Air pollution exposure and risk of adverse obstetric and neonatal outcomes among women with type 1 diabetes

Aims/Hypothesis: Women with type 1 diabetes have increased risk for poor obstetric outcomes. Prenatal air pollution exposure is also associated with adverse outcomes for women and infants. We examined whether women with type 1 diabetes are more vulnerable than other women to pollution-associated risks during pregnancy. Methods: In singleton deliveries from the Consortium on Safe Labor (2002-2008), obstetric and neonatal outcomes were compared for women with type 1 diabetes (n=507) and women without autoimmune disease (n=204,384). Preconception, trimester, and whole pregnancy average air pollutant exposure (ozone (O3), carbon monoxide (CO), particulate matter \u3e10 microns (PM10), PM \u3e2.5 microns (PM2.5), sulfur dioxide (SO2), nitrogen oxides (NOx)) were estimated using modified Community Multiscale Air Quality models. Poisson regression models with diabetes*pollutant interaction terms estimated relative risks and 95% confidence intervals for adverse outcomes, adjusted for maternal characteristics and geographic region. Results: For whole pregnancy exposure to SO2, women with type 1 diabetes had 15% increased risk (RR:1.15 95%CI:1.01,1.31) and women without autoimmune disease had 5% increased risk (RR:1.05 95%CI:1.05,1.06) for small for gestational age birth (pinteraction=0.09). Additionally, whole pregnancy O3 exposure was associated with 10% increased risk (RR:1.10 95%CI:1.02,1.17) among women with type 1 diabetes and 2% increased risk (RR:1.02 95%CI:1.00,1.04) among women without autoimmune disease for perinatal mortality (pinteraction=0.08). Similar patterns were observed between PM2.5 exposure and spontaneous preterm birth. Conclusions: Pregnant women with type 1 diabetes may be at greater risk for adverse outcomes when exposed to air pollution than women without autoimmune disease

Obstetric and neonatal complications among women with autoimmune disease

Background: The impact of autoimmune diseases on pregnancy remains understudied on a population level. Examination of obstetric and neonatal outcomes among women with autoimmune disease and their infants can provide important insights for clinical management. Methods: Autoimmune diseases and outcomes were identified using medical records. Cesarean delivery, preterm birth, preeclampsia, small for gestational age (SGA), neonatal intensive care (NICU) admission, neonatal respiratory distress syndrome (RDS), and perinatal mortality risk was assessed. Poisson regression with robust standard errors estimated relative risks (RR) and 95% confidence intervals (95% CI) with adjustment for maternal characteristics and other chronic conditions. Results: Women with T1DM were at increased risk for nearly all outcomes including RDS (RR: 3.62; 95% CI: 2.84, 4.62), perinatal mortality (RR: 2.35; 95% CI: 1.12, 4.91), cesarean delivery (RR: 2.16; 95% CI: 2.02, 2.32) and preterm birth (RR: 3.52; 95% CI: 3.17, 3.91). Women with SLE also had higher risk for preterm delivery (RR: 2.90; 95% CI: 2.42, 3.48) and RDS (RR:2.99; 95% CI: 1.99, 4.51) as did women with Crohn’s (cesarean delivery RR:1.31, 95% CI: 1.08, 1.60; preterm delivery RR: 1.84, 95% CI: 1.37, 2.49. RA increased risk for SGA (RR:1.66; 95% CI: 1.08, 2.55). Conclusion(s): Despite the heterogeneity in autoimmune diseases, we observed elevated preterm birth risk for most women with autoimmune disease. SLE and T1DM appeared to confer increased risk for a wide range of adverse outcomes

DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases

Background Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. Results We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. Conclusion We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. Clinical trial registration ClinicalTrials.gov, NCT0091213

Exposition maternelle à la pollution de l’air au cours de la grossesse : caractérisation de l’exposition, de ses déterminants, et association avec la croissance fœtale dans deux cohortes complémentaires

