Growth patterns in infants born to women with pregestational overweight/obesity supplemented with docosahexaenoic acid during pregnancy.

BACKGROUND: Previous studies of maternal docosahexaenoic acid (DHA) supplementation during pregnancy have controversial and contrasting results on the short and long-term effects on early child growth. The impact of this nutritional intervention on the postnatal growth patterns in the offspring of women with pregestational overweight/obesity (PGO) also remains controversial. OBJECTIVE: To analyze the postnatal growth patterns during the first 4 months of life in the offspring of women with PGO randomly supplemented with 800 mg/day (PGO-800) compared with normative doses of 200 mg/day (PGO-200) of DHA during pregnancy (<15 weeks of gestation until delivery). METHODS: This study evaluated the growth patterns during the first 4 months of life of 169 infants of the women that participated in the MIGHT study (NCT02574767). We included the infants of women from the PGO-200 (n = 81) and PGO-800 group (n = 88). The growth patterns (weight, length, and head circumference) and change in z-score (WHO charts) were evaluated. RESULTS: Throughout the first 4 months of life, the infants of the PGO-800 group had lower weight-for-length z-score (coef. -0.65, 95% confidence interval [CI] -1.07, -0.22, p = 0.003) and lower body mass index-for-age z-score (coef. -0.56, 95% CI -0.99, -0.12, p = 0.012) compared with the PGO-200 group adjusted by maternal body mass index, gestational weight gain, gestational age, insulin in cord blood and infant feeding (exclusive breastfed, not breastfed, and partially breastfed). CONCLUSIONS: Maternal supplementation with DHA during pregnancy could beneficially limit the offspring's postnatal weight gain during the first 4 months of life.

The role of mesenchymal stem cells in early programming of adipose tissue in the offspring of women with obesity.

Maternal obesity is a well-known risk factor for developing premature obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes in the progeny. The development of white adipose tissue is a dynamic process that starts during prenatal life: fat depots laid down in utero are associated with the proportion of fat in children later on. How early this programming takes place is still unknown. However, recent evidence shows that mesenchymal stem cells (MSC), the embryonic adipocyte precursor cells, show signatures of the early setting of an adipogenic committed phenotype when exposed to maternal obesity. This review aims to present current findings on the cellular adaptations of MSCs from the offspring of women with obesity and how the metabolic environment of MSCs could affect the early commitment towards adipocytes. In conclusion, maternal obesity can induce early programming of fetal adipose tissue by conditioning MSCs. These cells have higher expression of adipogenic markers, altered insulin signalling and mitochondrial performance, compared to MSCs of neonates from lean pregnancies. Fetal MSCs imprinting by maternal obesity could help explain the increased risk of childhood obesity and development of further noncommunicable diseases.

Nrf2 pre-recruitment at Enhancer 2 is a hallmark of H2 O2 -induced epigenetic transcriptional memory in the HMOX1 gene in human umbilical artery endothelial cells.

Maternal obesity (MO) is a significant cause of increased cardiometabolic risk in offspring, who present endothelial dysfunction at birth. Alterations in physiologic and cellular redox status are strongly associated with altered gene regulation in arterial endothelium. However, specific mechanisms by which the pro-oxidant fetal environment in MO could modulate the vascular gene expression and function during the offspring's postnatal life are elusive. We tested if oxidative stress could reprogram the antioxidant-coding gene's response to a pro-oxidant challenge through an epigenetic transcriptional memory (ETM) mechanism. A pro-oxidant double-hit protocol was applied to human umbilical artery endothelial cells (HUAECs) and EA.hy 926 endothelial cell lines. The ETM acquisition in the HMOX1 gene was analyzed by RT-qPCR. HMOX1 mRNA decay was evaluated by Actinomycin-D treatment and RT-qPCR. To assess the chromatin accessibility and the enrichment of NRF2, RNAP2, and phosphorylation at serin-5 of RNAP2, at HMOX1 gene regulatory regions, were used DNase HS-qPCR and ChIP-qPCR assays, respectively. The CpG methylation pattern at the HMOX1 core promoter was analyzed by DNA bisulfite conversion and Sanger sequencing. Data were analyzed using two-way ANOVA, and p < 0.05 was statistically significant. Using a pro-oxidant double-hit protocol, we found that the Heme Oxygenase gene (HMOX1) presents an ETM response associated with changes in the chromatin structure at the promoter and gene regulatory regions. The ETM response was characterized by a paused-RNA Polymerase 2 and NRF2 enrichment at the transcription start site and Enhancer 2 of the HMOX1 gene, respectively. Changes in DNA methylation pattern at the HMOX1 promoter were not a hallmark of this oxidative stress-induced ETM. These data suggest that a pro-oxidant milieu could trigger an ETM at the vascular level, indicating a potential epigenetic mechanism involved in the increased cardiovascular risk in the offspring of women with obesity.

