To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks’ gestation. A total of 21,659 infants were randomly divided into two groups, HDP  and non-HDP , at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term  and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death  and a decreased risk for severe intraventricular haemorrhage  and periventricular leukomalacia . In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death , severe intraventricular haemorrhage , periventricular leukomalacia , neonatal seizures  and cerebral palsy  at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups . Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical. HDP is characterised by hypertension during pregnancy and includes preeclampsia, which is accompanied by endothelial dysfunction and defined as a new onset of hypertension with either proteinuria or end-organ dysfunction after 20 weeks of gestation5. Approximately 20–50% of infants born to mothers with HDP develop fetal growth restriction (FGR) because of placental dysfunction7, and these affected infants are susceptible to lifelong adverse consequences and a poor quality of life9. Hypertensive disorders of pregnancy (HDP) affects 5–13% of all pregnancies11. Additionally, recent meta-analyses have found that infants exposed to maternal HDP have an increased risk for autism spectrum disorders or attention deficit hyperactivity disorder13. Conversely, several reports have found a lower mortality rate and a lower incidence of severe brain injuries such as intraventricular haemorrhage (IVH) or periventricular leukomalacia (PVL) among very preterm infants born to mothers with HDP16. Currently, the impact of maternal HDP on neurological outcomes in infants, especially very preterm infants, is still controversial. In addition, little evidence is available regarding the association between maternal HDP and early childhood neurological outcomes in very preterm infants.Increasing evidence suggests that intrauterine exposure to maternal HDP has a negative impact on preterm infants’ neurological outcomes including cerebral palsy (CP), low developmental quotient (DQ) and cognitive dysfunctionThe aim of this study was to evaluate the impact of maternal HDP on the short-term  and medium-term (3 years of age) mortality and neurological outcomes of extremely and very preterm infants using a nationwide neonatal database.17. Information on maternal characteristics, neonatal outcomes and postnatal management were collected by manual research, anonymised, and then registered in the NRNJ database. Written informed consent was obtained from all parents of the infants at each participating institution. This study was approved by the institutional ethics board of Nagoya University  and the Japan Neonatal Network Executive Committee. All research was performed in accordance with relevant guidelines and regulations.This was a retrospective cohort study based on the database of the Neonatal Research Network of Japan (NRNJ) from January 2003 to December 2015. Data on neonates born before 32 weeks’ gestation and weighing ≤ 1,500 g were prospectively collected from perinatal centres participating in the NRNJ since 2003. The number of Level II and III neonatal intensive care units (NICUs) participating in the NRNJ has been increasing in recent years. By 2015, there were more than 150 units with approximately 3,000–4,000 neonates being registered in the database every yearSingleton neonates weighing ≤ 1,500 g and born between 22 and 31 weeks’ gestation were included in this study  was used for the evaluation of DQ. The KSPD comprises three categories including Postural-Motor (P-M), Cognitive-Adaptive (C-A) and Language-Social (L-S) areas. We calculated DQ by averaging the scores of the three categories and adjusting according to developmental or chronological age. In this study, DQ at 3 years of age was adjusted according to chronological age. In general, DQ of < 70 indicates neurodevelopmental delay. The KSPD is a neurodevelopmental assessment tool for use in early childhood in Japan, and it is well correlated with the Bayley III Cognitive and Language scales as previously reported22. Short-term outcomes  were evaluated at NICU discharge, and medium-term outcomes  were evaluated at approximately 36 months of age.HDP was defined as hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) during pregnancyt test or chi-square test, respectively. The short- and medium-term neurological outcomes were compared between the HDP and non-HDP groups. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated by univariate logistic regression models. We then evaluated the adjusted ORs using three types of multivariate logistic regression models after the adjustment for covariates including diabetes mellitus (DM) or gestational diabetes mellitus (GDM), histological chorioamnionitis (CAM), administration of antenatal corticosteroids, mode of delivery, infant sex, and birth weight . We then evaluated the incidence of mortality and adverse neurological outcomes stratified by weeks of gestation at birth without adjustment of covariates. In addition, two subgroup analyses were performed to eliminate the negative effect of histological CAM on neonatal outcomes and to confirm whether our results were consistent within the different ranges of gestational age at birth. First, we analysed outcomes after excluding cases with histological CAM from both groups. Second, we evaluated outcomes after infants in both groups were divided into two subgroups (22–27 weeks and 28–31 weeks of gestation at birth). Statistical significance was defined as a p-value < 0.05. All statistical analyses were performed with SAS version 9.4 .Continuous and categorical variables were compared using Student’s p = 1.0, Table During the study period, 44,668 infants were registered in the NRNJ database. After 22,998 infants were excluded, the remaining 21,659 infants were randomly divided into two groups after 1:1 stratification matching . The crude OR of in-hospital death  was higher in the HDP group < 28 weeks’ gestation in univariate analysis; however, the adjusted OR , PVL and CP compared with those without HDP after adjustment for covariates including birth weight. This result was supported by additional subgroup analyses to eliminate the effect of CAM on outcomes and to confirm whether these results were consistent with two different ranges of gestational age (22–27 weeks and 28–31 weeks of gestation). Our study suggested that the mortality and neurological outcomes for infants born to mothers with HDP were better than those for infants without HDP among extremely and very preterm infants if the background of the infants is exactly the same except for the presence of HDP.16. However, in the unadjusted analysis, stratified by gestational age, the incidence of in-hospital death, CP and DQ of < 70 in the HDP group was higher than that of the non-HDP group before 28 weeks’ gestation. This was also consistent with prior reports16.The adjusted ORs of severe brain injury in the HDP group were approximately half the ORs in the non-HDP group based on multivariate analyses. Our results were similar to prior studies, which showed a reduced risk of severe brain injury in preterm infants born to mothers with HDP23. The birth weights of preterm infants, particularly extremely preterm infants, born to mothers with HDP were considerably lower than those of infants born to mothers without HDP; thus because HDP is frequently accompanied by fetal growth restrictions , birth weight contributed most to short-term mortalityThere are several possible explanations for the decreased risk for mortality and severe adverse neurological outcomes in infants born to mothers with HDP if all covariates were identical except for the presence of HDP. First, there may be more infants who develop a poor prognosis in the non-HDP group; second, there may be a higher glucocorticoid level in the HDP group because of the endogenous production of fetal glucocorticoids; third, anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) may inhibit vascular endothelial growth factor (VEGF) signaling, resulting in protection from IVH and fourth, more mothers in the HDP group may have received magnesium sulfate prior to delivery.26. However, we found that excluding women with histological CAM from both groups resulted in similar outcomes when all women were included. Additionally, although severe FGR, placental abruption, and non-reassuring fetal status are more likely to be in mothers with HDP in general, the outcomes of the HDP group tended to be better. Unfortunately, our database did not include the causes of preterm delivery (iatrogenic or spontaneous) or information about placental abruption; therefore, we could not exclude these infants. However, the effect of these infants on the overall results may be limited because they were rare.It is possible that more infants in the non-HDP group had poor prognostic factors such as severe CAM, placental abruption and fetal distress. CAM is well-known to be associated with poor neurological outcomes in preterm infants29. These stressful circumstances may stimulate the endogenous production of fetal glucocorticoids31, resulting in accelerated fetal lung maturation and protection from severe IVH by the same mechanism as antenatal corticosteroid treatment32. This hypothesis is supported by clinical studies showing higher levels of cortisol in umbilical cord blood of pregnancies with preeclampsia or FGR34. Anti-angiogenic factors, such as sFlt-1 and sEng, are important in the development of HDP35. According to an in vitro study, these factors may inhibit VEGF signaling and vasculature in the germinal matrix, the usual site of IVH, resulting in protection from IVH36. Lastly, magnesium sulfate has a protective effect on severe brain injury in preterm infants37, and it is often administered to women with HDP to prevent eclampsia. Unfortunately, the NRNJ database did not include information on the use of magnesium sulfate. For all of these reasons, infants born to mothers with HDP may have a lower incidence of mortality and severe brain injury.Another hypothesis is that maternal HDP may have a protective effect on infants’ neurological outcomes. Fetuses in mothers with HDP, especially preeclampsia, are exposed to an adverse intrauterine environment including hypoxia, undernutrition, and various cytokines and anti-angiogenic factorsStrengths of this study include the assessment of both short- and medium-term mortality and neurological outcomes in extremely and very preterm infants born to mothers with HDP. In addition, we had a large sample size by accessing a nationwide database. We performed stratification matching to eliminate the effect of confounding variables in the selection of eligible infants. Finally, we performed several subgroups analyses to corroborate the results.43. In addition, preterm birth itself may have an influence on subsequent neurodevelopment45, and the causes of preterm delivery were unclear in the non-HDP group. Ultimately, it may be difficult to address the differential effect of HDP, prematurity and other factors on subsequent outcomes because all these independent factors occur simultaneously, and all of them may contribute to subsequent neurodevelopmental impairment.This study did have several limitations. First, the NRNJ database did not include information on certain maternal characteristics such as type and severity of HDP, administration of magnesium sulfate and the causes of preterm delivery (iatrogenic or spontaneous). Second, we were unable to evaluate the influence of NICU management and short-term outcomes on medium-term outcomes. In addition, the rate of follow-up examination at 3 years of age was less than half the initial population. It is possible that more infants with severe impairment were followed up resulting in selection bias. Finally, the aetiology of neurodevelopmental impairment is multifactorial with more causes in preterm than in term infantsExtremely and very preterm infants born to mothers with HDP were associated with an increased risk for mortality and adverse neurological outcomes because of lower birth weight; however, they were associated with a lower risk for mortality and adverse neurological outcomes in both the short- and medium-term than those not exposed to HDP, if all covariates were identical except for the presence of HDP. Therefore, the two-sidedness of HDP infants’ outcomes from different viewpoints should be taken into consideration.Supplementary Tables.Supplementary Figures.Supplementary Legend.


