Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial.Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22–37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo.This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth.NTR 5675. EudraCT-registration number: 2015-003220-31.Clinical trial registration number of the Dutch Trial Register:  Preterm birth (<37 weeks of gestation) is the most common cause of neonatal morbidity and mortality worldwide. Worldwide in 2010 an estimated 14.9 million neonates were born preterm of whom 1.6 million were born < 32 weeks of gestation [Preterm birth accounts for 70% of all neonatal mortality and for 40% of childhood neurological morbidity  resultinGestational age at birth determines to a large extent the health prospects of the neonate. The increased physical and mental health problems for preterm born children result in increased health costs, leading to a considerable economic burden for society .One third of preterm births are due to medical intervention because of maternal or fetal complications, while two third of preterm births occurs after spontaneous onset of the delivery . The strAn increasing body of evidence suggests that utero-placental ischemia plays a major role in the genesis of spontaneous preterm labour. Placental vascular pathology and placental bed pathology are common findings in women with a spontaneous preterm birth –13. AlsoIn the light of the possible similar underlying mechanism, preventive measures for ischemic placental disease might also be effective in preventing recurrent spontaneous preterm birth. The most successful intervention in the prevention of recurrent preeclampsia is low dose acetylsalicylic acid (aspirin or ASA). Aspirin acts as a thrombocyte aggregation inhibitor and it reduces prostaglandin synthesis through inhibition of the enzyme cyclooxygenase, thereby having an anti-inflammatory effect. A recent meta-analysis showed a reduction of preeclampsia with a RR 0.47 (0.34-0.65) if aspirin was initiated before 16 weeks of gestation . InteresFurthermore, in other groups of patients where aspirin is used to improve pregnancy outcomes there is also evidence suggesting an effect on spontaneous preterm birth.A recent IPD meta-analysis on preconception started low-dose aspirin treatment in IVF patients found a lower, though not statistically significant, incidence of preterm birth in women with a singleton pregnancy after adjustment for hypertensive pregnancy complications  .A Dutch randomized clinical trial on aspirin and low molecular weight heparins in patients with recurrent miscarriage showed the lowest incidence of preterm birth in the aspirin group of 1.6%, versus 10.1% in the combined (aspirin and Low Molecular Weight Heparin (LMWH)) group and 4.3% in the placebo group . AnotherAspirin is a safe intervention in pregnancy as a recent review commissioned by the 'U.S. Preventive Services Task Force' concluded . In viewThe objective of the study is to assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in preventing preterm birth when initiated in early pregnancy in women with a previous spontaneous preterm birth.www.studies-obsgyn.nl).A multicenter, randomized, double blinded, placebo controlled trial will be performed within the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynecology  trained doctors, midwifes or research nurses. After counseling and reading the patient information form, patients will be asked for written consent. We will provide patient information in Dutch as well as in English. After informed consent, patient data will be entered in a web-based database, which will also facilitate randomization.Women will randomly be double-blindly allocated to either aspirin administration or placebo administration in a 1:1 ratio: both participant and healthcare worker will be unaware of what group the women is allocated. Randomization will be performed centrally with the use of a random 2 : 4 block design.At study entry, baseline demographic, past obstetric and medical history will be recorded into the web-based Case Report Form (CRF) that is accessible through a closed part of a central website, OpenClinica. Details of delivery, maternal and neonatal assessments during pregnancy or post-partum are recorded in the CRF. The collected data will be coded and processed with adequate precautions to ensure patient confidentially.Eligible women will be randomized by a web-based central randomization system to low dose aspirin 80 mg one tablet a day or placebo one tablet a day, preferably taken in the evening. Administration will be initiated between 8 and 16 weeks of gestation and will be continued up to 36 weeks of gestation or up to delivery, whatever comes first. Other preventive measures such as administration of progesterone, cerclage or pessary will be provided according local protocols for prevention of preterm birth derived from the national guidelines .All details on delivery, maternal and neonatal assessments and admission during pregnancy are recorded in the CRF that is accessible through the website. Mortality and morbidity will be specified for the mother and the child until date of discharge from hospital or 3 months of corrected age. We plan long term follow-up of the children at age of 24 and 60 months to examine (neuro-) developmental outcomes.The primary outcome measure will be preterm birth, defined as birth at a GA of less than 37 weeks. The most important secondary outcome is a composite of poor neonatal outcome (including bronchopulmonary dysplasia (BPD), periventricular leucomalacia (PVL) > grade 1, intraventricular hemorrhage (IVH) > grade 2, necrotizing enterocolitis (NEC) > stage 1, retinopathy of prematurity (ROP), culture proven sepsis and perinatal death). The individual components of the composite outcome will also be assessed separately.The diagnosis of BPD will be made at 36 weeks of postmenstrual age, if a neonate has received supplemental oxygen for at least 28 days. Classification will take place using an oxygen reduction test . PVL > gAdditional secondary neonatal outcomes are number of days on ventilation support ), infant respiratory distress syndrome (IRDS) that requires treatment with surfactant, patent ductus arteriosus (PDA) that requires medical or surgical treatment, cerebellar bleeding, days of admission on the NICU, convulsions, asphyxia, proven meningitis, pneumothorax and total days in hospital until 3 months corrected age.Furthermore, preterm birth rates at ≤ 28 weeks, ≤ 32 weeks, ≤ 34 weeks of gestation will be assessed as a group and will also be analyzed separately as spontaneous, indicated or as a combination. Growth restriction will be analyzed and birth weight will be assessed both continuous and < p10. Separate assessment of birth weight will take place on fetal growth chart  and is dMaternal outcomes include maternal side effects, maternal mortality, hospital admissions in general and specifically due to threatened preterm labour with need for treatment with tocolysis and or corticosteroids for antenatal fetal lung ripening. Maternal morbidity due to hypertensive disease in pregnancy will be defined according to the ACOG-guideline ‘hypertension in pregnancy’ . PregnanOther maternal outcomes will be defined as follows: gestational diabetes as onset of diabetes after 20 weeks of gestation. The diagnosis of pulmonary edema will be based on clinical findings, thromboembolic disease will include both deep vein thrombosis and pulmonary embolism, maternal infection or inflammation will be a clinical diagnosis and major ante- or post-partum hemorrhage (blood loss ≥ 1 liter) will also be assessed.The core-outcomes for research concerning interventions to prevent preterm birth as defined by the CROWN-initiative  will be Costs will be measured from a healthcare perspective using case record forms until 3 months of corrected age of the infant. Costs will include costs of outpatient visits, hospital admissions, and the delivery. For the valuation of health care utilization, standard prices published in the Dutch costing guidelines will be used. Alternatively, hospital administration data or tariffs will be used if necessary. Medication use will be valued using prices of the Royal Dutch Society for Pharmacy.Hypothesis generating subgroup analyses will be performed for women with a previous preterm birth before and after 30 and 34 weeks GA, a history of preterm birth starting with contractions with intact membranes versus preterm premature rupture of membranes (PPROM), women additionally treated with progestagens versus no additional treatment, women with a short cervix (<25 mm before 24 weeks) in the current pregnancy and women who started using the study-medication at less than 12 weeks versus 12-16 weeks of gestation.Data will be analyzed according to the intention-to-treat principle. Participants will be kept in the study regardless of whether they decide to discontinue the study medication unless they explicitly withdraw permission to use their data. Because the results are all to be extracted from the medical records of the participants, it is not expected that there will be missing data. Best effort will be made to retrieve the data. If still there is missing data, this will be mentioned along with the reason. Baseline characteristics of the groups will be presented using percentages, means with 95% confidence intervals (CI) and medians with interquartile ranges, where appropriate. No interim analysis for efficacy will be performed, however an independent Data Safety and Monitoring Committee will be monitoring patient safety every 6 months, starting 9 months after the inclusion of the first patient.p-value of 0.05. The main outcome will be presented as absolute and relative risks  and numbers needed to treat (if applicable).The main outcome variable, ‘reduction in recurrent preterm birth’, will be assessed by comparing the event rates in the two groups using a chi-square test with a t-test if the outcome is normally distributed and with a non-parametric Mann-Whitney U test if skewed. These outcomes will be presented per group as means with standard deviation, geometric means with 95% CI, or as median with interquartile range, whichever appropriate.The secondary outcome is poor neonatal outcome. Categorical secondary outcomes will be assessed in the same way as the primary outcome, except that Fisher’s exact test will be used where appropriate. For continuous secondary outcomes, differences between groups will be assessed with the student’s A Kaplan–Meier plot of gestational age at delivery will be presented and the difference gestational age at birth between the study arms will be tested with the log-rank test. Along with this plot, the percentage non-delivered at 28, 30, 32, and 34 weeks will be presented per arm.A reduction of recurrent preterm birth from 36 to 23% (a reduction of 35%) can be detected if 406 patients are recruited . Because estimates are not consistent, the assumption of the occurrence of recurrent preterm birth was made based on the largest trial performed on prevention of preterm birth using progesterone [The economic evaluation will be performed from a healthcare perspective. The primary outcome will be costs (savings) per pre-term birth prevented. Missing cost and effect data will be imputed using multiple imputation. Cost and effect differences will be estimated using bivariate regression models with adjustment for confounders and effect modifiers if necessary. Bias-corrected accelerated bootstrapping (5000 replications) will be used to assess statistical uncertainty. Incremental cost-effectiveness ratios (ICERs) will be calculated by dividing the difference in costs by the differences in primary and secondary outcomes between the groups. Cost-effectiveness acceptability curves showing the probability that the intervention is cost-effective in comparison with usual care for a range of different ceiling ratios will also be estimated . In a buA data safety monitoring board is established to perform ongoing safety surveillance. Serious adverse events will be reported to the board every 6 months along with the treatment arm. No interim analysis for efficacy will be performed.Linking personal data with randomization number can only be done in the local clinics. Each participating clinic receives a login name and password to gain access to the web-secured database. The access is restricted to the database of the clinic to which the password and login name belongs. Full access to the entire database is restricted to some members of the research staff.Recurrent spontaneous preterm birth remains a large contributor to the perinatal morbidity and mortality as a result of preterm birth, with a need for additional preventive methods. Based on research that points in the direction of placental ischemia as a  cause of spontaneous preterm birth, interventions that improve the placentation may be effective in reducing the number of (recurrent) spontaneous preterm birth. This study is designed to provide evidence on the (cost-) effectiveness of low dose aspirin in comparison with placebo in preventing preterm birth in women with a history of spontaneous preterm birth. Low dose aspirin is considered safe in pregnancy and is already widely embedded in the obstetric practice for other indications. Therefore, if aspirin is proven to be effective in reducing recurrent spontaneous preterm birth, it would be easy to implement in daily practice.


