N = 7528) predicted GA in a holdout “replication” sample (N = 2139). Our findings help to clarify the effects of PTB on brain structure into late childhood across the GA spectrum.Approximately 10% of births are preterm , which confers risk for cognitive, behavioral, and mental health challenges. Using the large and relatively diverse  Adolescent Brain Cognitive Development Study (ABCD Study), we characterized the impact of PTB on brain structure in middle-late childhood (9–10 years). The ABCD sample covers the GA spectrum, and the large sample size  permits consideration of how associations between PTB and brain structure are impacted by GA, sex, birthweight, and analytic choices such as controlling for total brain size. We found a pattern of relative cortical thinning in temporoparietal and dorsal prefrontal regions and thickening of medial prefrontal and occipital regions in PTB compared with children born full term (≥37 weeks GA). This pattern was apparent when controlling for mean thickness and when considering moderate (>32 and <37 weeks GA) and very PTB (≤32 weeks GA) separately, relative to full term birth. Surface area (SA) and subcortical volumes showed reductions in PTB children that were largely attenuated when controlling for brain size. Effects on cortical thickness (CT) and surface area were partially mediated by birthweight. Although boys are at increased risk for adverse outcomes following PTB, there was limited evidence of sex differences of PTB effects. Finally, cortical thickness effects estimated in a “discovery” sample ( Preterm birth (PTB) affects ∼10% of children and increases the risk of neurodevelopmental and mental health challenges. Here, we examined long-term effects of PTB on brain structure in middle-late childhood in the large and relatively diverse Adolescent Brain Cognitive Development (ABCD) sample. We further assessed the influence of gestational age, sex, birthweight, controlling for brain size and data quality. Our findings replicate a pattern of occipitotemporal and dorsal prefrontal cortical thinning in PTB that was seen in both moderate preterm and very preterm relative to full-term birth. Effects were similar in males and females and partially mediated by birthweight. Our findings suggest that community-recruited children born preterm show a pattern of structural alterations on a continuum that relates to gestational age and birthweight.An estimated 10% of infants are born preterm , sociodemographic differences between preterm and control groups , and sofThe Adolescent Brain Cognitive Development Study (ABCD Study) presents a unique opportunity to characterize long-term impacts of PTB in a large and sociodemographically diverse sample. ABCD covers the spectrum from FTB to very PTB (≤32 weeks GA). There is a growing interest in characterizing brain differences in children born moderately preterm (>32 and <37 weeks GA), given evidence of increased cognitive and behavioral challenges relative to their FTB peers . FurtherWe use an estimation statistics approach  to map aThe ABCD study is following roughly 11,500 participants from the ages of 9–11 into early adulthood at 21 sites across the United States and was designed to reflect sociodemographic diversity . For ourFor the analyses described here, we looked at the structural characteristics derived from T1-weighted images. Full details on MRI image acquisition is described elsewhere . BrieflyWe used image quality ratings provided with the ABCD data release to filter the sample based on quality of the T1-weighted MRI images. Image quality was rated from 0 to 3  on five components of the MRI image quality: motion, pial overestimation, white matter underestimation, inhomogeneity, and artifact. Further, a score for findings on the MRI image was reported from 0 to 4 . Any participant who had a score of 2 or above in any of the five components of the MRI image quality or who did not have a score of 1 or 2 in the MRI findings score were excluded. Because head motion can influence data quality and subsequent analyses , we alsoN = 7528) was used as the discovery sample, and the remaining 20% of the sample (N = 2139) were used as a replication sample. The ABCD Study has 21 data collection sites and four of these sites were enriched for the sampling of twins  and therefore also had higher rates of PTB as PTB is more likely in twin pregnancies . Given that lower GA is associated with increased risk of adverse outcomes, analyses were run assessing linear effects of weeks born preterm. Among parents who reported that their child was born preterm, smaller numbers were reported for infants born 1 (N = 40), 2 (N = 137), or 3 (N = 182) weeks preterm, relative to four (N = 401) weeks preterm . After four weeks preterm there was a monotonically decreasing number of participants with increasing number of weeks preterm (N = 359). Next, we assigned numerical values associated with an increasing number of weeks born preterm, with four weeks coded as 2 (N = 401), five weeks coded as 3 (N = 186), six weeks coded as 4 (N = 169), seven weeks coded as 5 (N = 76), and eight weeks coded as 6 (N = 123). As the number of children in each incremental week became increasingly smaller, children born nine or more weeks preterm were coded as 7  were coded as 0. Follow-up analyses were conducted to assess the relative contribution of moderate PTB  left hemisphere cortical thickness and the (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download 10.1523/ENEURO.0196-22.2023.f2-2Extended Data Figure 2-2a, Positive β estimates are shown in red, indicating thicker cortical thickness with shorter gestational age. Negative β estimates are shown in blue, indicating thinner cortical thickness with shorter gestational age. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere cortical thickness and (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download Figure 2-2, TIF file.Preterm birth associations with cortical thickness without a control for mean hemispheric cortical thickness. 10.1523/ENEURO.0196-22.2023.f2-3Extended Data Figure 2-3a, Positive β estimates are shown in red, indicating thicker cortical thickness with shorter gestational age. Negative β estimates are shown in blue, indicating thinner cortical thickness with shorter gestational age. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere cortical thickness and (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download Figure 2-3, TIF file.Preterm birth associations with cortical thickness in stringent quality subsample. 10.1523/ENEURO.0196-22.2023.f2-4Extended Data Figure 2-4a, Positive β estimates are shown in red, indicating thicker cortical thickness in children who experienced a birth complication requiring hospital stay. Negative β estimates are shown in blue, indicating thinner cortical thickness in children who experienced a birth complication requiring hospital stay. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for right hemisphere cortical thickness; all estimated standardized βs of cortical regions in the left hemisphere had a 99% confidence interval that overlapped 0. a.u. = arbitrary units. Download Figure 2-4, TIF file.Birth complication associations with cortical thickness. 10.1523/ENEURO.0196-22.2023.f2-5Extended Data Figure 2-5a, Positive β estimates are shown in red, indicating thicker cortical thickness with shorter gestational age. Negative β estimates are shown in blue, indicating thinner cortical thickness with shorter gestational age. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere cortical thickness and (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download Figure 2-5, TIF file.Preterm birth associations with cortical thickness with a linear control for birth complications. 10.1523/ENEURO.0196-22.2023.f2-6Extended Data Figure 2-6a, Positive β estimates are shown in red, indicating thicker cortical thickness with shorter gestational age. Negative β estimates are shown in blue, indicating thinner cortical thickness with shorter gestational age. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere cortical thickness and (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download Figure 2-6, TIF file.Preterm birth associations with cortical thickness with a linear control for mean hemispheric cortical thickness using ComBat as the method of controlling variation between sites. Statistical analyses were conducted using R version 3.6.0  on a PC As regional metrics scale with overall brain size, and overall brain size is associated with preterm group  we used two approaches to model the data: (1) absolute effects uncontrolled for brain size, and (2) relative effect models controlling for linear associations with brain size. In models using brain size controls, we used a parameter appropriate to the structural parameter. For cortical thickness models, we used mean hemispheric cortical thickness and, for cortical surface area models, we used total hemispheric surface area. For subcortical volume models , we used whole brain volume.To assess model fit, we considered the distribution of the residuals by analyzing the quantile-quantile plot (Q-Q plot) for three randomly selected regions. All of the residuals examined had a linear Q-Q plot indicating normality except for those associated with the ventricular models, whose Q-Q plot was exponentially curved. We therefore used log-transformed regional ventricle volumes as the dependent variables in the ventricular models, which produced linear Q-Q plots of the residual distribution.In line with an estimation statistics framework , resultsp < 2e-16), and birthweight has been associated with variation in brain structure in childhood  conducting analyses for girls and boys separately, and (2) adding a sex*PTB interaction term to models of the full sample.We assessed generalizability of findings from the discovery to the replication sample by using the inverse β weights for each brain region to predict GA . Specifically, in models that were originally built as ROI_value ∼ β*PTB_category, for each high confidence region (99% CIs not overlapping zero) in the discovery sample, the effect estimates were inverted and multiplied by the ROI_value to predict GA in the replication sample and these predictions were averaged across regions of interest (ROIs). Each parameter was assessed separately  and a model was constructed considering all parameters. Predictive accuracy was assessed using a Spearman correlation because modeled/predicted values were categorical rather than continuous and confidence intervals around predictions were obtained with bootstrap resampling.https://github.com/BrayNeuroimagingLab/BNL_open/tree/main/abcdPTB. The code is available as The code described in the paper is freely available online at p-values for Fisher’s exact tests are shown for categorical variables  moderate preterm birth relative to full term birth and (b) very preterm birth relative to full term birth in all cortical regions. Estimated standardized βs are displayed with their 99% confidence intervals separately for the (top) left hemisphere cortical thickness and the (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download Figure 3-1, TIF file.Preterm birth associations with cortical thickness comparing  left hemisphere surface area and the (bottom) right hemisphere surface area. a.u. = arbitrary units. Download 10.1523/ENEURO.0196-22.2023.f4-2Extended Data Figure 4-2a, Positive β estimates are shown in red, indicating greater surface area with shorter gestational age. Negative β estimates are shown in blue, indicating smaller surface area with shorter gestational age. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere surface area and (bottom) right hemisphere surface area. a.u. = arbitrary units. Download Figure 4-2, TIF file.Preterm birth associations with cortical surface area without a control for total hemispheric cortical surface area. 10.1523/ENEURO.0196-22.2023.f4-3Extended Data Figure 4-3a, Positive β estimates are shown in red, indicating greater surface area with shorter gestational age. Negative β estimates are shown in blue, indicating smaller surface area with shorter gestational age. b, Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere surface area and (bottom) right hemisphere surface area. a.u. = arbitrary units. Download Figure 4-3, TIF file.Preterm birth associations with cortical surface area in stringent quality subsample. 