Higher levels of insulin-like growth factor-1 in cord blood associate with risk of asthma at age 3.

RATIONALE: Experimental studies and epidemiological data in adults suggest that somatomedin-C (insulin-like growth factor-1, IGF-1) may play a role in asthma by modulating airway inflammation, bronchial hyperreactivity, and airway smooth muscle hyperplasia. However, its role in children with asthma is not well understood. METHODS: We established a birth cohort with 339 Chilean pregnant mothers enrolled at the time of delivery from December 2014 to January 2016. We obtained cord blood at birth and followed the offspring every 6 months until 30 months of age, recording data on atopy, wheezing, and other respiratory illnesses. We measured IGF-1 in cord blood and determined the Asthma Predictive Index (API) at 30 months. The cohort was divided according to the API. RESULTS: Complete data were available for 307/339 (91%) dyads, including 44 preschoolers with API+ and 263 with API-. Demographic characteristics were similar between groups, but mothers of API+ children had a higher prevalence of obesity, previous use of oral contraceptives, and higher education than those of API- children. API+ children had higher birth weight and significantly higher IGF-1 in cord blood (37.4 ± 13.2 in API+ vs. 30.5 ± 13.0 ng/ml in API-, p = .01). In the multivariable analysis, IGF-1 in cord blood remained independently associated with a higher risk of asthma (adjusted OR for API+ per ng/ml higher IGF-1 = 1.03 [1.0-1.06], p = .015). CONCLUSIONS: Higher insulin-like growth factor-1 in cord blood is associated with asthma risk in the preschool years.

Metabolic Interaction Between Folate, Vitamin B12, and Polyunsaturated Fatty Acids in Pregnancy.

Fetal growth and development are influenced by maternal nutrition and gestational weight gain. Adequate intake of nutrients such as folate, vitamin B12, and docosahexaenoic acid (DHA) is essential for healthy fetal and placental development. Many countries have a national flour fortification program with folic acid (FA), together with pre-pregnancy supplementation of FA (400 µg/day) during the first trimester of pregnancy. The latter has been recommended by the WHO and adapted to local requirements by perinatal guidelines. On the other hand, in population studies, many women of childbearing age have vitamin B12 deficiency (<148 pmol/L), which can be additionally masked by high FA intake and maternal pregestational obesity. Under these conditions, these patients could be having pregnancies in a folate/vitamin B12 imbalance, which is associated with higher adiposity, insulin resistance, altered lipid metabolism, and low DHA levels in their offspring. However, if these neonatal consequences of maternal pregestational obesity and folate/vitamin B12 imbalance can be reverted by DHA supplementation during pregnancy has not been addressed. This chapter reviews the literature and exposes the current gaps in knowledge and challenges in maternal nutrition with a life-course perspective.

DHA Supplementation during Pregnancy in Women with Obesity Normalizes IGF2R Levels in the Placenta of Male Newborns.