Objective. To determine reference values of biceps, triceps, subscapular, and suprailiac skinfold thickness measurements in term Nigerian newborns. Method. A prospective cross-sectional study over a six-month period (Dec 2010–May 2011) was carried out on term and healthy neonates delivered between 37 and 41 weeks. The anthropometric measurements were taken within the first 48 hours of life including the skinfold thickness. The skinfold thickness measurements were taken at four sites, namely, triceps, biceps, subscapular, and suprailiac, using Harpenden skinfold calipers. The mean of two readings was recorded. Result. A total of one thousand one hundred and sixty-eight neonates were studied. The birth weight ranged between 2000 g and 5000 g with a mean birth weight of the neonates at 3259 ± 470 g. The mean birth weight of the males (3339 ± 0.45) was significantly higher than that of females (3200 ± 0.44) (p < 0.0001). Female neonates had higher mean values of triceps, subscapular, and suprailiac skinfold thickness  while male neonates had higher mean value of biceps skinfold thickness (p = 0.008). Females also had higher mean values of the sum of skinfold thicknesses at all four sites and the sum at the two truncal sites at every stratified gestational age. Conclusions. The sex specific percentile chart developed for skinfold thickness measurements can be used to detect deviation from the reference population such that infants who are at risk of nutritional or health problems are identified early, and intervention is instituted promptly.Skin fold thickness (SFT) measurement is a reliable, cheap, simple, noninvasive method of body fat estimation at all ages including the neonatal period. Skinfold thickness (SFT) measurement is a reliable, cheap, simple, noninvasive method of body fat estimation at all ages including the newborn period . It measData on skinfold thickness can be utilized in a number of ways. Firstly, they can be directly compared with reference values in an attempt to determine adequacy, deficiency, or excess. In doing this, results from one site or the summation of results from two or more sites may be compared with reference values . In otheSkinfold thickness values can also be introduced into predictive mathematical formulae to derive body fat indices like percentage body fat and hence derive fat mass and fat-free mass . Measure2 [Skinfold thickness is measured in millimeters using special calipers , 10. The2 . Sites o2 . In chil2 –15.Like every anthropometric measurement, error of measurement is a problem. The skill of the observer and the quality of caliper are key issues. To eliminate error, the author was trained to use the caliper by an anthropometrist, a certified member of the International Society for the Advancement of Kinanthropometry (ISAK). All measurement was taken by only one observer, the author.Why Skinfold Thickness Is Measured? Birth weight has traditionally been used as the single most important factor for determining neonatal survival perhaps because of its ease of measurement. However, it does not provide all the answers as it may still fall within normal limits even when a fetus has suffered some degree of acute weight loss in pregnancy. Some healthy babies may be constitutionally small but not undernourished. It is thus important to look beyond birth weight alone in determining neonatal outcome. SFT measurements are more complicated but more realistic and body fat values obtained by SFT measurement have been validated with gold standards like dual energy X-ray absorptiometry (DEXA) [y (DEXA) . Aim of Study. The aim of the study was to describe the pattern of and determine the reference values of skinfold thickness in term newborns at the Lagos State University Teaching Hospital, Ikeja, Nigeria.The study was carried out in the lying-in wards of the Obstetrics and Gynecology Unit of Lagos State University Teaching Hospital which was temporarily moved to the newly built Maternal and Child Centers at Ifako-Ijaiye and Isolo General Hospitals both in Lagos State during the period of study. The predominant ethnic group in Lagos is Yoruba though other Nigerian ethnic groups are well represented in the state.Neonates were consecutively recruited from the lying-in wards (as they room with their mothers) until the desired sample size was attained from the 1 December 2010 to the 31 May 2011. Neonates delivered at full term (37 weeks to 41 weeks), singleton babies, and babies apparently well within the first 48 hours of life were included in the study while, babies with gross congenital defect, multiple births, and babies whose parents do not give their consent were excluded from the study.Infants of diabetic mothers were not excluded from this study as we set out to investigate the relationship between birth weight and skinfold thickness in term newborns. Also, the incidence rate of diabetic pregnancies is reportedly low at about 0.64/1000 births/year . The useAn informed written consent was obtained from each mother. The study protocol was approved by the Lagos State University Teaching Hospital Ethical Review Committee.The instruments used include Harpenden® skinfold caliper, and a self-designed pro forma used to collect relevant information, an electronic weighing scale to measure birth weight, and an infantometer to measure the length of the neonate. The pro forma was validated by the certified anthropometrist a certified member of the International Society for the Advancement of Kinanthropometry (ISAK) who trained one of the researchers for six months and ensured proficiency before the actual study was conducted.The neonate was examined thoroughly within the first 48 hours of life by the researcher for evidence of congenital malformation and signs of illnesses like pyrexia, jaundice, hepatomegaly, and cardiac murmur.Birth weight was measured with the baby being nude using an electronic weighing scale (KINLee), which is accurate up to 2000 grams in 5-gram increments. The weighing scale was regularly calibrated after every 50th use according to the manufacturer's manual.The gestational age of the baby was calculated from the date of the mother's last normal menstrual period. Where this was not known, the report of an early ultrasound scan done in the first trimester of pregnancy was used to estimate gestational age . ModifieThe length of the neonate was taken using an infantometer which is an instrument with a firm and flat or horizontal calibrated surface with two ends, a fixed end and a movable end. The infant is laid supine on the infantometer with the head placed at the fixed end of the infantometer in such a way that the occiput and the pupils are on the same vertical plane with the feet placed on the movable end and lower limbs extended gently but firmly held down by an assistant. The length (which is the distance between the two ends) is read off the calibrated horizontal surface in centimeters and to the nearest 0.1 centimeters . The meaThe skinfold thickness method is based on measuring a pinch of skin precisely at several standardized sites on the body to determine the subcutaneous fat layer.For the biceps and triceps skinfolds, the landmark was determined by measuring the mid distance between the acromion process of the right humerus (shoulder) and the olecranon process (elbow) of the same limb. The mid distance was marked on the skin anteriorly to measure the biceps skinfold and posteriorly to measure the triceps skinfold with the arm by the side of the body.Subscapular skinfold thickness (SBS) is measured 1-2 cm below the inferior angle of the scapular. Skinfolds were raised over this point and held throughout the measurement with the caliper applied at right angle to the raised fold and the reading on the dial taken allowing full pressure of the caliper by a complete release of the trigger. The reading was made approximately 2-3 seconds after application as it is known that the fold cannot be held too long as the subcutaneous fat may be compressed. This was done with the neonate sleeping or resting on the mother's chest.Suprailiac skinfold (SPS) is raised immediately superior to the iliac crest in line with the natural angle of the iliac crest at the anterior axillary line . The calMeasurement was made by lifting the skin with the thumb and index finger with care being taken to exclude any underlying muscle . This waAll the skinfold measurements were taken on the right side of the body for consistency , 21, wheSum of skinfold measurements ∑SFT = (TS + BS + SBS + SPS).Central to total skinfold measurement ratio: SPS + SBS/∑SFT.The following indices were calculated from the skinfold measurement. Quality assurance was ensured by ensuring that all skinfold thickness measurements were taken by one person who had been trained by a certified member of the International Society for the Advancement of Kinanthropometry (ISAK). Two measurements were taken at each site at least 15 seconds apart and the mean of the two readings was recorded. Calipers are cleaned before and after use on subjects and dial indicator at zero before measurement is taken.n is desired sample size. z is standard normal deviation usually set at 1.96 and corresponds to 95% confidence level. σ is standard deviation of the population sample as reported in an earlier study [ er study .E is mean (of the sum of skinfold measurements from an earlier study) [ r study)  × 0.05 bSample size was calculated using the formula (1)n=z×σ2 Gestational age was stratified and the formula was used to calculate the number of neonates recruited for the study at each gestational age and for each gender. The sample size was doubled to total of 1168 (one thousand one hundred and sixty-eight) subjects because the larger the sample size, the more the probability of its being representative of the population from which subjects were selected.The study was approved by the Lagos State University Teaching Hospital Ethical Review Committee (LREC/10/08/144).t-test were used where appropriate for comparing discrete and continuous data, where applicable. Multiple regression analysis was carried out to determine predictors of skinfold thickness. Probability  less than 0.05 was interpreted as statistically significant .p = 0.021) and 40 weeks (<0.001). A similar pattern was noted with respect to subscapular SFT with an additional observation of significant difference at 37 weeks. Further, at all gestational ages, the mean suprailiac SFT was significantly higher in females. A different trend was however noted with respect to biceps SFT in which males had higher values at all gestational ages except at 40 weeks. The overall figure for males was significantly higher (p = 0.008) and this was reflected at 38 weeks (p = 0.029) and 39 weeks (p = 0.035).The overall mean triceps SFT was higher in females at each gestational age, being most significant at 39 weeks (p < 0.001), 40 weeks (p < 0.001), and 41 weeks (p = 0.002) and overall (p = 0.003).The SFT at the subscapular and suprailiac sites were summed up in The pattern of overall central to total skinfold thickness ratio, that is, the sum of the subscapular and suprailiac skinfold thicknesses divided by the total sum of SFT at the four sites (SBS + SPS)/∑SFT as shown in Figures Selected percentile landmarks were derived for SFT at individual sites for the sum of SFT . Across The correlation matrices for birth weight categories and skinfold measurement are shown in p-value from ANOVA was consistently <0.001. The mean birth weights of males and females within each birth weight group were similar – generally within 30 g of each other. The females however, had consistently higher mean triceps and subscapular SFT (p was at least 0.046). The males had higher values of skinfold thickness at the biceps in those weighing ≥ 3500 g while the females had higher values in babies < 3500 g. However, none of the observed differences reached significant levels (p ≥ 0.05). With the exception of low birth weight babies, females had greater mean values of suprailiac SFT than males in all birth