The aim of the study was to investigate the effect of antenatal iron-folic acid (IFA) supplementation on child stunting in Nepalese children age <2 years. A retrospective cohort study design was used, in which a pooled cohort of 5235 most recent live births 2 years prior to interview from three Nepal Demographic and Health Surveys  was analysed. The primary outcome was stunting in children age <2 years. The main exposure variable was antenatal IFA supplementation. Multivariate Poisson regression analysis was performed. In our sample, 31% and 10% of Nepalese children age <2 years were stunted and severely stunted, respectively. The adjusted relative risk of being stunted was 14% lower in children whose mothers used IFA supplements compared to those whose mothers did not use . Additionally, the adjusted relative risk of being stunted was significantly reduced by 23% when antenatal IFA supplementation was started ≤6 months with ≥90 IFA supplements used during pregnancy . Antenatal IFA supplementation significantly reduced the risk of stunting in Nepalese children age <2 years. The greatest impact on the risk reduction of child stunting was when IFA supplements were started ≤6 months with ≥90 supplements were used. Globally, 45% of under-five deaths can be attributed to child undernutrition . Low birMaternal anaemia in the first or second trimester of pregnancy increases the risk of prematurity and low birth weight . GloballStudies have documented a significant positive association between the use of IFA supplements during pregnancy and birth-weight ,7,8. TwoThe impact of exposure on the outcomes was evaluated using a retrospective cohort study design. Birth history information collected from representative samples of women of reproductive age in Nepal in 2001, 2006 and 2011 allowed us to identify cohorts of women from their most recent live birth within two years prior to interview. The antecedent exposure of the use of antenatal IFA supplements was collected retrospectively by maternal recall. The primary outcomes, low height-for-age in children less than 2 years of age, and maternally perceived small birth size, were measured at the same time the birth history information was recorded. Although the information on exposures and outcomes was collected at the same time, an important element of timing (a retrospective measurement of the use of IFA supplements prior to birth and onset of stunting) allowed causal inference to be assessed. The recall of the exposure was unlikely to be influenced by child’s birth size or stunting status since these data were collected as part of a multi-component survey covering various aspects of women’s reproductive and child health. Furthermore, the outcome status of the child would not be apparent to either the mother or interviewer as it required subsequent data processing.http://dhsprogram.com/). NDHS collects information about socio-demographic, health and nutrition indicators for a nationally representative sample of households through multistage cluster probability sampling [n = 2582) selected for the men questionnaire [We used the data on women’s most recent live births within 2 years prior to the date of interview from three Nepal Demographic and Health Surveys (NDHS) 2001 , 2006 1, and 201sampling . The samsampling ,10,14. Tsampling . All infsampling ,10,14. Fsampling ,10,14. An = 2629), the 2006 NDHS (n = 2103), and the 2011 NDHS (n = 971). Anthropometric measurements were not available for children <2 years of age who had died (n = 233); these children, and children <2 whose anthropometric measurements were not collected at the time of survey (n = 235) were not included in our analysis. Hence, our analytical sample comprises the 5235 most recent live births 2 years prior to interview whose anthropometric measurements were collected  of the child measured at the time of the survey. Height-for-age was the difference between the child’s measured height and the mean height of healthy children in the same age and sex group, expressed as the number of standard deviations or Z-score. A child was classified as being stunted if he/she had a height-for-age Z-score (HAZ) < −2. HAZ (continuous variable), severe stunting (defined as HAZ < −3) and maternal perception of birth size, based on maternal recall, were the secondary outcomes. The question for the maternal perception of birth size in the NDHS was: “When (NAME) was born, was he/she very large, larger than average, average, smaller than average, or very small?” We pooled categories to form a binary variable as “larger than or equal to the average birth size”  and “smaller than the average birth size” . Birth-weight was recorded in only 15% of our sample. We considered maternal perception of birth size a proxy for birth-weight .n = 14) were considered as implausible and were excluded from the analysis. In addition, we considered that the maximum number of supplements, that could be used, assuming once daily, were 150, 120, 90, 60 and 30 