Preterm birth is the most important cause of neonatal mortality and morbidity worldwide. The aim of this study was to identify factors associated with preterm birth and examine the heterogeneity and interactions between these factors.t-tests to compare the characteristics of age and body mass index, Chi-square tests for the other variables, and we used the Wald test to calculate the interaction between factors that may affect preterm birth. The heterogeneity test was used to study the relationship between subgroups. Multivariable logistic regression analysis was used to explore the associations between risk factors and preterm birth, which included all risk factors. All tests were 2-tailed, P < 0.05 was considered significant, and 95% confidence intervals were estimated for percentages.We collected data from 1607 pregnant women treated at Nanjing Maternity and Child Health Care Hospital in China. The women included in the study were divided into the full-term group and the preterm-birth group. We used P < .05): preeclampsia (PE), intrahepatic cholestasis, premature rupture of the membranes (PROM), placenta previa, chorioamnionitis, and scarred uterus. Five combinations of these factors were statistically significant (P < .05) in terms of heterogeneity: PE and PROM; placenta previa and polyhydramnios; chorioamnionitis and PE; PROM and maternal body mass index; and PROM and gestational diabetes mellitus. Ultimately, the 2 subgroups that showed interactions were PE and PROM and chorioamnionitis and PE.There was no statistical difference in basic characteristics such as age between the full-term and preterm groups. We found 6 independent risk factors that were associated with preterm birth (The interaction between different factors over the course of preterm birth cannot be ignored. When independent risk factors are combined with other diseases, such as PE combined with PROM or chorioamnionitis in this study, it may more likely result in preterm birth. Thus, this situation deserves particular clinical attention. As a serious social and health problem, the rate of preterm birth is 5% to 13% in most countries, resulting in 15 million preterm deliveries worldwide each year. Premature babies have an increased risk of death, and compared with term infants, premature babies are more likely to develop long-term neurological and developmental disorders. For example, 1 report showed that smokers have significantly higher rates of preterm birth than nonsmokers, and that quitting smoking early in pregnancy can reduce adverse pregnancy outcomes. The obstetric causes of preterm birth are mainly divided into medical indications , premature rupture of the membranes (PROM), and spontaneous preterm birth. Approximately 30% to 35% of all preterm births are caused by medical indications, 40% to 45% are caused by spontaneous preterm birth, and 25% to 30% are caused by PROM.Preterm birth is a highly complex process, influenced by multiple factors. According to recent studies, lifestyle and physiological conditions of the mother, such as maternal weight and smoking, are high-risk factors for preterm birth.The aim of this comprehensive study was to identify factors associated with singleton preterm birth and to determine whether the superposition of factors impacts preterm birth, to enable a greater focus on these conditions and to attempt to reduce the incidence of preterm births.22.1We performed a retrospective study and collected data by the random number method regarding 2673 pregnant women admitted to Nanjing Maternity and Child Health Care Hospital in China from 2012 to 2017. Of these women, we sequentially excluded women for whom the birth records were either lost (n = 333) or duplicated (n = 164) during follow-up. Women with a history of preterm birth (n = 173) were also excluded. Next, we excluded women who had multiparous pregnancies (n = 224) or abortions, induced labor, or stillbirths (n = 73). We also excluded women who had bacterial vaginosis or colpitis mycotica (n = 8) or cervical diseases (n = 19) during pregnancy, and women who had a history of heart, liver, or kidney diseases (n = 69). Finally, women with uterine malformations (n = 3) were also excluded. A total of 1607 singleton pregnancies were included for analysis . We counted all instances of the diseases affecting the population under study, and these were included in the test. Multivariable logistic regression analysis was used to explore the association between risk factors and preterm birth, which included all risk factors in Table P-value for heterogeneity between subgroups. We hypothesized that interactions could exist between the independent risk factors and preterm birth; therefore, these interaction terms were also assessed in our study using the Wald test. All tests were 2-tailed, P < .05 was considered significant, and 95% CI values were estimated for the percentages.We used Chi-square tests for categorical variables and 3P = 0.055). As shown in Table P < .001, Chi-square test). The BMI and other placental factors (such as battledore placenta) seemed to have an impact on preterm birth .The study population consisted of 1607 women. Demographic and clinical characteristics for full-term and preterm cases are shown in Table  Additionally, the conditions of these women may be milder, and their time of onset may be later than that of individuals who experienced preterm birth.Interestingly, among the entire group of 1,607 women, more women with gestational hypertension underwent full-term births (31%) than preterm births (3.4%). We considered that gestational hypertension may be transient, or it may represent early (before proteinuria) PE.3.1 we carried out multivariable logistic regression analyses on the factors in Table Because preterm birth is likely to be the result of multiple factors,P < .05)  Tables –7. In or) Tables .P for interaction = .048; Fig. P for interaction = .048; Fig. P for interaction < .001; Fig. We found that women with PE and overlapping chorioamnionitis were more likely to have preterm births than women without chorioamnionitis  among the evaluated factors, followed by PROM (16.8%), scarred uterus (14.2%), placenta previa (11.3%), ICP (8.9%), and chorioamnionitis (4.5%). These are common diseases that require further attention. Additionally, the underlying disease process may increase the risk of spontaneous preterm birth.,10 This idea is consistent with our findings. In our study, as an independent risk factor, we found that the odds of preterm birth among women with PE were 2.46 times greater (95% CI 1.78–3.40) than that of women without the condition. Chorioamnionitis, characterized by inflammation of embryonic membranes, was also an independent risk factor for preterm birth. Previous studies have reported that preterm birth is the result of chorioamnionitis, and approximately 25% of preterm births can be attributed to chorioamnionitis. In our study, the odds of preterm birth among women with chorioamnionitis were 13.14 times higher (95% CI 4.27–40.43) than those of women without chorioamnionitis. We also found that women with PE and overlapping chorioamnionitis had a higher risk of preterm birth than women only with PE.PE is a serious disease that only occurs in pregnancy after 20 weeks. Most of the women who develop PE may need to undergo iatrogenic delivery before 37 weeks gestation. The effects of pregnancy complications on the placental microbiota are still being explored, but to some extent, the results of the current study may indicate that the coexistence of PE and chorioamnionitis can impact preterm birth . Interestingly, compared to women with both PE and PROM, women who developed PE or PROM were more likely to deliver before 37 weeks. A previous study reported that the risk for preterm birth was 7.72 times higher for women with iatrogenic deliveries and PE than for women with spontaneous deliveries and no PE. Some unknown mechanisms may affect each other and lead to this result. To our knowledge, similar conclusions have not been found in other reports on the subject, as other articles are typically focused on the study of independent risk factors without interactions. A larger sample size may be required to verify the validity of this conclusion.In addition, the odds of preterm birth among women with PROM were 2.5 times greater (95% CI 1.68–3.77) than that of women without this condition in our study. PROM is always associated with inflammation and infection, which commonly cause spontaneous preterm birth. In our study, we found that placenta previa is a significant independent risk factor for preterm birth . Additionally, heterogeneity exists for preterm birth between women who develop placenta previa with polyhydramnios and those without polyhydramnios. However, we observed no interaction risk for preterm birth between placenta previa and polyhydramnios. Therefore, we must adequately screen pregnant women for both diseases. The risk of preterm birth appears to be approximately 20 times greater for women who develop placenta previa and polyhydramnios than for women who have only one of these diseases , although some articles have reported that 60% of PROM occurs at term.,18 GDM is a common gestational complication of women, and a previous study reported that GDM complicates 1% to 14% of pregnancies in the United States. However, in our study, we saw no interaction risk for preterm birth between PROM and GDM, despite heterogeneity in the subgroup. Notably, women with PROM and normal BMI were more at risk for preterm birth than women with a BMI ≥25 . This result may be influenced by the population base, because in the present study, there were many women with BMI ≥25 (n = 1233). Chorioamnionitis is usually caused by a bacterial infection in the presence of a ruptured membrane, and is considered a contributing factor to preterm birth. There were only 5 women who developed PROM with chorioamnionitis, and 4 of these women had preterm births. Thus, because of the low numbers, we could not perform statistical calculations. The presence of a scarred uterus seems to have no relationship with other diseases with regard to preterm birth, despite being an independent risk factor.Our study shows that PROM complicates 8% to 10% of all pregnancies and is a significant independent risk factor for preterm birth , and this number seems to be increasing. Every year, more than one million deaths are estimated to result from the associated complications.Methodology: Yating Qian.Resources: Ruizhe Jia.Software: Mingming Gao, Lei Zhang.Supervision: Hongjuan Ding.Writing – original draft: Jin Huang.Writing – review & editing: Jin Huang.