weight categories, with significant differences observed in the 3000–3499 g and 3500–3999 g groups. Also, the sum of skinfold thicknesses was consistently higher in females than males being significantly so in the 2500–2999 g, 3000–3499 g, 3500–3999 g groups (p was at least 0.001).The mean skinfold thickness values in both sexes according to the birth weight group is shown in R2) showed that the model was able to explain 64% of the variability of the predictors of SFT.The stepwise multiple regression analysis highlighted relationships between birth weight and SFT on adjusting for gender and gestation age. Birth weight was the first variable to enter the model, followed by gender and finally gestational age. Maternal age and other anthropometric indices were excluded by the stepwise procedure. In the final model, regression coefficient was strongest for birth weight and lowest for gestational age. The coefficient of determination (There were gender differences at various points of measurements with females having higher mean figures at the triceps, subscapular, and suprailiac SFT. The sum of subscapular and suprailiac SFT as well as the ratio between central fat and total body fat were also higher in females. A number of studies –26 have The few earlier studies that reported different patterns had relatively smaller sample sizes which may have suppressed manifestations of gender-related patterns.The mean birth weight of the term neonates in this study is comparable to the range of 3100–3167 g in earlier reports from different centers in the country –37 and eBody weight is the best independent predictor of body composition in preterm and term infants, accounting for 84% of the variation in fat mass; sex and length are additional determinants . Our stuIn comparison with an earlier study done in Ibadan Nigeria , the curBirth weight was significantly related to the triceps, biceps, subscapular, and suprailiac skinfold measurement as well as sum of skinfold measurement. These relationships were strongest with triceps and subscapular sites. This pattern of findings has been previously reported , 47 and The percentile charts, developed in the current study, show reference values for skinfold measurements at each site and the sum of skinfold measurement for both sexes. The skinfolds increased with increasing percentile and at every percentile the subscapular skinfolds were the highest followed by the triceps, the biceps, and the suprailiac skinfolds. The female neonates also had higher total sum of skinfold thickness compared to the males at each percentile. These observations have been previously documented in earlier studies , 2. ThisIn conclusion, the sex specific percentile chart developed for skinfold thickness measurements can be used to detect deviation from the reference population such that infants who are at risk of nutritional or health problems are identified early and get early intervention to reduce morbidity and mortality.


Background. Existing literature has documented a strong relationship between parental mental illness and child maltreatment, but little is known about the prevalence of mental illness among childbearing women. In the present study, linked administrative records were used to identify the prevalence of maternal mental health (MH) disorders documented at birth and determine the associated likelihood of maltreatment reports during infancy. Materials and Methods. Vital records for California’s 2006 birth cohort were linked to hospital discharge and Child Protective Services (CPS) records. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) billing codes from the mother’s delivery hospitalization were used to determine diagnosed maternal MH disorders for 551,232 infants born in 2006, and reports of alleged maltreatment were documented from CPS records. Vital birth records were used to control for sociodemographic factors. Finally, the associated risk of reported maltreatment during the first year of life was examined using generalized linear models. Results. Among infants in this statewide birth cohort, 2.8% were born to a mother with a documented MH disorder, of which 41.3% had documented maternal substance abuse issues versus less than 0.5% of infants born to mothers without a diagnosed MH disorder. Further, 34.6% of infants born to mothers with a MH disorder were reported to CPS within one year, and a majority of those reports were made within the first month of life (77.2%). In contrast, among children born to mothers without a MH disorder, 4.4% were reported to CPS during infancy. After controlling for sociodemographic factors, the rate of CPS reports during infancy for infants born to mothers with a MH disorder but no substance use disorder was 2.6 times that of infants born to mothers without a MH disorder . Among infants born to mothers with MH and substance use disorders, the rate of CPS reports during infancy was 5.69 times that of infants born to mothers without a MH disorder . Conclusions. Administrative records provide a method for identifying infants born to mothers with MH disorders, enabling researchers to track rates over time and generate population-level data to inform policy development and improve service delivery. The movement to deinstitutionalize psychiatric care in the 1970s led to notable increases in pregnancy and childbirth among women with diagnosed mental health (MH) disorders , low birGiven the broad range of functional impairments and severity in symptoms across MH disorders ,12,13, tThe International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes offer a standardized method for tracking population-level changes in diagnosis rates over time and have previously been used to document the prevalence of maternal MH and substance-related disorders ,17 and tThe analytic dataset was constructed by linking three administrative data sources from California: (1) vital birth records for all infants born in 2006; (2) maternal hospital discharge records corresponding to those births; and (3) CPS records for allegations of abuse or neglect made within 12 months of birth. The authors probabilistically linked birth records to CPS records using available unique  and non-unique  personal identifiers. Among infants reported to CPS and born in 2006, 92% were successfully linked to a birth record. In a separate linkage, 97% of maternal hospital discharge records were probabilistically linked to birth records as part of the ongoing California Vital Stats to Care Delivery Project . The twoThe dependent variable was defined as a first report of alleged maltreatment made to CPS during the first 12 months of life. All first reports of maltreatment were included, irrespective of whether the allegation was investigated or substantiated by CPS. Existing research has documented that infants reported to CPS are at heightened risk of negative outcomes, including re-reporting to CPS, placement into foster care, and critical injury and fatality, regardless of whether or not the allegations were substantiated ,22. The Maternal MH disorders were coded based on ICD-9-CM diagnostic codes . Up to 2. A list of ICD-9-CM substance exposure codes is also included in To characterize mothers diagnosed with a MH disorder and isolate the association between a diagnosed maternal MH disorder and CPS reports during infancy, several covariates available in the birth records were examined. Covariates included maternal race/ethnicity  and maternal age at first-ever birth in years . The decision to use maternal age at first-ever birth aligns with research indicating that the timing of a first birth is an important proxy for future outcomes of a mother and her children [2 tests to determine statistically significant variations (p < 0.05) based on a diagnosed MH disorder. Distributions of covariates were also assessed for specific MH diagnostic categories. The relationship between a diagnosed maternal MH disorder and CPS reporting was descriptively presented as the cumulative percentage of infants reported to CPS by month throughout the first year of life. To isolate the increased risk of CPS reporting associated with a diagnosed MH, a series of generalized linear models were estimated based on a Poisson distribution, log link, and robust standard error adjustments to account for binary outcomes [Covariate distributions were assessed using χoutcomes ,27. Estin = 15,516) were born to mothers with a documented MH disorder in their medical records. Overall, the majority (93.5%) of mothers with a MH disorder received the general diagnosis of 648.4 or “Mental disorders complicating pregnancy, childbirth, or the puerperium” (herein referred to as MH Disorder at Delivery). Births with a maternal MH disorder were associated with younger maternal age at first birth, a higher percentage of White mothers (49.2% vs. 27.0%), more coverage by public health insurance (56.3% vs. 48.2%), and higher rates of missing paternity on the birth certificate (27.5% vs. 8.7%). The percentage of mothers who received prenatal care during the first trimester was lower among mothers with a MH disorder (70.7% vs. 85.7%). Notably, 41.3% of infants with mothers who had a MH disorder had documented maternal substance abuse versus less than 0.5% of infants born to mothers without a diagnosed MH disorder.As shown in Differences emerged among mothers with specific diagnoses of psychotic, mood, or anxiety disorders at birth compared with the diagnosis of MH Disorder at Delivery. Mothers with at least one of these specific diagnoses tended to be older at the time of their first birth than mothers with a MH Disorder at Delivery diagnosis, with roughly 40% aged 30 years or older. Among mothers with diagnosed psychotic disorders, Black mothers were disproportionately represented. Nearly a quarter of mothers with a psychotic disorder were Black (23.4%) versus only 5.4% of mothers without a MH disorder. White mothers were overrepresented among those classified with mood and anxiety disorders. Public insurance covered 80.7% of births in which there was a diagnosed psychotic disorder, versus only 40.5% and 29.9% of those with mood and anxiety disorders, respectively. Nearly 50% of births to mothers with psychotic disorders were missing paternity, and one third had started prenatal care only after the first trimester or not at all. Underscoring the distinct profiles of mothers with specific MH disorder diagnoses versus a general diagnosis at delivery is the percentage of mothers with co-diagnosed substance exposure, which ranged from 5.4% (anxiety disorder) to 24.3% (psychotic disorder) for specific diagnoses compared to 44.0% for a MH Disorder at Delivery.Among children born to mothers with a documented psychotic disorder, 68.5% were reported to CPS during infancy. However, the cumulative percentage reported to CPS was much lower among mother-child dyads in which anxiety or mood disorders were diagnosed , yet these values were still twice as high as the percentage of those without any documented MH disorder (4.4%).p < 0.001) also emerged for births in which the specific diagnosis was for a mood or anxiety disorder.Model 2 additionally examined the influence of co-documented substance exposure on CPS reporting. The combined effect of a maternal MH disorder and substance exposure was associated with a rate of CPS reporting 5 to 21 times that of other infants. For example, among mothers with a MH Disorder at Delivery diagnosis but no co-occurring substance abuse disorder, the RR was 3.16 . The RR increased to 16.36  among mothers with a MH Disorder at Delivery diagnosis and comorbid substance use.Finally, in Model 3, attempts to better isolate the relationship between maternal MH disorders and CPS reporting by adjusting for the covariates presented in In the present study, linked administrative records were used to examine the relationship between maternal MH disorders documented at birth and CPS reporting during infancy. Several findings emerged that highlight the potential to not only use administrative records to monitor