supplements if a woman started in 5th, 6th, 7th, 8th, and 9th month of pregnancy, respectively. Records with reported number higher than the maximum number that could be consumed when started in 5th to 9th months of pregnancy were also excluded (n = 192). To evaluate the impact of the timing of initiation of supplements on the study outcomes, the time of the first antenatal care examination was considered as a surrogate for the start of supplements. As anaemia during first or second pregnancy trimester significantly increases the risk of low birth-weight [The main exposure variable was maternal use of IFA supplements during her last pregnancy within the last 2 years prior to the interview date. In NDHS, the interviewers asked the following questions: “During this pregnancy, were you given or did you buy any iron/folic acid tablets?” and “During the whole pregnancy, for how many days did you take the tablets?” A mother was classified as using antenatal IFA supplements if she reported taking supplements for at least a day during pregnancy. The effect of total number of IFA supplements used during pregnancy on primary outcomes was also assessed. Reports of use of >240 supplements .We assessed 24 potential confounding factors, classified as community-level and socioeconomic status; maternal and child characteristics; and perinatal health care services . To adjuAll analyses were undertaken using “svy” commands from Stata 13.1  to adjust for cluster sampling. Frequencies with weighted percentages were calculated. Poisson regression was used to analyse the study outcomes, except for HAZ, where linear regression was used. Univariate regression models were fitted for each potential factor. We used a multistage approach to determine the final multivariate regression models using a hierarchical approach . At the The Population Attributable Risk (PAR) was calculated to assess the risk of child stunting in the population of children 2 years of age that was attributable to women who did not use IFA supplements during pregnancy, and who did not start at or before 6 months and did not use ≥90 supplements during pregnancy. We assumed that the association between IFA supplementation and child’s stunting was causal and that removal of supplementation had no effect on the distribution of other risk factors. The following formula was used to calculate PAR ,21,22.Pin Nepal , and theThe distribution of community-level, socioeconomic status, maternal and child characteristics, and maternal antenatal care visits is presented in Factors associated with stunting in Nepalese children <2 years of age, presented in As the use of antenatal care services and IFA supplementation variables were correlated in our sample, therefore, we constructed a combined variable of use of other antenatal care services and IFA supplementation. Children whose mother used IFA supplements with or without use of other antenatal care services had lower adjusted relative risk of being stunted by 12%  compared to children whose mother did not use IFA or any other antenatal care services.The adjusted risk of being severely stunted in Nepalese children <2 years was significantly reduced by 37%  in children whose mother used IFA supplements compared to those whose mother did not use IFA supplements during pregnancy.Our estimates showed that 3.8% (95% CI = 0.26%–9.25%) of stunting could be attributed to non-use of antenatal IFA supplements in Nepalese children <2 years of age. With universal coverage of IFA supplements, stunting could be averted in 7500 Nepalese children <2 years of age annually. Similarly, we found that 8.4% (95% CI = 0.2%–18.4%) of stunting was attributed to not starting supplements at or before 6 months and not taking ≥90 supplements during pregnancy. If all Nepalese women started supplements at or before 6 months and consumed ≥90 supplements during pregnancy, stunting could be averted in 16800 Nepalese children <2 years of age per annum.The factors associated with the smaller than average birth size in Nepal, presented in The findings of adjusted linear regression analysis for HAZ are presented in We found that maternal use of IFA supplements during pregnancy significantly reduced the adjusted risk of stunting by 14% compared to mothers who never used supplements in Nepalese children <2 years of age. Further, the adjusted risk of being severely stunted was significantly reduced by 37% with use of antenatal IFA supplements in children <2 years of age. For children whose mother used ≥90 supplements the adjusted risk of being stunted was reduced by 22%. Children whose mother initiated IFA supplements at or before 6 months during pregnancy the adjusted risk of being stunted was reduced by 16%. With initiation of supplements at or before 6 months and use of ≥90 supplements during pregnancy, the adjusted risk of being stunted was reduced by 23% and these children had a higher adjusted mean HAZ. With universal coverage to start IFA supplements at or before 6 months