Congenital adrenal hyperplasia (CAH) is a common treatable disorder which is associated with life-threatening adrenal crisis, sexual ambiguity, and/or abnormal growth if undiagnosed. Newborn screening is a cost-effective tool to detect affected babies early after birth to optimize their treatment and follow-up. Newborn screening however is in its nascent stage in India where it is not yet introduced universally for all babies. The following review briefly highlights the challenges  and opportunities  associated with newborn screening for CAH in a large Indian birth cohort. Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders caused by inherited defects in steroid biosynthesis. It is most commonly caused by a deficiency of the enzyme 21 alpha hydroxylase, leading to the deficiency of mineralocorticoids and glucocorticoids and excess of sex steroids. The disease presentation may be classical, as salt-wasting (SW) or simple virilizing (SV), and non-classical. Classical CAH is most readily discernible when it presents with virilization in girls, but it may be missed in boys, who may manifest with life-threatening adrenal crisis within the first few weeks of life [In 2002, the Joint Lawson Wilkins Pediatric Endocrine Society/European Society for Pediatric Endocrinology Working Group recommended biochemical screening for classical CAH in the newborn period to reduce associated morbidity and mortality .The levels of 17OHP are influenced by maturity, stress, maternal steroid administration and age. Cord blood is easier and non-invasive, but is not recommended for CAH screening as the steroid surge at birth results in significantly higher 17OHP levels which can be difficult to interpret ,5. CapilIndia’s high annual birth rate of 17.8 births per 1000 results in the birth of over 4 million newborns per year, of which over 277 thousand are home births. Screening such a large cohort would not only need a robust newborn screening program, but also some mechanism to ensure that the babies born at their homes are not missed . In mediThere may be high false positive rates with the first-tier immunoassay due to cross-reactivity and physiological changes in the concentration of 17OHP during the first few days of life, especially in preterm neonates . ScreeniThe overall disease burden of CAH in India is not known but is likely to be significant. CAH remains the most common cause of female ambiguity and primary adrenal failure in Indian series underscoring the magnitude of the problem ,15,16. MThe incidence and prevalence of CAH in India is not known. However, CAH qualifies for screening in India, as per the Wilson and Jungner criteria as it is seen frequently in our country, is treatable when diagnosed early and might result in irreversible sequelae if left untreated . HoweverWith the Prenatal Diagnostic Act in place in India, identification of gender in the prenatal period is not permitted. The birth of a baby with sexual ambiguity comes with a considerable social stigma for the family. Unless the family is able to conceal genital ambiguity, affected babies are at risk of being whisked away and illegally adopted by Hijra (transgender groups). In India, gender reassignment from ‘male’ to a ‘female’ may be difficult for the affected families for fear of stigmatization . The proAmong an Indian cohort of81 children  with congenital adrenal hyperplasia due to 21 hydroxylase deficiency, two-thirds (57) had salt-wasting and the remaining had simple virilizing type. Twenty-five 31%) of these children had short stature and 45 (55.6%) had growth velocity below the reference range . CAH is % of thesIn a cohort study at British Columbia Children’s Hospital, the median age at diagnosis was 5 days  and 6 days  in unscreened and screened neonates, respectively. However, the cost of care was USD 33,770 per case in unscreened vs. USD 17,726 in screened newborns emphasizing the cost-effectiveness of CAH-NBS program . A cost-In India, 10% of deliveries are attended by untrained health personnel and only one-third of babies receive a health check-up by trained health-personnel within two days after birth . There iAs 17OHP levels vary significantly with gestational age, the cut-offs for NBS should be gestational age-specific. However, this may be a concern in cases where pregnancy may be unrecorded and accurate estimation of gestational age is unavailable. The very high proportion of pregnant Indian women with little antenatal care, and that birth weight of Indian babies tend to be lesser than the Western babies for comparable gestational age, underscore the need of local birth weight-based cutoffs. In such situation, birth weight-based cut-offs for 17OHP may be used based on recently compiled data from Indian cohort . SimilarGender assignment in India is performed immediately after the birth of a baby. This is a major concern for families with the birth of a virilized baby where male gender becomes the default gender within the patriarchal Indian culture. A study from southern India reported incorrect gender assignment in 6/24 (25%) girls, which was correctly reassigned in 5 babies within 1 month of birth, but at six years in the sixth patient . A largeLimited access to specialty endocrinology services and non-availability of appropriate treatment and follow-up facilities remain additional challenges for the babies with CAH, especially from the rural and remote areas. Hydrocortisone, being the drug of choice, has limited availability in remote parts of India, where patients may resort to use of alternative agents like prednisolone or dexamethasone. Chandigarh began newborn screening for CAH for all institutional deliveries in 2007, one of the first states in India to do so . HoweverThe lack of NBS across India, even for congenital hypothyroidism, which is a disorder that most developing programs would start with, underscores the need for increasing awareness about the utility of newborn screening in the Indian population. There is also limited public awareness in India about the need to test apparently healthy newborns for life-endangering congenital disorders like CAH. A funded publicity program with contributions from all healthcare professionals  will be needed to create this awareness and subsequent agreement to testing and follow up. NBS will have to be eventually integrated with existent maternal and child health programs to ensure universal coverage. Medical colleges and tertiary level hospitals can take the lead in offering NBS services which will later expand their services to cover outreach areas .hijra) groups, which are communities of transgender individuals, who are usually considered as social outcastes. This community not only lacks gender recognition and sexual expression, but also has to face limited employment, poor living conditions as well as discrimination on various fronts.A diagnosis of CAH is a lifelong identification which should be communicated to the family in a responsive manner. The communication should be done in a more sensitive manner with parents of affected female babies who presented with virilization. The correct gender of the baby should be communicated to the parents ensuring that privacy is maintained. The family is also counseled to maintain confidentiality of the diagnosis to decrease the likely risk of the baby being taken away by eunuch  has developed a patient education booklet in English and Hindi  . A similThe National Health Policy of India, 2017, promotes the provision of quality health care with dynamic cooperation between national and international partners and emphasizes promoting preventive health care, early detection and management of childhood problems . UniversNBS offers us hope for the timely detection of CAH. It will help in the timely instituting of therapy to prevent medical and psychosocial complications to improve disease outcomes and decrease the associated morbidity. The logistics for NBS-CAH are limited at present in the Indian context, primarily because of a lack of resources for newborn screening generally, but also because of the limited opportunities to reduce false positive tests by steroid profiling. However, considering not only the mortality and morbidity of severe CAH but also the sizeable population of this treatable condition in India, CAH may be an essential disorder to be screened and included in the core panel of NBS as this is introduced.