10.1523/ENEURO.0196-22.2023.f4-4Extended Data Figure 4-4a) moderate preterm birth relative to full term birth and (b) very preterm birth relative to full term birth. Estimated standardized βs of cortical regions whose 99% confidence interval do not overlap 0 are displayed for (top) left hemisphere surface area and (bottom) right hemisphere surface area for (c) moderate preterm birth relative to full term birth and (d) very preterm birth relative to full term birth. a.u. = arbitrary units. Download Figure 4-4, TIF file.Preterm birth associations with cortical surface area in moderate preterm birth relative to full term birth and very preterm birth relative to full term birth. Positive β estimates are shown in red, indicating greater surface area with shorter gestational age, and negative β estimates are shown in blue, indicating smaller surface area with shorter gestational age, for  left hemisphere cortical surface area and (bottom) right hemisphere cortical surface area. a.u. = arbitrary units. Download Figure 4-6, TIF file.Preterm birth associations with cortical surface area with a linear control for birth complications. In models assessing linear effects of weeks born preterm on subcortical, cerebellar, and log-transformed ventricular volumes and controlling for total brain volume , we foun10.1523/ENEURO.0196-22.2023.f5-1Extended Data Figure 5-1a) subcortical, (b) cerebellar, and (c) log-transformed ventricular volumes without a control for total brain volume. Estimated standardized βs with 99% confidence intervals are shown. a.u. = arbitrary units. Download Figure 5-1, TIF file.Preterm birth associations with  subcortical, (b) cerebellar, and (c) log-transformed ventricular volumes in stringent quality subsample. Estimated standardized βs with 99% confidence intervals are shown. a.u. = arbitrary units. Download Figure 5-2, TIF file.Preterm birth associations with  subcortical, (b) cerebellar, and (c) log-transformed ventricular volumes in moderate preterm birth relative to full term birth. Estimated standardized βs with 99% confidence intervals are shown. a.u. = arbitrary units. Download Figure 5-3, TIF file.Preterm birth associations with  subcortical, (b) cerebellar, and (c) log-transformed ventricular volumes in very preterm birth relative to full term birth. Estimated standardized βs with 99% confidence intervals are shown. a.u. = arbitrary units. Download Figure 5-4, TIF file.Preterm birth associations with  subcortical, (b) cerebellar, and (c) log-transformed ventricular volumes. Estimated standardized βs with 99% confidence intervals are shown. a.u. = arbitrary units. Download Figure 5-5, TIF file.Birth complication associations with  subcortical, (b) cerebellar, and (c) log-transformed ventricular volumes with a linear control for birth complications. Estimated standardized βs with 99% confidence intervals are shown. a.u. = arbitrary units. Download Figure 5-6, TIF file.Preterm birth associations with  males and (b) females in all cortical regions. Estimated standardized βs are displayed with their 99% confidence intervals separately for the (top) left hemisphere cortical thickness and the (bottom) right hemisphere cortical thickness. a.u. = arbitrary units. Download Figure 7-1, TIF file.Preterm birth associations with cortical thickness in  males and (b) females in all cortical regions. Estimated standardized βs are displayed with their 99% confidence intervals separately for the (top) left hemisphere surface area and the (bottom) right hemisphere surface area. a.u. = arbitrary units. Download Figure 8-1, TIF file.Preterm birth associations with cortical surface area in (s), compared predicted weeks born preterm to actual weeks born preterm. We found moderate prediction using cortical thickness, with predicted weeks born preterm correlated with actual preterm weeks at rs = 0.20  , cerebellar , and ventricular regions . Including all parameters in one predictive model showed the same association as that of CT alone .We used high-confidence parameter estimates from models that linearly controlled for brain-size effects in the discovery sample to predict weeks born preterm in the replication sample and, using Spearman correlations (rrs = 0.20), and that prediction was strongest for CT relative to other structural parameters.This study leveraged the large and diverse ABCD sample to comprehensively characterize long-term effects of PTB on brain structure in late childhood using an estimation statistics framework. Our main findings were that PTB is associated with a pattern of relative cortical thinning around dorsal prefrontal and temporoparietal junction regions and thickening of medial prefrontal and occipital regions when controlling for mean hemispheric CT. Surface area was reduced in ventral visual regions and increased in dorsal prefrontal, mid-cingulate, and anterior ventral-temporal regions. We found that absolute volumes were smaller in subcortical regions in PTB, but the effects of PTB were attenuated when total brain volume was taken into account. In cortical regions, effects appeared to be partly mediated by birthweight. We found largely overlapping effects in boys and girls and limited evidence for interaction effects between sex and weeks born preterm. Finally, we show that effects estimated in the discovery sample predicted gestational age in the replication sample with a small-to-moderate effect size  concur with several previous studies that have reported thinning in temporal and occipitoparietal regions in children born preterm . We furtIn typically developing children, cortical SA undergoes a distinct developmental trajectory  and has Somewhat surprisingly, we did not find strong evidence for enlarged ventricles, though we note that effect sizes were positive, as would be expected from previous literature . VentricBirth complications secondary to infection and inflammation are often seen in preterm born neonates which may confound the effects of preterm birth on brain structure in children . To consA relatively unique contribution of this work is that the PTB group was heavily weighted to moderate/late preterm birth. A growing number of studies suggest that although very/extremely preterm and low birthweight infants are at highest risk for adverse outcomes, for some outcomes there is a graded risk based on gestational age, and risk may be exacerbated by environmental factors . We findA previous analysis of ABCD data that covaried brain structure with cognitive, clinical, behavioral, and sociodemographic variables found that the strongest mode of variation related perinatal factors and obstetric complications to brain morphology, including regions that parallel findings here in occipital, orbitofrontal, temporal and parietal regions . A seconPreterm birth affects the brain in several ways. Developmental timing is altered, such that late developing brain structures undergo maturation under markedly different conditions ex-utero. There is increased risk of perinatal injury such as periventricular leukomalacia . InfantsSeveral studies have shown that boys are at elevated higher risk for adverse outcomes following PTB . In modeA goal of this analysis was to use a large sample to help address some inconsistencies in the literature on PTB. Indeed, recent work has reinforced that in brain-wide association studies, small samples can lead to inflated estimates of effect sizes, and that for associations between brain and behavioral outcomes, sample sizes in the thousands may be required . Work inPTB is known to impact cognitive challenges including general intellectual functioning , attentiWhile the strengths of this study include a large and sociodemographically diverse sample, a narrow age range limiting the influence of age effects, and multiparameter whole-brain examination, there are several notable limitations. The first is that the ABCD study did not set out to recruit children born preterm; therefore, the sample size of PTB children is relatively small, especially for lower GA groups whose brains are more affected. Further, perinatal variables were collected through self-report rather than chart review and many potential influences on perinatal brain development were not considered here . We note that several studies have found that painful procedures around the time of birth associates with brain structure and outcomes following preterm birth , and we To consider the impact of harmonization method, we include results from an analysis using ComBat  to examiWe used ROI-by-ROI values rather than a vertex-wise modeling, potentially leading to attenuation of effects that do not span entire regions. Although this is a childhood sample and therefore the brain is developing, analyses were conducted on cross-sectional rather than longitudinal data. While much of the work to date has been cross-sectional, a small number of longitudinal studies across childhood and adolescence have suggested relatively parallel development of structure across late childhood or adolescence , i.e., fIn sum, this study replicates previous findings of a pattern of fronto-temporoparietal thinning in PTB and thickening of occipital and medial prefrontal regions in a large and sociodemographically diverse late childhood sample. We extended this work by showing region-wise effect sizes with confidence intervals, finding that in this large population sample these effects may be partly mediated by birthweight and do not differ substantially between sexes. CT in high-confidence regions predicted GA in a “replication” sample, demonstrating generalizability of findings and the relative consistency of differences in cortical thickness in PTB children across samples.10.1523/ENEURO.0196-22.2023.ed1Extended Data 1https://github.com/BrayNeuroimagingLab/BNL_open/tree/main/abcdPTB. Download Extended Data 1, ZIP file.All code used for the statistical analyses described is freely available at


Exposure to poor indoor environment contributes to poor health outcomes. In this research, we aim to evaluate the association between the usage of different type household cooking fuel and congenital birth defects in Nepal, as well as investigate whether air ventilation usage had a modifying effect on the possible association.- This is a secondary analysis of multi-centric prospective cohort study evaluating Quality Improvement Project in 12 public referral hospitals of Nepal from 2017 to 2018. The study sample was 66,713 women with a newborn, whose information was available in hospital records and exit interviews. The association between cooking fuel type usage and congenital birth defects was investigated with adjusted multivariable logistic regression. To investigate the air ventilation usage, a stratified multivariable logistic regression analysis was performed.-In the study population , 60.0% used polluting fuels for cooking and 89.6% did not have proper air ventilation. The prevalence rate of congenital birth defect was higher among the families who used polluting fuels for cooking than those who used cleaner fuels . Families using polluting fuels had higher odds  of having a child with a congenital birth defect compared to mothers using cleaner fuels adjusted with all available co-variates. Families not using ventilation while cooking had even higher but statistically insignificant odds of having a child with congenital birth defects  adjusted with all other variates.