Introduction: Insulin-like growth factor receptor 2 (IGF2R) regulates placental nutrient transport, and its soluble form is related to obesity in adults. If the placental expression of IGF2R is altered in women with obesity is unknown. Whether maternal supplementation with docosahexaenoic acid (DHA), a polyunsaturated fatty acid with anti-inflammatory properties, has a modulatory role in IGF2R's function has not been elucidated. We hypothesized that maternal obesity (Ob) would be associated with alterations in placental IGF2R expression, which may be prevented with DHA supplementation during pregnancy. Methods: At delivery, we obtained placentas from women with Ob (BMI ≥ 30 kg/m2, n = 17), Ob supplemented with 800 mg/day of DHA during pregnancy (Ob + DHA, n = 13), and normal-weight women (Nw, BMI ≥ 18.5 ≤ 24.9 kg/m2, n = 14). The IGF2R mRNA and protein were determined by RT-PCR and western blotting, respectively. Moreover, we quantified the gene expression of molecules that modulate the IGF2R function in the extracellular domain, such as TACE/ADAM17, PLAU, and IGF2. Mann-Whitney and Kruskal-Wallis nonparametric tests were used to compare results between two or three groups accordingly. Results: The IGF2R levels in the Ob placentas of the male offspring were higher than in the Nw group. The DHA supplementation prevented this effect, suggesting an unknown relationship between IGF2R-Ob-DHA in placental tissues. Conclusion: We report, for the first time, that DHA supplementation during pregnancy in women with obesity normalizes the increased IGF2R levels in male placentas, reducing the risk of adverse outcomes related to the IGF2/IGF2R system in male newborns.

Maternal obesity is associated with a higher number of regulatory-T-cells in newborns without affecting suppression.

BACKGROUND: Maternal obesity (MO) is associated with a higher risk of immune-mediated diseases in the offspring and higher leptin levels in cord blood (CB). This study evaluates the number and function of lymphocyte subtypes in CB related to MO and its relationship with leptin concentration and leptin receptor expression. METHODS: Pregnant women with (n = 32) or without obesity (n = 41) were enrolled at delivery. Cord blood mononuclear cells were separated with Ficoll-Hypaque. B and CD4+, regulatory and effector T cells were quantified by Flow Cytometry. Cord blood leptin concentration was measured by ELISA, and the leptin receptor (sLepR) on Treg cells was determined by Flow Cytometry. RESULTS: MO was associated with higher numbers of CD4+, Treg and effector T cells in the CB of their offspring, without differences in the suppressive function of Tregs. Female offspring had a higher number of these cells and a higher cord leptin concentration. Tregs expressed higher levels of sLepR than effector T cells, without differences between groups. CONCLUSIONS: MO is associated with changes in the newborn's immune profile, more evident in female newborns with higher leptin concentrations. More studies are needed to identify the mechanisms by which the high levels of cord leptin in the newborn of women with obesity could affect the offspring's immune system.

Functional consequences of SARS-CoV-2 infection in pregnant women, fetoplacental unit, and neonate.

The SARS-CoV-2 infection causes COVID-19 disease, characterized by acute respiratory distress syndrome, bilateral pneumonia, and organ failure. The consequences of maternal SARS-CoV-2 infection for the pregnant woman, fetus, and neonate are controversial. Thus, it is required to determine whether there is viral and non-viral vertical transmission in COVID-19. The disease caused by SARS-CoV-2 leads to functional alterations in asymptomatic and symptomatic pregnant women, the fetoplacental unit and the neonate. Several diseases of pregnancy, including COVID-19, affect the fetoplacental function, which causes in utero programming for young and adult diseases. A generalized inflammatory state and a higher risk of infection are seen in pregnant women with COVID-19. Obesity, diabetes mellitus, and hypertension may increase the vulnerability of pregnant women to infection by SARS-CoV-2. Alpha, Delta, and Omicron variants of SARS-CoV-2 show specific mutations that seem to increase the capacity of the virus to infect the pregnant woman, likely due to increasing its interaction via the virus S protein and angiotensin-converting enzyme 2 receptors. This review shows the literature addressing to what extent COVID-19 in pregnancy affects the pregnant woman, fetoplacental unit, and neonate. Prospective studies that are key in managing SARS-CoV-2 infection in pregnancy are discussed.

