Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice.We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index  and one comparator U.S. state  to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors.Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6–6.0 and 2.8–5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25–50% and 11–16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted.very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions.We have quantified the causes of variation in preterm birth rates among countries with  Preterm birth (birth occurring before 37 weeks of gestation) is an enormous global public health challenge, with 15 million infants born preterm every year and an estimated 35% of deaths in the first 4 weeks of life directly attributable to prematurity . In 2013The World Health Organization (WHO) "Born Too Soon" report (1) concluded that a 50% reduction of preterm birth specific mortality in resource-poor countries is achievable by 2025. On the other hand, the prevention opportunity is weak based on current proven interventions. Assuming even optimum coverage and historical-level reductions of best-in-class countries, a miniscule 5% rate reduction in preterm birth is possible in 39 countries with very high human development index (VHHDI). This is a shockingly small absolute reduction opportunity  given the substantial disease burden of preterm birth [Risk factors known to be associated with preterm birth include multiple medical, genetic, environmental and socioeconomic factors, not always considered in combination –8. PreviImportant differences in preterm birth rates exist across countries. Among countries with VHHDI, preterm birth rates vary widely, in 2010 from 5.3 per 100 live births in Latvia to 14.7 per 100 live births in Cyprus [The purpose of our study was to perform the most robust cross-country analysis of preterm birth etiology undertaken to date, utilizing individual patient-level pregnancy and birth data from select countries with VHHDI to 1) assess the relative contributions of known risk factors of preterm birth to individual preterm birth risk, 2) assess the impact of each factor on population preterm birth rates , 3) estimate the potential impact of three key intervention areas  and 4) explain variability of preterm birth rates across selected countries with VHHDI. A secondary purpose was to perform a systematic review of multivariate studies of preterm birth risk factors in order to situate our analysis.We conducted five distinct and interrelated analyses as part of this effort. See We performed a literature search of multivariate studies of preterm birth risk factors published since 1985 using the combination of key words "premature", "preterm" and "risk", in Web of Science (Thomson Reuters) and MEDLINE . This search yielded ~11,500 search results, following which we excluded studies that considered fewer than 6 non-clinical maternal or fetal risk factors as covariates . We included all risk factors considered by at least 3 studies. Where categorical variables were reported, we reported the category having the largest significant odds ratio .Individual patient risk refers to the increased likelihood of giving birth preterm for an individual woman with the risk factor. 2) Population attributable risk refers to the contribution of that risk factor to the overall population preterm birth rate, and is a function of both the increase in risk when the risk factor is present and the prevalence of the risk factor in that population. Individual patient risk is relevant to an individual patient as well as to obstetricians and midwives seeking to understand and estimate a given patient's risk and determine appropriate clinical care given the presence of a set of risk factors. Population preterm birth rate by contrast is relevant to policymakers and public health clinicians seeking to reduce the overall preterm birth rate.We use two terms throughout this study to describe the contribution of preterm birth risk factors. 1) Based on published literature, internet searches and prior knowledge of the authors, we identified a convenient sample of international individual patient-level data sources with at least 5 years of pregnancy outcome data, encompassing at least 10 clinical and non-clinical variables. Based on data robustness  and access provisions , we included individual patient-level datasets from four countries .http://www.uzis.cz/en); New Zealand, the National Maternity Collection maintained by the New Zealand Ministry of Health ; Slovenia, the Slovenian National Perinatal Information System maintained by the Slovenian National Institute of Public Health (http://www.nijz.si/); Sweden, the Swedish Medical Birth Register maintained by the Swedish National Board of Health and Welfare  and complemented by linked data from Statistics Sweden (www.scb.se). All these data sources have been previously described [Data sources were as follows: Czech Republic, the National Registry of Reproduction Health—Mothers at Childbirth and Newborns  as previously described [As a comparator, we also included data from one state in the USA  using the vital statistics linked birth/death file from the California Department of Health Services  spontaneous preterm birth , and (2) provider-initiated preterm birth before 37 weeks of gestation, whether medically indicated or not . GestatiWe further classified risk factors into 3 broad intervention areas which we termed, 1) research, 2) policy and public health, and 3) clinical practice. We did this for heuristic purposes, and made these distinctions based on our working group's expertise, as we were unable to find literature on any other group that had attempted to do this. The intervention area "research" comprises risk factors for which current biological or etiological understanding is insufficient to prevent preterm birth utilizing currently available clinical practice and/ or policy. Thus, more research is needed, specifically likely to involve cell biology or molecular underpinning responsible for association lacking an ostensible plausible explanation. "Policy and public health" interventions arises from risk factors whose prevalence could be impacted by policy and /or public health interventions and only to a limited extent by the actions of individual practitioners. "Clinical practice" interventions involve addressing risk factors whose prevalence could be directly impacted by clinicians adjusting their practice . Some risk factors  are relevant to both "policy and public health" and "clinical practice" and were thus considered into both categories.In order to determine the independent contribution (i.e. after accounting for the impact of other factors) of each risk factor to an individual's risk for preterm birth, we created a model for each country including all risk factors. For analyses on the individual patient-level datasets Figs , data weTo determine subpopulations with the greatest risk of developing preterm birth, we combined all four of the whole country datasets  and the California state dataset to generate a total database of ~ 4.1 million singleton pregnancies. We then analyzed risk factors common to all five datasets. The risk factors were combined to define subpopulations each with a unique combination of preterm birth risk factors. Subpopulations with prevalence below 1 in 10,000 were excluded.Prob(PTB|RF) is the probability of preterm birth given the risk factor RF, Prob(RF) is the prevalence of the risk factor RF, and AME(RF) is the average marginal effect of the risk factor RF. The latter is defined asE indicates the expectation, Y1 is the outcome that would be obtained if a subject had the risk factor, and Y0 is the outcome that would be obtained if a subject had the risk factor [As reflected in k factor , 18. TheWe illustrate in Systematic review of multivariate studies on preterm birth risk factors identified a total of 18 studies that considered a minimum of 6 non-clinical maternal or fetal risk factors as covariates  were conducted within populations smaller than 15,000. Because data were generated in disparate locations and not subjected to a common template, the risk factors analyzed in each study were understandably variable both in number and types of risk factors collected. Very few studies  included more than 20 risk factors. For the 18 identified risk factors that were interrogated in at least 3 studies, reported odds ratios varied across studies up to 9-fold . At pregThe contributions of each risk factor (or combination thereof) to individual preterm birth risk was estimated using logistic regression analysis of the large individual patient-level datasets from four countries , and compared these results to one heavily populated state from the United States with robust pregnancy data  . After eOdds ratios for each risk factor  were remIn our stratification analysis, prior preterm birth remained by far the strongest risk factors for both provider-initiated and spontaneous preterm birth . Education, smoking, and maternal age constitute the main contributors to preterm birth amenable to policy and public health intervention. The baseline rates for lowest-risk populations  appear consistent across countries, ranging from 2.1% in Sweden to 3.2% in Slovenia. This rate reflects the risk for a pregnancy in which the mother is multiparous, has a female baby, has had no prior preterm birth, does not develop preeclampsia, is from the highest education group, andis characterized by lowest-risk categories.To estimate the contribution of individual risk factors for preterm birth on overall k factor . Risk fak factor . With thk factor . AlthougWe sought to estimate the relative contributions of identified risk factors to differences in preterm birth rate observed between Sweden (the country with the lowest preterm birth rate in our data set) and 15 other VHHDI countries (see 2 = 0.96) to the overall difference in preterm birth rate between that country and Sweden, ranging from 0.1% (Japan) to 6.2% (Bahrain). Among all risk factors considered, preeclampsia, low education, multifetal gestation, previous preterm birth, and smoking are the main risk factors accounting for explainable differences among countries.The net contribution of the known set of preterm birth risk factors evaluated in this study is insufficient to explain the overall differences in preterm birth rates observed among other countries with VHHDI and Sweden . On averThe unprecedented individual patient-level dataset  and newly applied analytic approaches allowed us to make several intriguing advances with this study. First, we robustly confirmed prior preterm birth and preeclampsia as the top individual risk factors. We also robustly clarified the magnitude of impact of other risk factors, confirming some prior findings while not confirming others. Second, we identified nulliparity and male baby sex as the top contributors to the population preterm rate, and we found that unknown factors requiring further research to act upon account for ~2/3 of the preterm birth rate. Third, we found that