- The usage of polluted fuels for cooking has an increased odds of congenital birth defects with no significant association with ventilation. This study adds to the increasing knowledge on the adverse effect of polluting fuels for cooking and the need for action to reduce this exposure.The online version contains supplementary material available at 10.1186/s13690-023-01169-1. Birth defects increase the risk of neonatal and childhood mortality and disability –3. AnnuaGlobally, an estimation of 2.6 billion people donot practice or have access to safe and clean cooking practices –15. ManyMaternal exposure to household air pollution can increase the risk for adverse pregnancy and childbirth outcomes: stillbirths and low birth weight . EnvironFurthermore, passive or maternal smoking contributes to the household air pollution and fetal exposure during pregnancy and therefore, can highly increase the risk of some birth defects , 24. MorThe aim of this research is to study the association between household cooking fuel type usage and congenital birth defects in Nepal and investigate whether ventilation usage in the kitchen while cooking moderates this possible association.This study is a secondary analysis of a prospective cohort study for Nepal Perinatal Quality Improvement Project (NePeriQIP).The primary study was conducted in 12 different referral hospitals in Nepal to evaluate the effect of quality improvement package on perinatal outcomes. Of the public referral hospitals of the country, hospitals which had an annual birth of 1000 were selected. All these hospitals had comprehensive emergency obstetric and newborn care (CEONC) set up for managing complicated birth and special newborn care unit for managing sick newborns. In special newborn care units, sick newborns both outborn’s and inborn’s were admitted with standard operating protocol for managing sick newborns. The standard clinical definition of congenital birth defect in these hospitals was any structural anomalies that occur during intrauterine period (before birth) and identified during the clinical examination after birth (immediately after birth and before discharge), 27.Women admitted in the study hospitals with the gestational age ≥ 22 weeks for childbirth with fetal heart sound at admission were eligible for the primary study. Women who consented to the primary study with information extracted on clinical evaluation of congenital birth defect and interview with women at discharge were eligible for this study. Exclusion criteria was woman with antepartum stillbirth (no signs of life before labour) and no fetal heartbeat sound during the arrival to labor ward.Data collection- For the primary study, an independent data collection team was established in the 12 hospitals. The data collectors assessed the eligibility of women for enrollment and consented eligible participants to the study. The data collector followed each woman from the time of admission until discharge and extracted the demographic, obstetric and neonatal clinical information from maternity register and individual patient record book in a paper form. During the record extraction, all newborn care information including congenital birth defect was extracted. At the time of discharge, each woman was interviewed on their socio-economic status, housing conditions, use fuel for cooking and kitchen ventilation in the house. The data extraction tool and interview questionnaire were pre-tested for their reliability before the start of the study. The data collection was done between the April 2017 and October 2018 in all 12 hospitals at the same time.Exposure - The cleaner fuel included electricity, liquid petroleum gas (LPG), biogas, and natural gas usage. The polluting fuel include firewood and kerosene usage. The variable was collected through interview with woman.Outcome-The studied outcome variable was newborns with a diagnosed structural anomalies occurring during intrauterine period detected on clinical examination immediately after birth and at the time of discharge. The variable information was collected through clinical record extraction.Other covariates.Maternal educational level was categorized in three groups: no education, primary education  and, secondary  and higher. The variable was collected through interview with woman.Ethnicity was defined as two categorical groups: advantaged and disadvantaged. Advantaged group included Brahmin/Chhetri, since they are classified as higher class in Nepal. Similarly, disadvantaged group included Dalit, Madhesi, Muslim, Janajati and others, since they are seen as a lower class in Nepal . The varHousehold monthly income - We usedSex of the child categories as male and female. The variable information was collected through clinical record extraction.Parity defined as nulliparous as 0 previous birth, primiparous as 1 previous birth and multiparous as two or more previous births. The variable information was collected through clinical record extraction.The access to kitchen ventilation defined as kitchen having chimney, hood or either. The variable information was collected through interview with woman.Bivariate analysis was performed to assess the crude associations between all the included variables and birth defects with outcome of interest.The chosen confounders for adjusting were maternal age; maternal education; ethnicity; and household monthly income. Factors affecting to congenital birth defects were included in the study as variance reduction: sex of the child; parity; and single -or multiple pregnancy. Firstly, unadjusted logistic regression was performed between the exposure and outcome. Thereafter, adjusted logistic regressions were performed to control for the confounding factors that are related to both to the exposure and the outcome according to existing literature , 30, 31.Separate stratified multivariable regression analysis with air ventilation usage (yes and no) was conducted to see whether air ventilation is an effect modifier of the association. The stratified analysis was conducted among participants not using air ventilation while cooking  and separately among participants using air ventilation . Both unadjusted and adjusted models were conducted. In the adjusted model of participants not using air ventilation, birth defects were adjusted for exposure (cooking fuel type usage) and all covariates . Whereas, in adjusted model of participants using air ventilation, birth defects and cooking fuel type usage were adjusted for covariates . The estimates between the covariates are not interpreted in this study. The specific covariates were selected based on existing literature, in order to avoid the impact of multicollinearity.The total number of women enrolled in the study was 87,989, among whom 67,052 participated in the pre-discharge exit interview with 66,713 women-newborn pair with all required data available. . The prevalence of congenital birth defect was higher among families who had no ventilation in the kitchen than those who had ventilation but statistically insignificant . The prevalence rate of congenital birth defect was higher among the women less than 20 years (6.9/1000) and those age 35 years or above (6.7/1000 compared to 20–34 years old (3.8/1000) (p = 0.031). The prevalence rate was higher among the relatively disadvantaged ethnicities than the relatively advantaged ethnicity . The prevalence rate was higher among the household with lowest income than those with highest income . The prevalence rate was higher among female newborns than male infants . The prevalence rate was higher among newborns born to multiparous women than those born to nulliparous women . Lastly, the prevalence rate was also higher among singleton born than multiple born newborns . , compared to the women using cleaner fuel.  were using polluting fuel and 23 806 (39.8%) were using cleaner fuel. Whereas among participant using air ventilation, 4010 (58.1%) were using polluting fuel and 2897 (41.9%) were using cleaner fuel  on the association between household cooking fuel type usage and birth defects 2017–2018 in NepalSupplementary Material 1:


Background: Literature worldwide has linked periodontitis to preterm births and/or low-birth-weight infants. However, to our knowledge, research on this topic is scarce in India. The United Nations Children's Fund (UNICEF) reports that South Asian nations, particularly India, have the highest rates of preterm births and low-birth-weight infants as well as periodontitis due to poor socioeconomic conditions. Overall, 70% of perinatal fatalities result from prematurity and/or low birth weight, which also increases the incidence of morbidity and drives up the cost of postpartum care by a factor of ten. The frequency and severity of the illness may be greater among the Indian population due to their poor socioeconomic status. To lower the mortality rate and the cost of postnatal care, it is necessary to investigate the impact and severity of the effect of periodontal conditions on pregnancy outcomes in India.Materials and methods: Following the collection of obstetric and prenatal records from the hospital in compliance with inclusion and exclusion criteria, a sample of 150 pregnant women were chosen from public healthcare clinics for the research. Within three days of delivery following enrolment in the trial, a single physician recorded each subject's periodontal condition using the University of North Carolina-15 (UNC-15) probe under artificial lighting and the Russell periodontal index. The gestational age was calculated based on the latest menstrual cycle, and a medical professional would order an ultrasound if they felt it was essential. The doctor weighed the newborns soon after delivery and in accordance with this prenatal record. The acquired data was analyzed using a suitable statistical analysis technique.Results: The severity of a pregnant woman's periodontal disease was significantly correlated with the infant's birth weight and gestational age. Preterm births and low-birth-weight infants became more prevalent as the severity of the periodontal disease rose.Conclusion: The results demonstrated that periodontal disease in pregnant women may increase the risk of preterm delivery and low birth weight in infants. The concept that periodontal disease might influence systemic health is not new. Miller originally published his “focal infection theory” in 1981 suggesting that “microorganisms or their waste products gain an entry to parts of the body adjacent or remote from the mouth” .During an editorial in 1952, the Journal of the American Medical Association stated, “Many patients with disease caused by foci of infection have not been relieved of their symptoms by removal of the foci. Many patients with these same diseases have no focus on infection; also, foci of infection are as common in apparently healthy persons as those with disease” . For theAny live baby weighing less than 2500 g was designated as low birth weight (LBW) by WHO in 1995, while those weighing less than 1500 g were designated as very low birth weight (VLBW). WHO considers a birth that takes place before 37 weeks of pregnancy to be premature. PTLBW births are responsible for more than 33% of infant mortality, and even among the survivors, the prevalence of congenital neurological impairments and other developmental problems is elevated . InitialThe emphasis on the uterus has turned away from other putative sources of infection due to the likelihood that diseases outside the fetal placental unit may impact preterm and low-birth-weight (PLBW) births. Periodontal disease has been related to an overgrowth of gram-negative bacteria in the periodontal tissues, leading to a delayed rise in local levels of prostaglandins and inflammatory cytokines and an increase in the number of synthetic flammables in the blood. PLBW births may be the result of periodontal disease in two ways: either through the production of inflammatory mediators or through a bacterial attack on the amnion. Notably, increasing attention is being given to the role that infection plays. Women who have asymptomatic bacteriuria or who are abnormally colonized by pathogenic micro-organisms are at an increased risk of having preterm births due to conditions including prelabour rupture of membranes, premature labour, and chorioamnionitis. Although the exact role of maternal infection in premature births is still up for debate, it is possible that elevated levels of inflammatory mediators, which shorten the gestational period, are a secondary result of an infection in the vaginal tract or elsewhere in the mother. There are several potential routes for microorganisms to acquire access to the choriodecidual sac and the amniotic fluid and foetus inside of it, including the vagina, the cervix, the endometrium , and the bloodstream.Periodontal disease, especially severe periodontitis, has been related to other systemic disorders, including chronic lung illness, asthma, insulin-dependent diabetes mellitus, and disorders of the heart and blood vessels (including endocarditis and coronary heart disease). One study found that PLBW babies were seven times more likely to be delivered by mothers with periodontal disease. Animal studies have also demonstrated that infection with microorganisms linked to gram-negative periodontitis might have an unfavourable impact on the mother and her unborn child. When the periodontal infection Porphyromonas gingivalis was injected subcutaneously into the dorsal region of pregnant hamsters, the birth weight of the offspring was reduced by 25% compared