population-level dynamics, but also generate new knowledge concerning the relationship between maternal MH and CPS involvement.First, this study provides a statewide estimate of the prevalence of infants born to mothers with MH disorders in the 2006 birth cohort. The percentage of MH disorders documented in the hospital delivery records of mothers in California increased from 1.7% in 1995  to 2.8% Second, the present study produced a first-ever estimate of the occurrence of alleged maltreatment among infants born to mothers with MH disorders among both publicly and privately insured mothers in California. Statewide, one third of infants born to mothers with a MH disorder were reported to CPS by 12 months of age compared to fewer than one in every 20 infant born to a mother without a documented MH disorder. There were notable differences in the likelihood of CPS reporting by the specific MH disorder diagnosed. Overall, two thirds of infants born to mothers with a psychotic disorder were reported to CPS, which represents a rate more than 4 times that of infants born to mothers without a MH disorder after controlling for other risk factors at birth. Infants born to mothers with a mood disorder were more than twice as likely to have a CPS report, and infants born to mothers with an anxiety disorder experienced a small, but significant increase relative to infants of mothers without a MH disorder. Parental MH information is not always made available to child welfare social workers, and when provided, it is not systematically documented within CPS record systems when available. These findings provide useful estimates for understanding the scope of MH supports needed to service CPS-involved families. Further, the variations observed among CPS contact across the different types of MH disorders have implications for the development of child safety and risk-assessment tools and case-related decision making .Third, for a majority of infants born to mothers with MH diagnoses who experienced a CPS report, the first report was made during the first month of life. This early reporting pattern indicates that those making a report to CPS were concerned about the mother’s capacity to care for her infant shortly after delivery and responded proactively. One could argue that high rates of CPS reporting immediately following childbirth may be more indicative of preconceptions about mental illness than of actual risk to a child’s safety. However, results from the present study also indicate that mothers with MH disorders who were not reported to CPS immediately following childbirth still had a comparatively higher occurrence of CPS reports by the infant’s first birthday compared with infants born to mothers without a MH diagnosis. This finding supports earlier work suggesting that maternal mental illness may have a lasting impact on an infant’s safety and wellbeing . The decFinally, the present study highlights the risk associated with co-occurring MH and substance abuse diagnoses. Previous literature has documented an association among child maltreatment, parental mental illness , and subThere are at least four limitations to this study. First, ICD codes are an imperfect measure of maternal mental illness, as all administrative data analyses are limited by errors in data entry , suggestInfants born to mothers with a diagnosed MH disorder at the time of birth have a heightened likelihood of experiencing early CPS involvement, particularly in infants born to mothers with psychotic disorders or with a comorbid substance use disorder. CPS reports are most likely to occur during the child’s first month of life, making this a critical window for intervention. Early identification of infants born to mothers with MH disorders and co-occurring substance abuse should be viewed as an opportunity to provide parents with integrated support services early to prevent the occurrence of child maltreatment. Administrative records provide a cost-effective method for developing population-level data to inform policy development and improve service delivery.


Staphylococcus, Enterococcus, Enterobacter, and finally Bifidobacterium. The Enterococcus phase was only observed among the extremely premature infants and appeared to delay the microbiota succession. The results indicate that hospitalized preterm infants receiving breast milk may develop a normal microbiota resembling that of term infants.The intestinal microbiota is an important contributor to the health of preterm infants, and may be destabilized by a number of environmental factors and treatment modalities. How to promote the development of a healthy microbiota in preterm infants is largely unknown. We collected fecal samples from 45 breastfed preterm very low birth weight (birth weight < 1500 g) infants from birth until 60 days postnatal age to characterize the intestinal microbiota development during the first weeks of life in preterm infants. Fecal microbiota composition was determined by 16S rRNA amplicon sequencing. The main driver of microbiota development was gestational age; antibiotic use had strong but temporary effects and birth mode had little influence. Microbiota development proceeded in four phases indicated by the dominance of  Preterm infants have an immature intestine with underdeveloped peristalsis, barrier function and immunity, which makes the intestine a potential source of infections and inflammation3. Several studies have shown that the intestinal microbiota in preterm infants differ from that of healthy term infants11. Common anomalies are the bloom of opportunistic and potentially pathogenic bacteria such as Enterobacter, Enterococcus, and Staphylococcus7. Many common practices, caesarean section14, antibiotic use15, and formula feeding16, may disrupt normal microbiota development. Moreover, studies with small groups of infants have indicated that both NEC and late-onset sepsis are associated with alterations in the microbiota11, and that the microbiota composition correlates with signs of pain and distress17. Modification of the microbiota by probiotics or breast milk may reduce the risk of NEC in preterm infants19. Thus, promoting a healthy microbiota development in preterm infants is important, and a key question is whether natural colonization and succession of the microbiota is possible in these infants. For rational decision-making and consideration of therapies in the future, information on the microbiota development in preterm infants is essential. Although studies on the preterm microbiota have been conducted11, they involve only a handful of infants and none show detailed microbiota succession.Prematurity is a risk factor for infant morbidity and mortalityTo establish a defined and predictive picture of the preterm infant microbiota development, we analyzed 262 fecal samples from 45 preterm infants using deep 16S rRNA amplicon sequencing.20.The samples were collected during a randomized controlled trial conducted in 2010 at Akershus and Oslo University Hospitals, Norway. The study was approved by the Regional Committee for Medical and Health Research Ethics, Norway (Reference number: 2009/1946) and performed in accordance with the principles of the Helsinki Declaration. Written informed consent was obtained from the parents. The study was registered in Clinical Trials (registration number NCT01103219) on 12. April 2010. The trial was designed to investigate the effect of enhanced nutrient supply to very low birth weight infants  as previously described20. Twenty-one infants were classified as extremely premature (EP) and 24 as moderately or very premature (MVP). Caesarean delivery was common, especially in the MVP group , critically sick mother/sibling (3), congenital anomaly (1) and omissions during enrollment (2). Thus, 50 infants were included in the trial. Three infants died during the first weeks of life and two infants were excluded due to critical illness and congenital heart disease. Hence, 45 VLBW infants were included in the present study investigating the microbiota development. Twenty-four of these infants received enhanced nutrient supply, i.e. increased supply of energy, protein, fat, the long-chain polyunsaturated fatty acids (PUFA) and vitamin AFour types of antibiotics were given to the infants: aminoglycosides  usually combined with ampicillin/ekvacillin (N = 26), and vancomycin (N = 6) usually combined with cephalosporin (N = 12). Ampicillin and cephalosporin were not given alone. The antibiotics were all given intravenously. Vancomycin was not given to any of the infants during the first 10 days of life.Fecal samples were collected from diapers at different intervals from birth until discharge from the hospitals . The median (range) number of samples per infant was 6 (2–11). Fresh samples were collected from diapers and frozen at −80 °C until analyzed. In total 262 fecal samples were analyzed.21, which utilizes USEARCH22 for quality filtering, clustering of reads into species-like operational taxonomic units (OTUs), and taxonomic annotation. The analysis procedure was validated using artificial microbial communities of known composition21. Specifically, we assessed how the observed microbiota composition depended on read length. We found that the forward reads trimmed to 100–150 nucleotides resulted in better correspondence to the actual composition in the artificial communities than using long, merged paired-end reads , which summarizes the multivariate microbiota data into a few variables, was conducted using Bray-Curtis dissimilarities with the R-package vegan23. Associations between the most abundant bacterial groups with the host factors postmenstrual age, postnatal age, and birth mode  as well as antibiotic courses (aminoglycoside or vancomycin) were tested using generalized additive mixed models (GAMM), with negative binomial error distribution (function gam in the package mgcv24), subject ID as the random variable, and the number of reads as the offset.The statistical analyses were conducted using the R package marehttp://www.ebi.ac.uk/ena).The data are available in Supplementary Table 25 in which 9 fecal samples were collected from 187 infants during the first 15 postnatal weeks .To compare the microbiota development in the premature infants to the microbiota in term-born healthy infants, we included previously reported 16S rRNA–based microbiota composition data from a Dutch infant cohortBifidobacterium, Enterobacter, Staphylococcus or Enterococcus, represented >50% of the reads in a given sample  and even more clearly with postmenstrual age . After adjusting for postmenstrual age, postnatal age explained only 2% of the variation (p = 0.002). With increasing postmenstrual age, the infants progressed from Staphylococcus-Enterococcus-dominated composition to Enterobacter and finally towards Bifidobacterium-dominated microbiota , which explained 20% of the variation in Staphylococcus abundance, while postnatal age explained an additional 8% of the variation (p < 0.0001). Vaginally born infants had a higher abundance of Staphylococcus, although birth mode explained only 1% Staphylococcus abundance (p = 0.004). Individuality covered 8% of the variation in Staphylococcus (p = 0.016).Phase 1 was nts Fig. . The abuEnterococcus dominance, peaking at 30 weeks and ending by 35 weeks postmenstrual age . Enterococcus abundance showed high individuality, subject ID explaining 30% of the variation (p < 0.0001).Phase 2 was age Fig. . PostmenEnterobacteriaceae dominance (mainly genus Enterobacter in the preterm infants), peaking on average at 35 weeks postmenstrual age , and postnatal age explained 4% (p = 0.22). Vaginal birth was associated with lower abundance of Enterobacter .Phase 3 was age Fig. . The terBifidobacterium, which began to develop gradually after 30 weeks postmenstrual age. Postmenstrual age explained 11% of the variation in Bifidobacterium abundance (p < 0.0001), and postnatal age explained 5% (p = 0.39). There was considerable individuality in Bifidobacterium abundances, ID explaining 24% (p < 0.0001), while birth mode explained 1% (p = 0.22).Phase 4 was characterized by a high abundance of To assess the effect of antibiotic treatments on the microbiota, we focused on the period before and after antibiotic courses, and estimated the effect of aminoglycoside and vancomycin antibiotics after adjusting for postmenstrual age, postnatal age, and birth mode. The responses to the antibiotics were generally temporary and the microbiota appeared to recover within days Fig. . FurtherIn terms of total DNA, microbiota richness, and microbiota development index, 37% of the infants responded temporarily to aminoglycoside  is given.Unlike most previous studies, our cohort included many infants with a fairly normal microbiota development, achieving high abundance of bifidobacteria. All infants in our study received human milk from the first days of life. Breast milk feeding is known to increase the abundance of bifidobacteria in infantsEnterococcus. Future research on interventions to improve the microbial colonization in extremely premature infants and infants with patterns indicating abnormal developmental patterns, could improve short- and long-term outcomes.Our results suggest that normal-like microbiota development in preterm infants in the hospital setting is possible, particularly among moderately premature infants receiving breast milk. In the extremely premature infants, development appeared to be disrupted by persistently increased abundance of Supplementary InformationSupplementary Table 1