the contribution of risk factors to preterm birth burden is remarkably similar across countries–both in terms of individual risk as well as population preterm rate. Fourth, we found that we are unable to account for ~2/3 of the difference in preterm birth rates between Sweden and 15 other countries with VHHDI. In addition to these intriguing advances, even though robust preterm birth prediction remains elusive, our analysis allows an improved capability to robustly assess preterm birth risk for an individual pregnant patient with a given set of risk factors.We not surprisingly found previous preterm birth to be the strongest individual risk factor for both spontaneous and provider-initiated preterm birth  appears to have the greatest single impact on population preterm birth rates across all risk factors considered, accounting for up to 28% of the total rate in Sweden. This impact is incremental to that driven by higher incidence of preeclampsia in nulliparous pregnancies, and could in part be due to the same unknown factors responsible for risk associated with recurrent preterm birth. Male sex has been previously identified as a risk factor for preterm birth . SimilarOther significant risk factors, albeit with lower odds ratios  confirmed through this analysis include chronic hypertension, pregestational diabetes mellitus, older maternal age, and ART, all holding for both spontaneous and provider-initiated preterm birth. Previous cesarean section is associated in our analysis with an increased risk of spontaneous preterm birth (odds ratios 1.4–1.9) but appears protective for provider-initiated preterm birth (odds ratios 0.5–0.9). This most likely reflects risks of early birth related to need for repeat cesarean delivery.2) is a significant risk factor for both spontaneous and provider-initiated preterm birth , whereas being overweight (BMI 25.0–29.9 kg/m2) or slightly obese  are not (OR 0.9–1.1). Interestingly, being very obese  is a risk factor of preterm birth in Sweden and in California , as has been recently reported, but not in Slovenia [We confirmed robustly several other risk factors whose effects were not always consistent in every study using much smaller data sets or lacking multivariate analysis. Being underweight . OuAs expected, our results from the comparator U.S. state of California indicate an increased risk for preterm birth among Non-Hispanic Blacks (odds ratio 1.6). Inasmuch as we had ethnicity data only from New Zealand among the other countries analyzed, we are unable to fully explore the relationship of ethnicity to preterm birth that was evident in the California data. Since New Zealand’s patient population is fairly homogeneous compared to California’s very heterogenous population, we did not expect to find a relationship with ethnicity in that country nor might we in the relatively homogenous populations of Sweden, Slovenia or the Czech Republic. We also lacked sufficient information in the datasets to explore any possible association between migration and preterm birth.Several investigators have recently addressed how differences in risk factor prevalence could explain variations in preterm birth rates across countries. A recent review summarized differences in preterm birth risk factors, reproductive health policy and medical practice, and measurement issues across European countries . ZeitlinAlthough we used very large validated datasets and multiple independent predictors, we were only able to achieve modest levels of combined specificity and sensitivity for the prediction of preterm birth  would have a preterm birth risk of <4%, and a woman with a prior preterm birth, preeclampsia, and prior c-section would have a 48% chance of a preterm birth. A further activity for this working group is to disseminate widely this capability to providers and potentially to patients. Although we do not yet know if this capability can be beneficial for clinical practice, certainly predictive capacity should be helpful as effective interventions become validated.Our study is the first multi-country analysis to interrogate the impact of individual preterm birth risk factors within and across countries with VHHDI. High grade individual patient-level data from approximately 4.1 million singleton pregnancies were made available for analysis, including 2.8 million from 4 countries  and 1.3 million from a large comparator U.S. state . We were able to assess in various combinations the association of 21 individual risk factors with preterm birth, adjusting for multiple confounding effects. This unique dataset also enabled us to perform a first-of-its-kind analysis in preterm birth. We were able to look beyond simply individual risk to explore relative contributions of risk factors to population preterm birth rates.The present investigation was limited to countries with VHHDI because of the scarcity of very high quality validated data collected in rigidly managed, monitored and nationally supported systems in low-income countries, even though such countries generally have higher rates of preterm births . We haveIn conclusion, our results strongly support the need for additional research to elucidate biological basis of many of the known associations with preterm birth. First, previous preterm birth is the top risk factor of preterm birth according to our logistic model, but as discussed above this risk factor is surely a surrogate for genetic, epigenetic and environmental causes not ostensibly captured among the risk factors for which we controlled. Likely these same causes are also responsible for the contribution of nulliparity to preterm birth. Second, classification of the risk factors into intervention areas highlights the importance for more etiologic research into the 65% of risk factors not susceptible to current policy, public health, or to clinical intervention . Third, the aggregated contribution of known risk factors is insufficient to explain differences in preterm birth rates observed between Sweden and 15 other countries with VHHDI. Overall, our results suggest that impactful progress in the prevention of preterm birth countries with VHHDI will only be made possible by research into the biology of human parturition.S1 AppendixIt also includes the formulas and data sources used for the cross-country comparison as well as six supplementary figures and five supplementary tables.(DOCX)Click here for additional data file.


To investigate the association between the ratio of apolipoprotein B (apo B) / apolipoprotein A1 (apo A1) with all-cause mortality and cardiovascular events in peritoneal dialysis (PD) patients.Eight hundred and sixty incident PD patients were enrolled from November 1, 2005, to February 28, 2017, and followed until May 31, 2017. Outcomes were all-cause mortality and cardiovascular events. Associations between the apo B/apo A1 ratio with all-cause mortality and cardiovascular events were evaluated using multivariable-adjusted Cox models.P = 0.040) and for cardiovascular events of 2.04 .Of the 860 patients, the mean age was 49.9 ± 14.5 years, 57.6% were men, and 19.3% were diabetic patients. The median apo B/apo A1 ratio was 0.65 (range: 0.22–2.24). During a median follow-up period of 27 months , 202 deaths, and 145 cardiovascular events were recorded. After adjustment for age, sex, body mass index, diabetes, cardiovascular disease, systolic blood pressure, total Kt/V, estimated glomerular filtration rate, hemoglobin level, neutrophil to lymphocyte ratio and albumin, triglyceride, and cholesterol, as well as the use of lipid-lowering agents, the highest apo B/apo A1 ratio tertile was significantly associated with a hazard ratio for all-cause mortality of 1.60 (95% CI: 1.02 to 2.49, An increased apo B/apo A1 ratio was independently associated with all-cause mortality and cardiovascular events in PD patients. Peritoneal dialysis (PD) patients have an increased risk of morbidity and mortality associated with cardiovascular disease (CVD), which is, at least in part, due to lipid abnormalities, typically called uremic dyslipidemia . PatientLDL-C is widely recognized as the major atherogenic lipoprotein and is considered the primary therapeutic target for coronary heart disease . FurtherRecently, Sato et al.  indicatehttps://jamanetwork.com/journals/jama/fullarticle/1760318) and approved by the Human Ethics Committees of Nanchang University.We studied all incident patients who used PD as their first renal replacement treatment modality and were followed up at the PD center of The First Affiliated Hospital, Nanchang University, Jiangxi, China from November 1, 2005, to February 28, 2017. Inclusion criteria were age ≥ 18 years at the start of PD and survival for at least 90 days from the first PD therapy. The patients who were catheterized in other hospitals, transferred from permanent HD, or failed renal transplantation were excluded in this study. The study was conducted in compliance with the ethical principles of the Helsinki Declaration , and presence of diabetes and CVD. Clinical and biochemical data at the initiation of PD included body mass index, blood pressure, medication use, hemoglobin, serum albumin, serum creatinine, blood urea nitrogen, total cholesterol (CHOL), TG, HDL-C, LDL-C, Apo B, Apo A1, Lp (a). Immunoturbidimetric method was used to measure apo B and apo A1 concentrations. All baseline data were obtained during the first 1–3 months of PD. Baseline residual renal function was assessed by eGFR using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Cardiovascular events were defined by the first occurrence of myocardial infarction, stroke, heart failure, hospitalization for unstable angina, peripheral vascular event, sudden death, death associated with a cardiovascular procedure, or death due to aneurysm dissection or rupture, fatal pulmonary embolism, or death due to other or unknown cardiovascular cause  after thP < 0.05 in the univariate Cox analyses or thought to be clinical significant were chosen for multivariate Cox proportional hazards regression. The results were expressed as the hazard ratio (HR) and 95% confidence interval (95% CI). All descriptive and multivariate analyses were conducted using SPSS version 22.0 . A value of P < 0.05 was considered statistically significant.Patients with apo B/apo A1 ratio were classified into tertiles (Ts): T1 ≤ 0.545, T2 = 0.545-0.769, T3>0.769. Participant characteristics were calculated by Ts of apo B/apo A1. Results were expressed as frequencies and percentages for categorical variables, means and standard deviations (SDs) for normally distributed continuous variables, and medians and interquartile ranges for continuous variables not normally distributed. Chi-squared, one-way ANOVA, or Kruskal–Wallis tests were used to test for differences in categorical or continuous factors among different categories of apo B/apo A1. Survival times were estimated from Kaplan–Meier curves, and differences in survival probabilities among groups were assessed using the log-rank test. The associations between apo B/apo A1 ratio and all-cause mortality and cardiovascular events