The concept of DOHaD (Developmental Origins of Health and Disease) postulates that environmental exposures during the development phase (fetal life and early life) would have major consequences on future health. The reduction in birth weight is considered both as a marker of these aggressions suffered by the fetus during pregnancy and as an indicator of the future health of the child. Epidemiological studies of air pollution effect are challenging in terms of exposure assessment to air pollutants.The general objective of this thesis is to characterize the effect of air pollutants on fetal growth by improving the characterization of exposures and the control of potential confounding biases compared to previous studies.In a first part, we studied the socio-economic determinants of exposure to ambient air pollution in the French national ELFE study including 18000 mother-child couple. Maternal exposure to fine particulate (PM2.5), PM10 and NO2 was estimated using a dispersion model which combined a fine spatial (1x1km grid) and temporal (daily data) resolution. In France, in urban areas, pregnant women in the most socially deprived neighborhoods were the most exposed to air pollution.The second part of this work focused on the characterization of the association between maternal exposure to atmospheric pollution (estimated in outdoor air) and birth weight of the child in the ELFE cohort. Once the confounding factors were taken into account using the propensity score, we highlighted a deleterious effect of exposure to particulate matters during the third trimester of pregnancy on birth weight.In a third part, we compared different approaches to assess exposure to air pollution in pregnant women, including personal measures, in 40 women from the SEPAGES-feasibility cohort. Incorporation of space-time activity only slightly modified the estimated exposure levels in outdoor air to the home address. Conversely, exposure estimates were strongly affected by the incorporation of indoor levels of air pollution or when exposures were assessed using personal dosimeters.This justified, in a fourth part, the study of the association between the exposure to air pollution estimated by personal dosimeters and the fetal growth in the SEPAGES cohort including 471 couples-child triads from the Grenoble urban areas. Personal exposures to PM2.5 (n=174, more strongly during the 1st trimester) and to NO2 (n=327, more strongly during the 3rd trimester) were associated to decreases in birth weight. Our estimates of the association with PM2.5 were stronger than estimates from the ELFE cohort.In conclusion, this work comes to reinforce the literature on the deleterious effect of air pollution on birth weight. This thesis, based on two complementary cohorts, has also illustrated the concept of the compromise between bias and variance between studies using outdoor exposure models (which could be performed on large geographical areas allowing larges sample size and exposure contrasts and with possibly confounders and high degree of exposure misclassification) and cohorts using personal dosimeters (generally conducted on small sample size, in more homogeneous population, with less confounders and better estimation of exposure to air pollution).Le concept de DOHaD (Developmental Origins of Health and Disease) postule que les expositions environnementales subies durant la phase de développement (vie fœtale et premières années de la vie) ont des conséquences majeures sur la santé ultérieure. La diminution du poids de naissance est considérée à la fois comme un marqueur de ces agressions subies par le fœtus au cours de la grossesse et comme un indicateur de la santé future de l’enfant. La recherche en épidémiologie sur les effets de la pollution atmosphérique doit faire face au défi de l’évaluation de l’exposition aux polluants atmosphériques.L’objectif général de cette thèse était de caractériser l’effet des polluants atmosphériques sur la croissance fœtale, en améliorant la caractérisation des expositions et le contrôle des biais de confusion potentiels par rapport aux études antérieures.Dans une première partie, nous avons étudié les déterminants socio-économiques de l'exposition à la pollution de l’air ambiant dans l’étude nationale Française ELFE, incluant 18 000 couples mères-enfants. L'exposition maternelle aux particules fines (PM2,5), PM10 et au NO2 a été estimée à l'adresse du domicile à partir de modèles de dispersion avec des résolutions spatiale (1x1 km) et temporelle (données journalières) fines. En France, dans les zones urbaines, les femmes enceintes des quartiers les plus défavorisés étaient les plus exposées à la pollution atmosphérique.La deuxième partie de ce travail a porté sur la caractérisation de l'association entre les niveaux pollution atmosphérique dans l’air extérieur durant la grossesse et le poids de naissance de l’enfant, toujours dans la cohorte ELFE. Une fois les facteurs de confusion pris en compte à l’aide d’un score de propension, nous avons mis en évidence un effet délétère de l’exposition aux particules en suspension dans l’air au cours du troisième trimestre de grossesse sur le poids de naissance.Dans une troisième partie, nous avons comparé différentes approches pour évaluer l'exposition à la pollution atmosphérique chez la femme enceinte, incluant des mesures personnelles, chez 40 femmes de la cohorte SEPAGES-faisabilité. La considération du budget espace-temps ne modifiait que très légèrement les niveaux d’exposition estimés dans l’air extérieur à l’adresse du domicile. En revanche, l’exposition estimée était fortement modifiée par la prise en compte des niveaux de pollution atmosphérique à l’intérieur du domicile, ou quand l’exposition était l’estimée à l’aide de dosimètres personnels.Ceci a justifié, dans une quatrième partie, d’étudier l'association entre l’exposition à la pollution atmosphérique estimée à l'aide de mesures personnelles et le développement du fœtus dans la cohorte grenobloise SEPAGES, incluant 471 triades couples-enfant. L’exposition personnelle aux PM2,5 (n=174, plus nettement au 1er trimestre) et au NO2 (n=327, plus nettement au 3ème trimestre) étaient associées à une diminution du poids de naissance. L’estimation ponctuelle de l’association avec les PM2,5 était bien plus forte que dans la cohorte ELFE.En conclusion, ce travail vient renforcer la littérature sur l’effet délétère de la pollution atmosphérique sur le poids de naissance. Cette thèse, basée sur deux cohortes complémentaires, a également permis d’illustrer le compromis entre biais et variance entre les études s’appuyant sur des modèles d’exposition extérieurs (pouvant être réalisées sur de vastes zones géographiques permettant des effectifs et contrastes d’exposition larges et avec potentiellement des biais de confusion et d’erreur de mesure sur l’exposition importants) et les cohortes s’appuyant sur des dosimètres personnels (généralement conduites sur des zones plus limitées, dans une population plus homogène, avec moins de biais de confusion potentiels et une meilleure estimation de l’exposition)