Exposure to hypothermia is somehow unavoidable when a baby comes to life. This is the reason why any possible effort should be made by every caregiver involved during birth, from labour to transfer into the maternity ward, to reduce it. Hypothermia has widely shown to be related to several neonatal problems, and the risks are more relevant when the babies are born prematurely.An observational study was conducted in April 2016 to assess the current practises to avoid hypothermia at birth in 20 Italian neonatal units. Each unit introduced local improvements in clinical practice and the same observational study was repeated 1 year later.p < 0.0001), delayed cord clamping practice > 60″  and skin-to-skin practice > 60′ . Statistical correlations with the risk of hypothermia were found for delivery room (OR 0.88 (CI 95%0.83–0.94), p < 0.0001) and maternal temperature (OR 0.57 (CI 95% 0.48–0.67), p < 0.0001).A total of 4722 babies were analysed. An overall increase in adherence to local and international recommendations emerged from our study. Significant differences between 2016 and 2017 were found in regard to neonatal temperature at nursery entry (36.3 °C vs 36.5 °C, respectively, Periodical assessment of the delivery room practice has shown to be effective in improving adherence to the international recommendations. Relationship between neonatal hypothermia and several other variables including the delivery room and mother temperature underlines how neonatal thermoregulation starts immediately after birth. Hence, a multi-disciplinary approach is needed to provide the optimal environment for a safe birth. Adaptation to extra-uterine life is a complex process, including a rapid and sudden change in thermal homeostasis of the baby. Once they leave maternal milieu, in fact, all babies are exposed to an unequivocal tendency towards hypothermia, which is inversely proportional to their gestational age (GA). Maintenance of thermal homeostasis is crucial for the success of postnatal transition and its imbalances have been reported to be responsible for glycaemic disorders, respiratory distress and increased mortality , 2. ThusThermal care practices have long been a milestone of neonatal care, and temperature maintenance for newborns has evolved over the years, including the use of different devices (such as radiant warmers and heated mattresses) and family-led practices  . DeliverBoth hypothermia and hyperthermia should be avoided during stabilisation and upon admission to the neonatal unit, and for this reason, systematic monitoring of temperature  is therefore advisable to prevent inappropriate uncontrolled temperature variations.The ideal range for newborn body temperature is not unequivocally defined, but there is consensus on a target range between 36.5 °C and 37.5° , 5.In clinical practice, this goal is not routinely achieved, due to either scarce adherence to the international recommendations or to the different procedures adopted by caregivers.To investigate the current clinical practice, an observational study was carried out in 20 neonatal units in Lombardy , enrolling 2376 newborn infants born in April 2016. Data were collected through an ad hoc questionnaire and were fully anonymized.This study revealed unexpected findings on thermoregulation in the DR. Although neither significant adverse events nor increased morbidity were recorded, infants at nursery entry showed a median body temperature below the suggested range . Also, differences between centres were detected regarding the management after birth. These findings were presented through an oral presentation during the annual regional meeting of Italian Neonatology Society in 2017  of 36.4 (35.0–38.8) vs 36.6 (34.7–39.1), No clinical adverse events was reported in either cohort and the lowest neonatal temperature (34.3 °C) was associated with water birth.Our data describe the clinical management of temperature control in the DR in a representative cohort of infants born in Lombardy  in April 2017, after local implementations in clinical practice were introduced. Significant differences have been found regarding the incidence of hypothermia after birth and regarding the proper duration of DCC and StS. Maternal temperature at birth and DR temperature have also shown correlation with neonatal temperature after birth.An important goal for all the caregivers attending the DR is to provide the best setting for both mother and her baby in term of comfort and safety. Since the influence of body temperature on newly born infants have been widely investigated and has shown to be related to several adverse outcomes , 2, greaOur data showed that the median neonatal body temperature when admitted to the nursery was slightly lower than that suggested by international recommendations , 9. HoweOur cohorts included mainly healthy term and only a few late preterm infants (4.3%), and this could explain why no adverse events were reported. In fact, moderate (32–34 weeks’ GA) and especially very (28–32 weeks’ GA) and extremely preterm infants (< 28 week’s GA) are indeed at much higher risks for complications when exposed to hypothermia, though mild and brief as it is in the period between birth and maternity ward entry. This aspect warrants to be underlined to sensitise all the caregivers involved from labour until birth.Available evidence shows that StS is one of the most effective procedures for homeostasis maintenance in the newborns , 3. BondOur data showed that, although overall StS practice decreased significantly after 1 year, in 2017 StS contact > 60 min was performed in about 2/3 of the babies and increased significantly as compared to 2016. However, again we must consider that our cohorts included mainly term or late preterm infants, born by vaginal delivery in most cases, where immediate clinical interventions are rarely needed. We have no data on the reasons why the StS contact was either not performed or interrupted earlier than recommended. It would be interesting to further explore this aspect for a better understanding of the limitations encountered by operators. In our cohort, the risk of hypothermia was significantly reduced when StS was performed for > 60 min. This interesting finding suggests that, in StS, “duration matters”. For this reason, we believe that there is still room for improvement, in order to make StS of appropriate duration a perinatal standard of care.We also evaluated the impact of DCC on hypothermia. Its benefits have been shown by several randomized trials, and include increased placental transfusion, cardiovascular stability, cerebral oxygenation and lower risk for both severe intraventricular haemorrhage and late-onset sepsis . The higIn the 2017 study, we extended data collection to maternal and DR temperature, since we hypothesized that maternal temperature could influence the maintenance of baby’s body temperature and also that there could be an interaction between DR temperature and mother-infant’s homeostasis. During prenatal life, fetal temperature is about 0.5 °C higher than maternal one and variations in maternal temperatures affect the fetus. At birth, the baby undergoes a sudden change in the surrounding temperature. Thus, several approaches are advisable to limit this thermal shock. Our data showed that maternal temperature significantly affected that of the neonate, However, mothers of hypothermic babies had a median temperature of just 0.2 °C lower than those of normotermic neonates. Of note, according to our results, 1 °C increase in maternal temperature is associated with about 40% reduction of risk for neonatal hypothermia. This interesting finding highlighted how even apparently minimal difference can have a major clinical impact on neonates. The control of maternal temperature in the DR is challenging for obstetricians, especially when caesarean section is performed. In fact, women who underwent this surgery frequently experience a decrease in temperature, which often remains undetected . Operatip = 0.0003). Moreover, the increase of 1 °C in the DR temperature led to about 10% reduction of the risk of neonatal hypothermia. These results support the recommendation to avoid temperature below 25 °C.Delivery room warming seems to be one of the most useful intervention to maintain both maternal and neonatal normothermia. As shown by Horn and colleagues, the use of passive insulation only (e.g. blankets) is less effective than active forced-air warming . The EurOur data, however, should be interpreted with caution, since this study has some limitations.First, we cannot provide detailed descriptions of the local policies implemented in each unit after 2016 since they were not standardized between all the participants. These preclude us from drawing broad conclusion on how to implement effectively neonatal practices immediately after birth.We did not differentiate between tertiary and primary centers. This might have affected our findings, since it is reasonable to assume that there are slight differences in the DR management between centers of different levels of care. In addition, logistics may quite vary between centers, thus temperature measurement could have been markedly affected, biasing the interpretation of the results. Also, we did not perform a detailed analysis of the effects of GA on the incidence of hypothermia, given the lack of very premature infants in our cohorts and the paucity of late preterm. All these aspects warrant further investigations.Given the extreme vulnerability to body temperature decrease of newly born infants, it is crucial to provide the optimal thermoregulation from the DR. Our study suggests that periodic audits of the current practice are effective in identifying and improving critical aspects of DR management that may result in neonatal hypothermia. In addition, it confirms that several practices at birth play a role in reducing the risk of neonatal hypothermia; in particular, even moderate changes in the DR and in the maternal body temperature can affect the baby’s thermal homeostasis.


Intrauterine growth restriction (IUGR) is a common reason for perinatal morbidity and mortality. Also, it is often complicated with fetal distress. Melatonin is widely known as an anti-oxidant agent, and it might decrease the damage of tissues caused by hypoxia. It is also known that levels of pro- and anti-inflammatory cytokines are changed during pregnancy. Placental growth factor (PlGF) is responsible for the angiogenesis in the placenta. We aimed to investigate whether the level of melatonin, cytokines, and PlGF in umbilical blood after birth is different in the case of IUGR compared to normal fetuses. Fourteen women whose pregnancies were complicated with IUGR were included in the study group. The presence of IUGR was confirmed by ultrasound fetometry in the third pregnancy trimester, 30-36 weeks of gestation. All patients delivered their children vaginally after 37 weeks of pregnancy. The cases of severe fetal distress that required a caesarian section, obstetrical forceps, or vacuum extraction of the fetus were excluded from the study. We found that the concentrations of cytokines did not differ significantly between the groups. Also, no significant difference in the daytime of delivery was found between the groups. The concentrations of melatonin and PlGF in the umbilical blood at labor were significantly lowered in the case of IUGR compared to normal pregnancies. This fact, as we consider, is caused by altered production of melatonin and PlGF by the placenta. Therefore, the protective action of these two factors for the fetus at labor is decreased in IUGR. The neuroendocrine system of a pregnant woman plays a crucial role in the successful development of pregnancy. The pineal gland (epiphysis) is one of the most important parts of this system. It produces and secrets such hormones as melatonin and serotonin. Melatonin (5-methoxy-N-acetyltryptamine) chemically belongs to the class of indols, and it easily crosses the blood-brain barrier , 2. The Placental Growth Factor (PlGF), among others, can also be considered as such a marker. PlGF has a pro-angiogenic effect on the placental tissue; it also stimulates the proliferation of the trophoblast, and it has been known as a predictor and a diagnostic marker of pre-eclampsia , 10. On The impact of melatonin on the immune system, especially on the cytokine level, is being widely studied nowadays. Melatonin decreases stress-induced inflammation  and reduBased on the above-mentioned facts, the primary conclusion that can be drawn is that the changed levels of melatonin, PlGF, and cytokines both in the blood plasma of a pregnant woman and umbilical blood might be relevant in the diagnosis of PI and IUGR.The study was conducted on 14 women whose pregnancies were complicated with IUGR. The presence of IUGR was confirmed by ultrasound fetometry in the third pregnancy trimester, at 36 weeks of gestation (the estimated bodyweight of the fetus was below the third percentile for the current pregnancy term). The control group consisted of 13 women who had uncomplicated pregnancies. All patients delivered their children vaginally after 37 weeks of pregnancy. The cases of severe fetal distress, which required a caesarian section, obstetrical forceps, or vacuum extraction of the fetus, were excluded from the study. All the cases of IUGR were confirmed after the birth of fetuses. The umbilical blood was taken immediately after a baby’s birth from the placental side of the clamped and cut umbilical cord before the birth of the placenta.The concentrations of melatonin and PlGF were assayed using an ELISA kit manufactured by “IB” (Germany); the concentrations of pro-inflammatory  and anti-inflammatory  cytokines were measured using diagnostic kits manufactured by “Vector Best” (Ukraine).Statistical data were calculated using the MedCalc software, developed by “MedCalc Software” . The results were estimated using the Mann-Whitney U-test for small groups. A P-value <0.05 was considered statistically significant.The study was approved by the Biological and Medical Ethics Committee of the Higher State Educational Establishment of Ukraine “Bukovinian State Medical University” , and was carried out following The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. All the patients involved in the study gave their consent for participation and publication of the study’s results.We did not find any statistical difference in the daytime of delivery between groups.The levels of melatonin in the umbilical blood taken from the patients from the studied groups are represented in As can be seen in The levels of PlGF in the umbilical blood taken from the patients in the studied groups are represented in It has been established that the concentration of PlGF in the umbilical blood taken during labor from women whose pregnancies were complicated with IUGR was 1.57 times lower than women who had uncomplicated pregnancies, p<0.05 .The levels of pro-inflammatory cytokines taken from the umbilical blood during labor from the examined patients are represented in Data represented in The results of studying the levels of anti-inflammatory cytokines in the umbilical blood sampled during labor from women in the studied groups are represented in Based on the data represented in Analysis of correlation links between studied indexes showed a moderate correlation between IL-1-β and TNF-α in the group of women who had uncomplicated pregnancies , we established that melatonin has a moderate correlation with one of the main pro-inflammatory cytokines, namely IL-1-β, if the pregnancy is complicated with IUGR. In the control group, this correlation was also moderate but negative. Based on this fact, we suggest that melatonin plays the role of a moderator in the inflammatory reaction of the placental tissue, which is clearly expressed in the case of PI, manifesting as IUGR . Anti-inOur study has certain strengths, such as the strict inclusion criteria , sampling of the umbilical cord was performed during the third period of labor, immediately after the birth of the fetus  and estimation of correlation links between studied indexes. However, it was also limited by the small number of patients included in the study.The concentrations of melatonin and PlGF in the umbilical blood during labor are significantly lower in the case of IUGR compared to normal pregnancies. This fact, as we consider, is caused by the altered production of melatonin and PlGF by the placenta. Therefore, the protective action of these two factors for the fetus during labor is decreased in the case of IUGR.The authors declare that there is no conflict of interest.


