Tanzania is one of the Sub-Saharan African country with nearly 12 out of 60 million people being adolescent. The prevalence of child marriage is higher with one out of every three girls being married before reaching their 18th birthday, 5 % being married by the age of 15, and 31% by the age of 18 years. Literature shows early pregnancy is associated with Low Birth Weight (LBW) and stunting among children under 5 years. This paper explores variation and factors associated with low birth weight and stunting among children born by adolescent and non-adolescent mothers.Data from 13,266 women with children under 5 years collected as part of the 2015/2016 TDHS was re-analyzed using STATA version 14 software while accounting for survey design. A total of 6385 women (of which 7.2% were adolescent) and 8852 women (of which 6.7% were adolescent) were involved in the analysis of child birth weight and stunting respectively. Descriptive statistics stratified by maternal age was conducted with LBW and stunting as outcome variables followed by logistic regressions models controlling for confounding variables.The proportion of obese or overweight adolescent and non-adolescent mothers was 11.8 and 36.5% respectively. Antenatal care (ANC) attendance, areas of residence and social economic status were very similar in the two maternal age groups. Non- adolescent mothers had reduced odds of giving birth to LBW babies compared to adolescent mothers (Adjusted Odds Ratio (AOR) = 0.34; 95% CI: 0.22–0.50). Maternal undernutrition , being divorced, separated or widowed  and having at least four ANC visits  were significantly associated with reduced odds of having a LBW. Child stunting was not associated with maternal age. Maternal high socioeconomic status  and maternal obesity or overweight  were negatively associated with stunting. Child birth weight, sex, and age were significantly associated with stunting.Maternal age was a predictor of LBW but not stunting. ANC attendance and not living with a spouse increase the risk of LBW babies. Stunting was associated with low maternal body mass index (BMI), low socioeconomic status, child birth weight, gender, and age. A multi-sectoral approach is needed to address child nutrition problems with teenagers ‘specific intervention that offer emotional support, and health education during pregnancies for improving immediate and later life child birth outcomes. Globally about 1.2 billion people are adolescents aged 10–19 years .Tanzania has a population of approximately 60 million people of which 12 million are adolescents aged 10–19 years . The couChildbearing during adolescence is linked to a number of challenges. Teen mothers often have less structural resources, less educated, and lack financial independence as compared to adult mothers in both high, low, and middle-income countries . Often, Overall, it is estimated that 15 to 20% of all births worldwide are LBW, representing more than 20 million births a year . The estDespite the overwhelming evidence on adolescent social and economic vulnerabilities, little is known about how maternal age contributes to low birth weight and childhood stunting in Tanzania. This paper explored variation and factors associated with LBW and stunting among children born by adolescent and non-adolescent mothers using data collected as part of the 2015/2016 Tanzania Demographic and Health Survey (TDHS) [Secondary data analysis of the 2015/2016 TDHS was done focusing on adolescent and non-adolescent mothers aged 15–49 years with their children 0–59 months. The TDHS is a national representative cross-sectional survey done after every 5 years to monitor and evaluate population health, nutrition, and maternal indicators including feeding practices and health care seeking behaviors. It contained information collected from 13,400 households located in Zanzibar and mainland Tanzania. The survey employed a two-stage stratified sampling design with the first stage involving independent sampling of 59 strata by population proportion to size (PPS). The second stage involved random sampling of households located in each of the selected cluster. The detailed sampling procedures has been published in the 2015/2016 TDHS report [All women aged 15–49 who were usual residents or slept in the selected households the night before the survey were eligible for the interview. Anthropometric measurements (height and weight) of child and that of caretakers were taken at household level on the day of survey. Weight measurements were obtained with an electronic SECA 874 flat scale designed for mobile use and Height was measured with a Shorr board measuring board. Children younger than 24 months or shorter than 85 cm were measured lying down on the board (recumbent length) and standing height taken for older or taller children.The 2015/2016 TDHS dataset was downloaded from the DHS website after completing the registration and fulfillment of the conditions related to the protection of sensitive data. A total of 13,634 eligible women were identified from 1782 households sampled. Of interviewed women, 27% (2904) were adolescents aged 15–19 years. Analysis was conducted in a sample of women who had a live birth 5 years preceding the survey using STATA version 14 software accounting for survey design. A total of 8852 women (600 adolescent and 8252 non adolescent) with child anthropometric data and 6386 women (459 adolescent and 5927 non adolescent) with child birth weight data was analyzed.Variable were categorized as per DHS guideline with the normative category used as a reference group in regression analysis . Maternap-values at 95% significant level. b) Variable selection; from prior knowledge, child sex was considered as forced variable in the model and maternal employment was ignored as it was highly correlated with social economic status. One variable at a time from a list of candidate variables obtained from a univariate analysis was then included in the model with and without adjustment of forced variables to help understanding the effect of forced variables. The choice of the “best” predictor to be included in the model was then decided based on the change in exposure effect estimate. Each time a new variable was added in the model, evidence of confounding and multicollinearity was assessed by comparing the effect estimates and standard errors between the “univariate” and “multivariate” models estimates c) Multivariable model were fitted by adding explanatory variables that were removed from the models in step “b” one at a time to helps exploring their effect when added to the model in presence of other variables in the model. Variables that resulted into positive changes in the mean square error were then included in the model. The process was repeated until all variables that provided precise estimates of exposure variables were selected. The final model includes maternal age, marital status, maternal BMI, number of ANC visits, and child sex.Frequencies and percentage were used to presents results from descriptive analysis stratified by outcome variables. Univariate logistic regression models were fitted independently with stunting and birth weight as outcome variables while adjusting for socioeconomic and demographic characteristics such as age, height, weight (for both mother and children), maternal characteristics  and uptake of maternal care. As anticipated, logistic regression analysis was not done separately for each maternal age (adolescent and adult mothers) due to small sample size particularly in the adolescent population. A pooled analysis was done instead for each outcome variable with maternal age as a main exposure. A forward selection procedure was applied during modelling with variable selection based on change in exposure effect estimate. The procedure involved four main steps: a) descriptive analysis and preliminary investigations for association between variables while paying attention to the sizes of effects as well as Protocol, study procedures and questionnaires for DHS surveys was reviewed and approved by Institutional Review Board (IRB) and by the National Medical Research committee of Tanzania prior to the 2015 data collection. Before the interviews, written informed consent was obtained from all participants. For illiterate population, a written consent form was presented orally to them in the presence of legally authorized representative or witness such as a family member, friend, or someone independent of the research team. A parent or guardian provided consent for the child or adolescent to be involved in the study. Interviews were performed as privately as possible with each eligible respondent interviewed in the absence of another person.Overall, 14.3% of adolescents and 6.3% of non-adolescent mothers gave birth to low-birth-weight babies  was considered as a main exposure as explain in the method section. Overall, non-adolescent mothers have reduced odds of giving birth to LBW babies when compared to adolescent mothers in both univariate and multivariate analysis. The odds of delivering a LBW babies decreases from 0.41 (95% CI: 0.29–0.57) in crude analysis to 0.34 (95% CI: 0.22–0.50) in adjusted analysis   was significantly associated with childhood stunting  with children found in higher socioeconomic group having higher odds of being stunted compared to those in lower socioeconomic group. Children born with low birth weight were 2.4 times more likely to be stunted (95% CI: 1.80–3.20) compared to those born with normal birth weight. Female children were less likely to be stunted  when compared to male. Also, children whose age were beyond 1 year had 3 times high odds of being stunted as compared to those with less than 1 year. Further, maternal body structure was significantly associated with child stunting. Children born with overweight or obese mothers had reduced odds of being stunted  when compared to mothers with normal BMI  and stunting. Our findings showed that children who were born with LBW had two times high chance of being stunted compared to those born with normal weight. This is in line with the studies conducted in Rwanda, Indonesia and Ethiopia , 39. LBWWe found LBW was significantly associated with maternal age with adolescent mothers being at higher risk of giving birth to LBW babies as compared to non-adolescent mothers. Maternal ANC attendance and being divorced, separated or widowed were also showed significantly association with LBW. The findings also show stunting is not associated with maternal age even after controlling for socioeconomic status, maternal nutrition status and child characteristics . A multi-sectoral approach is needed in addressing child nutrition problems with teenagers ‘specific intervention that offer emotional support, and health education during pregnancies for improving immediate and later life child birth outcomes.Variability in availability of birth weight data might have biased the results since only 64% of live births had birth weight measurement. The study has a sample of 13,266 women of which only 2904 were adolescent mothers. The unequal sample size by maternal age might have affected the statistical power of the study as some of the estimates may be over or under-reported. Since the this was secondary analysis of the data, some important clues might be missing concerning the causal relationship of dependent factors and outcome. For example, the study revealed out that boys were more stunted than girls but the reasons behind this are incomprehensive. The detailed list of strength and weakness of the DHS dataset have been documented by Corsi et al. .The finding reflects the needs of a multi-sectoral approach in addressing child nutrition problems with teenagers ‘specific intervention that offer emotional support, and health education before and during pregnancies for better child birth outcomes. Stakeholders and policy makers are likely to use these findings for changing policies and designing of community related intervention that target adolescent and non-adolescent mothers.