To analyze perinatal features of children with autism spectrum disorder (ASD).th minute Apgar score <7). Data were analyzed using the difference between proportions test, being significant p<0.05. Retrospective review of the medical records of 75 children with ASD, between January 2008 and January 2015. Inclusion criteria were diagnosis of ASD based on DSM-5 criteria, and the informed consent form signed by the person who is legally responsible. The exclusion criterion was missing on the medical record. The variables analyzed were maternal age, prematurity , low birth weight , and perinatal asphyxia . Premature birth occurred in 14 (18.7%) patients, perinatal asphyxia in 6 (8.0%), and low birth weight in 32 (42.6%) patients. The prevalence of prematurity, low birth weight, and perinatal asphyxia among the children in our study was higher than the general prevalence of these conditions among all live births in our country, region, and state, which are, respectively, 11.5, 2.3, and 8.5% in Brazil; 11.0, 2.2, and 8.5% in Southern Brazil; and 10.5, 2.0, and 8.4% in the state of Paraná.  Our findings show a higher prevalence of prematurity, low birth weight, and perinatal asphyxia among children with ASD. Some limitations are the retrospective study design, and the small sample size. Large prospective studies are needed to clarify the possible association between perinatal complications and ASD. Genetic and environmental factors interact, and reveal a multifactorial disorder.,,,,,,,,The dramatically increased survival rates for preterm infants in the previous decade highlight concerns regarding the long-term neurologic effects of preterm birth. Premature birth has repeatedly been found to increase the risk of ASD.,Low birth weight is a condition that has a direct association with prematurity. However, there is evidence that being a low birth weight neonate is an independent risk factor for the development of ASD, especially if the infant was small for gestational age (SGA).Given the rise in ASD prevalence, significant related morbidities and its impact in life quality, it is fundamental to investigate risk factors and possible etiologies that may contribute to an early diagnosis and intervention. The goal of our research is to describe perinatal features of children with ASD, which has been previously associated with its etiologyWe retrospectively reviewed the medical records of all the children with ASD admitted to one of the Neuropediatrics’ ambulatory care centers of Pequeno Principe Hospital, in Curitiba, Brazil, between January 2008 and January 2015, evaluating them for perinatal features. This was a convenience sampling. In order to be included in the study, the participants had to have a diagnosis of ASD based on DSM-5 clinical criteria, established by an expert clinical evaluation, as well as the informed consent form signed by the person who is legally responsible. The exclusion criterion was missing on the medical record. All the 75 children admitted to the ambulatory met the criteria. Sample size calculation was not performed.Clinical variables included maternal age at the time of the infant’s birth, prematurity, defined as gestational age under 37 weeks at birth, low birth weight , and perinatal asphyxia, defined as Apgar score lower than 7 at the 5th minute after birth. These data were precisely registered on the patients´ medical records on the occasion of the first visit, and it was collected from the child´s personal health record in the hospital of birth. Other variables, regarding pregnancy and peripartum period, such as gestational bleeding, gestational diabetes, maternal infections, cesarean section, and abnormal presentation were not available in the patient´s medical records, and therefore were not analyzed in this study. We also did not have information about paternal age and some neonatal comorbidities, such as intracranial bleeding, seizures, or time spent in neonatal intensive care unit. All patients underwent magnetic resonance imaging (MRI) of the brain.We then compared the prevalence of prematurity, low birth weight, and perinatal asphyxia among the children with ASD in our study, with the prevalence among all the live births in the year 2013 in the State of Paraná, as well as in the southern region of Brazil, and in the whole country. Statistical analysis was performed using the difference between proportions test (5% significance level). The tests were conducted by statistical software .The local Ethics Committee on Research Involving Human Subjects (number registration - 44905015.0.0000.0097) approved all aspects of this research.From January 2008 to January 2015, 75 patients with ASD were admitted to one of the Neuopediatrics’ ambulatory care centers of Pequeno Principe Hospital, in Curitiba, Brazil, and all of them were included in the study. Of them, 28 (37.3%) were female and 47 (62.7%) were male. The age at diagnosis ranged from 12 to 58 months (33.7±12.2 months). Maternal age at pregnancy ranged from 21.4 to 38.6 years (29.8±4.1 years).Premature birth occurred in 14 (18.7%) patients: birth at 26 weeks , at 28 weeks , at 30 weeks , at 32 weeks , at 33 weeks , at 34 weeks , and at 35 weeks . Perinatal asphyxia occurred in 6 patients (8.0%). The two conditions were associated in three patients. Low birth weight occurred in 32 (42.6%) patients. Fourteen patients who were low birth weight newborns were also premature. None of the patients presented congenital malformations.p=0.044 and 0.034, respectively). Comparing the prevalence of preterm births in Brazil with the prevalence among children with ASD in the study, the prevalence of preterm birth was also higher among children with ASD, but there was no significant difference (p=0.055).According to SINASC data, the prevalence of prematurity among all live births in Brazil, in Southern Brazil, and in the State of Paraná in the year 2013 was 11.5, 11.0, and 10.5%, respectively.p=0.034, 0.032, and 0.028, respectively).The estimated prevalence of perinatal asphyxia in Brazil, in Southern Brazil, and in the State of Paraná in the year 2013 was 2.3, 2.2, and 2.0%, respectively.p=0.000) for each of the regions analyzed. We also did the same analyses with the low birth weight newborns in our study group who were not premature (18 patients), and obtained the same results (p=0.000).In the year 2013, 8.5% of the neonates in Brazil were born with less than 2,500 g. The prevalence was exactly the same in Southern Brazil, and very close in the State of Paraná (8.4%). When we compared these numbers with the prevalence of low birth weight infants in our study, we find very significant differences (All patients included in the study underwent MRI examination of the brain. In 19 (25.3%) patients, the MRI was reported to be abnormal. Seventeen of these patients were premature and/or had suffered perinatal asphyxia. The follow abnormalities were found: cerebral atrophy , agenesis of the corpus callosum , multicystic encephalomalacia , periventricular leukomalacia , agenesis of the corpus callosum and cerebral atrophy , hydrocephalus and cerebral atrophy , periventricular leukomalacia and cerebral atrophy , periventricular leukomalacia and gliosis in the left frontal lobe , and periventricular leukomalacia and hydrocephalus .,,,The exact cause of autism spectrum disorder is unknown, but it is thought to be associated with an interaction of genes and environmental factors.,,in utero environment, due to endocrine and hormonal factors, which can lead to more obstetrical complications.,,,,,,,,,,,Advanced maternal age is one topic of interest often studied as a risk factor for ASD, and it is related to both genetic and environmental risk factors.A recent meta-analysis supported an association between advanced maternal age and risk of autism. The relative risk of autism in mothers aged 35 years or older compared with mothers aged 25-29 years was 1.52.,,,,,Many studies have examined the association between prematurity and the development of ASD.,,,On the other hand, it is unclear whether ASD is related to prematurity itself or to prematurity-related comorbidities.p=0.055, 0.044, and 0.034, respectively). However, we did not have information about perinatal comorbidities, so we could not do an adjusted analysis for these factors.In our study, the prevalence of prematurity among autistic children was higher than the general prevalence of prematurity in our country, region, and state .Another fact that supports the idea that early brain insult could predispose to ASD is the association between perinatal asphyxia and ASD, suggested in many studies.p<0.001). This is in accord with what has been demonstrated in previous studies.,,,p=0.029). SGA infants had a 70.0% increased odds for autism compared with adequate for gestational age infants .The prevalence of low birth weight infants in our study was much higher than the general prevalence in our country, region, and state (p=0.000). These findings suggest that low birth weight may possibly be associated with ASD, independent of prematurity. We did not have access to data for SGA prevalence in our country, and therefore we did not include this variable in our analysis.Still regarding birth weight, when we analyzed only the group of low birth weight infants who were not premature (18 patients), we also obtained significative differences comparing to the general population (The 17 patients with prematurity and/or perinatal asphyxia in our study showed abnormalities on MRI. The emerging literature of structural and functional neuroimaging in autism may reveal some underlying abnormalities of the central nervous system.Our findings suggest that prematurity, perinatal asphyxia, and low birth weight may be associated with ASD, strengthening the theory that early brain injury is involved in the pathogenesis of autism. This is of prime importance, since these conditions are modifiable risk factors. However, the fact that this is a retrospective study and we had a convenience sample, a small sample size, and did not have a control group should lead to some limitations in our conclusions. Also, confounding factors that we could not evaluate must be considered. In fact, one of the difficulties in studying perinatal features is that many of the variables are not independent from each other. Large prospective, population-based studies may help to confirm the findings of our study, as well as to identify modifiable risk factors, to then allow early interventions, aiming at the reduction of the current increasing prevalence of ASD.