were examined in Cox proportional hazards models. The censored data included switching to HD, renal transplantation, moving to another center, declining additional treatment, loss to follow-up, or still at our PD center on May 31, 2017. Unadjusted associations were first examined followed by adjustments for age and sex, diabetes and CVD, systolic blood pressure (SBP), body mass index (BMI), total urea clearances (tKt/V) and eGFR, hemoglobin, neutrophil to lymphocyte ratio (N/L), albumin. Next, TG, CHOL as well as lipid lowering agents were added to examine whether apo B/apo A1 ratio was independently associated with mortality and cardiovascular events. Covariates with A total of 1011 incident PD patients were recruited and monitored in our hospital. Thirty-four of the patients were excluded by our experimental criteria and listed as below: 3 subjects were under 18 years of age, 2 subjects were transferred from failed renal transplantation, 8 subjects were transferred from permanent HD, and 21 subjects were treated with PD for less than 3 months. The remaining 977 patients were enrolled. Of the 977 patients, 117 patients did not measure baseline levels of apolipoproteins. Finally, 860 patients were found to be eligible for analysis. During the PD procedure, the conventional PD dialysis fluids include 1.5% or 2.5% dextrose and the twin-bag system was applied for all PD patients. For the management of dyslipidemia in the patients, lipid-lowering agents were formulated and given to the patients (10.3%). As shown in Fig. P < 0.05). No significant differences among age, sex, CVD, blood pressure, albumin, and lipid-lowering agents use were observed  and the characteristics of the patients stratified by tertiles of the apo B/apo A1 ratio are displayed in Table r = 0.60 and − 0.51, respectively). Apo B was strongly correlated with LDL and the ratio of apo B/apo A1 . On the other hand, the ratio of N/L was negatively correlated with apo A1 (r = − 0.10) but not with apo B   . By the end of the study, 202 patients (23.5%) were died and recorded. Fifty-two patients (6.0%) had received kidney transplantation, 127 patients (14.8%) were transferred to HD, 6 patients (0.7%) transferred to other PD centers, 20 patients (2.3%) patients discontinued follow-up, and the remaining 453 patients (52.7%) were still followed in our PD center. Of the 202 deaths, 108 were caused by CVD (53.5%), 16 were caused by infectious disease (7.9%), 3 were due to malignancy (1.5%), 16 were caused by cachexia (7.9%), and 19 and 40 cases  were caused by other and unknown reasons, respectively. The correlation between all-cause mortality and the apo B/apo A1 ratio was evaluated using Kaplan–Meier methods, which are shown in Fig. 17) Fig. . The car21) Fig. . The assIn this retrospective cohort study, we identified the correlation between the serum apo B/apo A1 ratio and PD patient characteristics. We found, for the first time, that a higher apo B/apo A1 ratio is strongly correlated with increased all-cause mortality and cardiovascular events in PD patients. Consistent with the empirical results from HD patients and non-CKD patients , 12–15, Apo B is a key basal unit of atherogenic lipoprotein including VLDL, IDL, and LDL. Since each of these lipoproteins detects only one apo B molecule, apo B measurements have been used to determine the precise number of the atherogenic lipoproteins in patients . PreviouIn contrast to apo B, apo A1 is a main constituent of HDL. Although each HDL particle contains five apo A1 molecules, systemic apo A1 levels have been used as an indicator for HDL cholesterol concentrations . The relThe apo B/apo A1 ratio is a typical marker for the atherogenic /antiatherogenic condition, and a higher apo B/apo A1 ratio represents progression in the atherosclerotic state. Previous studies have suggested that a high apo B/apo A1 ratio strongly correlates with pathophysiological markers of atherosclerosis defined by coronary angiography , 20, andAlthough the apo B/apo A1 ratio is considered as a risk predictor for CVD mortality in the general population , 30, to The present study also has limitations to discuss. First, this is a retrospective study, which can only lead to associations but not causality. Second, the number of patients is relatively small. Third, in this study, we only applied the baseline data but did not exclude patients who had already taken lipid-lowering medications, nor considered the data changes during the follow-up period. Fourth, because of the limited sample size, the potential risk factors were not all adjusted in this cohort study. Hence, the effects of residual confounding factors cannot be eliminated completely. Our future studies will address the improvement of these issues.In summary, despite conflicting evidence of lipid effects on the prognosis of PD patients, our results found significant associations between the apo B/apo A1 ratio, cardiovascular events, and all-cause mortality in PD patients. The apo B/apo A1 ratio can serve as a risk marker for the risk of the CVDs and mortality in PD patients.


Rapid economic and cultural transition in the United Arab Emirates has been accompanied by a rise in chronic disease. Early childhood is known to affect health outcomes in adulthood. This prospective longitudinal study examined the general health of Emirati infants born in a government maternity hospital in the Emirate of Abu Dhabi in October 2002.n = 94), six (n = 59) and 15 months postpartum (n = 52). Data are presented using univariate statistics.One hundred twenty-five women, who had recently given birth, were interviewed as part of a larger study encompassing a wide range of cultural, social, and behavioural aspects of health. They were then re-interviewed at three (p = 0.00). Iron supplementation during pregnancy was associated with fewer underweight infants . No associations were found between infant birth weight and maternal age, age at marriage, consanguinity, education level, current maternal employment, parity, pre-existing anaemia or anaemia in pregnancy, diabetes, folic acid intake, multivitamin intake or infant gender.In this study seven infants (6%) were born prematurely and four infants (3%) were classified as small for gestational age, while 11 (9%) of the infants weighed less than 2500 g. Low birth weight infants (LBW) were significantly more likely to require treatment in the neonatal intensive care unit (OR = 30.83, Maternally-reported infant health issues, vaccination, medication, breast-feeding and infant nutrition, and use of secure car seats are also reported.The health of infants at birth in this UAE sample showed improvements compared to previous studies. The proportion of LBW infants is decreasing and continuing improvements in health care in the UAE are having a positive impact on infant health. The United Arab Emirates (UAE) is a country that is undergoing rapid modernisation yet is experiencing high levels of chronic disease; particularly obesity, heart disease and diabetes . SusceptGlobally, in 2015 2.7 million children died in their first 28 days of life resulting in a neonatal mortality rate of approximately 19 per 1000 live births . Almost In the postnatal period common causes of death and disability include: pre-maturity (birth before 37 weeks of gestation); neonatal sepsis; respiratory infections; neonatal tetanus; cord infections; congenital anomalies; and birth trauma or asphyxia . In deveIn the UAE, it is now mandatory for all women to give birth in hospital with trained staff in attendance, and facilities are on a par with many maternity hospitals in developed countries. Neonatal mortality in the UAE has significantly decreased since 1978 from 17.8 deaths per 1000 births to 3.5 deaths per 1000 births in 2015 . Seven of the infants (6%) were born preterm and as expected were more likely to be admitted to the NICU. Four of the infants were small for gestational age suggesting that, if their recorded gestational ages were accurate, they had suffered IUGR.LBW infants were significantly more likely to require treatment in the neonatal intensive care unit (NICU) [OR = 30.83, All but three of the 11 LBW infants weighed more than 2 kg. The lightest infant was born at 26 weeks gestation and weighed 710 g, whilst another was born at 25 weeks gestation, weighing 780 g. The third infant weighed 1.49 kg and suffered cardiac issues but remained in the study for the duration. Eight of the infants in the study were admitted to the NICU immediately after birth. The reasons for admission varied and included: preterm/very low birth weight; pre-term/intrauterine growth restriction; ileal atresia; tachypnoea; and congenital myopathy. No relationships between NICU admittance and consanguinity, maternal age, or education level, regular check-ups during the pregnancy, or maternal desire for the pregnancy were found.The Apgar scores taken at one and 5 min after birth were slightly higher for the boys than for the girls at 1 min but this was not statistically significant. No significant relationships were found between length of gestation period and birth weight with Apgar scores. No infant received a critical score at 5 min after birth.Data relating to the initiation and duration of breastfeeding and consumption of additional liquids and foods during infancy in this cohort have been extensively reported in a previous publication . Exclusin = 24, 46%), but only 5 (10%) had concerns regarding infant growth.At 15 months of age most of the infants were taking meals with the rest of the family, with only five being fed separately. All the infants consumed a varied diet by 14 or 15 months, eating the same food as the rest of the family at least some of the time. The most commonly consumed foods were: rice, apples, banana, mango, kiwifruit, potato, squash, carrots, beans, meat, fish, confectionery, eggs, biscuits, bread, yogurt, cheese. All the infants, with just one exception, consumed French fries. Twenty-five (48%) of the infants were reported as frequently eating French fries, which were also popular as a snack between meals. Other popular snack choices included: biscuits, confectionery, yogurt and fruit. The infants consumed a range of beverages; water and pure fruit juices being the most popular. Five infants (10%) had consumed tea; four were given coffee (8%), while three (6%) had been given carbonated soft drinks. Many of the participants expressed concern that their baby was not eating enough (n = 5) of mothers reported that their infants were placed in a secure car seat when travelling during the first 3 months of life. Most infants were held in the arms of an adult in either the front or back seats , eczema , food allergies , heart problems  congenital myopathy  and eye problems .Chronic infant health issues reported included: asthma  of the infants had not received all the recommended vaccinations, due to infant illness and lack of transportation. Six (7%) infants had not had a health check. Sixty eight of the infants (81%) had between one and four check-ups during the first 3 months of life, and ten infants (12%) had five or more. The