Parental body mass index (BMI) is associated with pregnancy outcomes. But the effect of parental prepregnancy BMI on offspring conceived via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), especially the birth defect, remains to be determined. This study aimed to investigate the associations of parental prepregnancy BMI with neonatal outcomes and birth defect in fresh embryo transfer cycles.We conducted a retrospective cohort study including 5741 couples in their first fresh IVF/ICSI cycles admitted to Women’s Hospital, School of Medicine, Zhejiang University from January 2013 to July 2016. The primary outcome was birth defects, which was classified according to the International Classification of Diseases, 10th Revision. Secondary outcomes included preterm delivery rate, infant gender, birth weight, small-for-gestational age (SGA) and large-for-gestational age (LGA). Multilevel regression analyses were used to assess the associations of parental prepregnancy BMI with neonatal outcomes and birth defect.2 had higher odds of LGA than those with BMI < 25 kg/m2. The birth defect rate was significantly higher when paternal prepregnancy BMI ≥25 kg/m2 in IVF cycles  and maternal BMI ≥25 kg/m2 in ICSI cycles . For subcategories of birth defects, only the odds of congenital malformations of musculoskeletal system was significantly increased in IVF offspring with paternal BMI ≥25 kg/m2 . For twins, there was no significant difference among four groups, except for the lower birth weight of IVF female infants.In singletons, couples with prepregnancy BMI ≥25 kg/m2 is associated with higher incidence of LGA in IVF/ICSI singletons. Paternal prepregnancy BMI ≥25 kg/m2 was likely to have higher risk of birth defect in IVF offspring than those with BMI < 25 kg/m2, particularly in the musculoskeletal system. It is essential for overweight or obesity couples to lose weight before IVF/ICSI treatments.Parental prepregnancy BMI ≥25 kg/mThe online version contains supplementary material available at 10.1186/s12884-021-04261-y. Overweight and obesity are becoming one of the most important worldwide health issue. The prevalence of overweight and obesity has increased globally over the past decades . In ChinOverweight and obesity are associated with the risk of many diseases, such as hypertension, cardiovascular diseases, diabetes and cancer –4. In reIn addition, birth defect is a global health problem which can result in death or disability of offspring. A lot of studies had discussed different maternal or paternal factors, like advanced age, lifestyle, obesity and chronic diseases, which would improve the birth defect rate of natural pregnancy or pregnancy that does not distinguish between natural and assisted reproduction –17. SomeThe current study aimed to estimate the effects of parental prepregnancy BMI on the neonatal outcomes and birth defect of offspring via IVF/ICSI. To the author’s knowledge, this analysis is the first to investigate the association of paternal prepregnancy BMI with the birth defect risk of ART offspring. Analyses were also stratified by conventional IVF or ICSI to investigate potential ART procedures differences.This study was approved by the ethnic committee in Women’s Hospital, School of Medicine, Zhejiang University (reference: IRB-20200364-R) and all data were collected from the electronic medical record system in the department of Reproductive Medicine Center. Couples who underwent first IVF/ICSI fresh embryo transfer cycles with autologous oocytes from January 2013 to July 2016 were analyzed. The exclusion criteria were as follows:1) maternal age > 45 years; 2) couples with severe complication before pregnancy, such as diabetes, hypertension, heart or liver disease; 3) couples with a history of smoking or drinking; 4) couples underwent preimplantation genetic testing; 5) data were incomplete or incorrect in the database. A history of smoking was defined as a patient who smoked 1 or more cigarettes per day for at least the previous six months .2); group B ; group C ; group D .Prepregnancy weight and height of all couples were measured by a trained nurse. BMI was calculated as weight divided by squared height. All 5741 couples were divided into four groups based on the parental prepregnancy BMI according to the classification criteria of the World Health Organization: group A  into 9 subcategories. Two additional categories, ‘any birth defect’ and ‘multiple birth defects’, were used in our study. Any birth defect was defined as at least one subcategory of birth defects and multiple birth defects were defined as more than one subcategory of birth defects.Secondary outcomes included live birth rate, delivery method, preterm delivery rate, infant gender, birth weight, low birth weight (birth weight < 2500 g), macrosomia (birth weight ≥ 4000 g), SGA and LGA. Live birth was defined as at least one live infant born at 28 weeks or more of gestation. Delivery methods include cesarean section and vaginal delivery. Preterm delivery was defined as a delivery occurring before 37 gestational weeks. The definition of SGA was the birth weight less than the 10th percentile for the gestational age and sex. LGA was defined as weighing greater than 90th percentile for the gestational age and sex. The 2014 reference of Chinese infants from 28 to 44 gestation weeks was used as the reference in this study .Covariates included: parental age (in years), reason for ART , primary infertility or secondary infertility, duration of infertility (in years), number of oocytes retrieved, IVF or ICSI, number of two pronuclear (2PN) zygotes, number of embryos transferred.SPSS statistics 22.0 (IBM) was used for all statistical data analyses. All continuous variables, such as parental age, BMI and birth weight were presented as the mean ± SD and compared by means of analysis of variance. Categorical variables, such as live birth, LGA, SGA and birth defect, were presented as frequencies and percentages and compared by means of chi-square tests. Fisher’s exact test was used if the number of cycles or participants in one or more categories was less than five.Subgroup analyses was performed by the conventional IVF or ICSI and the singletons or twin delivery. Multilevel logistic regression was used to explore the effect of parental prepregnancy BMI on live birth, mode of delivery, infant gender, low birth weight, macrosomia, SGA, LGA and any birth defect, which were described as odds ratio (OR) with 95% confidence intervals (CIs). Multilevel linear regression analyses were used to investigate the association between parental prepregnancy BMI and birth weight, which was described as unstandardized regression coefficient (B) with 95% CIs. All analyses were adjusted for parental age, type of infertility, duration of infertility, ovulatory dysfunction and endometriosis, which were described as adjusted odds ratio (aOR) or adjusted regression coefficient (aB) with 95% CIs.2 and paternal prepregnancy BMI ≥25 kg/m2) according to paternal prepregnancy BMI to dig deeper into the effect of paternal prepregnancy BMI on the subcategories of birth defects for singletons conceived via IVF. Logistic regression was used to analyze IVF cycles separately. Analyses were adjusted for parental age, maternal BMI, type of infertility, duration of infertility, ovulatory dysfunction and endometriosis. P values < 0.05 was considered statistically significant and all tests were 2-tailed.Additionally, all IVF cycles was stratified into two groups  underwent IVF treatment and 1566 couples (27.3%) underwent ICSI treatment. The included couples delivered 2583 neonates . 1366 singletons and 952 twins have information about birth defect . There were significant differences in the proportion of primary infertility, ovulatory dysfunction, endometriosis and ART method across the parental prepregnancy BMI categories . No difference appeared across the BMI categories when comparing the proportion of diminished ovarian reserve, tubal factor, uterine factor, male factor and unexplained infertility.Table P = 0.022) when analyzing IVF cycles only. After adjustment for parental age, duration of infertility, type of infertility, women with ovulatory dysfunction and endometriosis, couples with maternal prepregnancy BMI ≥25 kg/m2 was associated with lower live birth rate compared with both parental prepregnancy BMI <25 kg/m2 .The IVF/ICSI treatment outcomes are summarized in Table SP < 0.05). No significant difference was observed for birth weight when considering all IVF or ICSI singletons. However, the birth weight of female newborns in IVF subgroup increased significantly with higher BMI categories, ranging from 3.17Kg (SD 0.42) in group A  to 3.35Kg (SD 0.45) in group D . LGA occurred more frequently in higher parental prepregnancy BMI categories, with the incidence of 16.1% in group B, 21.5% in group C and 20.0% in group D compared to 10.2% in group A for IVF subgroup and the incidence of 26.2% in group C and 31.8% in group D compared to 12.4% in group A for ICSI subgroup. No significant difference in gestational age, premature birth rate, low birth weight infant rate and SGA rate was observed among BMI categories.We analyzed the clinical data of 1534 singletons and 1046 twins Table . For sinFor twins, except for the birth weight of female newborns and the proportion of low birth weight in IVF subgroup, there was no difference among four BMI categories.2 had a trend towards an increased risk of cesarean section  and a two-fold increased risk of low birth weight infant  compared to couples with both parental prepregnancy BMI < 25 kg/m2. Couples with both parental prepregnancy BMI ≥25 kg/m2 had a three-fold increased risk of fetal macrosomia . Higher risk of LGA was observed for couples with maternal and paternal prepregnancy BMI ≥25 kg/m2, independent or combined, than both parental BMI < 25 kg/m2 . Female singletons from the couples with maternal prepregnancy BMI ≥25 kg/m2 had higher birth weight  than both parental BMI < 25 kg/m2, and similar trend was observed for couples with both parental prepregnancy BMI ≥25 kg/m2   and a three-fold higher risk of fetal macrosomia  compared to couples with both parental prepregnancy BMI < 25 kg/m2. Couples with maternal prepregnancy BMI ≥25 kg/m2 had a nearly three-fold higher risk of LGA , for couples with both parental prepregnancy BMI ≥25 kg/m2 a similar trend  was observed.Table 2 had lower birth weight 0.04) than both parental BMI < 25 kg/m2 , 6.98% for IVF offspring (n = 988) and 5.82% for ICSI offspring (n = 378). Regarding twins, the prevalence of any birth defect was 6.72% for all IVF/ICSI offspring (n = 952), 7.01% for IVF offspring (n = 742) and 5.71% for ICSI offspring (n = 210).Among 1366 singletons and 952 twins with information about birth defect, 155(6.69%) children were diagnosed as birth defect. Among all singletons, the prevalence of any birth defect was 6.67% for all IVF/ICSI offspring  compared to couples with both parental prepregnancy BMI < 25 kg/m2. For ICSI singletons, couples with maternal prepregnancy BMI ≥25 kg/m2 had a four-fold higher risk of any birth defect  compared to couples with both parental prepregnancy BMI < 25 kg/m2. No association was seen between parental prepregnancy BMI and any birth defect of twins.Table 2 and 314(31.8%) singletons with paternal prepregnancy BMI ≥25 kg/m2. Table 2 had a four-fold increased risk of congenital malformations of the musculoskeletal system  compared to couples with paternal prepregnancy BMI < 25 kg/m2. This association still remained after adjustment for confounding factors . No association was seen between paternal prepregnancy BMI and risk of other subcategories of birth defects.All singletons conceived via IVF were further grouped based on paternal prepregnancy BMI as follows: 674(68.2%) singletons with paternal prepregnancy BMI < 25 kg/mAs risk factors of poor reproductive condition, overweight and obesity are likely more common in infertile couples. Compared with spontaneous pregnancy, couples seeking ART treatments are more concerned about the live birth rate and the health of offspring. Our study explored the effect of parental prepregnancy BMI on the neonatal outcomes and birth defect in fresh autologous cycles, which