Maternal exposure to air pollution during pregnancy : characterization of exposure, its determinants, and association with fetal growth in two complementary cohorts

Le concept de DOHaD (Developmental Origins of Health and Disease) postule que les expositions environnementales subies durant la phase de développement (vie fœtale et premières années de la vie) ont des conséquences majeures sur la santé ultérieure. La diminution du poids de naissance est considérée à la fois comme un marqueur de ces agressions subies par le fœtus au cours de la grossesse et comme un indicateur de la santé future de l’enfant. La recherche en épidémiologie sur les effets de la pollution atmosphérique doit faire face au défi de l’évaluation de l’exposition aux polluants atmosphériques.L’objectif général de cette thèse était de caractériser l’effet des polluants atmosphériques sur la croissance fœtale, en améliorant la caractérisation des expositions et le contrôle des biais de confusion potentiels par rapport aux études antérieures.Dans une première partie, nous avons étudié les déterminants socio-économiques de l'exposition à la pollution de l’air ambiant dans l’étude nationale Française ELFE, incluant 18 000 couples mères-enfants. L'exposition maternelle aux particules fines (PM2,5), PM10 et au NO2 a été estimée à l'adresse du domicile à partir de modèles de dispersion avec des résolutions spatiale (1x1 km) et temporelle (données journalières) fines. En France, dans les zones urbaines, les femmes enceintes des quartiers les plus défavorisés étaient les plus exposées à la pollution atmosphérique.La deuxième partie de ce travail a porté sur la caractérisation de l'association entre les niveaux pollution atmosphérique dans l’air extérieur durant la grossesse et le poids de naissance de l’enfant, toujours dans la cohorte ELFE. Une fois les facteurs de confusion pris en compte à l’aide d’un score de propension, nous avons mis en évidence un effet délétère de l’exposition aux particules en suspension dans l’air au cours du troisième trimestre de grossesse sur le poids de naissance.Dans une troisième partie, nous avons comparé différentes approches pour évaluer l'exposition à la pollution atmosphérique chez la femme enceinte, incluant des mesures personnelles, chez 40 femmes de la cohorte SEPAGES-faisabilité. La considération du budget espace-temps ne modifiait que très légèrement les niveaux d’exposition estimés dans l’air extérieur à l’adresse du domicile. En revanche, l’exposition estimée était fortement modifiée par la prise en compte des niveaux de pollution atmosphérique à l’intérieur du domicile, ou quand l’exposition était l’estimée à l’aide de dosimètres personnels.Ceci a justifié, dans une quatrième partie, d’étudier l'association entre l’exposition à la pollution atmosphérique estimée à l'aide de mesures personnelles et le développement du fœtus dans la cohorte grenobloise SEPAGES, incluant 471 triades couples-enfant. L’exposition personnelle aux PM2,5 (n=174, plus nettement au 1er trimestre) et au NO2 (n=327, plus nettement au 3ème trimestre) étaient associées à une diminution du poids de naissance. L’estimation ponctuelle de l’association avec les PM2,5 était bien plus forte que dans la cohorte ELFE.En conclusion, ce travail vient renforcer la littérature sur l’effet délétère de la pollution atmosphérique sur le poids de naissance. Cette thèse, basée sur deux cohortes complémentaires, a également permis d’illustrer le compromis entre biais et variance entre les études s’appuyant sur des modèles d’exposition extérieurs (pouvant être réalisées sur de vastes zones géographiques permettant des