to offspring born to healthy mothers.The current research intended to examine whether the prevalence of a periodontal infection was connected to PTLBW after controlling for other known obstetric risk factors and confounders. Periodontal infection is a known risk factor in PTLBW.The study was conducted in the public health care clinic in the concerned area. Ethical clearance was obtained, and the IRB number was PIDS/ 2021/145. Before conducting the study, approval was obtained from the ethical committee. Prior to performing any examination, we made sure to acquire the patients’ approval for the treatment. Patients were included in a case-control study during the first 72 hours after giving birth. They were examined in accordance with a pre-formed questionnaire and periodontal examination charts. Afterwards, the patients were examined by a single examiner for the periodontal index given by Russell using the following clinical armamentarium.Then, the mothers’ and infants’ birth weights, and any obstetric risks were double-checked against the patients’ hospital records. The following variables were recorded: name, age sex, address, and occupation, nourishment status, the presence of anaemia during the pregnancy, the presence of sexually transmitted diseases such as HIV and syphilis, history of tobacco usage and alcohol drinking during pregnancy, usage of antibiotics during the pregnancy, date of delivery, period of the gestation, the weight of the infant, and any postnatal complications. After recording all the variables, 100 patients were selected after satisfying all the inclusion and exclusion criteria. Inclusion criteria included the following: duration of fewer than three days from giving birth, a normal or above average BMI, and natural conception and healthy pregnancy and delivery. The participants ranged in age from 18 to 35 years old. The exclusion criteria included the following: pregnancy-related urinary tract infections or bacterial vaginosis, previous exposure to antibiotics during pregnancy, prenatal history of alcohol or cigarette use, family history of premature birth, LBW, PTLBW children, abortion, or stillbirth, history of hypothyroidism, hypertension or diabetes, and sexually transmitted diseases .Afterwards, the study population was divided into two groups: Group I (control) included infants born at 37 weeks or more with a birth weight of more than 2500 g, considering them to have been born to "term" ; Group II (case) was the larger group and included the following subsets:Subgroup A : This group included the mothers whose infants were born at less than 37 weeks of pregnancy and weighed more than or equal to 2500 g.Subgroup B : This group included the mothers whose infants were born at 37 weeks or more and were considered to have been born at a healthy weight of less than 2500 g.Subgroup C : This group included the mothers who gave birth to infants under 2500 g at a gestational age of 37 weeks.For statistical analysis, the periodontal index values of the experimental group were compared to those of the control group. We determined their means, medians, and standard deviations. The Mann-Whitney U test was used to ascertain whether there is a connection between the qualitative periodontal statuses and the outcomes of the pregnancies. Without including the periodontal score, a chi-square test was used for the univariate analysis to determine whether or not there was a correlation between the dependent (pregnancy) and independent (other factors) variables. To examine whether or not any of the variables were linked to the pregnancy outcome after controlling for confounding factors, a logistic regression analysis was conducted. It was carried out for the primiparous mothers for the main risk factors found in the analysis done for all subjects.The total data collected were tabulated according to all the variables recorded. A total of 100 subjects were examined and categorized into two groups: 28 cases and 72 controls.The cases were mothers (A) who delivered infants after 37 weeks of gestation with a birth weight below 2500 g, (B) who delivered infants before 37 weeks of gestation with a birth weight above 2500 g, and (C) who delivered infants before 37 weeks of gestation with a birth weight below 2500 g. The controls were the mothers who delivered infants after 37 weeks of gestation with a birth weight above 2500 g. The periodontal status for each mother was calculated according to the periodontal index given by Russell. To nullify the effect of previous pregnancies, the data for the primiparous mothers were pooled to form the groups of cases and controls separately.Regarding the distribution of the study population according to the maternal demographic variables, Table The median age of the cases was 24.035, whereas the median age of the controls was 24.99. The ages of the cases and controls do not vary much. New-borns in the case group averaged 2.30 kilograms, whereas those in the average weight of the control group was 3.069 kilograms, indicating statistical significance. Furthermore, there was a statistically significant gap between the two groups in terms of age, with the cases having a much younger mean gestational age (36.61 weeks) than the controls (37.96 weeks) (Table2).The mean BMI for the cases and controls was 21.69 kg /m2 and 22.78 kg/m2, respectively, indicating that this factor was not statistically significant. Regarding the difference in periodontal status between the cases and controls, the periodontal score was defined by the periodontal index score recorded for the cases and controls. When compared to the controls, whose mean score was 0.7206 and standard deviation was 0.3940, the prevalence of periodontal disease was higher in the cases . Thus, a statistically significant link was established between a high periodontal index score and a higher risk of adverse birth outcomes using the Mann-Whitney U test (p< 0.05) . The average periodontal disease score for the cases was 2.4054 (SD = 0.9728), whereas the average score for the controls was 0.6817 (SD = 0.3797) , to check their association with the dependent variable, which was the pregnancy outcomes. The risk factors which were found to be significantly associated with the adverse pregnancy outcomes or cases were 1) Irregular teeth brushing habits 2) Pre-natal examination visits 3) Non-graduate educational level 4) Household income Table .Additionally, the participants’ ages  were not significantly linked to the incidence of a poor pregnancy outcome. Similarly, no discernible link was noted between the number of previous pregnancies (> 1 vs. 0) and the chance of a poor outcome for the current pregnancy  for the primiparous mothers. Due to its prevalence as a contributor to infant mortality and morbidity, obstetricians have devoted considerable time and energy to discussing and learning more about PB. Babies who are delivered early and/or weigh less than they should are more likely to have serious health problems, including severe cognitive impairments, epilepsy, and pathologic heart abnormalities . The leaPremature and/or underweight babies have been related to several different factors. 70 Premature delivery is often linked to infectious factors according to several studies. Inflammatory mediators that result from genitourinary tract infections such as bacterial vaginosis have been considered a physiologically feasible explanation for premature labour and early membrane rupture. It was also postulated that distant infections might contribute to premature LBW by way of the systemic circulation of bacterial vesicles and lipopolysaccharide (LPS). Nonetheless, the underlying processes of the hypothesized connection remain unclear .The collection of infectious illnesses known as periodontal disease is characterized by the inflammation of the gingival and periodontal tissues and the eventual loss of alveolar bone. Many different kinds of microorganisms, mostly gram-negative anaerobic and microaerophilic bacteria, live in the subgingival space and are responsible for both the initial development and the ongoing maintenance of the periodontal infection. The host's immune system plays a crucial role in the development of periodontal disease. Researchers have proposed that the pathogenesis of periodontal disease and PTLBW are similar to those of other maternal disorders . Pro-infEvidence suggests that periodontal disease, particularly advanced periodontitis, is linked to a number of medical issues, including diseases of the heart and blood vessels (such as endocarditis and coronary artery disease), respiratory problems, and diabetes mellitus. In 1996, researchers Offenbacher et al. discovered that mothers with periodontal disease had a sevenfold increased risk of having a child with LBW. The periodontal infection Porphyromonas gingivalis was injected subcutaneously into the dorsal region of pregnant hamsters , and theUsing the results of the aforementioned literature review as a starting point, the current study sought to determine whether or not maternal periodontal disease is related to the nutritional condition of infants and therefore whether or not it is associated with LBW. To reduce selection bias in this study, the pregnancy outcome was recorded first, and then the periodontal stats of the cases and controls were accessed. Hence, it can be stated that the results were not influenced by selection bias. The periodontal statuses of the study population were recorded within 72 hours of pregnancy, ensuring that there was little change in the periodontal status of the pregnant women during this time. This case-control research accounted for potential confounding factors in a well-defined cohort, hence reducing the likelihood of selection bias . When available, information from the maternity records was used to analyse the questionnaire's findings. Therefore, we have no reason to suspect that selection bias affected our findings.In the present study, the mean age of the mother was 24.035 years (cases) and 24.99 years (control) in the complete data set. The cases were found to be younger than in Offenbacher dataset . There wGenerally, research may employ many different ways to assess the severity of the clinical periodontal disease. In this study, the requirement to perform clinical examination on women who had just given birth motivated us to choose a periodontal index that could be used in a hospital setting. It was decided that Russell's periodontal index was the best screening tool because it is an epidemiologic index and has a real biological gradient in the environment it is meant for .Comparing the average BMI of the healthy controls to that of the cases showed no statistically significant difference, and this finding aligns with Romero et al. , who likStatistical analysis of the periodontal index scores revealed a significant difference between the groups (controls and cases), and this finding is consistent with previous work by Mokeem et al. . Women wThere may also be an underlying problem, either genetic or environmental, that increases the likelihood of both periodontal disease and premature delivery. Both severe instances of periodontitis and LBW have been connected to the existence of a pre-existing hyper-responsive inflammatory characteristic. Multiple studies have linked periodontal infections to LBW and premature delivery due to a condition called subclinical bacterial vaginosis . TherefoThe study's limitations were that it targeted a local population and had a small sample size.Multiple factors contribute to PB and LBW, making it a severe neonatal condition that causes hardship for families and a financial strain on the healthcare system. Smoking, heredity, alcohol intake, lack of prenatal care, insufficient maternal nutrition, urinogenital infection, and sexually transmitted diseases are all considered traditional risk factors. Premature birth and LBW are still poorly understood despite ongoing efforts to identify their root causes in the obstetrical context. Concerns have been raised about the link between maternal periodontal infection and unfavourable pregnancy outcomes, which is a growing topic of research due to the prevalence of premature and underweight infants. For over a decade, researchers have sought proof that periodontal disease and pregnancy are connected, but they have turned up with nothing. Thus, it is still a fascinating and attractive field to investigate, both in periodontology and obstetrics.