may offer advice for improving the effectiveness of ART treatment.2 was associated with lower live birth rate in IVF cycles. This finding is consistent with several previous published studies [Despite no significant differences in the number of oocytes retrieved, 2PN rate and clinical pregnancy rate among four groups, maternal prepregnancy BMI ≥25 kg/m studies –25. Howe studies . Ozgun e studies .After analyzing the neonatal outcomes of 1534 singletons, we observed that the proportion of LGA is significantly different across four groups in both IVF and ICSI cycles, especially the sizable increase in group C and group D. It suggested that increased parental prepregnancy BMI is a risk factor of LGA. This association has been partly found in previous studies. A study by Anzola et al. concluded that the percentage of LGA was influenced by a high maternal BMI in IVF-FET cycles . A retro2. Those findings are consistent with previous studies demonstrating higher incidence of fetal macrosomia and cesarean section with raised female BMI underwent IVF/ICSI treatment [In this study, parental overweight or obesity was associated with the higher odds of fetal macrosomia. In the meanwhile, the incidence of cesarean section markedly increased with maternal prepregnancy BMI ≥25 kg/mreatment , 34–36. reatment –39. Womereatment . The mec2 compared with group A. Other associations between the neonatal outcomes and parental prepregnancy BMI which we found in singletons were disappeared in twins. The differences of outcomes between the singletons and twins had been discussed in several previous studies. A retrospective population-based study in Canada showed that the association of maternal obesity with adverse pregnancy outcomes in twins is weaker than that observed in singletons [Regarding the neonatal outcomes of twins, only the birth weight of female infants significantly decreased for couples with maternal prepregnancy BMI ≥ 25 kg/mngletons . Anotherngletons . The insngletons –44.Birth defect is the most important outcome in our study. The prevalence of any birth defect was 6.69% for all births in our study. It was higher than the birth defects rate (5.6%) published by National Health Commission of China in 2012. On the one hand, many factors which are common in infertile population may improve the risk of birth defects, such as advanced age, environment pollution exposure and genetic factors , 45, 46.In our study, we observed that parental prepregnancy BMI ≥25 kg/m2 was associated with a higher risk of any birth defect in IVF/ICSI offspring. Some published studies have explored the association between maternal BMI and different subcategories of birth defects. A meta-analysis of 18 studies investigated that women with obesity were more likely to an infant with neural tube defects , cardiovascular anomalies  and other structural anomalies than mothers with normal BMI . AnotherOn further subcategory analysis, we found that paternal overweight or obesity was associated with a higher risk of congenital malformations of musculoskeletal system. A rat model study proposed that impaired muscle growth at 8 wk. of age in offspring from obese fathers is driven by a decrease in GH secretion and IGF-I level . Some stThere are some limitations in our study. One is that the sample size was small, especially of the subgroup of twins or ICSI. It may prevent us from accurately assessing the impact of increased parental prepregnancy BMI on neonatal outcomes and birth defects. Another limitation is that the study is retrospective cohort study. Part of the information about birth defects was collected by nurse via telephone, which may introduce recall bias. We tried to reduce risk of bias by explaining in detail the definition of birth defects and repeatedly confirming whether there is a hospital diagnosis certificate. Additionally, there is little research on the relationship between paternal prepregnancy BMI and birth defects of offspring after IVF/ICSI at present. More studies about this issue must be conducted in the future.2 have higher risk of the incidence of congenital malformations of the musculoskeletal system. As a rare study investigating the effect of paternal prepregnancy BMI on the birth defects, our study could serve as a reference for further research. According to findings from our study and previous studies, couples planning to get pregnant should be advised to control their weight before pregnancy. Strengthening public health education about balanced diet and healthy lifestyle may contribute to the prevention of birth defect.In summary, our study indicates that parental prepregnancy overweight or obesity has adverse effect on the neonatal outcomes and birth defect in fresh autologous cycles. Increased parental prepregnancy BMI, independently or combined, improves the odds of LGA and birth defect in singletons. For couples underwent IVF treatments, paternal prepregnancy BMI ≥25 kg/mAdditional file 1: Table S1. The cycle outcomes compared by maternal and paternal prepregnancy BMI.Additional file 2: Table S2. Associations between parental prepregnancy BMI and birth weight of IVF female newborns in multilevel linear regression analyses.


Does prenatal exposure to antipsychotics increase the risk of preterm birth, small for gestational age, attention-deficit/hyperactivity disorder (ADHD), or autism spectrum disorder (ASD)?In this cohort study of 411 251 mother-child pairs, there was not an increased risk of ADHD, ASD, preterm birth, and small for gestational age with prenatal use of antipsychotics. Maternal psychiatric disorders were associated with a significantly increased risk of ADHD and ASD, but not with preterm birth or small for gestational age in neonates.The findings of this study suggest that there is no association between prenatal exposure to antipsychotics and ADHD, ASD, preterm birth, and small for gestational age; however, underlying maternal psychiatric disorders may be associated with the risk of ADHD and ASD in children. The risk of birth and neurodevelopmental complications with prenatal exposure to antipsychotics is unclear.To evaluate the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems.This population-based cohort study included children born between January 2001 and January 2015 with follow-up to December 2019 who were identified by the Hong Kong Clinical Data Analysis and Reporting System. Pregnancies with maternal antidepressant/lithium exposure were removed. Primary analyses compared gestationally exposed and gestationally nonexposed individuals with propensity score fine stratification. Additional analyses included gestationally exposed individuals vs those with past exposure and a sibling-matched analysis to evaluate the effect of confounding by indication.Prenatal antipsychotic exposure.Preterm birth , small for gestational age , and first diagnosis of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children.The cohorts included 333 749 mother-child pairs for ADHD  and 411 251 pairs for ASD, preterm birth, and small for gestational age analyses . There were 13 196 children (3.95%) with a diagnosis of ADHD, 8715 (2.12%) with ASD, 33 891 (8.24%) preterm, and 7009 (1.70%) who were small for gestational age. The weighted hazard ratio (wHR) was 1.16  for ADHD and 1.06  for ASD, while the weighted odds ratio (wOR) was 1.40  for preterm birth and 1.36  for small for gestational age when comparing gestationally exposed with gestationally nonexposed individuals. Additional analyses showed no association when comparing gestationally exposed individuals with those with past exposure  and in a sibling-matched analysis .In this cohort study, the findings did not suggest that prenatal antipsychotics exposure increased the risk of ADHD, ASD, or small for gestational age. In the primary analysis, there was a small increased risk of preterm birth, but additional analyses comparing gestationally exposed individuals with those with past exposure and comparing gestationally exposed with gestationally nonexposed siblings did not support an increased risk. Given the benefits of treating psychosis during pregnancy, our findings do not support a recommendation for women to discontinue receipt of their regular antipsychotic treatment during pregnancy. This cohort study examines the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems. Recent studies found that antidepressant use during pregnancy may be associated with an increased risk of neurodevelopmental disorders and birth complications, including autism spectrum disorders (ASDs),4 attention-deficit/hyperactivity disorder (ADHD),5 preterm birth,6 and small for gestational age.6 However, these associations may be a consequence of confounding by indication of antidepressants and/or genetic factors.9Antipsychotics, including first-generation and second-generation antipsychotics, are increasingly prescribed for pregnant women10 However, this follow-up time was not long enough to capture outcomes like ADHD, for which a diagnosis is often deferred until a child is age 5 or 6 years.11 Thus, any association between the risk of neurodevelopmental disorders and antipsychotic use in pregnancy remains uncertain. Moreover, a systematic review that included studies published up to 2015 reported an increased risk of preterm birth and small for gestational age12; however, most of the included studies had limited adjustment for confounders. Furthermore, a later study found contradictory results; therefore, it generated further uncertainties as to these associations.13 Randomized clinical trials were not able to evaluate the safety of antipsychotic use during pregnancy because pregnant women are typically excluded from these studies. Thus, an observational study is a practical approach to investigate these associations.14 This study explored the associations between prenatal antipsychotic exposure and birth and neurodevelopmental complications  in children. Besides using a propensity score (PS) approach to address measured confounding from pregnancy and maternal characteristics, we also applied a sibling-matched analysis to account for unmeasured genetic and environmental factors that could be shared among the siblings; negative control analyses further supported the study conclusions.There are limited studies about the association between the use of antipsychotics in pregnancy and the risk of neurodevelopmental disorders in children. A UK study with 2 to 3 years of follow-up found no association between antipsychotic use in pregnancy and the risk of neurodevelopmental disorders in infants.We conducted a retrospective cohort study using the Clinical Data Analysis and Reporting System (CDARS), which contains the electronic health records of all residents (more than 7.4 million) from public hospitals and ambulatory clinics in Hong Kong.15 Data from CDARS have been used for various pharmacoepidemiological studies,18 including studies on maternal antipsychotics use1 and the risk of neurodevelopmental disorders because of prenatal medication use.7 Study protocols were approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster for CDARS database research. Informed consent was waived as this study did not have patient contact and used anonymized data.7 Children without valid mother-child linkage and incomplete birth information  were excluded.The study cohort included all pregnant episodes of females aged 15 to 50 years old who delivered a live birth between January 1, 2001, and December 31, 2015. Preterm birth and small for gestational age were identified and recorded at the delivery date. For ASD, all children had at least 3 years of follow-up by the end of the study period . For ADHD, we limited inclusion to deliveries between January 1, 2001, and December 31, 2013, to have at least 6 years of follow-up by the end of the study period . We defined a valid mother-child linkage as an exact match of mother and child patient identification numbers and delivery date, which are linked permanently and immediately after delivery. As a result, this linkage is highly accurate.7 To identify the start and 3 trimesters of pregnancy, the last menstrual period (LMP) was estimated by date of delivery minus gestational age at birth. The pregnancy period