect and random-effects meta-analyses to combine study-specific estimates of differences between the supplemented and control groups. A total of 6 RCTs (9 publications) involving 2847 participants were included. Summary estimates showed no effect of maternal supplementation on BMI in preschool (standardized mean difference (SMD)=0.07, 95% confidence interval (CI)=-0.22, 0.36, P=0.65) and school-aged children (SMD=0.12, 95% CI=-0.06, 0.30, P=0.20). Because of sparse data, it was not possible to pool study results relating to other adiposity measures. There is currently no evidence to support that n-3 LCPUFA supplementation during pregnancy and/or lactation favourably affects child adiposity. Further high-quality trials are needed.

Caesarean deliveries in the Mother-Child (Rhea) cohort in Crete, Greece: almost as frequent as vaginal births and even more common in first-time mothers.

BACKGROUND: Caesarean deliveries are on the increase in Greece and around the world. The objective of the present study was to assess the frequency of planned and emergency caesarean deliveries and their socio-demographic predictors in women with singleton pregnancies followed-up from early pregnancy to delivery. METHODS: The mother-child cohort in Crete examines a population sample of pregnant women recruited during one year beginning in February 2007. A cohort of 1096 women, with singleton pregnancies, was included in the present analyses. Multivariable Poisson regression models with robust error variance were used. RESULTS: Overall, 48% of the women had a caesarean delivery, with a higher percentage observed in women having their first child (52%). Maternal age was a predictor for caesarean deliveries; type of hospital was associated with the risk for an emergency caesarean, whereas women with lower education were at an increased risk of having a planned caesarean delivery among primiparae. Prior caesarean delivery was by far the strongest predictor (RR=7.68, 95% CI 5.71, 10.33) for a subsequent one among multiparae. CONCLUSIONS: Caesarean deliveries are almost as frequent as vaginal births in the study population and even more frequent in first-time mothers. The study findings support that risk factors are indeed mode of delivery and parity status specific. As such, it is becoming clearer which groups of women, especially first-time mothers, need to be targeted in future research and interventions so as to understand better and achieve an appropriate caesarean delivery risk.

Increased frequency of micronuclei in mononucleated lymphocytes and cytome analysis in healthy newborns as an early warning biomarkers of possible future health risks.

Impact of intrauterine development on health risks during adolescence and adulthood still needs to be investigated. The aim of study was to compare genome damage in newborns and mothers using the cytokinesis blocked micronucleus assay, nuclear division index (NDI), and centromere fluorescence in situ hybridization. The study was performed on 92 mothers and their newborns. Results showed that micronucleus frequency in binuclear T-lymphocytes (MNBN) in newborns was significantly lower than in mothers but higher in mononuclear T-lymphocytes (MNMONO). The NDI in the mothers was significantly higher than in the newborns. In newborns with <2500g birth weight, NDI was similar to the mothers'. Mothers have significantly more centromere negative micronuclei than newborns. A significantly higher NDI and MNBN was found in newborns with ≥2 MNMONO/1000 than in newborns with <2 MNMONO/1000. It is suggested that MOMN and NDI might be good candidates for biomarkers of health risks in newborns.

Maternal personality traits and risk of preterm birth and fetal growth restriction.

BACKGROUND/AIMS: Maternal personality may increase vulnerability to stress, which could lead to an unfavourable intrauterine environment to the fetus. We sought to investigate the impact of maternal personality traits on adverse birth outcomes such as preterm birth, and fetal growth restriction in the mother-child cohort study (RHEA Study) in Crete, Greece 2007-2009. METHODS: Five hundred and eighty pregnant women participating in "Rhea" cohort study completed the Eysenck Personality Questionnaire-Revised (EPQ-R) at 28-32 weeks of gestation. Information on anthropometric measures at birth was obtained from the hospital delivery logs and medical records. Fetal growth restriction was based on a customized model, and multivariate logistic regression models were used adjusting for confounders. RESULTS: A per unit increase in the EPQ Neuroticism scale increased the risk for fetal weight growth restriction by 9% [odds ratio (OR)=1.09, 95 percent CI: 1.01, 1.19)], and for fetal head circumference growth restriction by 6% [OR=1.06, 95 percent CI: 1.01, 1.18] after adjusting for maternal age, education, origin, marital status, working status, pre-pregnancy BMI, delivery type, parity, smoking, and alcohol intake during pregnancy. CONCLUSIONS: Maternal neuroticism, which predisposes to negative mood, may be a risk factor for fetal growth restriction.