Congenital diaphragmatic hernia: phosphodiesterase-5 and Arginase inhibitors prevent pulmonary vascular hypoplasia in rat lungs.

BACKGROUND: Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. OBJECTIVE: To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. METHODS: Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring's lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I-II expression, and activity. RESULTS: In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. CONCLUSION: These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. IMPACT: This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments' synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.

Interactions between a polygenic risk score for plasma docosahexaenoic fatty acid concentration, eating behaviour, and body composition in children.

BACKGROUND: The relationship between eating behaviour and current body weight has been described. However little is known about the effect of polyunsaturated fatty acids (PUFA) in this relationship. Genetic contribution to a certain condition is derived from a combination of small effects from many genetic variants, and polygenic risk scores (PRS) summarize these effects. A PRS based on a GWAS for plasma docosahexaenoic fatty acid (DHA) has been created, based on SNPs from 9 genes. OBJECTIVE: To analyze the interaction between the PRS for plasma DHA concentration, body composition and eating behaviour (using the Children Eating Behaviour Questionnaire) in childhood. SUBJECTS/METHODS: We analyzed a subsample of children from the Maternal, Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort with PRS and measurements of eating behaviour performed at 4 years of age (n = 210), 6 y (n = 177), and body fat determined by bioelectric impedance at 4 y and 6 y or by air displacement plethysmography and dual-energy X-ray absorptiometry at 8 y (n = 42 and n = 37). PRS was based on the GWAS from Lemaitre et al. 2011 (p threshold = p < 5*10-6), and a median split created low and high PRS groups (high PRS = higher DHA level). RESULTS: In ALSPAC children, we observed an association between PRS and plasma DHA concentration (ß = 0.100, p < 0.01) and proportion (ß = 0.107, p < 0.01). In MAVAN, there were interactions between PRS and body fat on pro-intake scores in childhood, in which low PRS and higher body fat were linked to altered behaviour. There were also interactions between PRS and pro-intake scores early in childhood on body fat later in childhood, suggesting that the genetic profile and eating behaviour influence the development of adiposity at later ages. CONCLUSIONS: A lower PRS (lower plasma PUFA) can be a risk factor for developing higher body fat associated with non-adaptive eating behaviour in childhood; it is possible that the higher PRS (higher plasma PUFA) is a protective feature.

Prevalence of filaggrin loss-of-function variants in Chilean population with and without atopic dermatitis.

BACKGROUND: Filaggrin (FLG) loss-of-function variants are major genetic risk factors for atopic dermatitis (AD), but these have not been studied in Latin American populations with and without AD. METHODS: FLG variants R501X and 2282del4 were genotyped in 275 Chilean adults with and without AD from the "Early origins of allergy and asthma" (ARIES) cohort and in 227 patients from an AD cohort based in Santiago, Chile. RESULTS: Among adults in the ARIES cohort, 3.3% were carriers of R501X and 2.9% of 2282del4 variants, all heterozygotes. In this cohort, 6.2% were FLG variant carriers: 11.1% of subjects reporting AD were carriers of FLG variants vs. 5.2% in those without AD (P = 0.13). In this first cohort, FLG variants were not significantly associated with asthma, allergic rhinitis, or food allergy. In the AD cohort, the prevalence of FLG variants was 7% for R501X, 2.2% for the 2282del4 variant, and 9.3% for the combined genotype. In this cohort, FLG variants were present in 15.5% of severe AD vs. 7.1% of mild-to-moderate AD subjects (P = 0.056). Evaluation of Chilean population from both cohorts combined (n = 502) revealed that FLG variants were not significantly associated with AD (OR = 1.92 [95% CI 0.95-3.9], P = 0.067) but were associated with asthma (OR = 2.16 [95% CI 1.02-4.56], P = 0.039). CONCLUSIONS: This is the first study to evaluate FLG loss-of-function variants R501X and 2282del4 in Latin American population, revealing a similar prevalence of these FLG variant carriers to that of European populations. Among Chileans, FLG variants were significantly associated with asthma but not AD.

