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Background and aimsPrepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts.Subjects and methodsThe study used data from three European birth cohorts (n = 116 children aged 6 years, n = 2466 children aged 10 years, and n = 437 young adults aged 26 years). Information on maternal prepregnancy BMI was obtained before or during pregnancy and offspring brain white matter microstructure was measured at age 6, 10, or 26 years. We used magnetic resonance imaging-derived fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter microstructure in the brainstem, callosal, limbic, association, and projection tracts. Linear regressions were fitted to examine the association of maternal BMI and offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related confounders, including education, smoking, and alcohol use.ResultsMaternal BMI was associated with higher FA and lower MD in multiple brain tracts, for example, association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. In each cohort maternal BMI was related to different white matter tract and thus no common associations across the cohorts were found.ConclusionsMaternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.

Single nucleotide polymorphisms (SNPs) in the genes encoding the fatty acid desaturase (FADS) and elongase (ELOVL) enzymes affect long-chain polyunsaturated fatty acid (LC-PUFA) production. We aimed to determine if these SNPs are associated with body mass index (BMI) or affect fatty acids (FAs) in pregnant women. Participants (n = 180) from the PREOBE cohort were grouped according to pre-pregnancy BMI: normal-weight (BMI = 18.5-24.9, n = 88) and overweight/obese (BMI≥25, n = 92). Plasma samples were analyzed at 24 weeks of gestation to measure FA levels in the phospholipid fraction. Selected SNPs were genotyped (7 in FADS1, 5 in FADS2, 3 in ELOVL2 and 2 in ELOVL5). Minor allele carriers of rs174545, rs174546, rs174548 and rs174553 (FADS1), and rs1535 and rs174583 (FADS2) were nominally associated with an increased risk of having a BMI≥25. Only for the normal-weight group, minor allele carriers of rs174537, rs174545, rs174546, and rs174553 (FADS1) were negatively associated with AA:DGLA index. Normal-weight women who were minor allele carriers of FADS SNPs had lower levels of AA, AA:DGLA and AA:LA indexes, and higher levels of DGLA, compared to major homozygotes. Among minor allele carriers of FADS2 and ELOVL2 SNPs, overweight/obese women showed higher DHA:EPA index than the normal-weight group; however, they did not present higher DHA concentrations than the normal-weight women. In conclusion, minor allele carriers of FADS SNPs have an increased risk of obesity. Maternal weight changes the effect of genotype on FA levels. Only in the normal-weight group, minor allele carriers of FADS SNPs displayed reduced enzymatic activity and FA levels. This suggests that women with a BMI≥25 are less affected by FADS genetic variants in this regard. In the presence of FADS2 and ELOVL2 SNPs, overweight/obese women showed higher n-3 LC-PUFA production indexes than women with normal weight, but this was not enough to obtain a higher n-3 LC-PUFA concentration.

Children born to obese mothers are at increased risk for obesity, but the mechanisms behind this association are not fully understood. Our study aimed to investigate differences in the functions encoded by the microbiome of infants at 18 months of age when the transition from early infant-feeding to solid family foods is established. To investigate the impact of maternal prepregnancy body mass index on infants’ gut microbiome, faecal samples from infants born to normoweight ( n  = 21) and obese mothers ( n  = 18) were analysed by 16S rRNA gene sequencing and a functional-inference-based microbiome analysis. Our results indicated that Firmicutes was significantly enriched in infants born to normoweight mothers whereas Bacteroidetes was significantly enriched in infants born to obese women. In both microbiomes, the greatest number of genes (>50%) that were assigned a function encoded for proteins involved in “metabolism” among tier 1 KEGG Orthology (KO) categories. At lower KO functional categories, the microbiome of infants born to normoweight mothers was characterized by a significant enrichment in the abundances of “pentose phosphate pathway” ( p  = 0.037), “lysine biosynthesis” ( p  = 0.043), “glycerolipid metabolism” ( p  = 0.042), and “C5-branched dibasic acid metabolism” ( p  = 0.045). Notably, the microbiome of infants born to obese mothers was significantly enriched in “streptomycin biosynthesis” ( p  = 0.047), “sulphur metabolism” ( p  = 0.041), “taurine and hypotaurine metabolism” ( p  = 0.036), and “lipopolysaccharide biosynthesis” ( p  = 0.043). In summary, our study showed that maternal prepregnancy obesity may imprint a selective gut microbial composition during late infancy with distinct functional performances.