Ectopia cordis is a congenital heart exposure defined as complete or partial protrusion of heart through ventral defect in the thoracoabdominal wall alone or with other viscera in cases of pentalogy of Cantrell. This condition was first described by Haller et al. in 1706; since then many advances have been made. Diagnosis of ectopia cordis is done prenatally in well-equipped health facility by antenatal ultrasound scan so that early diagnosis and management plan can be initiated. The index case was delivered to uneducated rural family and admitted at 3 days of life and survived for seven days, even though most literatures state that majority died within four days even with surgery. So, in view of this, we presented this case report to deliberately draw the attention of paediatrician/obstetrician to the fact that even though this condition is rare, proactive search and diagnosis should be made and early treatment should be instituted, so that such a child may be salvaged. Ectopia cordis (EC) is a rare congenital cardiac malformation defined as a defect in the anterior chest wall and abdominal wall with abnormal placement of the heart outside the thoracic cavity with associated defect in the parietal pericardium diaphragm, sternum, and in most cases cardiac malformations . EctopiaDespite advances in neonatal cardiac surgery, complete thoracic/thoracoabdominal ectopia cordis remains a surgical challenge with only few long-term survivors –10. We pB. F. M., an 11-day-old female neonate, admitted to the Special Care Baby Unit (SCBU) of University of Maiduguri Teaching Hospital, Maiduguri, Northeastern Nigeria, as referral case from Level II Hospital  with complaints of protrusion of heart through the anterior chest wall defect at birth. There was no history of bleeding or discharge from the site. There was no history of difficulty in breathing or cyanosis. The child was fed with expressed goat milk via feeding bottle as she could not be placed on direct breast-feeding due to her condition. There was no history of other malformations or defect in other parts of the body and there was no family history of congenital defect. There was no maternal history of ingestion of unprescribed medications, use of illicit drugs, cigarette smoking, or alcohol abuse. The mother also had no history of chronic ill health. Their source potable water is from cement well.Baby was delivered at home and attended to by traditional birth attendant without complications and she cried well at birth but with heart beating outside the chest wall and cord care with warm compression using wet rag and salt. Baby was the 3rd born of 3 children in a monogamous consanguineous marriage. Father is a 36-year-old rural subsistent farmer; both parents had no formal education.Examination finding at admission revealed an acutely ill-looking neonate who was globally pink and she was febrile with temperature of 37.7°C and she was anicteric and not dehydrated. She weighed 3.2 kilograms; length was 47 cm and head circumference was 33 cm.Diseased Organ. There was a midline anterior chest wall defect measuring 6 by 4 cm in the craniocaudal and horizontal diameters extending in between the nipples and there was an ulcer extending from the defect to the umbilical stump. The whole of the heart with irregular contour was outside the thoracic cavity leaving only the major vessels in the chest wall as seen in The neonate was dyspnoeic and tachypnoeic respiratory rate was 98 CPM; there was good air entry. Heart rate was 162 BPM; heart sound was 1st and 2nd only; there was no murmur heard. Abdominal examination was unremarkable with well-formed female external genitalia. She was conscious and alert, anterior fontanelle was patent, no other midline defects were identified, and primitive reflexes were normal with good tones.9/L, neutrophil = 56, lymphocyte = 40, basophil = 2, and monocyte = 2. Platelets = 400 × 109/L. E is electrolytes, U is urea, and C is creatinine; Na+ = 136 mmol/L, K+ = 3.4 mmol/L, Cl− = 98 mmol/L, HCO3− = 17 mmol/L, urea = 9.8 mmol/L, creatinine = 227 mmol/L, and Ca+ = 2.1 mml/L. Wound swab microscopy culture and sensitivity and blood culture yielded no bacterial growth.Working diagnosis of ectopia cordis to rule out pentalogy of Cantrell with presumed sepsis was made. Packed cell volume was 51%, WBC = 7.4 × 10Patient was commenced on cefuroxime, gentamycin, and metronidazole. Surgical consultation with cardiothoracic surgery was done at admission, while the protruding heart was covered with antibiotic impregnated (Sofra-Tulle) gauze as seen in Figures Ectopia cordis (EC), a congenital extrusion of heart through a defect on the anterior chest wall, currently has no known aetiology and most cases are sporadic . The devComplete or incomplete failure of midline fusion at this stage results in disorders varying from isolated EC to complete ventral evisceration. Genesis of EC has not been fully explained, although several theories have been offered. Popular theories are early rupture of the chorion and/or yolk sac and amniotic band syndrome , 13–15. The spectrum of defects corresponds to the timing of rupture. The findings in the literature suggest that rupture in the third week of gestation causes an arrest of cardiac descent which may be the cause of EC. Ectopia cordis with amniotic bands appears to be distinct from isolated EC. This suggests different aetiologies for ectopia cordis; such aetiologies like exposure to intrauterine drug use have been documented in literatures –17. The The various clinical types of EC have different prognosis. Cervical and thoracic ectopia is usually fatal within days, because the heart is exposed and malformed; however, our case had thoracoabdominal ectopia cordis. Abdominal ectopia cordis carries a better prognosis, probably because intracardiac abnormalities are rarer and the absence of omphalocele reduces the morbidity and mortality . EctopiaThe syndromic form known as pentalogy of Cantrell is extremely rare and usually incompatible with life; because of this, its exact incidence is not found in literature. In this condition, the heart is uncovered in 41%, covered with serous membrane in 31%, and covered with skin in 27% in a particular case series –24. In oOn the bases of embryological development, this syndrome is classified into two groups. The first group arises as a result of developmental failure of a segment of the mesoderm and comprises three of the defects, which include diaphragmatic defect , pericardial defect (which is closely related to faulty development of the transverse septum), and intracardiac lesions  , 22, 24.The second group includes the sternal and abdominal wall defect and appears to arise due to failure of migration of the paired primordial structures. Many variants of Cantrell's pentalogy have been described according to postulated embryological development of these defects , 25, 26.The prenatal diagnosis of ectopia cordis is carried out using ultrasound, which allows visualization of the heart outside the thoracic cavity. The diagnosis as reported by Bick et al.  and TongWhile ectopia cordis is generally considered to be an isolated, sporadic malformation, there have been a number of reports linking it to chromosomal abnormalities. Reported karyotype abnormalities include trisomy 18, Turner syndrome, 46,XX, and 17q+ . Carmi aThe ultimate management of the condition is surgical correction. The first attempted repair of ectopia cordis was performed in 1925 by Cutler and Wilens,  and KoopThe staged repair with the initial intervention is aimed at providing soft tissue coverage of the heart. If primary approximation with skin flaps cannot be achieved or if there is any haemodynamic compromise, then a split-thickness skin graft, cadaveric skin graft, or prosthetic materials can be sutured to the skin edges. The defect can then be reduced slowly over the ensuing weeks , 27, 36.The reduction of the heart into the thoracic cavity is carried out at a subsequent stage , 33. SimIn literature, most of the patients died within 4 days following surgical intervention whether the case was isolated ectopia cordis or pentalogy of Cantrell, while our patient, a case of isolated ectopia cordis, survived for 10 days before she died; to our minds, we failed the child; we failed to give her a chance to live despite giving us enough time to salvage her.In conclusion, this index case of EC survived for 10 days, and if aggressive surgical procedures were carried out without delay in the believe that this may enhance survival, probably this child could have lived. Ectopia cordis is a rare congenital malformation with a poor prognosis. Antenatal ultrasound scan is of great value in the prenatal assessment of this defect. The defect should be precisely located and its classification should be accurately determined; in view of the different types of ectopia cordis, even if the overall prognosis is not rewarding, their surgical approach varies as well as the ultimate outcome. The health care delivery in developing countries is poorly funded as consequence of poor policy formulation and implementation, thereby leaving it ill equipped, which might have contributed to the outcome of the index patients; otherwise this patient probably should not have died if our centre had facility for cardiac surgery. Therefore, this case report is another lesson to ponder upon so that the next child with ectopia cordis should not suffer the same fate.