Botryosphaeria dothidea is an important disease in China, which leads to serious economic losses during storage. Plant activators are compounds that induce resistance against pathogen infection and are considered as a promising alternative strategy to traditional chemical treatment. In the present study, butylated hydroxytoluene (BHT), a potential plant activator, was evaluated for its induced resistance against B. dothidea in postharvest apple fruits. The physiological and molecular mechanisms involved in induced resistance were also explored. The results showed that BHT treatment could trigger strong resistance in apple fruits against B. dothidea, and the optimum concentration was 200 μmol L–1 by immersion of fruits. BHT treatment significantly increased the activities of four defensive enzymes and alleviated lipid peroxidation by increasing antioxidant enzyme activities. In addition, salicylic acid (SA) content was enhanced by BHT treatment as well as the expression of three SA biosynthesis-related genes  and two defense genes (MdPR1 and MdPR5). Our results suggest that BHT-conferred resistance against B. dothidea might be mainly through increasing the activities of defense-related enzymes and activating SA signaling pathway, which may provide an alternative strategy to control apple ring rot in postharvest fruits.Apple ring rot caused by  Malus domestica Borkh.) is one of the most important fruit and is widely consumed worldwide. However, the apple fruit is susceptible to pathogenic fungi, one of which is Botryosphaeria dothidea  play a pivotal role in the regulation of plant defense response against pathogen invasion . HoweverStreptomyces rochei A-1 could induce resistance against B. dothidea infection in postharvest apple fruit and did not affect the external and internal fruit appearance . As a synthetic phenolic antioxidant, BHT has been widely used in foods and food-related products, such as packing . The stock solution (1 M in methanol) was filtered through a 0.22-μm filter for sterilization and stored at −20°C. The working concentration of BHT in this study was 0 (0.1% methanol as control), 50, 100, 200, and 500 μmol LBotryosphaeria dothidea LXS030101, which was used in our previous study  fruits were harvested at a commercial mature stage from a commercial orchard in Qingdao, China. For this study, fruits with uniform shape, size, and no physical injuries were selected. Before treatment, fruits were surface disinfected with 2% (v/v) sodium hypochlorite for 2 min, washed with tap water, and then air-dried for use in the experiments.–1). Then, all fruits were taken out, air-dried for 2 h at room temperature, and stored in plastic boxes. After 48 h of incubation at 25°C, three uniform wounds (5 mm wide and 3 mm deep) around the apple equator were punctured with a sterile borer . Disease incidence was calculated as the percentage of infected wounds, and lesion diameter was measured for infected wounds only. The experiment was conducted three times in triplicates with 10 fruits in each replicate group.Prior to pathogen inoculation, apple fruits were pre-treated with BHT according to the previous procedure with some modifications . Brieflyle borer . Each wo–1 (0.1% methanol as control) or 200 μmol L–1 of BHT solution, air-dried for 2 h, and then stored at 25°C with high relative humidity. Sample collection was performed following the method of Apple fruits were divided into two groups, immersed in 0 μmol L–1 of phosphate-buffered saline  containing 1% (w/v) polyvinylpyrrolidone (PVP) for PPO and PAL, and 50 mmol L–1 of sodium acetate buffer (pH 5.0) for GLU and CHI. The homogenate was centrifuged for 15 min at 12,000 g at 4°C, and the supernatants were used to determine the enzyme activities. The activities of PAL, PPO, GLU, and CHI were calculated on the basis of fresh weight (FW), which were expressed as U g–1 FW. All measurements were performed in triplicate with samples collected from three biological replicates.Phenylalanine ammonia lyase , polyphenol oxidase , β-1,3-glucanase , and chitinase  were assayed according to the method of –1 PBS (pH 7.0) containing 1% PVP (w/v). The CAT Assay Kit A007, POD Assay Kit A084, and SOD Assay Kit A001  were used to measure the enzyme activities, following the protocol provided by the manufacturers. The final activity was expressed as U g–1 FW. Three biological replicates were used in each treatment.To determine the activities of main antioxidant enzymes including catalase , peroxidase , and superoxide dismutase , 0.5 g of fruit tissues was homogenized with 5 ml of 100 mmol LB. dothidea inoculation; (iv) BHT + pathogen, fruits treated with 200 μmol L–1 of BHT followed by B. dothidea inoculation. Fruit tissues were collected at various intervals  as the description of To analyze the lipid peroxidation in apple fruits, four treatment groups were designed as follows: (i) control, fruits treated with 0.1% methanol; (ii) BHT, fruits treated with 200 μM of BHT solution; (iii) pathogen, fruits treated with 0.1% methanol followed by Spin column plant total RNA purification kit was used to extract total RNA from fruit tissues . After quantification by micro spectrophotometry, a total of 2 μg of RNA was used for first-strand cDNA synthesis, using the Prime Script RT Reagent Kit with gDNA Eraser .EF1a) was used as a reference gene, and the relative gene expression was normalized to the EF1a Ct value according to the formula 2–ΔΔCt. All experiments were carried out with at least three biological replicates.qRT-PCR was performed using SYBR Premix Ex Taq kit  according to the protocol provided by the manufacturer. Primers used for qRT-PCR are listed in g for 5 min, and the supernatant was collected and concentrated with nitrogen. Trichloroacetic acid was added to a concentration of 1 g L–1. The sample was extracted three times with 1:1 ethylacetate:cyclohexane and used to detect the free SA. For SAG detection, 8 mol L–1 of HCl was added into the water phase collected from the abovementioned steps. The sample was boiled for 30 min and extracted as the abovementioned method. Samples were analyzed by an Agilent 1260 . SA and SAG contents were expressed as micrograms per kilogram of FW, and the results were the average of four independent extractions. The experiment was repeated twice.Salicylic acid and SA glucoside (SAG) were extracted and measured from 0.3 g of fresh fruit tissue, as described by the previous method with some modifications . The samP value of less than 0.05.All the experiments were implemented using a completely randomized design. The biochemical and gene expression analyses of fruit tissues for each treatment were conducted in triplicate at each sampling point. The data were expressed as the mean ± standard deviation (SD). All data were subjected to analysis of variance (ANOVA) followed by Duncan’s multiple range tests. Statistical significance was determined with a –1 showed the strongest effect on mitigating ring rot development (–1 of BHT treatment decreased disease incidence by 25.56% and lesion diameter by 78.22% as compared with control at 7 dpi (The effectiveness of BHT for controlling apple ring rot in fruits was significantly affected by the concentrations of BHT . In the elopment . Althougat 7 dpi .P < 0.05) with varying patterns. PAL and PPO activities in BHT-treated fruits were remarkably enhanced at 2 days and then peaked at 5 and 3 days, which were 1.7-fold and 2.2-fold higher than those in the control fruits, respectively (P < 0.05) higher than that in the control fruits during the storage  activities showed no obvious changes throughout the experiment period; however, three enzyme activities markedly enhanced in BHT-treated fruits (P < 0.05) higher than those in the control fruits during the storage.To obtain more insights into the mechanisms of BHT in induced resistance against d fruits . CAT actP > 0.05) differences compared with that in the control fruits during the storage. Inoculation with B. dothidea resulted in a sharp rise of MDA content in apple fruits from 2 dpi, and the increase of MDA content was up to 197.77% and 251.86% more than the control at 4 and 7 dpi, respectively. However, MDA content in BHT plus B. dothidea-treated fruits increased slightly, and the enhancement was only 25.81 and 84.30% more than that of the control at 4 and 7 dpi, respectively.Malondialdehyde, a marker for monitoring lipid peroxidation caused by oxidative damage, was determined in four treatments and shown in PR1 and PR5 are widely used molecular markers that correlate with SA signaling activation (P < 0.05) increases of MdPR1 and MdPR5 transcript levels during the storage , which encodes an antifungal peptide, is reported to be induced by pathogen and is required for the activation of JA response pathway (COI1) is a JA receptor responsible for transducing JA signal to activate gene expression in JA signaling pathway (P > 0.05) were observed in the two JA signaling pathway marker genes (MdPDF1.2 and MdCOI1 transcript levels during the storage. pathway . Coronat pathway . In the er genes . MeanwhiCTR1) and ET response factor 3 (ERF3) are used as marker genes of ET signaling pathway , PAD4 , and EDS1 (enhanced disease susceptibility 1) are genes related to SA biosynthesis  at 24 and 48 h . In the previous work, BHT applied by adding to fruit wounds at 50∼1,000 μmol L–1 could significantly reduce lesion size, and BHT at 100 μmol L–1 was the most effective . In addition, our results also indicated that BHT treatment could enhance SA levels in apple fruits. These results suggested that BHT could regulate the phenylpropanoid pathway and stimulate the production of antimicrobial substances, which in turn contribute to the induced resistance in apple fruits against B. dothidea.The protection of plants from invasion by pathogens is largely dependent on the activation of a highly coordinated defense response. PAL, PPO, GLU, and CHI, the primary defensive enzymes, play important roles in plant defense responses against fungal infection and are widely used as markers to assess induced resistance . PAL is eactions . Zheng eH. pluvialis biotrophic pathogens (SID2, PAD4, and EDS1 were up-regulated significantly; and SA content increased remarkably in BHT-treated fruits, which led us to conclude that BHT-induced resistance against apple ring rot was mainly through the accumulation of SA content.Salicylic acid content and SA synthesis-related gene expression were also determined in this study, which helped us to further determine whether SA signaling pathway mediated the BHT-induced resistance in apply fruits against sistance . In applnfection . EDS1 anathogens . Based oBotryosphaeria dothidea. BHT could enhance the activities of defensive enzymes CHI, GLU, PAL, and PPO. Meanwhile, it increased antioxidant enzyme activities to alleviate lipid peroxidation. Furthermore, BHT treatment promoted SA content and up-regulated SA defense signaling, which is a crucial pathway in pathogen resistance. These data indicate that BHT confers resistance in