and use of ≥90 IFA supplements during pregnancy, stunting could be averted in 16800 Nepalese children <2 years of age each year.To our knowledge, the current study is the first adequately powered study to report a protective effect of antenatal IFA supplementation on child stunting in Nepal at national level. Our findings provide important evidence for policy-makers and program managers in developing countries dealing with maternal, newborn and child health, nutrition and supplementation programs. In Nepal, like many other developing countries, IFA supplements are given to pregnant women at or after 4 months of gestation. We found that a greater preventive effect of IFA supplementation on stunting was seen when supplements started at or before 6 months with use of ≥90 supplements during pregnancy. Similarly starting supplementation earlier in pregnancy and sustaining it throughout pregnancy has the greatest effect on reducing early neonatal mortality in Nepal and Pakistan . HoweverAn important strength of the current study was the appropriate timing progression in the data used for the analyses, in which the main study exposure, the use of IFA supplements during pregnancy was measured by maternal recall and was antecedent to the study outcomes. This timing sequence allows causal inference although the retrospective design is not as strong as a prospective cohort design. To minimise recall bias ,26,27, wOne limitation was that use of IFA during pregnancy was based on maternal recall and biochemical indicators of iron status could not be assessed. Maternal recall of number of IFA might not be accurate as reflected in the heaping of data for the number of supplements in intervals of 30 and this may have led to misclassification. Although analyses were adjusted for a number of potential confounding factors, mothers who took IFA were not randomly assigned and there is a possibility of remaining residual confounding. Similarly, blood samples were not taken in the 2001 NDHS and we could not include the child’s anaemia status. In addition, there is only information about consumption of fortified foods in the 24 h preceding the interview. Recent use of fortified foods is not an indicator of how long they have been used. Longer term use would be needed to expect an impact on growth. Hence, we did not adjust the regression models for this indicator. Some variables like maternal and paternal occupation within the last 12 months and maternal smoking status at the time of interview were not infant specific because these only presented the most recent conditions. These limitations may have led to an underestimate/overestimate of the effects of IFA. Our findings should therefore be interpreted with these caveats in mind, although the overall validity of the findings remains unchallenged.Our findings of the effect of IFA supplementation on birth size are consistent with meta-analyses which report 19%–20% reduction in low birth-weight with maternal use of IFA supplements during pregnancy ,7,8. A Cn = 44374) from low- and middle-income countries has found that low birth-weight (<2.5 kg within 72 h of birth), small for gestational age (<10th percentile) and prematurity  were associated with an increased odds of 2.92 (95% CI = 2.56–3.33), 2.32 (95% CI = 2.12–2.54), and 1.69 (95% CI = 1.48–1.93) for stunting in children 12–60 months of age, respectively. Further, small for gestational age and term infants with low birth-weight had higher odds of childhood stunting  compared to small for gestational age and term infants without low birth-weight  in low- and middle-income countries [In contrast to the preventive effect of IFA on childhood stunting in the current study, findings from two follow-up studies of the cluster randomised controlled trials from China  and Nepaountries . NutritiOur PAR analysis showed that 8.5% of stunting was attributed to not starting supplements at or before 6 months and not taking ≥90 supplements during pregnancy. If all pregnant women were to start supplements at or before 6 months and take ≥90 supplements during pregnancy, stunting could be averted in 16800 Nepalese children <2 years of age each year. However, it is important to highlight that PAR estimates depends on the prevalence of exposure which might vary across populations. Nepal in the recent past has improved its IFA supplementation program by introducing a district-level intervention package . HoweverTo conclude, we found that use of antenatal IFA supplements significantly reduced the risk of being stunted and severely stunted in Nepalese children <2 years of age. The greatest effect on risk reduction was found with early initiation (at or before 6 months) with use of ≥90 IFA supplements during pregnancy, suggesting a timing- and dose-dependent response. This current evidence from Nepal supports the need to carry out prospective trials in low- and middle-income countries to examine the effect of IFA supplements during pregnancy on childhood stunting.