reasons given for not taking infants for health check-ups included: baby was not ill, mother was too busy, mother was ill, lack of transport, husband would not take mother to clinic, lack of knowledge on how to make an appointment.Data collected at 6 months after birth showed that all but one of the infants were now up to date with their vaccinations; the exception being due to problems with transportation and ill health.n = 52) had received medical check-ups. Thirty-two (62%) of the infants had received between four and seven check-ups while six (12%) had received more than eight. Reasons given for not having regular health checks for the infant included: infant was not ill , mother was too busy , lack of transportation , and one woman said that her husband would not take her. All infants had received all the recommended vaccinations, although two were behind schedule.By 14–15 months, all the infants  were asked about information and advice they had received regarding breastfeeding while in the hospital. Forty-eight (51%) of the women had received information regarding breastfeeding from hospital staff. The staff in the hospital had helped 63 (68%) of the participants to breastfeed during their stay in the hospital. However only 20 (22%) of the women reported receiving a phone number from the hospital staff to call midwives for help if they experienced any subsequent problems with breastfeeding. Only one mother who had decided to bottle feed before the birth was given advice on how to make bottles and given a gift pack containing samples of infant formula.At 3 months after birth the respondents (n = 58) were asked where they obtained information relating to the introduction of complementary foods. Most women found information through books and magazines , government health establishments , private health establishments , and family, friends or personal experience  while four women obtained information from the television and internet sources (7%).At 6 months after the birth, participants . Only nine of the 58 women had heard of SIDS and six of these had found out about it from television, two from family and friends and one from a doctor.The population of Abu Dhabi, the wealthiest of the seven emirates of the UAE, has experienced an exceptionally rapid transition from a subsistence existence to one of wealth and privilege within the space of 40 years. One would expect that infant health would improve during this transition due to access to better health resources. Indeed, this paper confirms that LBW, an important aspect of infant health at birth, has improved in Abu Dhabi and is similar to that of developed countries.LBW is a risk factor for numerous infant health issues, both acute and chronic. This study indicated an incidence of 8.8% of LBW; an improvement from the figures shown in the UAE Family Health Survey based on data from all the emirates, which found an incidence of 15% in 1995 . These fBetween 1992 and 1999, the UAE neonatal mortality rate was reported as 6.9 per 1000 live births, with preterm birth complications and lethal malformations accounting for 77% of all such deaths .Consanguineous marriages are common in the UAE and marriages between first cousins occur frequently . It is eThe number of infants born to adolescent women is declining in the UAE. Within this sample five women (4%) were below the age of 20 years. Green and Smith  found thAnaemia is viewed as a serious health problem in the Eastern Mediterranean region and WHO indicators for reproductive health show that 40.9% of women screened for anaemia during pregnancy had haemoglobin concentrations below 110 g/l . In the Iron supplementation is common in the UAE and supplements are routinely prescribed at maternity clinics, although this is only effective if women attend antenatal clinics early in pregnancy. The efficacy of supplementing women with iron pills during pregnancy to prevent and treat anaemia is well documented, although in developing countries, consideration also has to be given to the possible presence of other micro-nutrient deficiencies , 31. ResThe prevalence of breastfeeding and the introduction of complementary foods in this population has been previously reported by Gardner et al. . AlthougThe infants in this study suffered from the usual array of common childhood ailments. In addition, chronic infant health issues reported included: asthma, eczema, food allergies, heart problems, congenital myopathy and eye problems. Breathing difficulties and rashes were common suggesting that allergies may be common amongst this cohort. The prevalence of asthma and eczema in children in the Emirates has been reported as 13% and 11% respectively . A more Several of the mothers reported that their child had more serious or chronic conditions but these were relatively rare. The nature of the health services in Abu Dhabi offers a range of choices in health care or provision of medication. This was particularly the case in relation to medication with six of the participants relying on traditional healers to provide remedies for the infants. Depending on the composition of the remedy this may be cause for concern as some traditional herbal remedies have been associated with toxins or contamination, and may pose a threat to health .Mortality and injury resulting from road traffic accidents are common in the UAE , 38. AltThere are several limitations to this study that should be noted. These include subject attrition and low response rates on follow up, largely due to the mobility of this population, with many of the new mothers moving between extended family residences. This population was relatively healthy as mothers with ill or low birth weight infants may have declined to participate in the study. In addition, mothers in this culture may not be willing to admit to poor health in their children and health status may therefore be subjective. The use of the Apgar scores as a proxy of overall general health of new-borns has limitations. The exploratory descriptive nature of this study depicts a unique set of circumstances documented at a single point in time in Abu Dhabi, a rapidly developing city. This, combined with the relatively small number of subjects, serves to limit any claims this study might make about representativeness of the entire population.The health of infants born to the mothers in this UAE sample from Abu Dhabi showed marked improvement over previous studies. Although consanguinity among parents was high, no evidence for negative impacts on birth weight or prematurity was found. The proportion of LBW infants was decreasing and continuing improvements in health care in the UAE are having a positive impact on infant health. To further improve infant health outcomes for mothers and infants in the United Arab Emirates, more research and the implementation of health education programmes would be beneficial.


The overall impact findings were that the intervention had no significant effect on maternal or perinatal mortality or maternal morbidity, despite having positive effects on essential birth practices.In the article “Improving Adherence to Essential Birth Practices Using the WHO Safe Childbirth Checklist With Peer Coaching: Experience From 60 Public Health Facilities in Uttar Pradesh, India” by Megan Marx Delaney, Pinki Maji, Tapan Kalita, et al., which appeared in the June 2017 issue  of GHSP, the authors assessed birth attendants' adherence to essential birth practices in 60 public health facilities in Uttar Pradesh, India. At the time of publication of this article, we noted at the end of the Abstract field that we would update this article by including a reference to the impact findings of the intervention, which were pending publication in another journal. Those impact findings have now been published in the These impact findings are now referenced at the end of the Abstract.


Weight catch-up preceded height catch-up. Protein intake in early infancy correlated highly significantly with abdominal fat mass , but not with lean body mass at 9.5 years . In contrast to nutrient intake, birth weight was associated with lean body mass . Early protein and carbohydrate intake were associated with high-density lipoprotein (HDL)-cholesterol, and early catch-up growth correlated with fasting insulin at follow-up. Stepwise linear regression demonstrated that protein intake predicted fat mass (p < 0.05), whereas only gender and birth weight standard deviation score (SDS) contributed significantly to lean body mass variation (p < 0.05). Our results suggest an important impact of early nutrient intake on body composition and metabolism in later childhood in ELBW children.To evaluate body composition, metabolism and growth as well as their interaction with early nutrition in former extremely low birth weight infants (ELBW), we assessed qualitative and quantitative nutritional intake during initial hospitalization and infantile growth parameters in 61 former ELBW infants with a birth weight <1000 g. In two follow-up exams, physical and biochemical development were measured at 5.7 and at 9.5 years. At the second follow-up, in addition to biochemical reassessment, body composition was analyzed by dual-energy x-ray absorptiometry (DEXA). Protein intake between birth and discharge was associated with weight gain in the first six months of life ( Decreased birth weight can have a persisting impact on metabolic health in later life . In addiPreliminary animal data suggest that the macronutrient content of late fetal or early postnatal nutrition might influence later body composition . TherefoIn part, this might be due to the fact that energy supply in extremely low birth weight infants (ELBWs) often does not reach recommendations from guidelines in the first weeks after birth . MissingOn the other hand, rapid catch-up growth following an initial growth restraint after preterm birth bears a higher risk of metabolic alterations later in life . This isWe hypothesized that in the special cohort of extremely low birth weight infants, the first signs of metabolic syndrome and altered body composition may be already present in early childhood and that these are related to early life events including the nutritional regimen. To establish clear cause/effect relationships between early nutrition and subsequent morbidity, controlled human intervention trials in these groups at risk would be highly desirable. However, even today, feeding of critically ill preterm infants in the neonatal intensive care units (NICUs) remains a balancing act and makes controlled trials with strict adherence to nutritive protocols very difficult if not impossible. We thus performed a longitudinal single-center follow-up study in ELBW infants and focused on the development of height, weight, and metabolism. In addition, we assessed body composition at the last follow-up exam at a mean age of 9.5 years.The initial study population consisted of 175 extremely low birth weight infants who were born at the Department of Neonatology at the University Hospital of Bonn in the years 1999–2002, per definition born with a birth