apple fruits against B. dothidea, possibly by increasing defensive enzyme activities and activating SA signaling pathway. Therefore, our study strongly supports the application of BHT as a new plant activator to inhibit postharvest decay caused by B. dothidea in apple fruits.Butylated hydroxytoluene treatment triggered remarkable disease resistance against apple ring rot caused by The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.YH and CS carried out the experiments and analyzed the data with the help of XG and SL. SL analyzed the data of gene expression and prepared the figure. YH and CW wrote the manuscript with help from all authors. BL performed the manuscript revision and provided part of the financial support. XG reviewed and edited the manuscript. All authors approved its final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The healthy immigrant paradox refers to the unexpected health advantages of immigrant groups settled in host countries. In this population-based study we analyze immigrant advantages in birthweight decomposing differences between infants born to immigrant mothers from specific origins.Using publicly available data from Spanish Vital Statistics for the period 2007–2017, differential birthweights among several groups of immigrants were estimated with an ordinary least squares regression. The Oaxaca–Blinder regression-based decomposition method was then applied to identify the extent to which differences in birthweight between groups corresponded to compositional disparities or to other factors.N = 542,137) confirmed the healthy immigrant paradox for certain immigrant populations settled in Spain. Compared with infants born to mothers from high-income countries, the adjusted birthweight was higher for infants born to mothers from non-high- income European countries , mothers from African countries , and mothers from Latin American countries , but lower for infants born to mothers from Asian non-high-income countries . Decomposition analysis showed that when compared with infants born to mothers from high-income countries, compositional heterogeneity accounts for a substantial proportion of the difference in birthweights. For example, it accounts for 53.5%  of the difference in birthweights for infants born to mothers from non-high-income European countries, 70.9%  for those born to mothers from African countries, and 38.5%  for those born to mothers from Latin American countries.Our analysis of singleton live births to migrant mothers in Spain between 2007 and 2017  and does not necessarily correspond to other medical, environmental, or behavioral factors. The healthy immigrant paradox describes a phenomenon observed in many countries where immigrants who have just moved to a host country have better health outcomes than the native populations of the host country. An interesting variation of this paradox is when immigrants from high-income societies have worse health results in the host countries than immigrants from low- and middle-income societies. These phenomena have been rightly considered “paradoxical” as migrants coming from the developing world are more exposed to adverse conditions in host countries, which would be expected to take an immediate toll on their health , 2. PeriTo date, several explanations for the healthy immigrant paradox have been provided. One of the most popular explanations is the immigrant selectivity hypothesis. This hypothesis is based on the assumption that immigrants are not a random sample of their home country populations. Those who choose to migrate may differ from their home country population, and this selection may occur on many observable and unobservable traits, including socio-economic characteristics and health . In contEmpirical findings from a vast body of research have revealed several social factors that have a significant impact on immigrant birthweight. There is evidence that the socio-economic status, in terms of educational attainment and occupational position, has a positive impact on the health of mothers and their children through improved work and economic conditions, psycho-social resources, and healthy lifestyle choices –20. HoweNulliparity is also usually associated with a significantly increased risk of low birthweight. However, grand multiparity and great grand multiparity are also associated with low birthweight . Non-linSpain is a very good case in point to analyze the health outcomes of immigrants. In the last two decades, Spain has become a receiving country for immigrants from Latin America, Africa, Asia and high- and non-high-income European countries  and its Available data from Spain seem to confirm the healthy immigrant pattern in terms of perinatal health. The estimation of differences between the birthweights of native- and immigrant-born infants shows that the latter tend to weigh more , 32–34. These theoretical and empirical studies are useful for understanding how and why the gradient in birthweights between immigrants from different origins depends on the specific composition of immigrant subpopulations. This includes the differential distributions of certain characteristics of mothers , fathers (age and migratory status), and births , and their differential associations with birthweight across these migrant groups. On the one hand, younger, primiparous, non-married, less educated and low-class migrant mothers are expected to deliver babies with less weight. On the other, mothers without Spanish citizenship as well as older and migrant fathers tend to have heavier babies. Finally, complicated and cesarean deliveries should be positively associated to birthweight. Since these characteristics are not necessarily evenly distributed among different immigrant communities, stating specific predictions about their net aggregate impact on birthweight is not sensible until the respective composition of each group is known. However, considering these factors, we hypothesized that birthweight vary, to some extent, based on the distributions of specific features between groups of immigrants from different origins.This study specifically aimed to decompose differences in birthweight between infants born to immigrant mothers from specific origins and to estimate how those differences are due to uneven distributions of relevant characteristics and/or other unspecified factors. First, we compared the composition of several immigrant groups to identify traits that might cause differences in birthweight. Second, we ran an ordinary least squares (OLS) linear regression model, with birthweight as the main outcome and the region of origin as the main exposure. The model’s results allowed us to estimate adjusted differences in birthweight between infants whose mothers have migrated from different origins. Lastly, using decomposition, we analyzed the extent to which differences in birthweight are associated with disparities in the composition of known characteristics of immigrant groups from different origins.To date, research on patterns and determinants of birthweight among immigrants in Spain has been limited by a relative scarcity of data. Researchers have usually used data from Spanish Vital Statistics , which offers basic information regarding some characteristics of births, new-born infants, and their parents. Using this same data source and following previous population-based studies on birthweights in Spain –37, we dp values and confidence intervals as per convention, as plausible measures of the variability of our estimates.1The original annual datasets are available at the Spanish National Statistical Office  webpage and are fully accessible to the public. We have aggregated yearly individual microdata of all births registered in Spain from 2007 to 2017 into a new database. These registers include all births occurred in Spain irrespective of the legal status of the mother  and contain several characteristics of the deliveries and infants, as well as some sociodemographic information about their parents. It is important to emphasize that this new database constitutes a complete representation of all births that occurred in the country in the period considered. Although not strictly necessary, we also offer The main outcome variable was the registered birthweight, from the Spanish vital statistics data, for the period 2017–2017. The mean birthweight of infants born to immigrant mothers from different origins is a valid indicator of perinatal health, as well as a strong predictor of mid- and long-term health-related outcomes as has been shown in previous research , 24, 38.Our main exposure variable was the mother’s country of origin, which was coded into the following five main groups of countries according to their development level and geographic location: high-income countries ; non-high-income European countries ; Latin American countries (LACs); African countries (AFCs); and Asian countries (ASCs) not previously included in HICs. The distinction between high-income and non-high-income countries has been established following the 2007 World Bank’s classification according to which the threshold for high-income is a gross national income (GNI) per capita of 11,455 US dollars .In our analysis, we included several covariates to control for possible confounders. Birth characteristics included infant sex , birth order , labor complications  and cesarean delivery . The mother’s characteristics included age at birth , marital status , and citizenship . As a measure of socio-economic status (SES), we used the mother’s educational attainment . To complement the measure of SES, we included the highest occupational status of the mother or father as a measure of family occupational class . Two of the father’s characteristics—age and migratory status —were also included. Table We used two analytical approaches. First, we applied OLS regression models to estimate the effects of the different exposures, in particular the country of origin and the socio-demographic and socio-economic variables, on birthweight. Regression modelling implicitly assumes that the distribution of features is similar for all individuals in the sample. Therefore, if there are substantial differences in the distributions of certain features, regression might be insufficient to capture their effects on the study outcomes. To overcome this limitation we applied a regression-based decomposition technique, developed by Blinder  and OaxaThis paper is entirely and exclusively based on microdata from Spanish Vital Statistics. The information on births, obtained from bulletins originally registered in civil registers, is processed and offered by INE. All the data used in this study are available to the public. All the individual information contained in the microdata has been duly anonymized by INE. Hence, no ethical or governmental permissions were required for this study.Considerable variations were observed in specific socio-demographic features between immigrant mothers of different origins residing in Spain. Descriptive results