Exposome and foetoplacental vascular dysfunction in gestational diabetes mellitus.

A balanced communication between the mother, placenta and foetus is crucial to reach a successful pregnancy. Several windows of exposure to environmental toxins are present during pregnancy. When the women metabolic status is affected by a disease or environmental toxin, the foetus is impacted and may result in altered development and growth. Gestational diabetes mellitus (GDM) is a disease of pregnancy characterised by abnormal glucose metabolism affecting the mother and foetus. This disease of pregnancy associates with postnatal consequences for the child and the mother. The whole endogenous and exogenous environmental factors is defined as the exposome. Endogenous insults conform to the endo-exposome, and disruptors contained in the immediate environment are the ecto-exposome. Some components of the endo-exposome, such as Selenium, vitamins D and B12, adenosine, and a high-fat diet, and ecto-exposome, such as the heavy metals Arsenic, Mercury, Lead and Copper, and per- and polyfluoroakyl substances, result in adverse pregnancies, including an elevated risk of GDM or gestational diabesity. The impact of the exposome on the human placenta's vascular physiology and function in GDM and gestational diabesity is reviewed.

The asthma predictive index as a surrogate diagnostic tool in preschoolers: Analysis of a longitudinal birth cohort.

Diagnosing asthma in preschool children remains an unsolved challenge, at a time when early identification would allow for better education and treatment to prevent morbidity and lung function deterioration. OBJECTIVE: To evaluate if the asthma predictive index (API) can be used as surrogate for asthma diagnosis in preschoolers. METHODS: Birth cohort of 339 pregnant women enrolled at delivery and their offspring, who were followed for atopy, wheezing, and other respiratory illnesses through 30 months of age. The API was determined at 30 months of age by the researchers; and examined its association with physician-diagnosed asthma during the first 30 months, made independently by the primary care physician not involved in the study. RESULTS: Among 307 offspring with complete follow-up, 44 (14.3%) were API+. Maternal body mass index, maternal education, past oral contraceptive use, birthweight, placenta weight, age of daycare at 12 m, gastroesophageal reflux disease at 12 m, acute otitis media at 18 m, bronchiolitis, croup and pneumonia, cord blood adiponectin were all associated with API+. In the multivariable analysis, API+ was associated with almost sixfold odds of asthma diagnosis (adjusted OR = 5.7, 95% CI [2.6-12.3]), after adjusting for the relevant covariates above including respiratory infections like bronchiolitis and pneumonia. The API sensitivity was 48%, specificity 92%, 61% PPV, 88% NPV, 6.4 LR+, 0.56 LR-, 0.84 diagnosis accuracy. The adjusted odds for asthma was 11.4. CONCLUSIONS: This longitudinal birth cohort suggests, for first time, that API (a structured definition for asthma), could be used as a diagnostic tool, not only as a prognostic tool, in toddlers and preschoolers.

Gestational diabesity and foetoplacental vascular dysfunction.

Gestational diabetes mellitus (GDM) shows a deficiency in the metabolism of D-glucose and other nutrients, thereby negatively affecting the foetoplacental vascular endothelium. Maternal hyperglycaemia and hyperinsulinemia play an important role in the aetiology of GDM. A combination of these and other factors predisposes women to developing GDM with pre-pregnancy normal weight, viz. classic GDM. However, women with GDM and prepregnancy obesity (gestational diabesity, GDty) or overweight (GDMow) show a different metabolic status than women with classic GDM. GDty and GDMow are associated with altered l-arginine/nitric oxide and insulin/adenosine axis signalling in the human foetoplacental microvascular and macrovascular endothelium. These alterations differ from those observed in classic GDM. Here, we have reviewed the consequences of GDty and GDMow in the modulation of foetoplacental endothelial cell function, highlighting studies describing the modulation of intracellular pH homeostasis and the potential implications of NO generation and adenosine signalling in GDty-associated foetal vascular insulin resistance. Moreover, with an increase in the rate of obesity in women of childbearing age worldwide, the prevalence of GDty is expected to increase in the next decades. Therefore, we emphasize that women with GDty and GDMow should be characterized with a different metabolic state from that of women with classic GDM to develop a more specific therapeutic approach for protecting the mother and foetus.