Limited efforts have been paid to explore the underlying genetic mechanisms of birth by caesarian section (CS) affecting the risks of adult anxiety and self-harm.Using UK Biobank cohort, the logistic regression model was first applied to evaluate the associations of adult anxiety and self-harm with birth by CS. Using birth by CS as exposure variables, genome-wide by environment interaction study (GWEIS) was then applied by PLINK2.0 to identify associated genes interacting with birth by CS for anxiety and self-harm.P = 4.86 × 10− 5), and self-harm . GWEIS revealed multiple suggestive genes interacted with birth by CS for anxiety, such as DKK2  and ATXN1 . For self-harm, significant gene-environment interactions of birth by CS on self-harm were detected, such as ALDH1A2  and DAB1 .In the observational study, significant associations were observed between birth by CS and anxiety (odds ratio (OR) = 1.24; 95% confidence interval (CI), 1.12–1.38; Our results suggested that birth by CS was associated with the risk of adult anxiety and self-harm. We also discovered some genes interacted with birth by CS might influence the risk of anxiety and self-harm, which may provide novel clues for the pathogenesis of those mental disorders.The online version contains supplementary material available at 10.1186/s12888-023-04720-0. Mental disorder is a behavioral or mental pattern that causes significant distress or impairment of personal functioning . AccordiGenetic factors are demonstrated to play an important role in the development of common mental disorders. In a large population-based cohort  genome-wide association study, three independent loci  were identified to significantly associated with suicidality . In addiCaesarean section (CS), a surgery to deliver babies, can reduce the mortality of mothers, fetuses, and newborns to a certain extent. However, excessive selection of CS poses a threat to both short-term and long-term maternal and child health . OffspriIn this study, we aimed to explore the effects of birth by CS on adult anxiety and self-harm in UK Biobank cohort and to further investigate its underlying genetic mechanisms. First, we estimated the association of birth by CS with the risk of anxiety and self-harm through a logistic regression model. GWEIS was then applied to explore the genetic variation interaction between birth by CS and the risk of anxiety and self-harm. Our study holds the potential for clarifying the functional relevance of birth by CS with adult anxiety and self-harm.UK Biobank has electronic signed consent from the study participants and ethical approval was obtained from Northwest Multi-Center Research Ethics Committee (reference 11/NW/0382) and has been conducted in accordance with the ethical standards, according to the Declaration of Helsinki, and according to national and international guidelines. All patients gave written informed consent to participate after verbal and written information.The UK Biobank study is a large prospective cohort study that included health, hospital records and genetic data from 502,656 participants aged 40–69 in 2006 and 2010 . We usedGenotyping, quality control and imputation were performed by the UK Biobank. DNA samples of all participants in the UK Biobank were genotyped using either the Affymetrix UK BiLEVE  or Affymetrix UK Biobank Axiom  array . SNPs weBirth by CS was collected from the response to the UK Biobank online “Thoughts and Feelings” digestive health questionnaire: “Were you birth by caesarian section?” by choosing “Do not know (-121)”, “No (0)”, “Yes (1)” and “Prefer not to answer (-818)”. The subjects whose answers are “Do not know (-121)” and “Prefer not to answer (-818)” were excluded from this study.The case group criteria of anxiety were defined self-reported according to two UK Biobank fields: 20,002 and 20,544. Anxiety was selected based on the code 1287 from ID 20,002 and code 15 from ID 20,544 as cases. In order to obtain a comprehensive and accurate control group, we strictly set the control group threshold by Davis et al. research , which iAccording to the previous study , self-hahttps://www.r-project.org/).The associations between birth by CS and anxiety, self-harm behavior were estimated using a logistic regression model. The exposures variable was birth by CS and the outcome variables were anxiety and self-harm. Sex, age, cigarette smoking, alcohol drinking and the first 10 principle components of population structure were adjusted as covariates. Beta coefficient or odd ration (OR) with 95% confidence intervals (CI) and p-values were calculated by the logistic regression model. All statistical analyses were conducted by R 3.5.3  was used to investigate the location of the SNPs to identify the associated genes and for the functional annotation [P = 5.0 × 10− 8 for genome-wide by environment interaction effects. The Manhattan plots were generated using FUMA [https://fuma.ctglab.nl/).Let  factors . Specifi factors , 29, addnotation . Systemanotation . The devnotation . A signiing FUMA  (found ahttp://locuszoom.sph.umich.edu/locuszoom/) by uploading summary statistics from the birth by caesarean section and anxiety and self-harm GWEIS, respectively.LocusZoom plots  were created using the LocusZoom tool   age was 56.42 (7.48) years old. 14,556 participants were classified into case group, among which 472 were birth by CS and 14,094 were not birth by CS. A total of 96,492 participants answered the self-harm-related questions including 56,081 were female and the mean (SD) age was 56.21 (7.54) years old. 14,445 participants were classified into case group, among which 471 were birth by CS and 13,947 were not birth by CS (Table P = 4.86 × 10− 5), and self-harm  . In UK Biobank cohort, significant associations were observed between birth by CS and anxiety (odds ratio (OR) = 1.24; 95% confidence interval (CI), 1.12–1.38; GC anxiety = 1.18, showing some bias, so we performed genomic control to adjust P value. We identified a total of 45 suggestive SNPs interacting with birth by CS, such as DKK2 , rs62389045 located in ATXN1 , and rs62522074 located in COL22A1 . In addition, seven SNPs occur near in DIP2C, including rs61831032  were identified as suggestive SNPs. , DAB1 , and LRRFIP1 . rs140171389 (P = 4.03 × 10− 8) occurs near in CELSR1 and rs75563143(P = 4.45 × 10− 8) occurs near in COLEC12 were also identified as significant SNPs.  and self-harm  in UK Biobank cohort, suggesting that birth by CS significantly increases the risks for both anxiety and self-harm in adults. These findings underline the need for a politics and program approach in responding to requests for a planned CS when there are no apparent increased risks from vaginal delivery.It has been suggested by a previous systematic review and meta-analysis that birth by CS is associated with certain neurodevelopmental and psychiatric disorders , 34, 35,ATXN1  showed the highest OR value of 2.17, implying this genetic variant exhibits the highest risk interacting with birth by CS for anxiety. DKK2 rs13137764, P = 1.24 × 10− 9, adjusted P = 2.68 × 10− 7; rs13148189, P = 1.34 × 10− 9, adjusted P = 2.83 × 10− 7) and ANTX1 were observed as significant genes for anxiety. DKK2 is an important member of the DKK gene family. The DKK gene family is an ancient and evolutionarily conserved gene family [DKK gene family plays an important role in embryonic development, neural regeneration, synaptogenesis and so on [DKK2 converges on β-catenin using distinct transduction pathways required to activate Wnt/β-catenin signaling and induce neural crest cells [DKK2 on anxiety. We found DKK2 interacting with birth by CS for anxiety. Further in vivo and in vitro functional studies are needed on this effect.Our GWEIS identified a total of 45 significant SNPs interacting with birth by CS for anxiety Table . Among we family . In recest cells . HoweverATXN1), the gene mutated in spinocerebellar ataxia type 1 (SCA1), is another significant candidate genetic variant interacting with birth by CS for anxiety. Lu et al. performed a series of behavioral tests on the ATXN1–with its paralog ataxin 1–like (ATXN1L) conditional knockout mouse lines to assess general activity, anxiety, learning and memory, and social behavior [ANTX1 gene within the amygdala [Ataxin-1  and DAB1  showed the OR value greater than 2.00, implying remarkable risk factors for self-harm. rs117077436 (P = 3.09 × 10− 09) has the highest OR value of 11.34, but there is limited research focused on its risk for self-harm. According to a previous study, after nonfatal self-harm, adolescents and young adults were at a markedly elevated risk of suicide [ALDH1A2, encodes an enzyme for astrocyte-derived retinoic acid, is a key neuronal morphogen with relevance for schizophrenia. For example, Wan et al. observed a positive association between ALDH1A2 and schizophrenics in the Chinese population [ALDH1A2 was identified to be the second-most significant site [DAB1, a key component of the Reelin pathway [DAB1 conditional knockout mice showed hyperactivity, decreased anxiety-like behavior, and a deficit in spatial reference and working memory [COL22A1  DIP2C  were observed by GWEIS for anxiety; LRRFIP1  and ANPEP  were observed by GWEIS for self-harm, but limited epidemiological and biological evidence illustrated their potential effects. Therefore, further studies are needed to confirm our findings and clarify the potential roles of novel genetic variants in the pathogenesis of mental health.GWEIS also identified a total of 24 significant SNPs interacting with birth by CS for self-harm with pulation . In a meant site . DAB1, a pathway , is suffg memory . The resg memory . Teixeirg memory . Other sIn contrast with GWAS, GWEIS discovered some novel genes that might influence the risk of anxiety and self-harm. Previous studies focused on the genetic effect on mental disorders, less studies have assessed the interaction role of genes and environment on the mechanism of these complex diseases. Our study demonstrated the interactive association between birth by CS and anxiety, and self-harm. As far as we know, this is the first systemic study exploring the effect of birth by CS as an environmental factor on mental disorders for adults. Our study holds great potential for clarifying the functional relevance of birth by CS with mental disorders and provides novel clues for the pathogenesis of those mental disorders.However, some limitations of this study should be noted. Like GWAS, some significant SNPs found by GWEIS are located in non-coding regions, which still poses challenges for us to better illustrate our results. Compared with the general population, participants recruited in UK Biobank are healthier and live in the poorer socioeconomic areas , called In summary, we observed significant associations between birth by CS and the risk of adult anxiety and self-harm using UK Biobank cohort. GWEIS analysis identified multiple candidate genes which may serve as the underlying genetic mechanisms of the observed association. These findings highlight the importance of policies and strategies to prevent unnecessary CS.Below is the link to the electronic supplementary material.Supplementary Material 1: Supplementary Table 1. Association between anxiety, self-harm behavior and age and sex, respectivelySupplementary Material 2: Supplementary Figure 1. LocusZoom plot of anxiety associations with birth by caesarean sectionSupplementary Material 3: Supplementary Figure 2. LocusZoom plot of self-harm associations with birth by caesarean section