weight below 1000 g. A total of 49 children died in the postnatal period, 27 had moved and were not accessible, and 38 refused to take part in the study.First follow-up examination: A total of 61 children with a mean age of 5.7 ± 0.9 years participated in the first follow-up examination at the Children’s Hospital in Bonn in 2006. The focus of the first follow-up examination was on auxological development. Subjects with chronic or syndromal disorders or with handicaps after severe intraventricular hemorrhages or necrotizing enterocolitis were excluded. For more details see [ails see .Second follow-up examination: At the second follow-up in 2010, a total of 39  healthy children  participated in the re-examination. Twenty-two families from the initial cohort could not be convinced to take part in the follow-up. The main reasons for not participating were having moved to more distant locations and unwillingness to travel, fear of stress to the children or refusal to participate in the dual energy X-ray absorptiometry (DEXA) analysis. All but eight of the children  were prepubertal. The children’s parents and the children themselves were asked for written informed consent and agreed to the study. The protocol was approved by the Medical Ethics Committee of the Faculty of Medicine at the University of Bonn and the Federal Agency for Radiation Safety .Nutritional intake from birth until discharge was collected retrospectively from patients’ files. The following components were analyzed: total daily energy-, carbohydrate-, lipid- and protein-intake. For analysis, we calculated the average daily nutritional intake of each component over the whole in-patient stay, expressed in g/kg/day. Due to the fact that our cohort consisted of ELBW infants, strict adherence to a detailed nutritional protocol was not possible, in particular in critically ill infants. Several ELBW infants had to switch from oral to parenteral nutrition during clinical deterioration; therefore, the amino acid composition of the protein intake differed between patients and was not part of this analysis. Not prescribed, but actually taken amounts of nutrients were used for calculations.Growth parameters (weight and height) at birth and during postnatal in-patient stay were gathered retrospectively from patients’ files. Data concerning growth during infancy were collected from regular paediatric screening examinations. Children were seen at a mean age of one, two and four years as part of the recommended German prevention program. The first follow-up examination as part of the study protocol, was performed at a mean age of 5.7 years. Mean age at the second follow-up examination was 9.5 years. All children underwent standardized auxological measurements which were always conducted by the same person. All children were weighed with the same scales while wearing underclothes. Height was determined by the same fixed stadiometer in all cases. For analysis, age was corrected for preterm birth until two years of age. Weight and height standard deviation-scores were calculated using German reference data ,13. BodyIn addition to the outlined auxological parameters, we measured triceps’ skinfold thickness with a calibrated calliper according to standardized reference manuals. For analysis, reference data for standard deviation scores were derived from Gerver and coworkers 2001 .Measurement of body composition only took place at the second follow-up examination with a mean age of 9.5 years. Lean body mass, total and regional  fat mass were measured using dual-energy x-ray absorptiometry . The DXA scans were all performed with the same standard dose apiece (76 kV/0.15 mA/0.4 µGym²). During the examination, every child wore shorts and lay in a standardized position on the back. We did not have to use sedatives. For analysis, reference data for standard deviation scores were provided from GE Lunar Body Composition Software .Venous blood samples for laboratory analysis were collected from all children between 08:00 a.m. and 10:00 a.m. in a fasting state. Levels of insulin were measured with an Immulite 2000 analyzer  with the lowest detection limit at 2.0 µU/mL). Total cholesterol, HDL- and low-density lipoprotein (LDL)-cholesterol, triglycerides were measured with Vista 3000T .We defined “catch-up growth” as an increase of weight or length of >1 SDS during an interval of six months.p value < 0.05; a statistical trend was assumed for p values between 0.05 and 0.1.Statistical analysis was performed using the SPSS software . Non-parametric tests were used whenever data were not normally distributed. Relationships between variables were examined by non-parametric Spearman’s rank correlation, partial correlations or linear regression analysis. Linear regression analyses were calculated with lean body mass, fat mass, HDL-cholesterol and fasting insulin as dependent variables and sex, birth weight, early macronutrient intake, weight development and pubertal stage as independent variables. Sex was used as a categorical variable in these models. All variables not normally distributed were log-transformed in these models. Significance was defined as A comparison of weight and height development of our study cohort is shown in The time pattern of height development differed from weight development: Height-SDS also declined from birth onwards. In contrast to weight development, the lowest mean height occurred at 0.5 years of age. The highest height catch-up took place between 0.5 and 1 year of age (+4.28 SDS) followed by a slower catch-up growth in height up to 2 years of age. At 9.5 years of age, target height-SDS  was reached by one third of the cohort.BMI-SDS declined until 1 year of age and continually increased up to the time of the second follow-up examination.r = 0.505; p < 0.01). Weight development during further follow-up is depicted in p < 0.05). None of the other nutritional components  correlated with catch-up growth in weight between discharge and 0.5 years of age. Catch-up growth in height between 0.5 and 1 year of age was not influenced by nutritional intake.The higher the average protein intake between birth and discharge from hospital, the more pronounced was the subsequent weight gain. This correlation was particularly present in the time interval of catch-up growth from discharge to 0.5 years of age ; between discharge and 1.0 year 0.464 (p < 0.05); between discharge and 2.0 years 0.364 (p = 0.052); between discharge and 4.0 years 0.211 (n.s.); between discharge and 5.7 years 0.428 (p < 0.05); and between discharge and 9.5 years 0.542 (p < 0.01).As outlined in p < 0.05).Absolute height-SDS was positively associated with lean body mass at every measurement from birth onwards. Contrary to weight development, absolute height-SDS did not correlate with fat mass at any point of time. Stepwise linear regression demonstrated that birth weight-SDS and gender contributed significantly to lean body mass variation , whereas weight from birth to 6 months of age correlated only with variation in fat mass , but not lean body mass . However, in the stepwise multiple regression analysis, neither catch-up in weight nor height contributed significantly to the variation in lean body mass or fat mass, respectively.Height development from birth to six months of age correlated significantly with variation in lean body mass , whereas regarding fasting insulin levels, only catch-up in weight between birth and six months of age contributed significantly (p < 0.05). Stepwise linear regression demonstrated that protein and carbohydrate intake predicted HDL concentration at 9.5 years  and 4 g/kg/day  in accordance to current recommendations ,24.It has been controversially debated whether higher protein intake during initial hospitalization directly causes uremia, acidosis and hyperammonemia . ConcernHowever, the advantages of an earlier and higher amino acid intake in form of a high protein intake, on auxological parameters were also shown by many international studies: Concerning short-term consequences, Poindexter and coworkers could demonstrate that a parenteral supplementation of amino acids of >3 g/kg/day during the first five days of life was associated with a better growth outcome at 36 postmenstrual weeks in extremely low birth weight infants compared to infants who received less amino acids . At 18 mConsidering long-term outcome parameters, most studies evaluated the effect of early protein administration on cognitive performance ,18,19, wDue to the high morbidity of our ELBW cohort and the fact that this was a single center study, our sample size was small. Furthermore, since our analysis was focused on quantity and not quality of protein intake, we were unable to analyze whether the amino acid composition of early infant nutrition might play an additional role on the long-term metabolic health of ELBW infants. On the other hand, the single center setting was advantageous with regards to the homogeneous nutritional regime and the early intensive care of our study patients. In addition, it has to be taken into account that besides early postnatal nutrition, several other pre- and postnatal factors contribute to the outcome of preterm infants but were not part of our analysis.Postnatal weight and height development in extremely low birth weight infants occur during different time periods. A high amount of protein intake seems to ensure a rapid catch-up growth during the first months of life. At 9.5 years of age, however, the higher early protein supply was associated with a potentially negative impact on both body composition profile and metabolic phenotype. The higher the postnatal daily protein supply, the higher the percentage of abdominal fat mass and fasting insulin, and the lower the level of HDL-cholesterol. If confirmed in further studies, this should lead to a critical reevaluation of the nutrient regimen in low birth weight infants.


A 22-year-old female visited our hospital for a routine checkup, and a mass was incidentally found on chest radiography. She denied any medical or family history and did not complain of any symptoms. Other than obesity, physical examinations and laboratory tests were unremarkable. Contrast-enhanced chest computed tomography depicted a 2.4 cm, well-defined ovoid thin-walled cyst in the left paravertebral space adjacent to the tenth vertebra . RadioloIn the histological examination, the cyst was lined by flattened, cuboidal or ciliated columnar epithelium supported by underlying fibrous stroma . The epiCysts arising in the mediastinum are relatively rare, accounting for 12-30% of mediastinal masses  insistedMediastinal Müllerian cysts follow a benign course with no reported recurrence so that surgical excision is the treatment of choice. The mediastinal Müllerian cyst is a recently established type of mediastinal cyst, which should be considered in the differential diagnosis of mediastinal cysts located in the paravertebral space of the posterior mediastinum in perimenopausal women or even in young women that are obese or have a previous gynecological history or hormonal abnormalities.