Although birth weight is considered as a fetal determinant of the development of adult-onset diabetes mellitus (DM), its public health importance relative to adult body mass index (BMI) remains unclear. We aimed to examine the association between adult-onset DM and birth weight in relation to adult BMI.We conducted a self-administered questionnaire as a baseline survey of the Japanese Nurses' Health Study cohort between 2001 and 2007. Exclusion criteria were applied to the volunteer sample of 49,927 female nurses , and data from 26,949 female nurses aged 30 years or older were used. The association between history of DM diagnosis and birth weight was analyzed using logistic regression.A linear inverse association was observed between birth weight and DM, after adjustment for age, BMI, and parental history of DM. The odds ratio for developing DM per 100 g increase in birth weight was 0.93 . The association was unchanged when birth weight was converted to percentile for gestational age. In the BMI-stratified analysis, the odds ratio for DM in the <2500 g birth weight group reached 4.75  among women with normal low BMI (18.5–20.9).Birth weight and its percentile for gestational age were associated with adult-onset DM. Attention should be paid to the risk of DM among women born with low weight, even when their current BMI is normal. •Association of birth weight and adult-onset DM was analyzed using JNHS study data.•Odds ratio for developing DM per 100 g increase in birth weight was 0.93.•The link was also observed when birth weight percentile for gestational age was used.•Low birth weight was associated with adult-onset DM, even with normal current BMI. Adult-onset diabetes mellitus (DM) is a major global medical burden. Globally, an estimated 1.3 million deaths were attributed to DM in 2010, twice as many as in 1990.The association between birth weight and adult-onset DM is biologically explained as an adaptation to intrauterine undernutrition.In Japan, the prevalence of low birth weight has been increasing. According to the national statistics from 2012, the proportions of infants with a birth weight of less than 2500 g were 8.5% in males and 10.7% in females. These proportions were almost double those from 1980 .The present study aimed to examine the association between adult-onset DM and birth weight using data from a cohort of Japanese female nurses. To clarify the meaning of the association in the practice of public health and obstetrics, current BMI categories were used as adjustment, stratification, or combined independent variables, and the effect of birth weight for gestational age was examined using percentile score based on fetal growth curve.The baseline data from the cohort of the Japanese Nurses' Health Study (JNHS) were used. JNHS is an ongoing prospective cohort study in female nurses that was started in 2001.2), and maternal or paternal history of DM.The variables used in the present study were history of adult-onset DM diagnosis, birth weight , current BMI . To examine the effect of large birth weight in detail, an additional analysis was done in which the highest birth weight group was divided into two categories (3500–3999 g and ≥4000 g).Logistic regression analysis was performed with adult-onset DM status as the dependent variable and birth weight as the independent variable. An age-adjusted model, an age- and current BMI-adjusted model (model 1), and a model additionally adjusted for maternal/paternal history of DM (model 2) were applied. Stratified analyses were performed according to BMI, presence or absence of maternal/paternal history of DM, and smoking status. The 3000–3499 g birth weight category was used as the reference. Because there were few women in the BMI category of <18.5 kg/m2). The combined category of BMI of 18.5–20.9 kg/m2 and birth weight of 3000–3499 g was used as a reference to calculate odds ratios because the category was most frequent within the normal or ordinary range.In order to compare the effects between birth weight and BMI, a model using a combination of birth weight and current BMI as the independent variable was applied. The participants were classified into a total of 16 categories according to the combination of the four birth weight categories and the four BMI categories , 70th–89th, and ≥90th.In order to check the validity of the outcome variable, sensitivity analysis was performed using a dependent variable of DM defined by a combination of data, including a fasting plasma glucose level of ≥126 mg/dL and the use of DM drugs, obtained from the baseline questionnaire survey. Analysis including only women with DM diagnosed within the previous 3 years was also done.Ethical approval for the study was obtained from the Ethics Review Committees of the Faculty of Medicine, Gunma University and the National Institute of Public Health.p < 0.001). The mean gestational age increased as birth weight increased . There was a U-shaped association between current BMI and birth weight , and the 2500–2999 g birth weight group had the lowest current BMI. Current smokers accounted for approximately 18% of the participants, and the number of current smokers tended to be larger in groups with a higher birth weight . The proportion of women with adult-onset DM ranged from 0.6% to 1.6%, and was smaller in the groups with a higher birth weight . The number of women with a paternal history of DM tended to be smaller in the groups with a higher birth weight, whereas the number of women with a maternal history of DM tended to be larger in the groups with a higher birth weight . Women with a maternal history of DM accounted for 9.5% and 12.9% of those with a birth weight of 3500–3999 g and ≥4000 g group, respectively, whereas the percentages were 7%–8% for those with a birth weight less than 3500 g.p = 0.013), with a significant odds ratio of 4.75  for the birth weight <2500 g compared with the reference birth weight group (3000–3499 g). Although without statistical significance, the BMI groups between 21.0 and 24.9 kg/m2 also showed a similar tendency . Among the women with a BMI of 27.0 kg/m2 or higher, the prevalence of DM was significantly higher in the <2500 g, 2500–2999 g, and ≥3500 g birth weight groups than the reference birth weight group, with point estimates of odds ratios exceeding 2.0. The trend indicating a lower prevalence of DM in those with a higher birth weight was also shown in analyses according to the presence or absence of paternal history of DM and smoking status. The analysis according to maternal history of DM revealed a significant association between birth weight and DM status only in women without a maternal history of DM . Interaction between parental history of DM and birth weight was significant for maternal but not paternal history of DM . Regarding the factors other than body weight, the age-adjusted odds ratio of paternal history of DM, maternal history of DM, and current smoking was 3.48 , 3.73 , and 1.02 , respectively.2 or higher had a significantly higher DM prevalence regardless of their birth weight, with an odds ratio exceeding 13.0 compared with the reference group with a birth weight of 3000–3499 g and a BMI of 18.5–20.9 kg/m2. The maximum odds ratio reached 40.4  for those with a birth weight of <2500 g and a BMI of >25.0 kg/m2. Women born with a birth weight of less than 2500 g had significantly higher prevalence of DM than the reference group, regardless of their current BMI.p = 0.001). Compared to the group at the 30th–69th percentile of birth weight, the odds ratios for developing DM were 1.63 in the group at the 10th–29th percentile  and 2.59 in the group below the 10th percentile . This trend persisted in the analysis that included only women born at full term. The analysis on birth weight percentiles according to the BMI categories revealed that, even among women with normal BMI (22.0–24.9), the prevalence of DM was significantly higher in women with a lower birth weight percentile . Among women with a normal but small BMI (18.5–21.9), the prevalence of DM was significantly higher in the <10 percentile category, with an odds ratio 3.01 . The trend indicating a lower prevalence of DM in those with a higher birth weight percentile was also shown in analyses according to the presence or absence of paternal history of DM. Similar to the result of the analysis of birth weight categories per se, the analysis according to maternal history of DM revealed an association between birth weight percentile and DM status only in women without a maternal history of DM. Interaction between parental history of DM and birth weight percentile was significant for maternal but not paternal history of DM . Regarding smoking status, a significant association between birth weight percentile and DM was observed in never smokers alone.p = 0.006, after adjustment of age, BMI, and parental DM history). Moreover, analysis that included only women with DM diagnosed within the previous 3 years revealed the same results .In the sensitivity analysis about the dependent variable of DM, using a combination of a fasting plasma glucose level of ≥126 mg/dL and the use of DM drugs revealed a similar inverse association between birth weight and DM  per 100 g increase in birth weight adjusted for age, current BMI, and parental history of DM corresponds to an odds ratio of 0.48 per 1 kg increase . This indicates a more substantial association than that found in the meta-analysis reported in 2010 .2), the risk of DM is high regardless of birth weight, whereas women with a normal BMI tended to have a high risk of DM when they were born with a low birth weight or their birth weight was small for gestational age. In Japan, at present, obesity is defined as a BMI of ≥25.0 kg/m2, and preventive measures against lifestyle-related diseases, including DM, are implemented at this BMI level. The results of the present study show the importance of being aware of the increased risk of DM in adults with a lower birth weight even when their BMI is within a normal range.The association between birth weight and adult-onset DM was different according to BMI in adulthood. Specifically, in overweight adults . Given the fact that the prevalence of low birth weight has recently been increasing in Japan,In the present study, the younger the participants were, the higher birth weights they tended to have . This isThe strength of the present study is that the women were widely distributed throughout Japan and were healthcare workers.The limitations of the present study include the cross-sectional study design, which restricts our ability to make causal inference. However, the inversion of cause and effect is unlikely to occur, because the onset of DM occurred long after birth, and the association between birth weight and DM is not established well enough to bias the participants' reports. Although it has been pointed out that adjustment for BMI may lead to a false association between birth weight and adult DM,p < 0.001). For 24 women who provided written records  in the validity survey, the consistency of birth weight categories between these records and the responses to the baseline survey was also high . These results show a sufficiently high accuracy of self-reported birth weight data in the female nurses included in this study.The validity of self-reported birth weight data was examined in a subsample of participants from the present study. In 120 women who provided birth weight in both the baseline survey and the validity survey, the test-retest consistency of birth weight was high  Grants-in-Aid for Scientific Research (24501367 and 18390195).This work was supported by None declared.Kota Katanoda: Conception and design, analysis, interpretation of data, and drafting the article. Mitsuhiko Noda, Atsushi Goto, Hideki Mizunuma, Jung Su Lee: Interpretation of data, and revising the article. Kunihiko Hayashi: Conception and design, interpretation of data, and revising the article.