provided in Table P < 0.01), AFC infants , and LAC infants  weigh more than HIC infants, whereas ASC infants weigh the least .Figure The regression model estimates  out of the 50.2 g of overall difference in birthweight. In three categories, the NHI-EUR births are much more prevalent than HIC births, accounting for most of the difference: age of mother , non-Spanish citizenship , and immigrant father . Interestingly, differences in education reduced the gap between HIC and NHI-EUR birthweights by 7.6 g  due to their concentration in the lower educational ranks. In the case of AFC infants, 63.3  of the 89.3 g of overall difference with HIC infants (70%) is accounted for by compositional effects. Among these, disparities in birth order , marital status of the mother , foreign citizenship of the mother , and immigrant father  account for more than half (65%) of the overall gap in birthweight between these groups. In turn, the contrast between HIC and LAC births revealed that the explained difference accounts for 27.7 g , or 38.5%, of the overall difference, a proportion lower than the two previous comparisons. Birth order , educational status , and immigrant father  make the bulk of the difference. Finally, when birth outcomes of HIC and ASC mothers were compared, decomposition showed a different pattern, with compositional effects increasing the birthweight of Asian infants , and unexplained factors decreasing it , with an overall balance of no significant difference. Among compositional factors that increase the birthweight of ASC newborns, birth order , foreign citizenship of the mother , and immigrant father  stand out as contributing factors.In general, differences in birthweight obey both the composition (explained portion) and coefficient effects (unexplained portion), but vary in proportion depending on the region of origin. In a comparison between HIC and NHI-EUR infants, compositional differences were found to account for 26.9 (95% CI: 24.0–29.7, This article contributes to the literature on disparities in perinatal health of immigrant populations by providing two main findings. First, our results on birthweight show strong population-based evidence of a large number of “healthy immigrants” residing in Spain. However, not every immigrant matches this description, as immigrant birth outcomes vary significantly depending on the origin of the immigrant mother.Unadjusted differences in birthweight between HIC infants and ASC infants were negligible. When adjusted for several relevant covariates, the sign of difference became negative, and Asian infants were found to weigh less than HIC infants. These results concur with previous findings showing elevated rates of low birthweight and smaller infants among ASC mothers having migrated from low- and middle-income countries and living in high-income host countries , 43, 44.In contrast, AFC, LAC and NHI-EUR mothers give birth to infants heavier than those from HIC mothers. By implication, these immigrant infants are also heavier than those born to Spanish native mothers. Moreover, AFC and LAC autochthonous populations are reported to have lower birthweights compared with European populations , 46. TheOur research confirms that the healthy immigrant paradox is not a universal phenomenon and depends strongly on immigrants’ origin. More precisely, mothers from high-income countries tend to be similar to Spanish native mothers but have worse birth outcomes than mothers from mid- and lower-income countries, except for Asian ones. This finding, which has already been observed in other countries , 47, impSecond, our study contributes to a better understanding of the mechanisms behind the differential perinatal outcomes of immigrant mothers. Although several studies identified specific characteristics that might shape differences in birth weight among immigrant mothers residing in Spain , 35, 48,Our results show that compositional effects are especially salient among AFC newborns, as they account for 70% of the increase in birthweight compared with those in HIC newborns. Parity, the mother’s marital status and foreign citizenship, and ethnic intermarriage composition are the more important factors, with a very high prevalence of second and higher birth orders and married, foreign and homogamic mothers. For births to LAC mothers, composition effects account for almost 40% of the overall disparity with HIC mothers. In this case, compositional differences in high birth orders, intermediate levels of education, and ethnic endogamy are decisive. Immigrant mothers and infants from NIH-EUR countries show similar results to LAC mothers and infants in the portion of birthweight difference attributable to compositional effects, but the relevant characteristics for the explained portion of the gap are those related to citizenship of mothers and intermarriage, with high proportions of unnaturalized and homogamic mothers. Finally, among ASC infants, some compositional characteristics, such as birth order and a high prevalence of ethnic homogamy, tend to increase their birthweight and make up for the baseline disadvantages in birthweight.Our results imply that despite several unobserved characteristics that might play an important role in explaining differences in birthweight among immigrants in Spain, a significant portion of the advantages in birthweight between immigrant groups is attributable to the compositions of the groups. Composition effects have the benefit of being self-explanatory: differences simply arise from the dissimilar distributions of certain traits across groups. In other words, AFC, LAC, and NIH-EUR immigrants owe a significant part of the observable advantage in birthweight over HIC immigrants to their particular group compositions. Even ASC immigrant mothers offset part of their original basal disadvantage in birthweight thanks to their group composition. A significant part of the perinatal health advantages of certain immigrant groups is only a by-product of their group composition and does not correspond to medical, environmental, or behavioral factors.Although important predictors of birthweight such as maternal age, birth order, multiple pregnancies and obstetric complications were controlled for in this study, other predictors were not. These uncontrolled predictors include chronic maternal conditions, infections and nutritional status, exposure to poor environmental conditions, and tobacco, alcohol, or drug consumption. A lack of control for these predictors is the main limitation to our study because these unmeasured predictors could influence the outcome, if it were possible to include them in the models. Nevertheless, part of the unobserved heterogeneity associated with these neglected predictors should have been absorbed by sociodemographic covariables, such as marital status, educational attainment, family social class, citizenship acquisition, and intermarriage, that were included in the models. Previous studies  have sho


Children born small for gestational age have a higher risk of intellectual disability. We investigated associations of birth weight for gestational age percentile and gestational age with risk of intellectual disability in appropriate-for-gestational-age (AGA) children. We included 828,948 non-malformed term or post-term AGA singleton children  born between 1998 and 2009 based on data from the Swedish Medical Birth Register. Diagnosis of intellectual disability after 3 years of age was identified through the Patient Register. Using Cox regression models, we calculated hazard ratios (HRs) with 95% confidence intervals (CIs) of intellectual disability among children with different birth weight percentiles and gestational age in the whole population and in a subpopulation of full siblings. A total of 1688 children were diagnosed with intellectual disability during follow-up. HRs (95% CIs) of intellectual disability for the low birth weight percentile groups  versus the reference group (40th–59th percentiles) were 1.43 (1.22–1.67) and 1.28 (1.10–1.50) in population analysis and 1.52 (1.00–2.31) and 1.44 (1.00–2.09) in sibling comparison analysis. The increased risk for low birth weight percentiles in population analysis was stable irrespective of gestational age. A weak U-shaped association between gestational age and intellectual disability was observed in population analysis, although not in sibling comparison analysis. These findings suggest that among AGA children born at term or post-term, lower birth weight percentiles within the normal range are associated with increased risk of intellectual disability, regardless of gestational age.The online version of this article (10.1007/s10654-019-00590-7) contains supplementary material, which is available to authorized users. Intellectual disability refers to a group of disorders characterized by significant cognitive limitations and limitation of adaptive functions that affects between 1 and 3% of the world’s population . IntellePreterm birth  is another known risk factor for cognitive deficits . The risBased on data from Swedish national registries, we aimed to investigate associations of birth weight percentile and gestational age with risk of intellectual disability in non-malformed, term or post-term, AGA children. We performed population analysis and sibling comparison analysis, the latter of which was to control for unmeasured familial confounding factors shared by siblings. We also assessed the joint impact of birth weight percentile and gestational age with regard to risk of intellectual disability.This was a cohort study based on data from several Swedish national registries, including the Medical Birth Register, Patient Register, Cause of Death Register, Education Register, Total Population Register, and Multi-Generation Register. The unique personal identity number assigned to all Swedish residents enables individual record linkage between different registries . The MedWe identified all singleton live born infants between January 1st, 1998 and December 31st, 2009 from the Medical Birth Register . We excluded infants who had missing personal identity numbers , infants whose mothers (n = 426) or fathers (n = 7724) had missing personal identity numbers, infants with missing data on gestational age (n = 872), and infants with missing (n = 3198) or implausible (n = 702) data on birth weight for gestational age, the latter of which were defined as values below or above the 5 times standard deviation from the mean. We restricted the study population to infants born AGA at term or post-term, and, as a result, we excluded 54,288 preterm infants, 85,721 SGA infants and 103,202 large for gestational age (LGA) infants . We also excluded infants who were diagnosed with major malformations  as recorded in the Medical Birth Register or in the Patient Register during the first year of age  .Since reliable and validated assessment tools of intellectual function such as the Wechsler scale measurements, utilized in Sweden and globally, are only partially available from 