Glucocorticoids are essential in mammals to mature fetal organs and tissues in order to survive after birth. Hence, antenatal glucocorticoid treatment  can be life-saving in preterm babies and is commonly used in women at risk of preterm birth. While the effects of glucocorticoids on lung maturation have been well described, the effects on the fetal heart remain less clear. Experiments in mice have shown that endogenous glucocorticoid action is required to mature the fetal heart. However, whether the potent synthetic glucocorticoids used in antenatal corticosteroid therapy have similar maturational effects on the fetal heart is less clear. Moreover, antenatal corticosteroid therapy may increase the risk of cardiovascular disease in adulthood. Here, we present a narrative review of the evidence relating to the effects of antenatal glucocorticoid action on the fetal heart and discuss the implications for antenatal corticosteroid therapy. Through most of gestation, the mammalian fetus is maintained in a low glucocorticoid environment, with fetal glucocorticoid concentrations typically five- to ten-fold lower than maternal. As birth approaches, fetal plasma glucocorticoid concentration rises dramatically. This is essential for survival once born. Without glucocorticoid action, the lungs, heart and other organs and tissues are immature at birth, resulting in neonatal death . In human embryos, the adrenal cortex is discernible from the eighth week of gestation, though the morphology differs from the adult . Prior testation , but plaestation , approxiestation . In lateestation  and mateestation . Togethein utero is widely acknowledged to have detrimental long-term adverse effects in animals, including non-human primates, that increase the risk of cardiovascular and/or metabolic disease in adulthood  are routinely administered to women considered at imminent risk of preterm delivery . Antenatal corticosteroids are widely accepted to be the most effective therapy to reduce neonatal morbidity and mortality in preterm infants born between 24 and 34 weeks gestation: ACT reduces the incidence of neonatal death and the incidence and severity of respiratory distress syndrome, cerebral haemorrhage and necrotising enterocolitis  and the high-affinity mineralocorticoid receptor (MR or type I receptor). In mineralocorticoid target tissues, MR is co-expressed with 11β-HSD2, conferring mineralocorticoid specificity upon MR .Glucocorticoids, through GR, promote structural, functional and metabolic remodelling in mouse fetal cardiomyocytes . Mice wiNppa   axis associated with exogenous glucocorticoid administration. While SMGRKO mice reproduce much of the cardiac phenotype of global GR-knockout mice, some aspects differ. In contrast to global GR knockout mice, SMGRKO mice have normal-sized hearts, a normal E/A-wave ratio and normal cardiac expression of de, ANP) . The norde, ANP) . Indeed,de, ANP) . Excesside, ANP) . Similarestation . Restorain vitro. Treatment of mouse fetal cardiomyocytes with either dexamethasone or corticosterone for 24 h promotes their structural, functional and biochemical maturation  the enzyme that converts thyroxine (T4) into the more biologically active thyroid hormone, T3 (3 (3 in the fetus by inducing hepatic expression of D1 (responsible for producing most of the circulating T3), and downregulates placental clearance of T3 by the D3 enzyme , as do plasma glucose and free fatty acid concentrations, to fuel the increased energy needs . Endogen2 at birth  is reduced at birth  is an important factor in vulnerability to cardiac disease . In humaAlthough preterm birth is strongly associated with increased risk of cardiovascular disease in later life, the evidence to date suggests that effects of preterm birth on cardiac morphology and function are independent of antenatal corticosteroid exposure  and is ain utero. A modest but chronic maternal hypercortisolaemia in late gestation sheep altered the trajectory of myocyte maturation and increased expression of calcium signalling genes  and cardiovascular disease in adulthood is well known  or could result from ACT. The adrenal gland undergoes extensive remodelling immediately after term birth (POMC (encoding the precursor to ACTH) was reduced up to 12 weeks postnatally (What are the effects of ACT upon endogenous glucocorticoid production and how might this affect the fetal and/or neonatal heart? Maternal stress, perinatal adversity and exposure to inappropriately timed or excessive concentrations of glucocorticoids prenatally are all associated with life-long alterations in HPA axis activity . Relativrm birth  with regrm birth . Corticotnatally . HPA axiThese effects of ACT upon endogenous glucocorticoid production will have two consequences in the fetal and neonatal heart: First, in the short-term the HPA axis suppression will deprive cardiac MR of their glucocorticoid ligand. This will severely alter the cardiac MR/GR balance in favour of GR, for example, favouring the anti-proliferative effect of GR activation over the pro-proliferative effects of MR activation (ACT is an established and effective therapy to improve lung function in preterm infants, to reduce neonatal morbidity and mortality. However, increasing evidence suggests it is not always harm-free, particularly in infants delivered at or near term (More knowledge is urgently needed to inform future refinements to ACT. Current treatment protocols were largely established decades ago and are based on limited knowledge regarding optimal formulation, timing of dosage and efficacy at different gestational ages. A ‘one size fits all’ dosage applies, irrespective of maternal weight or gestational age. It seems likely that different processes during cardiac development may be affected by ACT at different gestational ages. With the increasing use of ACT in preterm infants as young as 22 weeks, it is important to elucidate how glucocorticoids may impact heart structure and function at different times. The manner of cardiomyocyte proliferation shapes the heart. If ACT alters cardiomyocyte proliferation, particularly in a region-dependent manner, then both shape and function will be affected . There mThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.


Folic acid supplementation during pregnancy has been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is unclear whether low folate status has effects on the developing brain. We evaluated the associations of maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal and postnatal head circumference in the offspring.Within a population-based prospective cohort, we measured maternal plasma folate concentrations at approximately 13 weeks of gestation (90 % range 10.5–17.2) and assessed folic acid supplementation by questionnaire (2001–2005). Up to 11 repeated measures of head circumference were obtained during foetal life (20 and 30 weeks of gestation) and childhood (between birth and age 6 years) in 5866 children (2002–2012).P < 0.001) faster per week per 1-SD higher maternal folate concentration. After adjustment for confounders, this association was attenuated to 0.004 SD per week . The association was independent of overall foetal growth. No associations were found between maternal folate concentrations and child postnatal head growth. Preconceptional start of folic acid supplementation was associated with larger prenatal head size, but not with prenatal or postnatal head growth.In unadjusted models, foetal head growth was 0.006 SD  contains supplementary material, which is available to authorized users. Supplementation with folic acid during embryonic development reduces the risk of neural tube defects in infants , 2. ThisEmerging evidence from observational research has shown that maternal folic acid supplementation during pregnancy is associated with reduced risk of several other neurodevelopmental disorders in offspring, including language delays , autism To further support a potential relationship between folic acid supplement use and neurodevelopmental disorders, nutritional biomarkers and biological intermediates can be examined. Blood folate concentration serves as a key nutritional biomarker. This can be measured in maternal blood and can serve as the endpoint of the determinants of folate status, i.e. after physiological absorption of folic acid supplements and folates from natural (or fortified) foods . Unlike Biological intermediates include structural alterations in the brain throughout pregnancy and early postnatal development. Head circumference (HC) can serve as a non-invasive and inexpensive proxy for foetal and early postnatal brain growth and development. HC is closely related to brain volume, particularly in the period before the skull is fully developed , 12. SevFolate is involved in a number of essential processes of growth and development, such as DNA synthesis and gene expression. Consequently, folate requirements are increased in periods of rapid growth, such as pregnancy. Low maternal folate concentrations directly limit the availability of folate to the foetal cells, which results in impairment of cell division and potentially impairs growth .growth was not considered as a pregnancy outcome [Earlier research provides inconsistent evidence for an association between maternal folate concentrations and HC at birth, and no evidence for an association between maternal folic acid supplementation and HC at birth . In a pr outcome . WhetherWe used the Generation R cohort to evaluate the associations of both maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured offspring prenatal and postnatal head size. We hypothesised that folic acid supplementation as well as higher folate concentrations is associated with increased head growth in the offspring.The subjects were participants in the Generation R Study, a population-based cohort from early foetal life onwards in Rotterdam, the Netherlands . The stuIn total, 8879 women were enrolled in the Generation R Study during pregnancy. Out of 8782 women with a singleton pregnancy, 6993 women (80 %) enrolled in the study before 18 weeks of gestation. We measured plasma folate concentration in early pregnancy in 5965 (85 %) of these women. We excluded 37 women since their measure of folate was above the assay range, resulting in valid folate concentrations at baseline for 5928 mothers. Twenty children died during the neonatal period and one was lost to follow-up before birth; these were excluded from this study. In total, at least one measure of foetal or child HC was obtained in 5866 children.n = 2153), (2) start within the first 10 weeks of pregnancy (n = 1602), (3) start after the first 10 weeks of pregnancy (n = 753) and (4) no use (n = 1358) [n = 1396) and ‘multivitamin use’ (n = 757) in additional analyses.Before 18 weeks of gestation , pregnant women were asked by questionnaire whether they used folic acid supplements or multivitamin preparations and when they started supplementation. In the Netherlands, both folic acid supplements and multivitamin preparations for pregnant women contain 400–500 µg folic acid; there is no mandatory food fortification with folic acid. In line with previous publications, we categorised folic acid supplement use in four groups: (1) preconceptional start (as recommended [ = 1358) . To distIn early pregnancy , venous blood samples were drawn, centrifuged and stored at −80 °C, as previously described . After tas a continuous variable (standard deviation scores (SDS)) andas a dichotomous variable, categorised into ‘folate-deficient’   or ‘normFolate concentration was analysed:Additional analyses were performed using a different cut-off ; 13.8 %).Foetal ultrasound measurements were performed at prenatal visits during each trimester of pregnancy , 21. FirHC was subsequently measured at birth and in up to seven visits at child healthcare centres at the ages of 0–2, 2, 3, 4, 5–10, 10–13 and 13–17 months. Gender of the child and gestational age at birth were extracted from medical records. HC was again measured at the Generation R research centre (mean age of 6.2 years).Gender and gestational age-adjusted SD scores were constructed for all measures of HC based on growth reference curves , 24. ThiSeveral maternal and child characteristics were selected as possible confounding variables, based on previous