While Trial of labour after previous cesarean section for women with no contraindication for vaginal delivery is an important strategy to reduce short- and long-term morbidity related with repeated cesarean section, the rate of cesarean section and repeated cesarean section with its complication are increasing.The objective of the study was to assess factors associated with successful vaginal birth among women with previous cesarean delivery in public hospitals of Ambo town in 2019.A case-control study was conducted in Ambo public Hospitals in 2019. A total of 243 clients were included, of which 81 clients were cases and 162 clients were controls with controls to cases ratio of 2. A Lottery method was applied to select the controls and cases were selected consecutively. Bivariate, followed by multivariate analyses, were conducted with 95% CI and p-value <0.05 to identify factors associated with successful vaginal birth after cesarean delivery.Parity three and four, labour monitoring with partograph , prior vaginal birth after caesareans , occiput-posterior position , duration of labour after admission less than 8 hours  and artificial rupture of membrane  were factors significantly associated with successful vaginal birth after previous cesarean section.The study shows that parity, duration of labour, previous history of successful vaginal birth after cesarean section, artificial rupture of membrane, and partograph monitoring of labour were associated with successful vaginal birth after previous cesarean section. All Women with a history of cesarean section should be counselled and encouraged to undergo a trial of labour as long as it is not contraindicated. Trial of labour after cesarean is a planned attempt to deliver vaginally by a woman who had a previous cesarean section, regardless of the outcome. Previously it was thought that if a woman had one cesarean delivery, all future pregnancies should be delivered in cesarean delivery. Currently, it is known that many women can undergo a trial of labour after cesarean delivery (TOLAC) Despite the WHO's recommendation of cesarean delivery rate of 10% - 15%, currently one in three 33%) women underwent a caesarean section, and both under and overuse of cesarean section equally leads to maternal and perinatal mortality and morbidity 3% women Labour after cesarean delivery is safe and appropriate for most women with a history of one or two prior cesarean births 12In recent years the rate of cesarean section has been increasing in Ethiopia. According to the national demographic health survey of Ethiopia, the overall percentage of deliveries attended by the caesarean section was 2% Institution based unmatched case control study was conducted from June to December, 2019.The study was conducted in public Hospitals of Ambo town. Ambo town is the capital of West shoa zone located at 114 km West of Addis Ababa. There are two public hospitals in the town Ambo University Referral Hospital and Ambo general Hospital. The two Hospitals offer a full range of comprehensive emergency obstetric care services such as operative delivery and serve for around 3.5 million residents of West Shoa zone, South West Shoa zone and neighbouring East Wollega zone.All mothers who had one previous cesarean section and allowed for trial of labour during the study period was the study population of the study. Cases were mothers with previous scar, allowed VBAC, started labour spontaneously, and delivered vaginally. Controls were mothers who delivered by cesarean section after trial of labour.Mothers who had one previous cesarean section and allowed for trial of labour were included.All mothers who were critically ill and unable to respond questions, referred from other health institution with complication or incomplete documentation were excluded.The sample size was determined using the sample size calculator of EPI version 7.1 for double population. The sample size was calculated with a 95% confidence interval and detecting the power of 80% with control to cases ratio of 2 and odds ratio of 2.54 and proportion of case among the exposed group of 20.4%. The maximum sample size 221 and considering a 10% non- response rate the final sample size was 243 of which 81 were cases and 162 were controls. Cases were selected consecutively with proportional allocation to each hospital. If there was more than one case present on the same day lottery method was applied to select cases. Controls were selected by lottery methods.The questionnaire consists of different parts that were developed from different previous literature and modified according to the local context. A structured questionnaire was used to collect the data through a face-to-face interview for the socio-demographic, presence of co-morbid medical illness in the past and present obstetric variables in the postnatal ward before the patient was discharged. Some of the current obstetrics information was obtained from the client's chart. The data collection tool was translated from English to Afaan Oromo for better understanding, then retranslated back to English by professional translators to check for consistency. Data were collected by four trained BSc midwives  and two MSc midwives were assigned for supervision. The collected data were checked for completeness and consistency by the data collection supervisor on a daily basis.Training was provided for two days about the objective of the study, the definition of terms in the questionnaire, issues of confidentiality and privacy, and data collection method. The collected data were checked for completeness and consistency by the supervisors and principal investigator. The data was checked for its completeness, coded, cleaned, and entered to Epi info version 7.1.2.0 then transferred to SPSS-version 25 for analysis. Appropriate descriptive analysis  were used to present the socio-demographic variables. A Chi-square test was used to identify significant characteristics difference among cases and controls. Factors associated with successful VBAC were analysed using a logistic regression model after checking for the goodness of fit test (Hosmer and Lemeshow test). All variables with a p-value <0.05 in the bivariate analysis were included in multivariate analysis to adjust for potential confounders associated with successful vaginal birth after previous cesarean section. Odds ratios and 95% confidence interval (CI) were computed. Variables with a p-value of <0.05 were considered factors significantly associated with successful vaginal birth after previous cesarean section in multivariate analysis.Successful vaginal birth after previous cesarean sectionSocio-demographic factors, age, education, income, occupationPast obstetric variables, parity, gestational agemembrane status at admission cervical dilation at admission duration of labour presence of meconium, position gestational age, birth weight, station, ANC follow upAttempt to deliver vaginally by a woman who had previous cesarean delivery, irrespective of the outcome.Vaginal birth following trial of labour in a woman who had a prior caesarean section delivery.A total of 239 women have participated in the study with a response rate of 98.35%. The mean (SD) age of the participants was 27.6(±5) for the cases and 28.1(±4.8), for controls. Among the respondents, 51(63.8%) of cases and 101(63.5%) of controls were in the age between 25 and 35 years of age. The respondent's age ranges from 18 to 42 years. Around half 120 (50.2%) of the mothers were housewives and 35(14.6%) do not have formal education. Monthly income had a significant difference among cases and controls. Age, educational status, occupation, and residence were comparable characteristics in cases and controls .Fifty-two (67.2%) of cases had three and more birth history and among controls, more than half (59.7%) of mothers had a history of only two births. Parity and history of prior successful VBAC had a significant difference between the cases and controls, other variables were comparable in both the cases and control groups as shown . Among tAll mothers included in the cases as well as in the controls had antenatal care (ANC) follow up at least once in this pregnancy. Among mothers who have ANC visit about 68.8% of the cases and 53.2% of the controls had four and above visit. Around 81(50.9%) of controls and 33(41.2%) of cases came to the hospitals at the gestational age of less than 40 weeks. Fifty-four (67.5%) of cases an68(42.8%) of controls were admitted in the active phase of labour. Among cases and controls, there was no significant difference in place of ANC, estimated fetal weight, neonatal weight, and neonatal outcomes . Among cMonthly income, parity, prior VBAC, number of ANC visit, cervical dilatation, the position of the presenting part, status of the membrane at admission, station, partograph utilization, duration of labour, and ARM were significantly associated with successful vaginal birth after previous cesarean section in bivariate analysis. To control the potential confounding effect, those variables having a p-value less than 0.5 in the bivariate analysis were entered into multiple logistic regression with enter method. Parity three and four, prior successful vaginal birth after cesarean section, partograph followed labour, duration of labour after admission and artificial rupture of the membrane during labour were significantly associated with successful VBAC after adjusting for other variables in multivariate analysis .The purpose of the study was to identify factors associated with successful vaginal birth after a previous cesarean section among mothers who were eligible for a trial of labour after previous cesarean delivery in Ambo