The charge transfer, electric potential, band structure and magnetism of the pure and Cr doped Bi2Se3 film have been investigated. It is found that the competition between charge transfer and spin-orbit coupling (SOC) will lead to an electrically tunable band gap in Bi2Se3 film under external electric field. As Cr atom doped, the charge transfer of Bi2Se3 film under external electric field obviously decreases. Remarkably, the band gap of Cr doped Bi2Se3 film can be greatly engineered by the external electric field due to its special band structure. Furthermore, magnetic coupling of Cr-doped Bi2Se3 could be even mediated via the control of electric field. It is demonstrated that external electric field plays an important role on the electronic and magnetic properties of Cr-doped Bi2Se3 film. Our results may promote the development of electronic and spintronic applications of magnetic topological insulator.External electric field control of topological surface states (SSs) is significant for the next generation of condensed matter research and topological quantum devices. Here, we present a first-principles study of the SSs in the magnetic topological insulator (MTI) Cr-doped Bi This is due to the movement of electrons in the opposite direction of electric fieldet al. also reports that external electric field can close or reopen a gap for surface states of Bi2Se3 filmet al. even revealed that electric field can induce a quantum phase transition in the magnetic topological insulators2Se3 is still inconsistent. The efficient electric-field control of the electronic and magnetic properties in insulating Cr-doped Bi2Se3 remains elusive.The ability to modulate the band gap of Cr-doped Bi2Se3 film under external electric field. We find that the dopant of Cr atom can reduce the transfer of electrons in Bi2Se3, as well as the movement of atoms caused by the application of electric field. The band gap of the pure Bi2Se3 film under electric field is determined by the competition between the electrically tunable charge transfer and Rashba SOC. Significantly, the band gap of Cr-doped Bi2Se3 film can be engineered by the external electric field, due to the change of charge transfer and magnetism.In this paper, we performed a first-principles calculation within density functional theory (DFT) to investigate the pure and Cr-doped Bi2Se3 has a rhombohedral structure and is formed by stacking of weakly coupled quintuple layers (QLs) along its (001) direction. The order of layers in QLs is Se(1)-Bi-Se(2)-Bi-Se(1). It is previously revealed that the thicker the Bi2Se3 film is, the more sensitive to the external electric field2Se3 film becomes larger than 3QL, the band gap drastically reduces as the external electric field applied. Accordingly, the thickness of 3QL where the SSs appears is considered in this study. 2Se3 film. The lattice constant of a = b = 4.138 Å, c = 28.64 Å taken from the experimental data is chosen for the hexagonal Bi2Se3 (001) film of 3 QLs. In order to discuss the charge transfer and its response to the external electrical field, QL1, QL2 and QL3 are labeled, representing the upper, middle and lower surfaces, respectively. The outermost Bi atom from the upper surface is substituted by Cr atom, as illustrated in Crystalline Bi2Se3 SSs and Cr-doped Bi2Se3 SSs. It is well known that the radius of Cr atoms is smaller than Bi atoms. Hence the substitution of Cr renders that each layer of the QL1 approaches it. The thickness of QL1 decreases from 7.084 Å to 6.113 Å after doping (see 2Se322θ) of each QL and the distance (d) between QLs with the electric field of 0 and 0.1 V/Å. We can find that, under the same electric field of 0.1 V/Å, the atom structure of the pure Bi2Se3 film undergoes an obvious change, while the doped film remains constant. It suggests that the atom structure of the doped system is more robust against the external electric field. As shown in 2Se3 3QLs film under electric fields of 0 and 0.1 V/Å, respectively. For the pure 3QL-Bi2Se3 film, the APEPs of two surfaces have the same value of 6.0 eV. As the external electric field is applied (Eext = 0.1 V/Å), the upper and the lower surfaces have different APEPs of 3.6 eV and 8.2 eV, respectively. In the Cr doped case, the APEPs of two surfaces slightly reduce to 5.6 eV when Eext = 0 V/Å. While for the electric field of 0.1 V/Å, the upper and the lower surfaces have less difference than the pure case. The calculated APEPs in Cr doped Bi2Se3 are 5.0 eV and 6.3 eV for the upper and the lower surfaces, respectively. This result reflects that the upper surface QL1 undergoes an accumulation of electrons, while the lower surface QL3 exports electron when the external electric field is applied toward QL3. The electric potential difference of two surfaces is about 4.6 eV in the pure case, which is larger than that in the doped case with a value of 1.3 eV. It suggests that the doping of Cr in Bi2Se3 film will reduce the charge transfer caused by external electric field. For the robust atomic structure and the suppression of charge transfer in the Cr doped Bi2Se3 under the electric field, the main reason can be the movement of each atom in QL1 in ward to the Cr atom. As a result, the covalency of the chemical bonds of QL1 is enhanced, leading to a local redistribution of electrons232Se3 film, as shown in Firstly, we study the difference between the atom structures of pure Biping see . This re see 2Se3θ of each2Se3 film with different external electric fields. When Eext = 0, we get a band gap of 0.111 eV, which is close to the experimental value of 0.138 eV2Se3, the SSs of QL1 (red) and QL3 (blue) are almost overlapping. Both of the two surfaces contribute to the valence band maximum (VBM) and conduction band minimum (CBM). However, as Cr atom doped, the TRS of Bi2Se3 film is broken202Se3, as can be seen in 2Se3 first decreases gradually and close at the field of 0.026 V/Å , where the trend is also predicted by Liu et al.et al.In our calculation, with the increase of electric field from the upper surface to the lower surface, the band gap of pure 3QL-Bi V/Å see . Further2Se3 film. 2Se3 film under the electric field of 0, 0.1, 0.2 and 0.3 V/Å, respectively. We can find that Rashba-like band splitting observed in band of pure 3QL-Bi2Se3 film vanishes in the doping system. Accompanied by the increase of electric field, CBM continuously rises up whereas VBM is pinned below the Fermi level. To clarify this phenomenon, we calculate the decomposed band structures for QL1 (red), QL2 (green) and QL3 (blue) in 2Se3 film. We conclude the trend in We then further investigate the mechanism that electric field directly impact on the band gaps in Cr doped Bi2Se3 film is also investigated. Result from a 2 × 2 × 1 supercell Bi2Se3 surface doped by two Cr atoms shows that ferromagnetic order is preferred . This result is consistent with refs B from 2.979 μB (at zero electric field). That is, the external electric field will also enhance the magnetic moment due to the change of charge transfer, which is revealed important to the RKKY mechanism by Zhang et al.In addition, magnetic order of Cr atom in Bi2Se3 film, the bands of upper and lower surfaces are degenerate at zero electric field as shown in 2Se3. As the electric field continues to increase, the enhanced charge transfer becomes dominant, resulting in the band gap close again, as shown in In order to better understand the influence of external electric field on the system, we describe the schematic diagram of band structure evolution under the increasing electric field. As illustrated in 2Se3 film will keep enlarging during the increase of the external electric field.For the Cr doped case as shown in 2Se3 films using first-principles calculations based on DFT. For the pure Bi2Se3 film, the external electric field will close the band gap at a critical value of 0.026 V/Å. As the electric field continues to increase, the gap may reopen and then close again, which indicates the band gap of Bi2Se3 is electrically tunable. The competition between electrically tunable charge transfer and Rashba SOC is responsible for this phenomenon. For the Cr doped Bi2Se3 film, investigation on the APEPs of the two surfaces has suggested that Cr atom doping will suppress the charge transfer, resulting in an inhibition of the external electric field. Calculated band structures indicate that VBM, which is dominated by the Cr atom-containing QL1 surface, is almost fixed under different external electric fields. As a result, the band gap of Cr doped case can be engineered by external electric field from 0.099 to 0.235 eV. Furthermore, magnetic coupling of MTI is revealed can also be manipulated under electric field. Our work provides a new route for engineering the SSs of MTI, promoting the future development of quantum computation and spintronic devices.In summary, we have investigated the effects of external electric field on the pure and Cr-doped 3QL-Biab initio simulation package (VASP)5153222Se3. We decouple adjacent atomic slabs by using a vacuum layer of 20 Å. All the atoms are allowed to move under the electric field until the forces on each of them are less than 0.02 eV/Å.All the first-principle density functional theory calculation was performed by Vienna How to cite this article: Zhang, J.-M. et al. Engineering Topological Surface State of Cr-doped Bi2Se3 under external electric field. Sci. Rep.7, 43626; doi: 10.1038/srep43626 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.