was defined as the period between the LMP and delivery date ; (2) those with mothers who used antipsychotics before pregnancy but whose mothers discontinued receipt of treatment when pregnant (past exposure); and (3) those who never used antipsychotics either before or during pregnancy (never exposed), within which subgroup analyses further classified into (1) never exposed with psychiatric disorders and (2) never exposed without psychiatric disorders  those whose mothers did not use antipsychotics during pregnancy , within whom we further specified a subgroup as gestationally nonexposed with psychiatric disorders ,19 ASD (ICD-9-CM: 299), preterm birth  and small for gestational age . Attention-deficit/hyperactivity disorder and ASD are typically diagnosed clinically in Hong Kong in accordance with the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5).21 Participants were followed up until the outcome onset, which was the end of the study period or death.Study outcomes were ADHD , and socioeconomic status.Covariates were identified for confounding adjustment. These variables included maternal age at delivery, calendar year at delivery, birth hospital, infant’s sex, parity, maternal underlying medical conditions  with a 95% CI were estimated to study the associations for neurodevelopmental outcomes using Cox proportional hazard regression models. Odds ratios (ORs) with a 95% CI were used to estimate the associations for birth outcomes by logistic regression models. Propensity score (PS) fine stratification weighting was used to address the differences in baseline covariates. The PS, the probability of receiving treatment that is conditional on the observed characteristics at baseline, can be applied to account for confounding effects in pharmacoepidemiology studies.. An increased risk of outcomes in the children of mothers among those with a past exposure indicates confounding by indication, as the infant was not exposed to antipsychotics. Similarly, gestationally exposed individuals were compared with those with past exposure to assess whether there was a difference in the risk of study outcomes. To assess the role of maternal psychiatric disorder, we restricted comparison cohorts to those never exposed. If maternal psychiatric disorder is associated with risk of outcomes in children, this introduces the possibility of confounding by indication. To focus on the population of women who were most clearly at risk for treatment with antipsychotics during pregnancy, we also compared gestationally exposed individuals with gestationally nonexposed individuals with psychiatric disorders. A sibling-matched analysis was conducted to control for shared genetic and social confounding factors at the family level. Stratified Cox/logistic regression with a separate stratum for each family identified by the mother’s unique identification number was used. Only inconsonant sibling pairs for maternal antipsychotic use and study outcomes could contribute to the estimates.We conducted several additional analyses to evaluate the effect of confounding by indication. We compared those with a past exposure with those never exposedP value of <.05 was considered statistically significant in all statistical analyses. SAS, version 9.4 (SAS Institute) and Stata, version 15 (StataCorp), were used for data management and analysis.Subgroup analyses and sensitivity analyses were conducted to test the validity of the initial analyses  or ORs (wORs) were 1.16  for ADHD, 1.06  for ASD, 1.40  for preterm birth, and 1.36  for small for gestational age , ASD , preterm birth , or small for gestational age . Results suggested no difference in the risk of all outcomes when comparing gestationally exposed vs past exposure.The risk of ADHD , preterm birth , or small for gestational age  was statistically significantly increased in the maternal past exposure group vs those never exposed. There was no evidence to support an increased risk of ASD .When the analysis was restricted to mothers who had never used antipsychotics, the risk of neurodevelopmental disorders was higher in mothers with psychiatric disorders . There is no evidence to support the risk of preterm birth  or small for gestational age .The sibling-matched analysis contained 23 308 mothers with 48 275 children in the ADHD cohort and 40 756 mothers with 85 257 infants in the ASD, preterm birth, and small for gestational age cohort. Eighteen of 160 exposed (11.25%) and 1906 of 48 115 unexposed siblings (3.96%) received a diagnosis of ADHD; 6 of 215 exposed (2.79%) and 1630 of 85 042 unexposed siblings (1.92%) had ASD; 33 of 215 exposed (14.88%) and 9270 of 85 042 unexposed children (10.90%) were preterm; and 4 of 215 exposed (1.86%) and1598 of 85 042 unexposed children (1.88%) were small for gestational age. There was no significantly increased risk of ADHD , ASD , preterm birth , or small for gestational age  in siblings of mothers who were gestationally exposed to antipsychotics compared with gestationally nonexposed .Most exposed women had long-term antipsychotic treatment throughout the entire pregnancy period; the evidence did not support any association between gestational antipsychotic exposure at different trimesters and the risk of study outcomes . InterprFrom the primary analysis, we can only rule out more than a 1.61-, 1.60-, 1.75-, and 2.14-fold higher risk for ADHD, ASD, preterm birth, and small for gestational age, respectively, between children with and without prenatal exposure to antipsychotics. However, considering the analyses of the negative control , siblingHowever, among pregnant women who were never exposed to antipsychotics, children born to mothers with psychiatric disorders had a higher risk of neurodevelopmental disorders (ASD and ADHD), but not negative birth outcomes  compared with those with mothers without psychiatric disorders. Furthermore, the risk was the same for unexposed siblings and exposed siblings. These results suggest that maternal psychiatric disorders are associated with a higher risk of neurodevelopmental disorders rather than gestational exposure to antipsychotic drugs. Moreover, gestational exposure to antipsychotic drugs is unlikely to pose a significant risk of preterm birth and small for gestational age in children. Although our estimates had relatively wide intervals, given the benefits of antipsychotic treatment, our findings do not support a recommendation for women to discontinue receipt of their regular antipsychotic treatment during pregnancy.14 Previous studies have usually addressed confounding by health and lifestyle factors and concomitant medication using simple matching methods.13 This study not only addressed these limitations, but has also expanded on them by using several advanced approaches  to address potential confounding factors and strengthen the reliability of our conclusion.Previous studies were limited by including relatively low numbers of women who were prescribed antipsychotics during pregnancy, inadequate duration of follow-up, inadequate mother-child record linkage, and poorly specified exposure time in the study design.10, who focused on general developmental disorders in children and had a limited follow-up time.10 Petersen et al10 and our study found no evidence to support an association between antipsychotic medication use during pregnancy and an increased risk of neurodevelopmental disorders in children. Our results are also consistent with another Canadian population-based study13 that found no evidence to support an increased risk of preterm birth or small for gestational age in children with antipsychotic exposure during pregnancy. Petersen et al10 and Vigod et al13 did not report any difference between the antipsychotic classes or sex of the child.13 However, our study shows that antipsychotic use during pregnancy was not associated with an additional risk of ADHD, ASD, preterm, or small for gestational age compared with those with a past exposure or those never exposed (with and without psychiatric disorders). It is important in future studies to identify whether a pregnant woman with active psychotic disorders would benefit from taking antipsychotics, including effective control of psychotic symptoms and minimal adverse effects to herself, offspring, and her family.Our findings are consistent with those of Petersen et al25; clinicians should observe on a case-by-case basis. Major adverse effects can occur if ongoing treatment is discontinued abruptly or antipsychotics are withheld during pregnancy. This study’s findings provide data to guide clinicians in decision-making.Our study results suggest that if pregnant women have a clinical need for antipsychotics (including first-generation and second-generation antipsychotics), clinicians should not stop administering regular treatment because of a fear of birth outcomes with ADHD, ASD, preterm birth, and small for gestational age. There has been a lengthy debate about a possible association between in-utero exposure to psychotropic medications and neurodevelopmental disorders or birth complications in children. Patients and clinicians have encountered difficulties in treating women with severe affective and psychotic disorders when trying to conceive and during pregnancy. Previous studies found that parents with psychiatric disorders are more likely to have offspring with neurodevelopmental disorders, such as ASD14Our study has several strengths. To our knowledge, this is the first study to use a population-based database to identify the association between prenatal antipsychotics exposure and the risk of ADHD or ASD in children separately with adequate follow-up time. We also evaluated the association using stratification by drug class and timing of exposure. To identify the exposures, we used electronic dispensing and prescribing records, which are free from recall bias. Moreover, we used complementary negative control analyses and sibling-matched analyses to address the possibility of confounding by indication. Deterministic linkage records between mothers and children, as well as explicit gestation age records, were available in CDARS, which enhanced the accuracy and reliability of our findings.26Second, poor antipsychotic adherence among patients with psychiatric disorders is common,27 and we cannot confirm whether patients took the prescribed medication, which may affect the accuracy of the results. We addressed the use misclassification using at least 2 prescriptions or a 56-day coverage time of prescriptions records and 1-week and 2-week prescription extension in the sensitivity analyses, which had similar results to our primary analyses. Third, CDARS is not primarily used for research purposes. Factors that may affect the risk of study outcomes, such as body mass index , smoking, and alcohol consumption status are not recorded in CDARS. However, we used a complementary negative control and sibling-matched analyses, which are unlikely to affect the interpretation of our findings. Fourth, as analyses were conducted using Hong Kong population data, it is unclear whether the results are generalizable. Although our study results are consistent with previous western studies,13 future research should be conducted in other settings. Fifth, the data extraction for this study was restricted based on the data minimization principle; therefore, we only have the relevant variables as presented in this study. Information on the indications for nonspontaneous cases was not available in the data set. Thus, we were unable to conduct the analysis on other birth defect outcomes. As suggested in a recent review,28 further studies on birth defects or malformation should be conducted. Lastly, large samples with adequate statistical power are necessary for sibling-matched analyses.29 Although we included all Hong Kong sibling samples, the sample size has insufficient power to detect small differences. Also, as exposed patients were limited, we lacked adequate power for a dose-response analysis of each drug.There are also several limitations. First, CDARS only includes public health care medical records; data from private hospitals and medical practitioners cannot be captured. However, children with neurodevelopmental disorders require comprehensive long-term treatment; thus, in Hong Kong, they usually receive care from the public sector.25 clinicians should inform individual patients about the benefits and potential risks of using antipsychotics during pregnancy.This study’s findings do not suggest an association between prenatal exposure to antipsychotics and the risk of ADHD, ASD, preterm birth, and small for gestational age. Given that maternal psychiatric disorders may increase neurodevelopmental disorder risk in children,