studies of maternal folate or foetal development , 26. Thesize at all separate time points of HC measurement.Folic acid supplementation and folate concentration were used as the independent variables in the analyses. In the analyses of folic acid supplementation, the group of mothers who did not use folic acid supplements comprised the reference group. In the analyses of folate deficiency, the group of mothers with normal folate concentrations comprised the reference group. We additionally used linear regression models to evaluate the associations between maternal folate concentrations with offspring head growth, we performed longitudinal analyses using unbalanced repeated measures analysis (mixed models). These analyses were performed separately for prenatal and postnatal head growth, since growth patterns as well as measurement methods differ between these developmental stages. Using maternal folate concentration as the independent variable, the model can be written as follows:β0 = intercept; gawks = gestational age in weeks; ε includes additional covariates for the adjusted model and error; similarly, a formula for folic acid supplementation as the independent variable can be defined). The term ‘β2 × folate’ tests the difference in intercept for each 1-SD higher folate concentration or comparing the folate-deficient group to the reference group. Gestational age was centred at 20 weeks of gestation in the prenatal models.To test the associations with offspring head 3 reflects the slope  and represents the average decline or increase in head growth per gestational week for each 1-SD higher folate concentration or in children of folate-deficient mothers versus the reference group. Thus, the weekly change in the SD score is multiplied by the average number of weeks of pregnancy to obtain the expected difference at birth. A random-effects model was applied for the intercept and gestational age to account for within- and between-individual variation. All other covariates were fitted as fixed effects. Longitudinal analyses were additionally adjusted for the effects of maternal ethnicity, smoking and educational level on head growth per week [n = 588) and 5 %  of the distribution of folate concentrations with the remaining 90 and 95 %, respectively, in secondary analyses.Coefficient βper week –31. We aBasic models were adjusted for gestational age at venipuncture, and gender and age of the foetus/child at assessment, if applicable. Subsequent models were additionally adjusted for the covariates mentioned earlier. Further, in the event of a significant association, we additionally adjusted for estimated foetal weight (EFW) to test whether maternal folic acid supplementation or folate status specifically affects offspring HC size/growth independent of overall growth. Finally, we explored potential effect modification by child gender in the fully adjusted models by including the interaction term between maternal folic acid use/folate concentration and child gender.Missing values of covariates were imputed using the Markov Chain Monte Carlo multiple imputation technique with predictive mean matching for continuous variables (0.1–21.4 % missing data). Five imputed datasets were generated. Subsequently, analyses were performed separately on each completed dataset and thereafter combined to one pooled estimate.Descriptive characteristics of the participating mothers and their children are presented in Table size at 20 weeks of gestation compared with children of mothers who did not use supplements during pregnancy. After adjustment for confounders, this association was only observed in foetuses of mothers who started supplementation before conception, similar to the previous report [B = 0.112, 95 % CI 0.028; 0.196, P < 0.01).Table s report . Maternagrowth in the offspring . Therefore, analyses were not further stratified by gender.With regard to potential effect modification, none of the interaction terms of maternal folic acid use with child gender  were statistically significant . After additional adjustment for EFW, the latter association of maternal preconceptional multivitamin use with foetal HC size disappeared , whereas the association of preconceptional folic acid use with foetal HC size did not .The effect of supplement use could not be attributed to other nutrients in the supplement: foetuses of mothers who started using any supplement before conception had a larger HC size. At 20 weeks of gestation, neither folate SD scores nor folate deficiency was associated with head size.The first part of Table B = 0.27, 95 % CI 0.03; 0.51, P = 0.03). Including quadratic terms of folate to the model did not improve the fit (data not shown). When using folate as a dichotomous variable, no associations were found between folate deficiency and offspring head size. Similar results were found using 8 nmol/L to define low maternal folate status.In the basic linear regression models, higher maternal folate concentration was associated with a larger child head size at 20 and 30 weeks of gestation, at birth, at age 5–10 months and at 6 years . Only at 30 weeks of gestation, this association was not accounted for by confounders. Additional adjustment for EFW attenuated the effect estimate, but the association remained statistically significant (growth are presented in Table P = 0.02). This results in an average estimated increase of 0.16 SD at birth, which translates into approximately 2.7 mm difference in HC at birth.The associations of maternal folate concentrations with offspring head B = 0.012, P = 0.018, see Online Resource 2; P for trend = 0.018). However, we did not observe greater foetal head growth in foetuses of mothers with a folate concentration in the extreme high ends of the folate distribution  compared with foetuses of mothers with a folate concentration in the remainder of the distribution.Again, including quadratic terms of folate to the model did not improve the fit (data not shown). In secondary analyses, maternal folate concentration was divided into quintiles, using the lowest quintile as the reference category (quintile 1). In a dose–response manner, foetuses of mothers with a folate concentration in the second through highest quintile had significantly greater prenatal head growth compared to foetuses of mothers with a folate concentration in the lowest quintile, although this difference was only statistically significant for those children of mothers with a folate concentration in the highest quintile , and analyses were not further stratified by gender.No associations were found between maternal folate concentrations or folate deficiency and postnatal head growth. These results did not change after exclusion of the birth measure of HC, which can be highly imprecise due to the moulding that takes place during the birth process. Again, none of the interaction terms of maternal folate concentration with child gender  were statistically significant  confounding, for example in terms of other nutrients in the diet, cannot be excluded.The strengths of our study are its large sample size, availability of plasma folate concentrations as opposed to dietary intake of folate, having multiple measures of offspring HC (starting in pregnancy) and the ability to adjust for a considerable number of covariates.The study also has its limitations. First, our assessment of maternal folate status was based on a single measure in blood plasma. One measurement, although indicative, is not a reliable reflection of a mother’s long-term folate status. Additionally, red blood cell instead of plasma folate would be a better measure of long-term folate status. On the other hand, plasma folate can be more reliably measured than red blood cell folate, as the serum/plasma folate assay is less complex to perform and requires less steps in handling the sample before analysis than the red cell folate assay , 36. To Higher maternal folate concentrations were associated with slightly increased foetal head growth from the second to the third trimester. Additionally, preconceptional start of folic acid supplementation was associated with a larger head size at 20 weeks of gestation. In the Netherlands, only about half of the women use folic acid supplements during the conceptional period , 37, 38,Supplementary material 1 (DOC 72 kb)Supplementary material 2 (DOC 38 kb)Below is the link to the electronic supplementary material.


Improving newborn health remains a global health priority. Little however is known about the neurodevelopmental consequences for survivors of complications in pregnancy, labour and the neonatal period in in low-income countries outside of small selective and typically urban facility studies. We ask which antenatal, birth and neonatal factors are associated with disability in childhood in a large community birth cohort from rural Nepal.6436 infants were recruited during a cluster randomised control trial (RCT) of participatory women's groups (ISRCTN31137309), of whom 6075 survived beyond 28 days. At mean age of 11∙5 years (range 9.5–13.1), 4219 children (27% lost to follow-up) were available for disability screening which was conducted by face-to-face interview using the Module on Child Functioning and Disability produced by the Washington Group/UNICEF. Hypothesised risk factors for disability underwent multivariable regression modelling.Overall prevalence of disability was 7.4%. Maternal underweight (OR 1.44 (95% CI 1.01–2.08)), maternal cohabitation under 16 years of age (OR 1.50 (1.13–2.00)), standardised infant weight at 1 month (OR 0.82 (0.71–0.95)) and reported infant diarrhoea and vomiting in the first month (OR 2.48 (1.58–3.89)) were significantly associated with disability adjusted for trial allocation. The majority of hypothesised risk factors, including prematurity, were not significant.Proxies for early marriage and low birth weight and a measure of maternal undernutrition were associated with increased odds of disability. The lack of association of most other recognised risk factors for adverse outcome and disability may be due to survival bias. In 2010, the global burden of disease survey estimated that 10% of disability adjusted life years were related to neonatal causes.In low-income countries, most of this burden is presumed to be from premature mortality.A 2013 review by Blencowe and colleagues highlighted a substantial gap in the evidence from low-income countries with most follow-up data based on small, high-risk cohorts.This is the first large, community recruited birth cohort from a low-income country to examine the relationship between known prenatal and perinatal risk factors with a positive disability screening tool at mean age 11.5 years.We found that the majority of known risk factors in this cohort, including prematurity, were not associated with later disability.Proxies for early marriage and low birth weight and a measure of maternal undernutrition were associated with increased odds of disability.Our findings broadly agree with the consensus that in high mortality low-income settings survival bias likely means most known perinatal risk factors are not associated with later disability.This relationship will need to be reassessed as neonatal mortality rates continue to fall in countries like Nepal.Our findings also emphasise the relationship between early marriage, poverty, malnutrition and poor developmental outcomes and the need to break this cycle.The Millennium Development Goals led to a renewed focus on reducing neonatal mortality in low-income country (LIC) settings but there has been a lack of attention to morbidity in survivors.9–11Sixty-one per cent of the world's children live in low and lower middle income countries, defined by The World Bank in 2015 as being those with a Gross National Income (GNI) per capita of US$4035 or less 2 of mixed mountainous terrain, with a population of more than 500 000 people. It has one district hospital with a ratio of 7852 people per hospital bed. In 2001–2003 when the study was recruited, the neonatal mortality rate was 39/1000 live births, 94% of babies in rural areas were born at home and just 13% with a skilled birth attendant.Nepal has a growing population of about 28.5 million people and a gross per capita income of US $730.2. Clusters were mapped on foot between 1999 and 2000 to identify every