Maternal Obesity Is Associated With Higher Cord Blood Adipokines in Offspring Most Notably in Females.

BACKGROUND: Deleterious long-term effects in the offspring from women with pregravid obesity have been described; however, the evidence supporting early metabolic and inflammatory markers in the offspring at birth and gender differences are conflicting. OBJECTIVE: The present study aimed to compare cord blood adipokines and cytokines concentrations and anthropometric characteristics of the offspring of women with maternal obesity (MO) and normal-weight mothers (NWM). Also, maternal and neonatal variables on the association of maternal body mass index (BMI) with cord blood adipokines were evaluated. METHODS: A cross-sectional analysis of a subsample of mother-child dyads participating in a cohort study (n = 221) was assessed. Anthropometrics, cord blood adipokines (leptin and adiponectin) and cytokines (interleukin [IL]-1ß, IL-4, IL-10, IL-12 p40, IL-12p70, IL-13, and tumor necrosis factor α) concentrations in the offspring of normal-weight women (BMI >18.5 and <24.9 kg/m2) and women with pregravid obesity (BMI > 30 kg/m2) without comorbidities was performed. RESULTS: Offspring from mothers with obesity had higher birth weight, a higher proportion of large for gestational age, higher ponderal index, and heavier placentae than offspring from normal-weight mothers (P < 0.05). Within the offspring from women with obesity, males had significantly higher weight, length, the proportion of large-for-gestational-age newborns, higher weight for length ratio. Males had more efficient placentas than females (P < 0.05). Higher adiponectin and leptin in both sexes and higher leptin in female offspring of mothers with obesity after adjusting for birth size (P < 0.05) were found. Higher IL-12p40 in the offspring of women with MO with no other differences in other cytokines among groups were evidenced. CONCLUSIONS: Maternal obesity associates with a higher concentration of adiponectin and leptin in their offspring at birth. There is a relevant effect on anthropometrics in male offspring and on leptin in female newborn. Further studies need to evaluate the extension of these effects in postnatal life. TRAIL IDENTIFICATION NUMBER: NCT02903134.

The effects of a combined intervention (docosahexaenoic acid supplementation and home-based dietary counseling) on metabolic control in obese and overweight pregnant women: the MIGHT study.