KATP) variants predict the risk of increased Apo B concentration (≥ 80 mg/dL) and related ASCVD remain less clear. We recruited 522 subjects with elevated Apo B concentration (≥ 80 mg/dL) and 522 counterpart subjects (< 80 mg/dL) from South China to assess the associations of KATP variants  with the risks of increased Apo B serum concentration (≥ 80 mg/dL), carotid artery stenosis (CAS) ≥ 50% and new-onset ischemic stroke (IS). Our results showed that only KATP SNP rs11046182 (GG genotype) was associated with increased risk of Apo B ≥ 80 mg/dL  and CAS ≥ 50% . After median 50.6-months follow-up, subjects carrying GG genotype of rs11046182 were associated with higher risk of new-onset IS . Further, the exosome-derived microRNAs (exo-miRs) expression profile was identified by next-generation sequencing. 41 exo-miRs were significantly differentially expressed under cross-talk status between high Apo B level (≥ 80 mg/dL) and KATP rs11046182. Our study demonstrated that KATP variant rs11046182 was associated with higher risks of elevated serum Apo B levels and its related ASCVD, and the possible mechanism was related to specific exo-miRs expression profile of KATP rs11046182.Serum concentration of apolipoprotein B (Apo B) is causally associated with arteriosclerosis cardiovascular disease (ASCVD) risk. Whether ATP-sensitive potassium channels ( Apolipoprotein B (Apo B) is the major protein constituent of low-density lipoprotein cholesterol (LDL-C). Increased serum level of LDL-C is recognized to be an independent risk factor for atherosclerotic-related events , such asKATP) plays as essential well-fidelity metabolic sensors, and also as an important end effector of ischemic preservation, indicating that KATP couples metabolic abnormalities to protection against ischemic-related injury. This also emphasizes KATP as novel targets for prevention and treatment of ASCVD. The structure of KATP is large heteromultimeric protein complex, consisted of four inwardly-rectifying potassium channel subunits  and four sulfonylurea receptor subunits . The Kir6.x pore-forming subunits are encoding respectively by KCNJ8 (Kir6.1) and KCNJ11 (Kir6.2)  while SURx regulatory subunits are respectively by ABCC8 (SUR1) and ABCC9 (SUR2) . The subunit constitution of KATP possibly remodel with different physiological and pathological circumstances, involving in substitute splicing of these coding genes as mentioned above, which can result in different subunits being functional in different status. The KATP has extremely high genetic diversity. KATP mutations were not only correlated with serum lipid disorder   –6 and AS(HDL-C)] , 8 but aeiotropy .KATP variants) to phenotype (elevated Apo B serum levels) remain elusive. In present study we investigate possible associations of KATP variants with the risks of increased Apo B serum levels (≥ 80 mg/dL) and ASCVD  in South China, and identify the plasma expression profile of exo-miRs among subjects under specific genotype (KATP variants)-phenotype (Apo B ≥ 80 mg/dL) correlations.The occurrence and development of elevated Apo B serum concentration and its related ASCVD arises from complex interaction between genetic and environment factors. The exosome-derived microRNAs (exo-miRs) are one of the main classes of non-coding RNAs, and play a critical role as bridge that links genetic and environment factors. Exosomes are important extracellular vesicles with lipid bilayer membrane, and carry cell-specific medium for mediating intercellular communication, especially microRNAs (miRs). The miRs are a class of small (about 22-25 nucleotides long) and endogenous single-stranded RNAs, with an established function of regulating genes at transcriptional and post-transcriptional steps. The exo-miRs take part in almost every physiological or pathological processes ranging from elevated Apo B level to ASCVD. However, the circulating expression profile of exo-miRs and its effect in the process from genotype (P<0.001), as shown in P>0.05), as shown in Participants with or without higher Apo B serum concentration (≥ 80 mg/dL) showed significant differences on serum concentration of TRIG, TC and LDL-C  , as shown in Only KATP rs11046182 was also correlated with elevated CAS ≥ 50% risk  while rs78148713 and rs147265929 were not , as shown in KATP rs145456027 will not be estimated due to possible bias.KATP rs11046182 were correlated with elevated new-onset IS risk  via a median follow-up of 50.6 months, as shown in Subjects carrying GG genotype of P>0.05) between the two genotypes (AA+GA vs. GG) of KATP rs11046182 among subjects with increased Apo B serum concentration (≥ 80 mg/dL).As shown in P < 0.05 as threshold cutoff to exclude the low expression of exo-miRs, 41 exo-miRs were then found to be obviously DE between the two genotypes (AA+GA vs. GG) of rs11046182, as shown in e.g., 193a-5p and 193b-5p), miR-320 , and miR-378 . In addition, only 6 of the 41 DE exo-miRs were found to be obviously DE between the two genotypes (AA+GA vs. GG) of rs11046182 in participants with decreased serum Apo B levels (< 80 mg/dL). 2 exo-miRs (miR-31-5p and miR-497-5p) were up-regulated and 4 exo-miRs  were down-regulated in subjects carrying GG genotype of rs11046182 compared to those with AA+GA genotype, as shown in KATP rs11046182.A total of 615 exo-miRs were detected by implementing strict data quality control. Using reads per million (RPM) values < 10, and e.g., protein, ion, DNA, enzyme and ATP) and activity regulation .Three terms of GO enriched categories analysis was carried out for those candidate target genes (CTGs) regulated by the top 10 DE exo-miRs, as shown in e.g., endocytosis, signaling pathways of PI3K-Akt, MAPK and Ras, and protein processing in endoplasmic reticulum, etc), metabolism-related diseases , and organismal systems , as shown in KEGG analyses of top 10 DE exo-miRs showed that the top 30 enrichment pathways were mainly associated with metabolic pathways, environmental information/genetic information processing  subjects with GG genotype of rs11046182, as shown in KATP SNPs with elevated Apo B serum concentration  Apo AI, KATP variants . Interestingly, in this study there was no significant difference on body mass index (BMI), SBP, P2hBS, hypersensitive C-reactive protein (HsCRP) in subjects with or without higher Apo B serum levels (≥ 80 mg/dL) (2), SBP (> 130 mmHg), P2hBS (> 7.8 mmol/L), HsCRP (> 3 mg/L) were higher than normal especially in higher Apo B level group, which was also complicated with higher serum levels of TRIG, TC and LDL-C. On the other hand, subjects with GG genotype of KATP rs11046182 were indeed related to higher serum levels of P2hBS and HsCRP besides high Apo B serum levels (KATP rs11046182 sustain a status of metabolic disorders and inflammation. Insulin resistance (IR) acts a major role in the pathogenesis of this process. Indeed, a previous study reported that KATP rs5219 was correlated with IR [KATP variants (rs1799854 and rs1799859), the effect was not existed in Caribbeans (rs5219) [To the best of our knowledge, this is the first comprehensive study to examine the possible associations of 80 mg/dL ) and ASC0 mg/dL) , but itsm levels . It is s with IR . The locKATP rs61688134 was associated with AMI among Italians [KATP rs1799854 was with stroke in diabetic Polish [KATP rs11046182 may be an optimal marker of elevated risk of Apo B related ASCVD.Cholesterol-rich, Apo B-containing lipoproteins are now widely accepted as the most important causal agents of ASCVD . CAS no Italians  while KAKATP rs11046182) to phenotype (Apo B ≥ 80 mg/dL) is still largely unclear. Our results firstly characterized the circulating expression profile of exo-miRs  run through the whole pathological processes from the accumulation of cardiovascular risk factors  to the occurrence of atherosclerotic-related events and even death. In addition, there were another four exo-miRs as follows: miR-1291, miR-4488, miR-4726-5p, and miR-7704. However, the relationships of the 4 exo-miRs with cardiovascular disease are still unknown, needing further research.The interplay between genetic and environment factors causes the development of dyslipidemia and related ASCVD. The circulating exo-miRs, as bridge that links genetic and environment factors, play an essential effect in physiological or pathological processes from elevated Apo B level to ASCVD. However, the expression profile of exo-miRs in biological process from genotype , iiR-17-3p , miR-210iR-17-3p  and miR-iR-17-3p  were sigiR-17-5p , miR-210iR-17-5p , miR-218iR-17-5p , miR-422iR-17-5p , miR-497iR-17-5p , miR-442iR-17-5p , miR-208iR-17-5p , miR-320iR-17-5p  and miR-iR-17-5p  reportediR-17-5p  who repoiR-17-5p  was relaiR-17-5p . Under te.g., glucose/lipid/protein metabolism, etc) under disease status  [To further evaluate the roles of exo-miRs under interaction between genetic and environment factors, GO and KEGG analysis for the top 10 DE exo-miRs related 1156 CTGs were carried out among elevated Apo B ≥ 80 mg/dL subjects with GG genotype of rs11046182. GO analyses  showed tand T2D) . These rKATP mutations with the risk of increased Apo B concentration (≥ 80 mg/dL) and ASCVD in South China, and characterize the circulating expression profile of exo-miRs under interplay status between genetic (KATP variants) and environmental (elevated Apo B serum levels) factors, intimating that the possible epigenetic modification effect of exo-miRs in development of dyslipidemia and its related atherosclerotic vascular events. The major disadvantages of the study were as follows: Firstly, due to the sample size (N=1044), large-scale subgroup analysis based on Apo B serum level (< 80 mg/dL vs. ≥ 80 mg/dL) and genotypes (GG vs. AA + GA) of KATP rs11046182 will help to further verify the hypothesis that the occurrence and development of increased Apo B serum concentration and its related ASCVD arises from complex interaction between genetic and environment factors. Secondly, Bonferroni correction was executed to correct significance thresholds, but false-positive results may still occur. Thirdly, a rudimentary bioinformatics analysis was only executed, and the non-specific effect and miss-distance effect may exist, owing to lack of verification at the cellular and molecular levels. Therefore, the results of the study should be interpreted carefully.The major advantage of the research was firstly evaluate the associations of KATP rs11046182 was correlated with increased risks of elevated serum Apo B concentration (≥ 80 mg/dL) and ASCVD, suggesting that this variant is a prospective clinical translational target for precision prevention and early-detection strategies for those disorders, and needs further verification by prospective studies with large sample sizes in different ethnic populations. The potential molecular regulatory may be involved in these significantly DE exo-miRs  and metabolic related pathways  under those cross-talk status, warrant further research.2) of estimated glomerular filtration rate (eGFR), (4) or (and) any other medical disorders or drugs that could result in kinds of dyslipidemia as mentioned above. Participant’s medical records were assembled via interviewing patient himself and physicians as well as reviewing of medical records. Standard analytical methods were performed to assess blood biochemical indexes on admission to the study. Bilateral carotid ultrasound was executed on enrollment to the study referring to relevant recommendations [The ethics approval (K-2017-043-02) of this study was granted from Guangzhou First People’s Hospital, South China University of Technology. The present study was conducted in consistent with the Helsinki Declaration and the ethics guidelines of the institutional. A total