household, followed by a baseline census to identify all female residents. In 2001, every eligible woman (married and aged 15–49) was interviewed and consented into the study. Recruitment took place between October 2001 and November 2003. Participants were visited monthly, and a pregnancy was registered when a woman ceased menstruation for 3 months in the absence of other explanation. Participants were interviewed 4 weeks postpartum for main outcomes of neonatal and maternal mortality. Thus, the baseline cohort was an entirely representative sample. In 2014, a long-term follow-up study of surviving and consenting participants was conducted and baseline (postpartum interview) and long-term follow-up data paired.This is a longitudinal study of a cohort of 6436 maternal infant dyads recruited to a cluster Randomised Control Trial (RCT) of perinatal women's participatory groups in Makwanpur, Nepal, which showed a sustainable and low cost decrease in neonatal and maternal mortality.Two rounds of follow-up interviews took place across the study site, 24 pairs of interviewers visited families and if the family had moved attempts to trace them via neighbours were made. Seven supervisors directly observed 18% of all interviews. Data described here were collected during the first round of follow-up interviews and included anthropometry, forward and backwards digit recall testing, and a disability screening questionnaire.Ethical approval for the study was obtained both from Nepal Health Research Council and the University College London research ethics committee. Informed verbal consent was granted by all participants prior to participation, which is more culturally appropriate in this setting than written consent.no difficulty (1), some difficulty (2), a lot of difficulty (3), cannot do at all (4). We defined a positive disability screen as at least some difficulty (>=2), in at least one domain. This is to use the most inclusive definition of disability and because of the very low prevalence of other definitions in this study (supplementary appendix table A1)The main outcome was disability as measured at face-to-face interview using the Module on Child Functioning and Disability (MCFD).10.1136/bmjgh-2017-000312.supp1Supplementary file 1To minimise the pitfalls of post hoc testing, prior to reviewing the dataset a list of factors known to be associated with poor developmental outcomes was drawn up. Maternal characteristics, antenatal care and complications, problems during labour, essential newborn care, harmful traditional practices and neonatal illness were included.Of note, as 93% of infants were classified as ‘smaller than usual’ at birth, we chose ‘very small’ as the best marker for LBW. Gestational age (GA) was calculated based on last monthly period (LMP) as recalled by the mother, it is only available as completed month's gestation and 96% of infants were born with a reported GA of 9 months. For epidemiological-based studies in these types of settings, this is the only method available with which to calculate GA. Antenatal ultrasound was, and by and large is still, not available in this and similar settings and as the majority of babies were born at home, clinical gestational assessment at birth was also not an option. Very few infants were born at <8 months (0.7%) and for analysis all infants <9 months (<36 weeks) are classified as preterm. Skilled birth attendance is defined by WHO criteria and includes ‘mid-level’ workers such as health assistants but excludes community health workers who may nonetheless have undergone some obstetric training.15Potential confounders considered were trial allocation and baseline socioeconomic status (SES) as measured by household asset ownership score. Asset-based scores have been shown to be a reliable and simple way to assess differences in SES in LIC.Weight was measured to the closest 100 g using a Tanita HS302 Solar Scale with participants in minimal clothing, stood in the centre of the scale with arms at sides and face forward. Standing heights of participants were measured to the nearest mm against a Shorr board. Both height and weight are the average of two measurements unless they differed by more than 4 mm or 400 g, respectively, in which case a third was taken and the average of the two closest was used. Stunting was defined as a height for age z-score <−2 according to WHO 2006 standards. Weight at 1 month was standardised to create a mean of 0 and SD of 1.2 for categorical variables, by two sample t-test for normally distributed continuous variables, and Mann-Whitney U test for non-normally distributed continuous variables. Collinearity was assessed by variance inflation factor scores with a score >10 indicating potentially significant collinearity. For some of the delivery variables such as hand washing, there were some ‘don't knows’ which are treated as missing data.Univariate analysis was performed by Pearson χTo build the final model, all the variables were ranked by their significance on univariate analysis and variables with a significance of <0.1 included in initial model. A backwards stepwise regression modelling approach was taken after included variables were checked for collinearity. Starting with the least significant variable on univariate analysis, variables were dropped and the model compared with the previous model by likelihood ratio testing. Variables were dropped permanently if the significance of the likelihood ratio test was ≥0.1 and retained if <0.1. The model was checked for confounding by trial allocation and SES. A variable was considered significantly confounded if the adjusted OR changed by more than 10% from the unadjusted model. The final models were model 1 (unadjusted), model 2  and model 3 (adjusted by household asset score). Due to missing data, only 3318 of the 4419 children screened for disability were included in the regression model which was carried out as a complete case analysis.To calculate population attributable risk (PAR), the relative risk (RR) was first estimated using log binomial regression. PAR (%) was then calculated using the formula [Pe(RR−1)]/[1+Pe was 11.5 years (range 9.5–13.1 years) and 51.5% were male. Fifty per cent were born to mothers in the intervention arm of the original trial. We suspect that survival bias is likely behind the lack of association between many known risk factors and later disability in this high burden cohort. Two hundred and eighty-eight (4.5%) of the total births were ‘very small’ but 110 of these were either stillborn or known to have died leaving just 2.9% of those screened. Likewise, of the 197 infants born preterm 118 (60%) had died before follow-up.Increased weight at 1 month was negatively associated with disability. Weight at 1 month is clearly linked to birth weight but will also be significantly affected by the neonatal period and is therefore not directly comparable. Maternal underweight is a known risk factor for LBW and preterm delivery and in severe cases may affect factors such as breast milk quality and supply leading to health consequences for infants.21Age of maternal cohabitation with husband is used here as a proxy for age at first pregnancy and early cohabitation is positively associated with childhood disability. Adolescent pregnancy is known to cause cessation of linear growth, and this is especially relevant in a population with high rates of childhood stunting who often undergo prolonged periods of catch-up growth.24A history of any neonatal illness, breathing difficulties or neonatal fever was not significantly associated with disability. It is possible again that survival bias is important here, perhaps with diarrhoea and vomiting being relatively mild symptoms and more severely ill infants being unlikely to survive. For instance, of the 865 infants who developed breathing problems in the neonatal period, 176 (20%) had died prior to follow-up.The presence of a skilled birth attendant also approached a significant association with decreased odds of disability. In a population like Makwanpur, skilled birth attendance is heavily confounded as it is much more likely when there are complications of labour.The limitations to the original trial were several fold, for logistic reasons, collecting birth weight was not feasible and complications of labour and pregnancy were reported symptomatically around a month after the event, some degree of recall bias is likely. The nearest proxy to birth weight is a subjective categorisation of size at birth but only 4.5% of children were born ‘very small’ and this measure likely significantly underestimates the prevalence of LBW in this cohort compared with other studies.The current study design is retrospective and opportunistic, and this has inherent limitations. We have aimed to minimise the risks of ‘data dredging’ by using a preconceived hypothesised list of variables, but there was a process of compromise involved in consummating this list with the available data. The total loss to follow-up was 27.3% which is excellent for a study of this size and setting. Most of those lost had moved out of the area, and there was no practical way to assess them without using substantial extra resources. As seen in at least some difficulty, in at least one domain they found a prevalence of 64% in Cameroon and 35% in India compared with 7.4% here. Using the stricter definition of at least a lot of difficulty, they found a prevalence of 9% in Cameroon and 4% in India to our 1%. However, of note our prevalence of 7.4% is in keeping with a systematic review of the global estimates of childhood disability in low and middle-income countries showing that despite a wide range in estimates (0.5%–18%), the majority clustered around 5%–10%.Since this study was undertaken, the results of validation testing of the MCFD in children from India and Cameron have been published and taken with the prevalence found here suggest that cultural interpretation of degree of difficulty may influence reporting and/or that differences in administration may lead to variation in interpretation of scales of difficulty.Despite these limitations, this is a unique and important study that examines the relationship between antenatal, birth and neonatal risk factors and later disability in a large birth cohort in a high burden country. A wealth of data collected during the original trial allowed a detailed assessment of birth environment. The cohort was recruited in the community where most infants are born, in contrast to the majority of small and facility recruited cohorts. The length of follow-up allows a more accurate assessment of later childhood disability as shorter follow-up periods can underestimate prevalence. This study addresses this previously discussed gap and for a community recruited cohort in an LIC it is relatively large. A review of the literature found it is twice the size of the nearest comparable study, whose primary outcome was cognitive test scores rather than disability screening.26Child marriage is recognised as both a symptom and cause of poverty. In Nepal, girls married under 20 are 20% less likely to have access to education and girls in the highest wealth quintile marry on average 2 years later than those in the lowest.32Our main finding that most risk factors are not associated with later disability is on the surface surprising, and we speculate that this is likely to be due to high mortality and survival bias in this population. Further data are required to confirm or refute this hypothesis and it is to be hoped that other large birth cohorts recruited from perinatal intervention studies in LIC, such as those from other perinatal women's group trials, will also be followed up to later childhood.Since this cohort was born, the neonatal mortality rate in Nepal has declined from 39 to 23 per 1000 live births.In this birth cohort from rural Nepal, the lack of association between most perinatal risk factors and later childhood disability may be due to high mortality and survival bias. However, proxies for early marriage and LBW and a measure of maternal undernutrition were associated with increased odds of disability. The relationship between poverty, maternal malnutrition and poor neurodevelopmental outcome is well recognised, and our findings here emphasise the importance of breaking this cycle.