This study analyzed how maternal obesity a ected fatty acids (FAs) in breast milk and their association with infant growth and cognition to raise awareness about the programming e ect of maternal health and to promote a healthy prenatal weight. Mother-child pairs (n = 78) were grouped per maternal pre-pregnancy body mass index (BMI): normal-weight (BMI = 18.5-24.99), overweight (BMI = 25-29.99) and obese (BMI > 30). Colostrum and mature milk FAs were determined. Infant anthropometry at 6, 18 and 36 months of age and cognition at 18 were analyzed. Mature milk exhibited lower arachidonic acid (AA) and docosahexaenoic acid (DHA), among others, than colostrum. Breast milk of non-normal weight mothers presented increased saturated FAs and n6:n3 ratio and decreased -linolenic acid (ALA), DHA and monounsaturated FAs. Infant BMI-for-age at 6 months of age was inversely associated with colostrum n6 (e.g., AA) and n3 (e.g., DHA) FAs and positively associated with n6:n3 ratio. Depending on the maternal weight, infant cognition was positively influenced by breast milk linoleic acid, n6 PUFAs, ALA, DHA and n3 LC-PUFAs, and negatively a ected by n6:n3 ratio. In conclusion, this study shows that maternal pre-pregnancy BMI can influence breast milk FAs and infant growth and cognition, endorsing the importance of a healthy weight in future generations.

Abstract Background: Maternal overweight, obesity, and gestational diabetes (GD) have been negatively associated with offspring development. Further knowledge regarding metabolic and nutritional alterations in these mother and their offspring are warranted. Methods: In an observational cohort study we included 331 pregnant women from Granada, Spain. The mothers were categorized into four groups according to BMI and their GD status; overweight (n:56), obese (n:64), GD (n:79), and healthy normal weight controls (n:132). We assessed maternal growth and nutritional biomarkers at 24 weeks (n = 269), 34 weeks (n = 310) and at delivery (n = 310) and the perinatal characteristics including cord blood biomarkers. Results: Obese and GD mothers had significantly lower weight gain during pregnancy and infant birth weight, waist circumference, and placental weight were higher in the obese group, including a significantly increased prevalence of macrosomia. Except for differences in markers of glucose metabolism (glucose, HbA1c, insulin and uric acid) we found at some measures that overweight and/or obese mothers had lower levels of transferrin saturation, hemoglobin, Vitamin B12 and folate and higher levels of C-reactive protein, erythrocyte sedimentation rate, ferritin, and cortisol. GD mothers had similar differences in hemoglobin and C-reactive protein but higher levels of folate. The latter was seen also in cord blood. Conclusions: We identified several metabolic alterations in overweight, obese and GD mothers compared to controls. Together with the observed differences in infant anthropometrics, these may be important biomarkers in future research regarding the programming of health and disease in children. Trial registration: The trial was registered at clinicaltrials.gov, identifier (NCT01634464). Keywords: Pregnancy, Maternal overweight, Maternal obesity, Gestational diabetes, Offspring, Fetal nutrition, Early programming, Vitamin B12, Folate, Iron status, Glucose metabolism