of 522 participants with increased Apo B serum levels (≥ 80 mg/dL) and 522 counterpart subjects (< 80 mg/dL) were enrolled to the research from South China. All participants with blood lipid disorder were newly identified referring to guidelines  as follondations .KATP single nucleotide polymorphisms (SNPs)  were genotyped with the MassARRAY (Sequenom) system as previously described methods [KATP variants based on the KATP gene sequence information in GenBank  . The SNPs determination accuracy was 100% for each variant of KATP.Four  methods . Primer 1521T>G) . The spePrimary follow-up end-point was new-onset IS. All stroke subjects were survivors of IS, and determined by magnetic resonance image and/or computed tomography scanning of the brain referring to relevant guidelines . Subjecthttp://www.mirbase.org).Another total of 10 participants from South China with only elevated serum Apo B concentration (≥ 80 mg/dL) were newly enrolled to the study . The Cox proportional hazards regression model was carried out to access the crude hazard ratios (HRs) for event free analysis of new-onset IS, adjusted HRs and their 95% confidence intervals (CIs) with corrections for potential covariates. A P value < 0.05 is statistically significant. All probabilities are two-tailed.The SPSS software  was used for statistical analyses. The Hardy-Weinberg equilibrium was evaluated for control subjects as shown in P value less than 0.05. Gene Ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed with the Fisher’s exact test and χ2 test, and followed by false discovery rate (FDR) correction. A corrected P value < 0.05 was performed to choose significant GO categories and KEGG pathways.The differentially expressed (DE) exo-miRs in increased Apo B levels (≥ 80 mg/dL) subjects with different genotypes (GG vs. AA+GA) of rs11046182 were analyzed with edgeR software referring to the criteria of |log2 (Fold Change)| no less than 1 and Supplementary MaterialSupplementary FiguresSupplementary Tables


Preterm birth is the leading cause of neonatal deaths in low middle-income countries (LMICs), yet there exists a paucity of high-quality data from these countries. Most modelling estimates are based on studies using inaccurate methods of gestational age assessment. We aimed to fill this gap by measuring the population-based burden of preterm birth using early ultrasound dating in five countries in South-Asian and sub-Saharan Africa.We identified women early in pregnancy  by home visits every 2-3 months  in 5 research sites in South-Asia and sub-Saharan Africa between July 2012 and September 2016. Trained sonographers performed an ultrasound scan for gestational age dating. Women were enrolled if they were 8-19 weeks pregnant on ultrasound. Women <8 weeks were rescheduled for repeat scans after 4 weeks, and identified women were followed through pregnancy until 6 weeks postpartum. Site-specific rates and proportions were calculated and a logistic regression model was used to predict the risk factors of preterm birth.Preterm birth rates ranged from 3.2% in Ghana to 15.7% in Pakistan. About 46% of all neonatal deaths occurred among preterm infants, 49% in South Asia and 40% in sub-Saharan Africa. Fourteen percent of all preterm infants died during the neonatal period. The mortality was 37.6% for early preterm babies (<34 weeks), 5.9% for late preterm babies (34 to <37 weeks), and 1.7% for term babies (37 to <42 weeks). Factors associated lower gestation at birth included South-Asian region (adjusted mean difference (Adj MD) = -6.2 days, 95% confidence interval (CI) = -5.5, -6.9), maternal morbidities , multiple pregnancies , adolescent pregnancy  and lowest wealth quintile .Preterm birth rates are higher in South Asia than in sub-Saharan Africa and contribute to 49% and 40% of all neonatal deaths in the two regions, respectively. Adolescent pregnancy and maternal morbidities are modifiable risk factors associated with preterm birth. Preterm birth is a leading cause of death in children under five years of age worldwide. Approximately 14.8 million babies were born preterm in 2014, accounting for 10.6% of all live births globally . GloballThe cut off for preterm birth defined above is, to an extent, arbitrary. Recent studies show that neonatal outcomes vary within the term group, with greater risks of adverse outcomes associated with early-term neonates than those born at 40 weeks of gestational age ,6. The “The preterm birth syndrome involves a complex interplay between various sociodemographic, environmental, and biological factors. Some of the factors identified in the literature include black sub-Saharan African ancestry, family history, prior history of preterm births and an interpregnancy interval of fewer than six months ,15. OtheWhile several studies have showcased global estimates and levels of preterm births, there is a general agreement about the gaps in existing data, particularly from South-Asian and sub-Saharan Africa. One important reason for this disproportionate reporting of data are absent or incomplete registries . Even thThe Alliance for Maternal and Newborn Health Improvement (AMANHI) gestational age group conducted a multi-country, population-based prospective cohort study to evaluate the diagnostic accuracy of simple methods for gestational age assessment . These methods were compared with gestational age calculated from early pregnancy ultrasound scans. The study protocol was previously published .We conducted a study in five community sites in South-Asia , sub-Saharan Africa  between July 2012 and September 2016. The detailed methods for enrollment and follow up are described elsewhere [We measured only the crown-rump length (CRL) if the pregnancy was less than 14 weeks (CRL<95mm), both biparietal diameter (BPD), and femur length (FL) if more than 14 weeks, and all three if within the 14th week. Thus, we conducted three measurements for each biometric parameter. We promptly referred women with major abnormalities or intrauterine fetal deaths to health facilities for appropriate management. The preterm birth rate was defined as all live births before 37 completed weeks of gestation divided by the total number of live births. Early to moderate preterm birth rate was defined as live births before 34 completed weeks of gestation, divided by the total live births. Small for gestational age was defined as newborns who were less than 10th centile for their gestational age using INTERGROWTH criterion .We established a birth notification system to capture birth outcomes as close to birth as possible, which included active surveillance, reporting by family members and key informants. All live births were then followed till 28 days of life to ascertain vital status. In case mortality was recorded, we conducted a detailed verbal autopsy interview after a culturally appropriate mourning period.Data were collected on paper and entered electronically at all sites except Zambia, where filled forms were scanned using TeleForms Software . Sites shared data to WHO quarterly for quality assurance and data monitoring. Any inconsistencies were flagged and resolved in consultation with data managers and investigators from the sites.P value of ≤0.10 at the univariate model and the site. In the analysis on the risk factor of preterm birth, we used different hierarchical models to obtain adjusted odds ratios (ORs) [Logistic regressions were performed to examine the association of gestational age and neonatal mortality and identify risk factors of preterm birth. A multivariate model was adjusted for variables with a os (ORs) . We calcEthical approval was obtained from WHO Ethical Review Committee (ERC) and all site ERC’s. Fieldworkers obtained consent from pregnant women in their local or preferred language.Of 13 814 women who had an ultrasound for gestational age assessment, 11 662 (84%) were enrolled. Of them, 10 763 (92%) women were followed up till birth. There were 10 581 live births registered in the study, of which 9974 were included in the analysis . Vital sAmong the 9974 live births across five sites, preterm birth rates ranged from 3.2% in Ghana to 15.7% in Pakistan  showed that the 95% limits of agreement ranged from -35.2 to 39.1 days  = 18.95)  resulted in neonatal deaths   was 62.2% (adjusted odds ratio (aOR) = 108.2, 95% confidence interval (CI) = 52.1, 224.1; South-Asia aOR = 162.0, 95% CI = 61.5, 427.7; sub-Saharan Africa aOR = 65.7, 95% CI = 17.8, 242.2). Risk of neonatal mortality in moderate preterm infants (32 to <34 weeks) was 20.8% , and the duration was shorter by 6.2 days in South-Asian sites than in sub-Saharan African sites (adjusted mean difference (aMD) = 6.2 days, 95% CI = 5.5, 6.9)  showed consistent results , many of which could have survived in high-income countries (HIC). In HIC, more than 90% of preterm babies born <28 weeks survive, while in LMICs, they die in the first few days . These fAssessing accurate gestational age is the first step to identify preterm birth and providing effective measures. In our study, regional differences in the burden of preterm birth disappeared when we used LMP to calculate gestational age. This points towards measurement error of using LMP to estimate gestational age and can be the reason for inconsistencies reported previously in the literature . In our Our study highlighted the importance of ensuring women with multiple gestations to be identified early by ultrasound and checked for any potential risk for PROM and other obstetric complications. In addition, comprehensive reproductive history, such as women’s previous history of preterm birth and stillbirths, needs to be examined for recurrent preterm birth. Prevention and diagnosis of maternal morbidity such as pre-eclampsia will help reduce preterm labour. All pregnant adolescents, especially with multiple gestations, should receive appropriate and timely antenatal care, including contraception use and health education activities. Poverty was a risk factor for preterm birth in our study. Lower socioeconomic status, in general, continues to influence developmental delay at two years of age for neonates born early and poor . ProgramThere are a few strengths of this study. This study was conducted in five sites in South-Asia and sub-Saharan Africa, which bear the highest burden of adverse birth outcomes. There, high-quality vital information on birth and deaths is sparse or non-existent. Second, this was a large population-based study in which pregnancies are identified by household surveillance of women of reproductive age. The sites also had a birth notification system to ensure early detection and identification of birth outcomes, resulting in low loss to follow up. Third, we used rigorous training to standardize sonographers to performs first-trimester ultrasound dating in all sites. Lastly, we were also able to compare two different methods for calculating gestational age, ie, LMP and ultrasound.We had a few limitations. First, anthropometric measurements, including the height and weight of the mothers, were not available for all women, which would have been helpful to examine the association of maternal BMI and preterm births. In Pakistan site, in particular, height measurements were available for only one-third of the women. Second, although this was a large population-based study with higher precision on the results, these results may not fully represent the entire country. All study sites are predominantly rural areas except Pakistan (Karachi) site that is peri-urban. Third, we enrolled women presenting at the antenatal care clinic before 20 weeks of gestation. This could lead to a selection bias if women seek antenatal care later in pregnancy have a higher or lower risk of preterm birth, however by study design, we used early ultrasound dating to have accurate gestational age dating.A population-based cohort study showed that the incidence of preterm birth is much higher in South-Asian sites than in sub-Saharan African sites. High rates of neonatal mortality among preterm births, particularly in very and moderate preterm babies, calls for urgent attention to developing policies and intervention packages to improve care around birth and early identification of high-risk pregnancies.