Influence of fetal glutathione S-transferase copy number variants on adverse reproductive outcomes.

A nested case-control association study was designed to investigate the influence of maternal and fetal copy number variants (CNVs) on reproductive outcomes. Genotypes of ten CNVs encompassing GST and CYP genes were assessed. Significant associations were only found for child CNV genotypes. In particular, the child GSTM1 insertion allele was associated with prematurity protection (odds ratio, 95% CI: 0.67, 0.51-0.89; P < 0.01), whereas the child GSTT2B insertion allele was associated with an increased risk of being small for gestational age (odds ratio, 95% CI: 1.33, 1.07-1.67; P = 0.01). The study highlights the role of the fetal genome in prenatal development and also the need to analyse CNVs in a systematic manner.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

The metabolic syndrome in early pregnancy and risk of gestational diabetes mellitus.

AIM: The objective of the present study was to determine whether or not maternal metabolic syndrome in early pregnancy in women without previous diabetes is associated with the development of gestational diabetes mellitus (GDM). METHODS: A total of 508 women from the Rhea study-involving a pregnant cohort in Crete, Greece (2007-2009)-with singleton pregnancies were included in the present analysis. Maternal fasting serum samples were collected and blood pressure measured before gestational week 15. The metabolic syndrome in early pregnancy was defined according to NHLBI/AHA criteria. Pregnant women were screened for GDM between weeks 24 and 28 of gestation, as defined by Carpenter and Coustan criteria. Multivariable log-binomial regression models were used to estimate the effect of the metabolic syndrome in early pregnancy on the risk of GDM, after adjusting for confounding factors. RESULTS: Women with the metabolic syndrome were at high risk of GDM (RR=3.17; 95% CI: 1.06-9.50). Among the components of the metabolic syndrome, the most significant risk factors were impaired fasting glucose (RR=4.92; 95% CI: 1.41-17.23) and pre-pregnancy obesity (RR=2.65; 95% CI: 1.23-5.70). A 10-mmHg rise in systolic and diastolic blood pressure increased the relative risk of GDM by 49% (RR=1.49; 95% CI: 1.10-2.02) and 34% (RR=1.34; 95% CI: 1.04-1.73), respectively, whereas a 1-unit increase in pre-pregnancy BMI increased the relative risk of GDM by 6% (RR=1.06; 95% CI: 1.01-1.12). CONCLUSION: These findings suggest that women with the metabolic syndrome in early pregnancy have a greater risk of developing GDM.

Mediterranean diet in pregnancy is protective for wheeze and atopy in childhood.

INTRODUCTION: Dietary intake of specific nutrients or food groups during pregnancy could play a role in the risk of asthma and atopy in offspring, but specific dietary patterns have not been implicated. The authors evaluated the impact of maternal (during pregnancy) and child adherence to a Mediterranean diet on asthma and atopy in childhood. METHODS: Women presenting for antenatal care at all general practices in Menorca, a Mediterranean island in Spain, over a 12 month period starting in mid-1997 were recruited. 460 children were included in the analysis after 6.5 years of follow-up. Maternal dietary intake during pregnancy and children's dietary intake at age 6.5 years were assessed by food frequency questionnaires, and adherence to a Mediterranean diet was evaluated by a priori defined scores. During follow-up, parents completed questionnaires on the child's respiratory and allergic symptoms. Children underwent skin prick tests with six common aeroallergens. RESULTS: The prevalence rates of persistent wheeze, atopic wheeze and atopy at age 6.5 years were 13.2%, 5.8% and 17.0%, respectively. One-third (36.1%) of mothers had a low quality Mediterranean diet during pregnancy according to the Mediterranean Diet Score, while the rest had a high score. A high Mediterranean Diet Score during pregnancy (at two levels, using "low" score as the reference) was found to be protective for persistent wheeze (OR 0.22; 95% CI 0.08 to 0.58), atopic wheeze (OR 0.30; 95% CI 0.10 to 0.90) and atopy (OR 0.55; 95% CI 0.31 to 0.97) at age 6.5 years after adjusting for potential confounders. Childhood adherence to a Mediterranean diet was negatively associated with persistent wheeze and atopy although the associations did not reach statistical significance. CONCLUSION: These results support a protective effect of a high level of adherence to a Mediterranean diet during pregnancy against asthma-like symptoms and atopy in childhood.