BACKGROUND: Lifestyle interventions have shown limited effectiveness in the prevention of gestational diabetes mellitus. The combination of lifestyle interventions with omega-3 polyunsaturated fatty acid supplementation could have a synergetic effect on maternal and offspring outcomes. OBJECTIVE: We evaluated the effects of docosahexaenoic acid supplementation among obese and overweight pregnant women (independently or combined with a dietary counseling intervention) on metabolic control in mothers and their offspring. STUDY DESIGN: This study was a randomized controlled trial with a 2×2 factorial design. The following inclusion criteria were used: <15 weeks of gestation; body mass index ≥25 kg/m2 at the first prenatal visit; singleton pregnancy; and 18 years of age or older. The recruited women (n=1002) were randomly allocated to 1 of the 4 parallel groups: Group 1: dietary counseling plus 800 mg/day of docosahexaenoic acid (n=250); Group 2: routine counseling plus 800 mg/day docosahexaenoic acid (n=252); Group 3: dietary counseling plus 200 mg/day docosahexaenoic acid (n=249); and Group 4: routine counseling plus 200 mg/day docosahexaenoic acid (n=251), considered as the reference group. The dietary intervention comprised 3 sessions, and it was focused on reducing the consumption of foods that most contributed to daily sugar intake. Primary outcomes were gestational diabetes mellitus defined according to the national guidelines; macrosomia (birthweight >4000 g); and neonatal insulin resistance (cord blood Homeostasis Model Assessment for Insulin Resistance ≥2.60), which was assessed in a subsample of 226 newborns. The analysis was by intention to treat and by efficacy. The trial was registered on ClinicalTrials.gov (NCT02574767). RESULTS: The overall incidence of gestational diabetes mellitus was 20.2% (Group 1, 21.0%; Group 2, 20.1%; Group 3, 18.9%; and Group 4, 20.9%). Mean birthweight was 3403.0 g (standard deviation, 575.3), and the incidence of macrosomia was 11.9% (Group 1, 13.2%; Group 2, 10.8%; Group 3, 11.5%; and Group 4, 12.1%). Median cord blood Homeostasis Model Assessment for Insulin Resistance was 0.9 (interquartile range, 0.6-1.7), and 10.2% showed cord blood insulin resistance (Group 1, 12.0%; Group 2, 12.0%; Group 3, 9.7%; and Group 4, 5.1%). No significant differences were found among groups regarding primary outcomes (P<.05). Glucose concentrations in the cord blood samples were lower in those adherents to the docosahexaenoic acid supplementation (P<.05). CONCLUSION: For women who were overweight or obese at the beginning of pregnancy, this combined intervention did not reduce the risk of gestational diabetes in mothers or macrosomia and insulin resistance in neonates.

Maternal obesity is associated with a sex-specific epigenetic programming in human neonatal monocytes.

Aim: To determine changes in global DNA methylation in monocytes from neonates of women with obesity, as markers of an immune programming resulting from maternal obesity. Materials & methods: Cord blood monocytes were obtained from neonates born to women with obesity and normal weight, genome-wide differentially methylated CpGs were determined using an Infinium MethylationEPIC-BeadChip (850K). Results: No clustering of samples according to maternal BMI was observed, but sex-specific analysis revealed 71,728 differentially methylated CpGs in female neonates from women with obesity (p < 0.01). DAVID analysis showed increased methylation levels within genes involved in the innate immune response and inflammation. Conclusion: Maternal obesity induces, in a sex-specific manner, an epigenetic programming of monocytes that could contribute to disease later in life. Clinical trial registry: This study is registered in ClinicalTrials.gov NCT02903134.

Leptin in Cord Blood Associates with Asthma Risk at Age 3 in the Offspring of Women with Gestational Obesity.

Rationale: Maternal obesity is associated with asthma in the offspring. Whether cord blood leptin is associated with risk of asthma in offspring is unclear.Objectives: To assess whether cord blood leptin from women with pregestational obesity predict preschool asthma.Methods: In this birth cohort study, we divided pregnant women into three weight categories during the first obstetric visit: normal (NL), overweight (OW), and obese (OB).Results: We followed the offspring recording atopy, wheezing, and other respiratory illnesses through 30 months of age. Cord blood and peripheral blood at 30 months of age were taken to measure cytokines, adipokines, metabolic biomarkers, and specific immunoglobulin E. Adjusted regression models were used to evaluate the association between maternal obesity and offspring asthma risk, defined by a positive Asthma Predictive Index. Three hundred thirty-nine mothers were recruited; 140 offspring were born from NL, 80 from OW, and 119 from OB mothers. OB women were older and less educated and had higher parity and higher C-section frequency. Offspring from OB women had higher birthweight, head circumference, and placental weight compared with other groups. The proportion of Asthma Predictive Index positive at 30 months of age was 12.2% in the NL, 14.7% in the OW, and 16.8% in the OB group (P = 0.18). Offspring from OB women had higher leptin, leptin/adiponectin ratio, interleukin-10, and insulin than the OW group and higher leptin than the NL group. In the adjusted analysis, offspring from OB mothers with high cord blood leptin had increased risk of asthma (adjusted odds ratio, 1.30; 95% confidence interval, 1.1-1.55; P = 0.003).Conclusions: Offspring from obese mothers with high cord blood leptin have 30% higher asthma risk at age 3.Clinical trial registered with ClinicalTrials.gov (NCT02903134).