town hospitals. In this study, parity it was found to be associated with successful vaginal birth after previous cesarean section. Women who had three and four deliveries were more than threefold more likely to give successful vaginal birth than women who had two deliveries. Consistently a Nigerian study reported that parity was a significant predictive factor for mode of delivery; the study sated that women with low parity were more likely to have caesarean delivery than those with high parity Previous successful VBAC was a significant factor for a successful vaginal birth after previous cesarean section. Mothers who had previous successful vaginal birth after cesarean section were five times more likely to give successful vaginal birth than mothers who had not had previous successful vaginal birth after cesarean section. In line with this study, a case-control study conducted in Addis Ababa reported that previous history of successful vaginal birth after a previous cesarean section was determinant of successful vaginal birth after previous cesarean section Artificial rupture of membrane (ARM) was significantly associated with successful vaginal birth after previous cesarean section. Women with whom their labour was augmented with artificial rupture of the membrane were 5 times more likely to have successful VBAC than their counterparts. Correspondingly a systematic review has reported that early amniotomy was associated with the reduction of cesarean delivery rate compared with routine care The position of the presenting part was also another factor associated with successful vaginal birth after cesarean section. Being occiput posterior position was 89.1% less likely to have a successful VBAC compared with being occiput anterior position. A study in Addis Ababa reports that having an occiput-posterior/transvers position was associated with low success for a vaginal birth after previous cesarean section In this study duration of labour was found to be a factor significantly associated with successful vaginal birth after previous cesarean section. Mothers whose duration of labour was less than 8 hours after admission was more than four times more likely to give vaginal delivery than mothers whose duration of labour was greater than 8 hours. A study in Tunisia reported that duration of labour greater than 8 hours was associated with poor prognostic factors for a successful vaginal birth after previous cesarean section In the current study, partograph utilization was associated with successful vaginal birth after previous cesarean section. Compared to women whose labour was not followed by partograph women whose labour was followed by partograph were more than four times more likely to give vaginal birth after previous cesarean section. Correspondingly a study in Northern Ethiopia, Adigrat, reported that labour monitored without partograph was significantly associated with an increased rate of cesarean delivery The study has its own limitations including a possible recall bias while reporting some variables like indications of previous CS and gestational age. Moreover, the result might be affected by the small sample size.The study findings indicated that parity, duration of labour, previous history of successful vaginal birth after cesarean section, artificial rupture of membrane, and partograph monitoring of labour were associated with successful vaginal birth after previous cesarean section. Labour should be monitored closely with partograph where possible since partograph can prevent premature decision for cesarean section and the duration of labour should be kept short as much as possible. All Women with a history of cesarean section should be counselled and encouraged to undergo a trial of labour if the indication of the previous cesarean section is recurrent.The study has its own limitations including a possible recall bias while reporting some variables like indications of previous CS and gestational age. Moreover, the result might be affected by the small sample size.


We examined associations among serial measures of linear growth and relative weight with adult body composition.Secondary data analysis of prospective birth cohort studies.Six birth cohorts from Brazil, Guatemala, India, the Philippines and South Africa.4173 individuals followed from birth to ages 22–46 years with complete and valid weight and height at birth, infancy, childhood and adolescence, and body composition in adult life.Birth weight and conditional size  in infancy, childhood and adolescence.Body mass index, fat mass index (FMI), fat-free mass index (FFMI), fat mass/fat-free mass ratio (FM/FFM), and waist circumference in young and mid-adulthood.In pooled analyses, a higher birth weight and relative weight gains in infancy, childhood and adolescence were positively associated with all adult outcomes. Relative weight gains in childhood and adolescence were the strongest predictors of adult body composition (β (95% CI) among men: FMI (childhood: 0.41 (0.26 to 0.55); adolescence: 0.39 (0.27 to 0.50)), FFMI (childhood: 0.50 (0.34 to 0.66); adolescence: 0.43 (0.32 to 0.55)), FM/FFM (childhood: 0.31 (0.16 to 0.47); adolescence: 0.31 (0.19 to 0.43))). Among women, similar patterns were observed, but, effect sizes in adolescence were slightly stronger than in childhood. Conditional height in infancy was positively associated with FMI (men: 0.08 (0.03 to 0.14); women: 0.11 (0.07 to 0.16)). Conditional height in childhood was positively but weakly associated with women’s adiposity. Site-specific and sex-stratified analyses showed consistency in the direction of estimates, although there were differences in their magnitude.Prenatal and postnatal relative weight gains were positive predictors of larger body size and increased adiposity in adulthood. A faster linear growth in infancy was a significant but weak predictor of higher adult adiposity. We analysed six well-characterised population-based prospective birth cohorts from five low and middle-income countries.We considered a two-compartment model of body composition (fat mass index and fat-free mass index), that were measured with gold standards and/or validated techniques at each study site.The use of conditional growth measures allowed us to break the high correlations among serial measures of weight and height to study the independent roles of linear growth and relative weight at specific age intervals.Attrition might be one source of selection bias given the long-lasting follow-up of these birth cohorts.Residual confounding by unmeasured characteristics such as diet, reproductive history and other lifestyle factors might bias the estimates.Low and middle-income countries (LMICs) have witnessed an increase in the prevalence of cardiometabolic risk factors such as diabetes, hypertension and obesity in the adult population.‘through its own programming by early growth, and/or through being a mediator of the programming process’.Adaptations in body composition might have an important role in the programming of cardiometabolic disease BMI in infancy, childhood and adolescence has a moderate to strong tracking into adult adiposity.There is a paucity of studies about the long-term effects of growth across the life span on adult body composition. Available evidence has primarily examined associations between prenatal and postnatal growth (mainly in infancy) with body composition in childhood and adolescence. In a recent literature review of publications between 2003 and 2018, only 6 out of 39 studies examined associations between weight gain during infancy and body composition in adult participants from LMICs.Pooled analyses of the Consortium of Health-Oriented Research in Transitional Societies (COHORTS), a consortium of birth cohorts from five LMICs,We conducted a secondary data analysis of COHORTS.2 or ≥ 60 kg/m2 and waist circumference ≤51 cm or ≥ 190 cm (n=1), and pregnancy at the moment of the anthropometric assessment (n=135). We also excluded those individuals with missing anthropometric data at birth, childhood or adolescence (n=6967), implausible values of weight and height considering the WHO Z-score thresholds (n=168),We selected one analytical sample for each study site . Of a to2) as a proxy of body size; (2) FMI to represent the fat compartment adjusted for size (FM in kg/height in metres2); (3) FFMI to represent the lean compartment adjusted for size (FFM in kg/height in metres2); (4) FM/FMM ratio (a higher ratio indicates a greater increment in the FM component); and (5) The waist circumference (centimetres) as a proxy of abdominal adiposity. We transformed these outcomes measures into Z-scores (SD units) to compare effect sizes within strata of site and sex, and among the measures.Study sites applied different standard methods to measure body composition in adult participants such as dual-energy X-ray absorptiometry, air-displacement plethysmography (BodPod), deuterium oxide dilution technique, bioimpedanceBirth weight was measured in all study sites, while birth length was available only in four of the six study sites (except Brazil 1982 and South Africa). In Brazil, anthropometric data at birth was measured at the hospitals by the research team (Brazil 1993) or by the hospital personnel (Brazil 1982) using paediatric scales.Trained research staff at each study site followed standard procedures to take anthropometric measures of length and/or height and weight in subsequent follow-ups (childhood and adolescence). Growth measures that represent linear growth (length/height) and mass accretion independent of linear size (relative weight) were measured in different periods at each study site. We identified four common or near ages where anthropometric data were available across all cohorts: (1) Birth, (2) Infancy , (3) Childhood , and (4) Adolescence . To be able to compare growth measures between study sites, we estimated sex-specific length/height-for-age and weight-for-age Z-scores  using the WHO growth standards.Repeated measures of linear growth and relative weight are strongly correlated. To eliminate this correlation, we estimated conditional size measures  by regressing current HAZ on previous HAZ and WAZ measures, and regressing current WAZ on current HAZ and all prior HAZ and WAZ measures, within strata of site and sex. This approach allowed us to identify if children’s growth deviates from their expected length/height or weight as estimated based on their own previous growth measurements and the growth of other children. We used birth weight as the anchor to estimate conditional growth measures (height and relative weight) in the