Background and objectives: Maternal metabolic status before and during pregnancy exerts an important influence on neurodevelopment and behavior in the offspring. Maternal characteristics may be a significant predictor of behavioral problems in childhood and mental health problems during adulthood. The aim of the present study was to analyse the effect of maternal obesity or gestational diabetes (GD) conditions on adaptive behavior and social-emotional development in their offspring at 6 and 18 months of life. Methods: From a total of 331 pregnant women participating in the PREOBE study, 215 pregnant women and their offspring were evaluated. The mothers were divided into 4 groups according to their pre-gestational body mass index or the development of GD: overweight (n:44), obese (n:32), GD (n:58), and healthy normal weight (n:81). Adaptive behavior and social-emotional development was assessed using the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and Bayley's III Social-Emotional scale. Differences in scores were analysed by ANOVA, MANCOVA and Chi-Square Test, using SPSS version 22.0. Results: At 6 months of life, those children born to obese mothers showed lower scores in social-emotional (p=0.005) and self-direction (p=0.035) skills, compared to those born to normal weight-healthy mothers. At 18 months of age, children born to overweight/obese mothers presented lower scores in self-direction (p=0.028), leisure (p=0.037) and self-care (p=0.024) than those born to normal weight-healthy mothers. However, in adjusted analysis by maternal age and cultural level, these results disappeared. Additionally, children born to normal weight-healthy and GD mothers showed higher scores in conceptual skills (communication, functional pre-academics and self direction) (p=0.001) than children born to obese/overweight mothers. Conclusions: Obesity or Overweight during pregnancy are associated to poorer child's social-emotional and adaptive behavior development at 6 and 18 months of life. Problems in early life to adapt to the natural and social demands of environment can be predictors of learning disorders or attention deficits. These results couldn help to understand the underlying aetiology of cognitive and behaviors problems in preschool children.

Background and objectives: Maternal diet and nutritional status are powerful determinants of development in utero and the first years of life.Women from disadvantaged groups tend to have the poorest quality diets which are translated into their offspring. We aimed to investigate the long-term influence of maternal obesity and gestational diabetes (GD) during pregnancy on their children diet up to 6 years of life. Methods: 119 children participating in the PREOBE study, born to overweight (n=16), obese (n=15), GD (n=35), and healthy normal weight pregnant women (n=53) were included in the present analysis.Children dietary intake was recorded using three days 24h dietary record (2 working days and 1 weekend day).Quantification of nutrient intake by each child was performed by using the DIAL nutritional software.MANCOVA were performed using SPSS version 23.0, and the results were adjusted for confounding factors (maternal age, weight gain during pregnancy, maternal education and family status).Bonferroni corrected post hoc comparisons were used to identify significant group differences. Results: Children born to GD mothers showed higher levels of fatty acids and trans- fatty acids intake than those born to normal weight (p=0,013 and p=0,006;respectively) and overweight mothers (p=0,026 and p=0,008;respectively). Children born to GD mothers showed higher levels of monounsaturated fatty acids (MUFA)-cis than those born to normal weight (p=0,034) and MUFA-trans respect to those born to normal weight and overweight mothers (p=0,031 and p=0,013;respectively).The intake of polyunsaturated fatty acids-trans were higher inchildren born to GD mothers than in those born to normal weight or overweight mothers (p=0,005 and p=0,002;respectively). Conclusions: At 6 years of age, children born to mothers who developed GD show an inadequate dietary intake of trans fatty acids from manufactured foods.Diabetic pregnant women are included by routine in medical and nutritional programs to prevent undesirable problems during pregnancy and on their offspring, and furthermore after this intervention, an improvement of their eating habits isusually expected. However, the present results reflect the turn back to poor eating habits in the diabetic mothers which are translated into their offspring up to school age.The consequences of this fact are unknown.Behavioural programs are needed to maintain healthy eating habits in the mothers and children.

Overweight, obesity, and gestational diabetes (GD) during pregnancy may negatively affect neurodevelopment in the offspring. However, the mechanisms are unclear and objective measures of neurodevelopment in infancy are scarce. We hypothesized that these maternal metabolic pathologies impair cortical visual evoked potentials (cVEPs), a proxy for visual and neuronal maturity. The PREOBE study included 331 pregnant women stratified into four groups; normal weight (controls), overweight, obesity, and GD (the latter including mothers with normal weight, overweight and obesity). In a subsample of the offspring at 3 months (n = 157) and at 18 months (n = 136), we assessed the latencies and amplitudes of the P100 wave from cVEPs and calculated visual acuity. At 3 months of age, visual acuity was significantly poorer in offspring born to GD mothers. At 18 months of age, there were no differences in visual acuity but infants born to GD mothers had significantly longer latencies of cVEPs when measured at 15', and 30' of arc. The group differences at 30' remained significant after confounder adjustment (mean [SD] 121.0 [16.0] vs. 112.6 [7.6] ms in controls, p = 0.007) and the most prolonged latencies were observed in offspring to GD mothers with concurrent overweight (128.9 [26.9] ms, p = 0.002) and obesity (118.5 [5.1] ms, p = 0.020). Infants born to mothers with GD, particularly those with concurrent overweight or obesity, have prolonged latencies of visual evoked potentials at 18 months of age, suggesting that this maternal metabolic profile have a long lasting, non-optimal, effect on infants´ brain development.