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

Preeclampsia is a pregnancy complication that appears after 20 weeks of gestation and is characterized by hypertension and proteinuria, affecting both mother and offspring. The cellular and molecular mechanisms that cause the development of preeclampsia are poorly understood. An important feature of preeclampsia is an increase in oxygen and nitrogen derived free radicals (reactive oxygen species/reactive nitrogen species (ROS/RNS), which seem to be central players setting the development and progression of preeclampsia. Cell-to-cell communication may be disrupted as well. Connexins (Cxs), a family of transmembrane proteins that form hemichannels and gap junction channels (GJCs), are essential in paracrine and autocrine cell communication, allowing the movement of signaling molecules between cells as well as between the cytoplasm and the extracellular media. GJCs and hemichannels are fundamental for communication between endothelial and smooth muscle cells and, therefore, in the control of vascular contraction and relaxation. In systemic vasculature, the activity of GJCs and hemichannels is modulated by ROS and RNS. Cxs participate in the development of the placenta and are expressed in placental vasculature. However, it is unknown whether Cxs are modulated by ROS/RNS in the placenta, or whether this potential modulation contributes to the pathogenesis of preeclampsia. Our review addresses the possible role of Cxs in preeclampsia, and the plausible modulation of Cxs-formed channels by ROS and RNS. We suggest these factors may contribute to the development of preeclampsia.

Effectiveness of a normative nutrition intervention in Chilean pregnant women on maternal and neonatal outcomes: the CHiMINCs study.

BACKGROUND: Some nutritional interventions have shown their efficacy in reducing gestational weight gain (GWG); however, their applicability in routine care is limited. OBJECTIVE: We assessed the effectiveness of a low-intensity and high-coverage nutritional intervention on maternal and offspring outcomes; the intervention enhanced existing nutritional health care standards and practices at the primary health care level in Chile. METHODS: This study was a cluster-randomized controlled trial of 12 primary health care centers (PHCCs) from Santiago, Chile. PHCCs were randomly allocated to either nutritional intervention [intervention group (IG), n = 5] or routine care [control group (CG), n = 7]. A total of 4631 pregnant women were recruited (IG, n = 2565; and CG, n = 2066). Primary outcomes were adequate GWG and glycemic control in mothers and birth weight, birth length, macrosomia, and large for gestational age in neonates. The intervention consisted of 4 key actions: training of health care professionals on nutritional recommendations, counseling of pregnant women on diet and physical activity recommendations, offering a physical activity program implemented in the participating PHCCs, and adequate referral to dietitians. Women randomly assigned to the CG received routine antenatal care. RESULTS: At baseline, the mean age was 26.1 y; 45% of women were primipara and 24% were obese. No differences were found in the percentage of women achieving adequate GWG (IG: 30.3%, compared with CG: 31.3%; OR: 0.94; 95% CI: 0.81, 1.09), but women in the IG had lower GWG than those in the CG (11.3 compared with 11.9 kg; mean difference: -0.63 kg; 95% CI: -1.19, -0.08). Effects of the intervention were significantly higher in women with obesity at the begining of pregnancy (mean difference: -1.24 kg; 95% CI: -2.18, -0.30; P for interaction < 0.05). No differences were found between groups regarding maternal glycemic control or neonatal outcomes. CONCLUSIONS: Our findings demonstrate that a low-intensity, high-coverage intervention delivered through the Chilean public health care system under standard operating conditions reduces GWG and has the potential for successful scale-up. This trial was registered at clinicaltrials.gov as NCT01916603.