main analysis of all cohorts. In separate models, we derived conditional growth measures using birth length as an anchor in the four study sites in which this variable was available. We estimated conditional height and conditional relative weight in four age intervals across all study sites: (1) Prenatal (from conception to birth captured though birth weight and birth length); (2) Infancy ; (3) Childhood ; and (4) Adolescence (48–180 months in five study sites and 102–180 months in the Philippines).Covariates: We identified potential confounders available at each study site such as birth characteristics , income and/or wealth index of child’s household at birth, maternal characteristics , paternal characteristics , reproductive factors (age at menarche) and age in adulthood . We built site-specific models stratified by sex given the biological differences in body composition.2 statistic to quantify the magnitude of between-study heterogeneity. As a rule of thumb an I2 equal to 25% is interpreted as low heterogeneity, 50% as moderate heterogeneity and 75% as substantial heterogeneity.The cohorts come from different study sites and data were collected in different periods, resulting in heterogeneity among site-specific estimates. We used a random-effects meta-analysis approach to pool effect sizes to account for this underlying heterogeneity. Given that our outcomes were continuous, we used the restricted maximum likelihood estimator to calculate the between-study heterogeneity (variance of the distribution of true effect sizes).To deal with missing data, we built sex-specific multiple imputation models at each study site. Missing data patterns are presented in Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.2 and the highest FMI. Among men, the proportion of excess weight ranged from 16.0% in South Africa to 73.2% in India, and among women it ranged from 44.5% in Brazil 1993 to 85.4% in Guatemala. Participants from Guatemala, India and Brazil 1982 had the highest FMI (women above 10 kg/m2 and men above 7 kg/m2). FFMI ranged from 15.5 kg/m2 to 20.2 kg/m2 in men, and from 13.7 kg/m2 to 17.7 kg/m2 in women. Other characteristics  of study participants at each study site are presented in We analysed data from a combined analytical sample of 4137 participants with complete and valid information of body composition in adulthood and anthropometry across the life course . The com2=83.9%) and conditional relative weight in adolescence among men (I2=78.0%) (2≥75%)  . The bet (2≥75%) .Site-specific estimates were consistent in magnitude and direction. Birth weight was positively associated with adult FMI in men and women from India and the Philippines, and in women from Brazil 1993. Conditional relative weights in infancy, childhood and adolescence were positively associated with adult FMI among men and women across all cohorts . Site-spSite-specific analyses of BMI and waist circumference showed similar effect sizes in direction and magnitude as pooled estimates. Relative weight gains in infancy, childhood and adolescence were predictors of higher BMI and waist circumference in adulthood across study sites, with a few exceptions .Conditional height in infancy was positively associated with FMI and FM/FFM ratio in adult life, but effect sizes were small (around 0.1) . None ofWe used conditionals derived from birth length as the anchor in models in four of the study sites. In these pooled analyses, we found that birth length was a weak but statistically significant predictor of higher FFMI and BMI in adult women . Other eBody size and composition indices should control for allometric scaling (differences in body compartments given differences in linear size) and should be independent of their denominator (height).In a pooled analysis of six prospective birth cohorts from five LMICs, we found that a higher birth weight predicted higher adult FFMI, FMI, BMI and waist circumference, but not adiposity (FM/FFM). Birth length was a positive predictor of FFMI and BMI, only among adult women. Higher relative weight gains in infancy, childhood and adolescence were associated with higher FFMI, FMI, FM/FFM ratio, BMI and waist circumference in adult life. Associations strengthened with age, thus, effect sizes were the strongest in childhood and adolescence, almost twice the magnitude of effect sizes in infancy, and four to five times the magnitude of birth estimates. Our findings also showed that a higher conditional height in infancy was a significant but weak predictor of higher FMI and BMI among adult men and women, and higher waist circumference among women. A higher conditional height in childhood was positively but weakly associated with women’s FMI, FM/FFM ratio and waist circumference.This updated analysis confirms previous results from COHORTSCompared with previous combined analyses of COHORTS, we examined for the first time the interval from childhood to adolescence. Our findings showed that relative weight gain in adolescence was associated with higher adult adiposity  in consistency with earlier studies in LMICs.A combination of biological, environmental, behavioural and sociodemographic factors is associated with weight gain and adiposity in childhood and adolescence that may not only persist later in life but might undermine the positive role of a healthy birth weight and linear growth early in life. Some of these factors are the medium to strong tracking of child and adolescent BMI into adult adiposity,Fewer studies have examined the role of linear growth on later body composition and results are mixed.Linear growth is determined by the hormonal regulation of the growth hormone (GH) secreted by the pituitary and the insulin-like growth factor 1 (IGF-1), an intermediary hormone between the GH and target tissues.Thus, increased growth in infancy, including a faster linear growth, might induce the long-lasting metabolic programming of the GH/IGF-1 axis and a subsequent increased risk of adiposity. However, the evidence on the role of linear growth on obesity risk and higher adiposity later in life is limited and inconclusive.Overall, larger weight gains across the life course were associated with larger body size and adiposity in adult life among men and women. However, among women, estimates for size in adolescence tended to be stronger than those for childhood, in contrast to the men, in whom childhood estimated tended to be stronger. Regarding conditional height, a faster liner growth in infancy was positively but weakly associated with higher adult adiposity among both men and women, and faster linear growth in childhood was positively associated with higher adiposity among adult women but not in men.Sex-based dimorphism in human growth patterns, body size and composition since the prenatal period, with pronounced differences in certain age intervals is well recognised.Some limitations of our analysis include: (1) Attrition as one source of selection bias given the long-lasting follow-up of these birth cohorts; (2) Residual confounding since we could not control for covariates such as diet, reproductive and life style factors; (3) Missing data of covariates (ranges between 0.1%–41%), for which we assumed MAR and applied multiple imputation techniques; and (4) As expected there was substantial between-study heterogeneity, mostly in associations of conditional relative weight in childhood and adolescence. Some reasons that might explain the observed heterogeneity, beyond the baseline differences in places and contexts, include: (a) The age intervals definition was guided by data availability, as not all children were measured at the same intervals; (b) Differences in sample sizes across study sites given that we had to restrict the analysis to participants with complete anthropometric data in the four age intervals to be able to estimate conditional growth measures; (c) Differences in the techniques and instruments to measure body composition which might be a source of information bias . In this regard, our research question intended to study the absolute increase in body composition not the relative estimate, and we assumed that all techniques, independent of the method and units used, ranked people in the same way. Additionally, we transformed all body composition measurements into SD units in each cohort and estimated standardised βs to be able to compare estimates between sites. To minimise the previous limitations, we used the random meta-analysis approach that not only considers the underlying heterogeneity when pooling estimates but also allows us to control for differences in sample sizes across study sites.Among the strengths of our analyses, we highlight the prospective and long follow-up of these six birth cohorts in LMICs. We used large sample sizes , and analysed two compartments of body composition (beyond BMI) that were measured using gold standards and/or validated techniques. We studied the independent association of linear growth and weight gain with body composition through the use of conditional growth measures, which allowed us to break the high correlation between weight and height and to study the independent role of linear growth and relative weight gain in specific age intervals. We selected the best model at each study site, fully adjusted by multiple confounders, and applied a random-effects meta-analysis that by default considers the heterogeneity between study sites.We are cautious with the generalizability of our results since we used selected birth cohorts which design was not intended to be representative of countries were information was collected, and given the social, demographic, economic, political and cultural differences in contexts and periods in which each cohort started. However, the consistency in magnitude and direction of effect sizes across study sites (six birth cohorts from five different cities around the world), indicates that our findings are robust and suggests that the long-term role of growth on body composition might apply to individuals from other LMICs with similar characteristics.In summary, our findings suggest that: (1) Growth in the first 1000 days of life has a small and long-lasting association with adult body size and composition; (2) Childhood and adolescence exhibit the strongest associations between relative weight gain with body size and composition in adulthood; and (3) A faster linear growth in infancy (girls and boys) and childhood (girls) predicts increased adiposity in adult life. Historical efforts to reduce growth faltering in LMICs have been successful, with little evidence to date of increases in BMI for age.