To study the effect of intestinal microecology on postnatal weight gain of very preterm infants in neonatal intensive care unit (NICU).Very preterm infants who met the inclusion criteria were enrolled. The subjects were divided into the extrauterine growth retardation (EUGR) group and normal growth group, and the growth was evaluated at 2 and 4 weeks after birth. Meanwhile, the stool samples were taken to perform16S ribosomal RNA (rRNA) high -throughput 16S rRNA sequencing of the intestinal microflora was performed on stool samples.A total of 22 infants were included. There was no significant difference in the alpha diversity indexes indices between the two groups at 2 weeks or 4 weeks after birth. The beta diversity analysis showed that the two groups had similar principal components of the intestinal microflora were similar between the two groups. Linear discriminant analysis (LDA) effect size (LEfSe) showed that 2 weeks after birth, the bacteria with an absolute LDA score (log10) higher than 4 included Streptococcaceae, Streptococcus, Bacteroidetes, Bacteroidales and Stenotrophomonas in the EUGR group and Enterococcaceae and Enterococcus in the control group. At the 4th week after birth, the bacteria with an absolute LDA score (log10) higher than 3 in the EUGR group includedwere Clostriaceae, Eubacteriaceae and Eubacterium. TheBy comparing the composition of the microbial community composition comparison showed, significant differences were found in the principal components of Enterococcus and Streptococcus on the family and genus levels at 2 weeks after birth. No Bifidobacterium was found in either group at 4 weeks after birth.Intestinal microecology is different between infants with EUGR and those with normal growth. The diversity and richness of the intestinal microflora in preterm infants at the NICU are significantly insufficient and change dynamically with time, and the establishment of intestinal homeostasis is obviously delayed.The online version contains supplementary material available at 10.1186/s13099-021-00445-1. Preterm infants can suffer from immature immune system and physiological characteristics. The establishment of the neonatal intensive care units (NICU) and the extensive development in advanced life support for preterm infants have generally improved their survival rate. Very premature infants need to be admitted to the NICU after birth and receive respiratory, nutritional, antibiotic and other support treatment. In 2019, the incidence of preterm infants was reported by the World Health Organization (WHO) to be about 10.6%, with an average of 14.8 million premature births per year. Among these births, more than 1.1 million happen in China, with an incidence of 6.9% . TherefoThe subjects of this study included very preterm infants with a gestational age of less than 32 weeks who were admitted to the NICU of Beijing Friendship Hospital affiliated to the Capital Medical University from January to December 2018. A total of 22 very preterm infants who met the inclusion criteria were finally included. Physical growth was assessed at 2 time points, 2 weeks and 4 weeks after birth. The infants were divided according to the body weight into the EUGR group and normal growth group. Meanwhile, stool samples were taken and stored at – 80 ℃ to perform 16S ribosomal RNA (rRNA) high-throughput sequencing of the intestinal microflora . Then, we analyzed the association between the extrauterine growth of very preterm infants and the intestinal microecology. This study was approved by the Ethics Committee of Beijing Friendship Hospital affiliated to the Capital Medical University. The infants' parents (or responsible relatives) gave written informed consent. The same nutrition strategy was followed with all the infants: all preterm infants were weaned within 24 h after admission. Early micro-feeding (10–15 ml/kg/d) was applied, if tolerable, then the amount of milk was gradually increased at the speed of 15–20 ml/kg/d. Parenteral nutrition support was given when total enteral feeding was not achieved.Physical growth was evaluated according to the Fenton growth chart for preterm infants (2013)  as folloThe inclusion criteria were as follows: (1) admission to the NICU immediately after birth; (2) a gestational age of 28–32 weeks, single pregnancy; (3) hospitalization time  >  28 days; (4) antibiotic treatment (Amoxicillin-potassium clavulanate/Piperacillin-tazobactam) after birth and for less than 5 days.The exclusion criteria were as follows: (1) severe congenital malformations and congenital genetic metabolic diseases; (2) discharged automatically with unclear outcomes after discharge; (3) incomplete data; (4) received probiotics during the collection of stool samples; (5) mixed feeding.The collection of the stool samples of preterm infants strictly followed the principle of aseptic operation and was performed on the 14th and 28th day after birth using a disposable sterile stool container and preserved at – 80 ℃. Next, the samples were sent to Allwegene Technology Inc. to perform DNA extraction, sequencing and bioinformatic analysis.http://ccb.jhu.edu/software/FLASH/index.shtml) [https://github.com/torognes/vsearch) [https://blast.ncbi.nlm.nih.gov/Blast.cgi) was used for sequence alignment, and the QIIME v1.8.0 software  [The FLASH v1.2.11 software   was usedvsearch)  softwareme.org/)  was used2 test. When the sample size was too small, the Fisher exact probability method was used for intergroup comparison. A p value  <  0.05 was considered to be statistically significant.The SPSS 20.0 software was used for data analysis. First, we performed statistical matching grouping to remove the effects of the feeding mode, delivery mode and antibiotics, and only the effects of intestinal microecology on growth were analyzed. Count data, such as the gestational age (stratification), gender, delivery mode and feeding mode, were compared using the Pearson’s χAmong the 22 very preterm infants included in the study, there were 14 males and 8 females. There were 8 cases at 28 to less than 30 weeks of gestational age, 6 cases at 30 to less than 31 weeks of gestational age and 8 cases at 31 to less than 32 weeks of gestational age. No significant differences were found in the gender ratio, delivery mode, feeding mode or gestational age stratification between the EUGR and control groups  and Shannon index (shannon) showed a stable pattern of the curve, which indicated that the sequencing depth was sufficient to reflect the vast majority of the microbial diversity in the samples, even when the sample size was increased, limited new species were produced. During the 2nd week after birth, an obvious difference in the Shannon index appeared between theEUGR and control groups, but this difference was statistically insignificant. Meanwhile, there was no significant difference in any of the other indexes such as chao1, observed_species and PD_whole_tree between the two groups at 2 weeks or 4 weeks after birth Fig. .Fig. 3AlThe results of the principal component analysis (PCA), principal co-ordinates analysis (PCOA) and non-metric multidimensional scaling (NMDS) analysis based on the OTU abundance in the stool samples showed that at 2 or 4 weeks after birth, the principal components of the intestinal microflora of the two groups could be roughly separated, despite their similarity. We use another dimensional reduction technique t-SNE and UMAP to interpret b diversity  effect size (LEfSe) can be used to compare multiple groups and perform subgroup comparison analysis, so as to find the species with an abundance that is significantly different between the groups. Based on the obtained species, an inter-group difference analysis was performed, followed by LDA to estimate the effect of each species on the difference. During the 2nd week after birth, the items with an absolute LDA higher than 4 in the EUGR group included Streptococcaceae, Streptococcus, Bacteroidetes, Bacteroidales and Stenotrophomonas, while those in the control group included Enterococcaceae and Enterococcus. On the other hand, during the 4th week after birth, the items with an absolute LDA higher than 3 in the EUGR group included Clostriaceae, Eubacteriaceae and Eubacterium Fig. . CompareAt 2 weeks after birth, there was a significant difference between the community principal components of the infants in the EUGR group and those in the normal control group on the family and genus levels. On the family level, the principal components in the control group were Enterococcaceae (53.95%) and Enterobacteriaceae (24.96%), while the Enterococcaceae content in the EUGR group significantly decreased to 23.45%, and there was no significant difference in the Enterobacteriaceae content (24.05%). Streptococcaceae accounted for 11.33% in the EUGR group and 2.58% in the control group, with a significant difference. On the genus level, the principal component of the control group was Enterococcus (53.92%), which accounted only for 26.44% in the EUGR group. The proportion of Streptococcus significantly differed between the two groups, accounting for 2.4% in the control group and 12.633% in the EUGR group  , 9. In tStenotrophomonas maltophilia were also significantly different between the two groups, they had low proportions in the community composition of the two groups, which has no clear clinical significance. Streptococcus is a common pathogen that causes early-onset neonatal infection. Group B streptococcus (GBS) is the most common cause of early septicemia and meningitis in neonates. The mortality of early-onset GBS infection in full-term infants is 2–3%, while it reaches 20% in preterm infants and 30% in preterm infants with a gestational age of less than 33 weeks [We performed a comparison between the composition of microbial community in the EUGR and control groups and found that Enterococcus was the dominant intestinal microflora in the two groups. However, the proportion of Enterococcus in the EUGR group was significantly lower than that in the control group, and the proportion of pathogenic bacteria, such as Streptococcus, was significantly increased. The LEfSe analysis showed that in the 2nd week after birth, Streptococcaceae and Streptococcus in the EUGR group and Enterococcaceae and Enterococcus in the control group were the most significantly different bacterial species between the two groups. Although the contents of Bacteroidetes, Bacteroidales and 33 weeks . An anal33 weeks . In Chin33 weeks  analyzed33 weeks  showed tEUGR represents a risk factor for neurodevelopmental abnormalities , 21. SinThe establishment of intestinal microecology in very preterm infants undergoes dynamic changes over time and differs between preterm infants with EUGR and those with normal growth. The diversity and richness of the intestinal microflora in preterm infants in the NICU are significantly insufficient. Early detection of the intestinal microflora and early intervention can improve the growth of very preterm infants. Probiotics have a high strain specificity in the intestinal tract, and different probiotics have different functions; questions such as the colonization rate and time (short-term or long-term), suitable strains and doses remain to be investigated. In future work, we will investigate the types of probiotics that can effectively reduce the growth retardation of very preterm infants when they are early administrated.Additional file1: Figure S1. t-SNE and UMAP. Additional file 2: Table S1. Comparison of communities at different levels at 2 weeks after birth (over 9%). Table S2. Comparison of communities at different levels at 4 weeks after birth (over 9%). Table S3. OTUs of the two groups at two weeks after birth. Table S4. OTUs of the two groups at four weeks after birth.