Brain development in fetal life and early infancy is critical to determine lifelong performance in various neuropsychological domains. Metabolic pathologies such as overweight, obesity, and gestational diabetes in pregnant women are prevalent and increasing risk factors that may adversely affect long-term brain development in their offspring. The objective of this research was to investigate the influence of maternal metabolic pathologies on the neurodevelopment of the offspring at 6 and 18 months of life. This was a prospective case-control study of 331 mother- and child pairs from Granada, Spain. The mothers were included during pregnancy into four groups according to their pre-gestational body mass index and their gestational diabetes status; overweight (n:56), obese (n:64), gestational diabetic (n:79), and healthy normal weight controls (n:132). At 6 months and 18 months we assessed the children with the Bayley III scales of neurodevelopment. At 6 months (n=215), we found significant group differences in cognition composite language, and expressive language. Post hoc test revealed unexpectedly higher scores in the obese group compared to the normal weight group and a similar trend in overweight and diabetic group. The effects on language remained significant after adjusting for confounders with an adjusted odds ratio for a value above median in composite language score of 3.3 (95% CI: 1.1, 10.0; p=0.035) for children of obese mothers. At 18 month (n=197), the offspring born to obese mothers had lost five points in language composite scores and the previous differences in language and cognition was replaced by a suggestive trend of lower gross motor scores in the overweight, obese, and diabetic groups. Infants of obese mothers had a temporary accelerated development of cognition and language, followed by a rapid deceleration until 18 months of age, particularly of language scores. This novel observation prompts further confirmative studies to explore possible placental and neurodevelopmental mechanisms involved.

Background and aim Maternal overweight and breastfeeding seem to have a significant impact on the gut microbiota colonization process, which co-occurs simultaneously with brain development and the establishment of the “microbiota-gut-brain axis”, which potentially may affect behavior later in life. This study aimed to examine the influence of maternal overweight, obesity and/or gestational diabetes on the offspring behavior at 3.5 years of age and its association with the gut microbiota already established at 18 months of life. Methods 156 children born to overweight (OV, n = 45), obese (OB, n = 40) and normoweight (NW, n = 71) pregnant women participating in the PREOBE study were included in the current analysis. Stool samples were collected at 18 months of life and gut microbiome was obtained by 16S rRNA gene sequencing. Behavioral problems were evaluated at 3.5 years by using the Child Behavior Checklist (CBCL). ANOVA, Chi-Square Test, ANCOVA, Spearman’s correlation, logistic regression model and generalized linear model (GLM) were performed. Results At 3.5 years of age, Children born to OV/OB mothers showed higher scores in behavioral problems than those born to NW mothers. Additionally, offspring born to OB mothers who developed gestational diabetes mellitus (GDM) presented higher scores in attention/deficit hyperactivity and externalizing problems than those born to GDM OV/NW mothers. Fusicatenibacter abundance found at 18 months of age was associated to lower scores in total, internalizing and pervasive developmental problems , while an unidentified genus within Clostridiales and Flavonifractor families abundance showed a positive correlation with anxiety/depression and somatic complaints , respectively. On the other hand, children born to mothers with higher BMI who were breastfed presented elevated anxiety , internalizing problems , externalizing problems and total problems scores; likewise, their gut microbiota composition at 18 months of age showed positive correlation with behavioral problems at 3.5 years: Actinobacteria abundance and somatic complaints and between Fusobacteria abundance and withdrawn behavior and pervasive developmental problems . Conclusions Our findings suggests that OV/OB and/or GDM during pregnancy is associated with higher behavioral problems scores in children at 3.5 years old. Additionally, associations between early life gut microbiota composition and later mental health in children was also found.