effectifs et contrastes d’exposition larges et avec potentiellement des biais de confusion et d’erreur de mesure sur l’exposition importants) et les cohortes s’appuyant sur des dosimètres personnels (généralement conduites sur des zones plus limitées, dans une population plus homogène, avec moins de biais de confusion potentiels et une meilleure estimation de l’exposition).The concept of DOHaD (Developmental Origins of Health and Disease) postulates that environmental exposures during the development phase (fetal life and early life) would have major consequences on future health. The reduction in birth weight is considered both as a marker of these aggressions suffered by the fetus during pregnancy and as an indicator of the future health of the child. Epidemiological studies of air pollution effect are challenging in terms of exposure assessment to air pollutants.The general objective of this thesis is to characterize the effect of air pollutants on fetal growth by improving the characterization of exposures and the control of potential confounding biases compared to previous studies.In a first part, we studied the socio-economic determinants of exposure to ambient air pollution in the French national ELFE study including 18000 mother-child couple. Maternal exposure to fine particulate (PM2.5), PM10 and NO2 was estimated using a dispersion model which combined a fine spatial (1x1km grid) and temporal (daily data) resolution. In France, in urban areas, pregnant women in the most socially deprived neighborhoods were the most exposed to air pollution.The second part of this work focused on the characterization of the association between maternal exposure to atmospheric pollution (estimated in outdoor air) and birth weight of the child in the ELFE cohort. Once the confounding factors were taken into account using the propensity score, we highlighted a deleterious effect of exposure to particulate matters during the third trimester of pregnancy on birth weight.In a third part, we compared different approaches to assess exposure to air pollution in pregnant women, including personal measures, in 40 women from the SEPAGES-feasibility cohort. Incorporation of space-time activity only slightly modified the estimated exposure levels in outdoor air to the home address. Conversely, exposure estimates were strongly affected by the incorporation of indoor levels of air pollution or when exposures were assessed using personal dosimeters.This justified, in a fourth part, the study of the association between the exposure to air pollution estimated by personal dosimeters and the fetal growth in the SEPAGES cohort including 471 couples-child triads from the Grenoble urban areas. Personal exposures to PM2.5 (n=174, more strongly during the 1st trimester) and to NO2 (n=327, more strongly during the 3rd trimester) were associated to decreases in birth weight. Our estimates of the association with PM2.5 were stronger than estimates from the ELFE cohort.In conclusion, this work comes to reinforce the literature on the deleterious effect of air pollution on birth weight. This thesis, based on two complementary cohorts, has also illustrated the concept of the compromise between bias and variance between studies using outdoor exposure models (which could be performed on large geographical areas allowing larges sample size and exposure contrasts and with possibly confounders and high degree of exposure misclassification) and cohorts using personal dosimeters (generally conducted on small sample size, in more homogeneous population, with less confounders and better estimation of exposure to air pollution)