2 years and 6 months of age , childreBirth weight was recorded for infants immediately after birth. Gestational age was assessed by ultrasonography offered during the early second trimester for 87.4% of all births, by the last menstrual period for 7.5% of all births, and by a postnatal assessment for 5.2% of all births in the cohort. From the ultrasound-based, sex-specific Swedish reference curve for fetal growth , we calcBirth weight percentiles were categorized into five groups: 10th–24th, 25th–39th, 40th–59th (reference), 60th–74th, and 75th–90th percentiles [Intellectual disability was defined as a hospital contact  with a clinical diagnosis of ICD-10 codes F70-F79 from the Patient Register. The severity of intellectual disability was further classified using corresponding ICD-10 codes (Supplementary Table 1). In a sensitivity analysis, we redefined the outcome as at least two hospital contacts for intellectual disability on separate dates. Information about clinical diagnosis and dates of admission and discharge were extracted from the Patient Register.2). We also included information on calendar period of delivery from the Medical Birth Register to control for temporal change in obstetric practice. We further obtained information about maternal educational level [We identified maternal and neonatal variables that have been associated with both birth weight for gestational age/gestational age and risk of intellectual disability and might therefore confound the associations under study. As a result, we extracted information on maternal age at delivery , 23, paral level , 32 fromal level , 34 fromal level , 25 wereWe first calculated crude incidence rates of intellectual disability across categories of maternal and neonatal characteristics.To assess the association between birth weight percentile and risk of intellectual disability, we calculated standardized incidence rates (SIRs) of intellectual disability across birth weight percentiles (every 10 percentiles), using the distribution of sex and year of delivery of the entire study population as the standard. As our study involved time-to-event data, we performed Cox proportional hazards regression and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of intellectual disability across the five birth weight percentile groups with 40th–59th as the reference. Ordinary Cox regression was used for population analysis, and stratified Cox regression for sibling comparison analysis. In the sibling comparison analysis, only full siblings discordant for both exposure  and outcome  were informative and thus were included. Attained age was used as the underlying time scale in the Cox models. To assess the potential dose–response pattern across the entire spectrum of birth weight percentiles, we performed an additional analysis by including children born SGA and LGA. To assess the potential non-linear relationship of intellectual disability with birth weight percentile on a continuous scale, we additionally used restricted cubic splines with three knots positioned at the 10th, 50th and 90th percentiles of the distribution of the exposure variable. HRs were estimated using the 50th birth weight percentile as the reference. A similar analytic approach as described above was performed to assess the association between gestational age and risk of intellectual disability.In population analysis, HRs were estimated after adjustment for maternal age, parity, educational level, country of birth, smoking, height, BMI, diabetic and hypertensive diseases, as well as child’s sex, calendar period of delivery, onset of labor, and mode of delivery. In sibling comparison analysis, adjustment was made for maternal age, parity, smoking, BMI, diabetic and hypertensive diseases, and child’s sex, calendar period of delivery, onset of labor, and mode of delivery. To account for the correlation among full siblings, we used a robust sandwich estimator to correct standard errors in all models.We estimated the joint impact of birth weight percentile and gestational age with risk of intellectual disability, using children born at 40 weeks and with a birth weight for gestational age from 40th to 59th percentile as the reference category. Only population analysis was performed due to the small numbers of outcomes in the subpopulation of full siblings.To assess the robustness of the overall associations assessed above, we conducted two sensitivity analyses. First, since we used complete case analysis in the primary analysis, results might have been biased due to missing values of covariates . We repeated the Cox regression analysis with missing values imputed through multiple imputation using chained equations. Ten imputations with 50 iterations each were implemented. Second, to improve the validity of diagnosis of intellectual disability, we redefined the outcome as having had an intellectual disability diagnosis in at least two hospital contacts, and repeated both population and sibling comparison analyses.To evaluate whether the associations of birth weight percentile and gestational age with risk of intellectual disability differed by severity of intellectual disability, we performed secondary analyses where we calculated SIRs and estimated HRs for each type of intellectual disability in both population and sibling comparison analyses.Data preparation was performed using SAS version 9.4, SAS institute Inc, Cary, NC, USA. Statistical analyses were performed using Stata version 15.1, StataCorp LP, College Station, TX, USA.A total of 1688 children were diagnosed with intellectual disability during a median follow-up of 5.5 years . The median age at diagnosis was 6.1 years (interquartile range: 4.4–8.7 years). The following maternal characteristics were related to higher incidence rates of intellectual disability among children: low (< 25 years) and high (≥ 35 years) age at delivery, increasing parity, lower educational level, non-Nordic origin, smoking during pregnancy, shorter stature, overweight and obesity , and diabetic or hypertensive diseases. Incidence rates were also increased for children delivered in more recent years, for children delivered by induced labor and by cesarean section, and for boys . Analyses where outcome was redefined as at least two diagnoses of intellectual disability also provided similar results regarding birth weight percentiles but showed weaker associations regarding gestational age (Supplementary Table 6).Among all children with intellectual disability, 47% (n = 787) had mild impairment. The SIRs of intellectual disability by severity across birth weight percentiles and gestational age are shown in Supplementary Figures 3 and 4 respectively. Similar to the overall association for any intellectual disability, the risk of mild intellectual disability was higher among children born at the 10th–24th and 25th–39th percentiles in population analysis and even higher in sibling comparison analysis. Risks of moderate and severe, other or unspecified types of intellectual disability were only significantly increased in children born at the 10th–24th percentiles in population analysis (Supplementary Table 7). Risks of mild and other or unspecified types of intellectual disability were higher in children born at 37–38 weeks, whereas risks of moderate and severe intellectual disability were higher in children born at 42 weeks or later in population analysis (Supplementary Table 8).In this nationwide population-based study of non-malformed, term or post-term, AGA children, we found that children born with lower birth weight percentiles had a higher risk of intellectual disability, both when compared with the general population, and with their siblings. A weak U-shaped association between gestational age and intellectual disability was observed in population analysis, indicating that children born early term or post-term had a higher risk of intellectual disability, although such pattern was not observed among siblings. The increased risk for low birth weight percentiles was stable irrespective of gestational age. Children with higher birth weight percentiles were at higher risk of intellectual disability if they were born post-term.In agreement with previous studies , we founA number of studies have examined the association between gestational age and cognitive level in children born at term or post-term , 36, 39.In this study, sibling comparison design was applied to control for unmeasured confounding factors shared by siblings. While associations regarding birth weight percentile persisted in sibling comparison analysis, associations for gestational age attenuated. This supports that variation in gestational age might be explained more by maternal genetic effect and shared (sibling) environment than other phenotypes such as birth weight . NeverthThe risk increase for lower birth weight percentile did not differ within the range of gestation age (≥ 37 weeks). This suggests that even for full term infants, failure to reach their optimal growth potential may increase the tendency for intellectual and adaptive difficulties, potentially resulted from, e.g., reduced total brain volume , 46. On Mild intellectual disability accounted for almost half of the cases and shows similar associations as any intellectual disability. The higher risk of mild intellectual disability for lower birth weight percentiles in sibling comparison analysis versus population analysis could, however, be a chance finding. The largely non-significant results for more severe and other types of intellectual disability may be attributed to lack of statistical power.A strength of the present study is the use of prospectively and independently collected information on exposures, outcome, and covariates based on Swedish national registries, which yielded sufficient statistical power to evaluate the risk of intellectual disability. Ultrasonography was performed to the majority of women (87% of births) which ensured optimal pregnancy dating. In addition to population analysis, we applied sibling comparison analysis to adjust associations for unmeasured genetic and environment factors shared by siblings. Although restriction to siblings might induce selection bias, this might be less of a concern in the present study which showed similar distributions of characteristics between the entire study population and the subpopulations of exposure- and outcome-discordant siblings. Some potential limitations deserve mentioning. Complete case analysis may have induced bias due to missing covariate information, but the multiple imputation analysis, despite the assumption of missing data at random , provideIn conclusion, lower birth weight percentiles are associated with higher risks of intellectual disability in AGA children born term or post-term, irrespective of gestational age. This study enriches the knowledge of short- and long-term neurological outcomes of non-optimal fetal growth in AGA infants .Supplementary material 1 (DOCX 4279 kb)Below is the link to the electronic supplementary material.