Being born before full gestation can have short-term and life-long health implications, yet it remains difficult to determine the risk of preterm birth among expectant mothers. Across different health settings, increasing attention is given to the health and behavioural consequences of adverse childhood experiences (ACEs) such as child abuse or neglect, or exposure to harmful household environments , and the potential value of understanding these hidden harms when supporting individuals and families. A large international evidence base describes the association between childhood adversity and early years outcomes for mothers and children. However, the relationship between maternal ACEs and preterm birth has received far less attention.Secondary analysis was carried out on anonymised cross-sectional data from health visiting services in south and west Wales that had previously captured information on mothers’ ACEs during routine contacts. Demographic data and information on mothers’ health were extracted from the Healthy Child Wales Programme.p = 0.025), neglect  and overall ACE exposure , with one in ten mothers (10.0%) who experienced ≥4 ACEs having preterm birth. Sub-analyses revealed a more pronounced relationship among mothers with no known chronic health conditions, with those with ≥4 ACEs and no known chronic condition four times more likely to give birth preterm .Half of all mothers sampled had experienced at least one ACE, with a history of ACEs more common among younger, white British mothers and those residing in deprived areas. Preterm birth was significantly independently associated with retrospective reports of childhood sexual abuse (adjusted odds ratio [AOR] = 3.83, 95% confidence interval [CI] = 1.19–12.32, Findings highlight the importance of the entire maternal experience. The experience of childhood adversity can have a lasting impact into and beyond the prenatal period, potentially increasing the risk of preterm birth, even among otherwise healthy women. Increasing our understanding of the potential perinatal outcomes associated with ACEs can help to inform how maternity services and partners offer trauma-sensitive support to mitigate some of the risks of early parturition, as well as target intergenerational cycles of adversity and poor health.The online version contains supplementary material available at 10.1186/s12884-022-04454-z. In the UK, infants born before 37 weeks gestation are considered preterm or premature. Preterm birth may follow spontaneous onset of early labour or may be the result of an obstetric intervention intended to reduce the risk of continued pregnancy, to either the child and/or the mother . Accordin = 7/9 identified studies) suggest ACEs increase the risk for preterm birth [Increasingly, the potential impact of trauma and, in particular, historic or childhood experiences of chronic or toxic stress, on a range of perinatal outcomes has been considered –18. Adverm birth . Althougrm birth , 29.Better understanding of the risk factors for preterm birth is an important element in both developing universal preventative measures, and in identifying those who are already at increased risk and may require additional support. Primary prevention interventions for preterm birth include nutritional supplementation and lifestyle and behaviour changes . CuAcross a wide range of health and healthcare issues, new research and policy is now considering the application of ACE-informed approaches (e.g. ). In hean = 49) were removed from the sample, leaving a final sample for analysis of 865.This study aims to explore the relationship between a history of ACEs and preterm birth among mothers engaged with health visiting services in south and west Wales. To our knowledge this is the first study to explore the associations between preterm birth and ACEs in a UK sample and furthers the evidence base on this topic through its examination of the role of maternal chronic health conditions on this relationship. Secondary analysis was carried out on anonymised cross-sectional data extracted from three health visiting services in urban and rural locations in south and west Wales in 2019/20. The study population is female primary caregivers (herein referred to as ‘mothers’) for whom ACE and Healthy Child Wales Programme (HCWP) data were made available by the health visiting services see . Health Data were extracted from the HCWP on mothers’ age, split into three discrete age categories . Owing to its protected category status under General Data Protection Regulation (GDPR), mothers were asked by their health visitor to indicate their ethnicity using only a dichotomous variable (‘white British’ or ‘Other’). In Wales, residential areas with higher deprivation are eligible for additional early years support services, in the form of Flying Start. Funding for Flying Start is allocated according to the estimated number of 0–3 year olds living in income benefit households in lower super output areas (LSOAs) of local authority areas. In 2018–19, over 36,000 children in Wales benefitted from Flying Start , which iAs part of the 6 weeks post-partum contact, health visitors routinely complete the Family Resilience Assessment Instrument and Tool (FRAIT). The FRAIT uses a series of questions and scales to assist health visitors in making robust, consistent and reliable assessments of family resilience and in identifying the support and interventions needed to help families to deal with adversity . The tooHealth visiting services providing data for this secondary analysis were those that had previously used a simplified version of established ACE questions from the Centers for Disease Control and Prevention short ACE tool  to retroAnalyses used chi squared tests for initial bivariate examination of the relationships between ACEs and preterm birth. Binary logistic regression was also used to examine the independent contributions of ACEs and demographics  to these outcomes. Three separate models were run to explore the effects of individual ACE types (Model 1), total ACE exposure (Model 2) and all ACE measures together (Model 3). Generalized Linear Models (GLMs) allow covariate and categorical variables to be fitted to dependent variables and the resultant model can be used to generate estimates for the dependent variable for given values of the independent variable . GLMs weOver 60 % (64.3%) of mothers in the study population were aged 26–35 years, with just under a quarter (23.0%) aged 16–25 years. Married (31.0%) and partnered/cohabiting mothers (39.3%) made up the majority of the sample, although around one in every five (21.4%) mothers chose not to disclose their relationship status. Reflective of the overall ethnic diversity of the adult population of Wales , 90.8% o2 = 21.073, p = 0.002). Reported experience of measured childhood adversity was also more common among white British mothers . Although no significant difference in ACE exposure was found by health visiting service/geographical area, mothers in Flying Start areas  reported higher overall ACE exposure  and a greater prevalence of the individual ACE types: physical abuse , witnessing domestic violence , household mental illness , household alcohol abuse , household drug abuse  and household member incarceration .Half of all mothers sampled (52.8%) reported that they had been exposed to one or more of the ten ACEs captured by the health visiting service, with 12.7% reporting high ACE exposure  and subsequent preterm birth . For this sample, a more pronounced significant relationship between overall ACE exposure and likelihood of preterm birth was revealed, with mothers exposed to ≥4 ACEs almost four times more likely to have given birth preterm  that would normally maintain homeostasis can have a negative effect on the body, resulting in increased risk of impaired health and disease processes, including preterm birth , 52. ProIn a population with such hidden harms, the value of understanding an individuals’ history of childhood adversity as a potential predictor for health impacts including preterm birth, and thus providing direction for targeted support or intervention, requires further consideration. In many health systems, midwifery services already routinely enquire about forms of victimization such as domestic violence and female genital mutilation , 64, witIt is important to note that not all individual ACEs showed an independent relationship with preterm birth, and many mothers with a history of ACEs gave birth at full gestation, highlighting that the relationship between early adversity and preterm birth is by no means deterministic. However, approaches to identifying ACEs may have universal benefits when working with families in the early years, to break known intergenerational cycles of adversity and help to prevent exposure to ACEs and associated risk of preterm birth in subsequent generations. Such work has the potential to not only support families during the critical period of the first thousand days for bonding, attachment and building resilience , 73, butFindings from this exploratory analysis should be interpreted in light of the following limitations. Firstly, prevalence of preterm birth identified in this sample is lower than national figures derived from the same time period (7.8% ). As theThe prevalence of ACEs retrospectively self-reported by mothers in this sample echoes that of adults in other primary health settings and national surveys, supporting the established premise that childhood adversity is not rare, and that experiences of different forms of victimisation or household dysfunction often co-occur. The widespread existence of ACEs in society highlights the need to consider different approaches to support those who have experienced childhood adversity across a variety of settings. With high ACE exposure associated with an increased risk of preterm birth as much as four fold among healthy mothers with no chronic health conditions, additional research is needed to explore this association in more detail, including the balance of influence for individual and cumulative ACEs on perinatal outcomes. Maternity and other services that engage with families during critical periods of child development may be uniquely placed, not only to offer trauma-sensitive support to deal with the impacts of ACEs and potentially mitigate some of the risks of early parturition, but also to help break cycles of adversity and health and social consequences for future generations.Additional file 1: Table A1. Bivariate association between individual ACEs and preterm birth.Additional file 2: Table A2. Inter-correlations between individual ACEs.Additional file 3: Table A3. Logistic regression of ACE exposure, demographics and their association with preterm birth among healthy* mothers.