Pleiotropic genetic influence on birth weight and childhood obesity

Abstract Childhood obesity is a global public health problem. Understanding the molecular mechanisms that underlie early origins of childhood obesity can facilitate interventions. Consistent phenotypic and genetic correlations have been found between childhood obesity traits and birth weight (a proxy for in-utero growth), suggesting shared genetic influences (pleiotropy). We aimed to (1) investigate whether there is significant shared genetic influence between birth weight and childhood obesity traits, and (2) to identify genetic loci with shared effects. Using a statistical approach that integrates summary statistics and functional annotations for paired traits, we found strong evidence of pleiotropy (P < 3.53 × 10–127) and enrichment of functional annotations (P < 1.62 × 10–39) between birth weight and childhood body mass index (BMI)/obesity. The pleiotropic loci were enriched for regulatory features in skeletal muscle, adipose and brain tissues and in cell lines derived from blood lymphocytes. At 5% false discovery rate, 6 loci were associated with birth weight and childhood BMI and 13 loci were associated with birth weight and childhood obesity. Out of these 19 loci, one locus (EBF1) was novel to childhood obesity and one locus (LMBR1L) was novel to both birth weight and childhood BMI/obesity. These findings give evidence of substantial shared genetic effects in the regulation of both fetal growth and childhood obesity

Is atmospheric pollution exposure during pregnancy associated with individual and contextual characteristics ? A nationwide study in France

BACKGROUND: Exposure to atmospheric pollutants is a danger for the health of pregnant mother and children. Our objective was to identify individual (socioeconomic and behavioural) and contextual factors associated with atmospheric pollution pregnancy exposure at the nationwide level. METHOD: Among 14 921 women from the French nationwide ELFE (French Longitudinal Study of Children) mother-child cohort recruited in 2011, outdoor exposure levels of PM2.5, PM10 (particulate matter <2.5 µm and <10 µm in diameter) and NO2 (nitrogen dioxide) were estimated at the pregnancy home address from a dispersion model with 1 km resolution. We used classification and regression trees (CART) and linear regression to characterise the association of atmospheric pollutants with individual (maternal age, body mass index, parity, education level, relationship status, smoking status) and contextual (European Deprivation Index, urbanisation level) factors. RESULTS: Patterns of associations were globally similar across pollutants. For the CART approach, the highest tertile of exposure included mainly women not in a relationship living in urban and socially deprived areas, with lower education level. Linear regression models identified different determinants of atmospheric pollutants exposure according to the residential urbanisation level. In urban areas, atmospheric pollutants exposure increased with social deprivation, while in rural areas a U-shaped relationship was observed. CONCLUSION: We highlighted social inequalities in atmospheric pollutants exposure according to contextual characteristics such as urbanisation level and social deprivation and also according to individual characteristics such as education, being in a relationship and smoking status. In French urban areas, pregnant women from the most deprived neighbourhoods were those most exposed to health-threatening atmospheric pollutants

Maternal asthma in relation to infant size and body composition

BACKGROUND: Asthma affects 10% of pregnancies and may influence offspring health, including infant size and body composition, through hypoxic and inflammatory pathways. OBJECTIVE: We sought to determine associations between maternal asthma and asthma phenotypes during pregnancy and infant size and body composition. METHODS: The B-WELL-Mom study (2015-19) is a prospective cohort of 418 pregnant persons with and without asthma recruited in the first trimester of pregnancy from 2 US obstetric clinics. Exposures were maternal self-reported active asthma (n = 311) or no asthma (n = 107), and asthma phenotypes were classified on the bases of atopy, onset, exercise induced, control, severity, symptomology, and exacerbations. Outcomes were infant weight, length, head circumference, and skinfold measurements at birth and postnatal follow-up, as well as fat and lean mass assessed by air displacement plethysmography at birth. Adjusted multivariable linear regression examined associations of maternal asthma and asthma phenotypes with infant outcomes. RESULTS: Offspring were born at a mean ± SD of 38 ± 2.3 weeks\u27 gestation and were 18 ± 2.2 weeks of age at postnatal follow-up. Infants of participants with asthma had a mean ± SD fat mass of 11.0 ± 4.2%, birth weight of 3045.8 ± 604.3 g, and postnatal follow-up weight of 6696.4 ± 964.2 g, which were not different from infants of participants without asthma (respectively, β [95% confidence interval]: -0.1 [-1.4, 1.3], -26.7 [-156.9, 103.4], and 107.5 [-117.3, 332.3]). Few associations were observed between asthma or asthma phenotypes and infant size or body composition. CONCLUSIONS: In a current obstetric cohort, maternal asthma during pregnancy was not associated with differential infant size or body composition