Children born preterm show persisting impairments in cognitive functioning, school achievement, and brain development. Most research has focused on implications of birth prior to 37 gestational weeks; however, the fetal central nervous system continues to make fundamental changes throughout gestation. Longer gestation is associated with reduced morbidity and mortality even among infants born during the period clinically defined as full term . The implications of shortened gestation among term infants for neurodevelopment are poorly understood. The present study prospectively evaluates 232 mothers and their full term infants  at three time points across the first postnatal year. We evaluate the association between gestational length and cognitive and motor development. Infants included in the study were full term (born between 37 and 41 weeks gestation). The present study uses the combination of Last Menstrual Period (LMP) and early ultrasound for accurate gestational dating. Hierarchical Linear Regression analyses revealed that longer gestational length is associated with higher scores on the Bayley scales of mental and motor development at 3, 6 and 12 months of age after considering socio-demographic, pregnancy, and infant-level covariates. Findings were identical using revised categories of early, term, and late term proposed by the Working Group for Defining Term Pregnancy. Our findings indicate that longer gestation, even among term infants, benefits both cognitive and motor development. Recent findings question the conventional 37-week cut off for preterm birth. A large literature indicates that children born preterm show persisting impairments in cognitive functioning, school achievement and brain development. Preterm birth is associated with altered hemispheric connections Longer gestation is associated with reduced morbidity and mortality even among infants born during the period clinically defined as full term  Little is known about the consequences of variation in gestational length among term infants for cognitive functioning and brain development. Rapid changes in the organization of the fetal brain continue into late gestation The present study prospectively evaluates mother-infant pairs across the first postnatal year and uses the American Congress of Obstetricians and Gynecologists (ACOG) standard, a combination of Last Menstrual Period (LMP) and early ultrasound for accurate gestational dating. We evaluate the association between gestational length and cognitive and motor development among full term infants assessed longitudinally at three time points during the first postnatal year.M GA = 39.46 weeks, SD = 1.06 weeks, M weight = 3418.10 g, SD = 419.71 g). All infants were normal and healthy at birth, and they had a median 5-minute Apgar score of 9 (range = 8–10). Additional descriptive information for the study sample is shown in Study participants included 232 mothers and their full term infants participating in a longitudinal study evaluating the role of early experiences on infant development. Women with singleton pregnancies less than 16 weeks gestational age (GA) were recruited from obstetric clinics in Southern California and followed longitudinally through 12 months postpartum. Women were eligible for participation in this study if they were English-speaking, non-smokers, over the age of 18, did not take steroid mediation, and for whom there was no evidence for drug or alcohol use during pregnancy. Twenty-three (8.9%) participants were excluded due to preterm birth, and 4 (1.5%) were removed due to post-term birth. The 232 infants  included in the current study were full term at birth– born between 37 weeks 0 days and 41 weeks 6 days gestation  was approved by the Institutional Review Board for Protection of Human Subjects at the University of California, Irvine.Gestational Age at Birth (GAB) was determined with standard (high-accuracy) ACOG guidelines (2009) using the last menstrual period and an ultrasound prior to 20 weeks gestational age. Additionally, parity, birth weight, and Apgar scores were recorded from the medical chart review. An extensive structured medical interview was conducted by a research nurse at each prenatal visit to assess current and past maternal health and pregnancy related complications. Additionally, maternal and infant medical records were reviewed to assess pregnancy complications and birth outcome. These two sources were used to derive a well-established index characterizing prenatal obstetric risk and considered in covariate analyses .nd ed. (BSID-II). Examiners were trained by a clinician with over 15 years of experience with the BSID and were directly supervised by a clinical psychologist. Videotaped assessments were reviewed monthly. Interrater reliability, calculated on 20% of the assessments at each age, was 95% at 3 and 6 months and 93% at 12 months. The BSID is a standardized developmental assessment Infant development was assessed at 3, 6, and 12 months postpartum using the Bayley Scales of Infant Development, 2Reliability, calculated using coefficient alpha based on the normalization samples on the BSID were between.83 and.92 for the ages assessed here. Conventional scoring of the BSID created composite MDI and PDI scaled scores by summing the total number of items achieved, corrected for basal effects. The raw scores were converted to scaled scores by reference to a developmental table. Mean scaled scores for the MDI and PDI are presented in p value of.10 or less were included as covariates. Variables associated with MDI  or PDI (ethnicity) in preliminary analyses were modeled as covariates at the ages they were associated with the corresponding outcomes in regression analyses. Age from conception at the time of testing  was not correlated with chronological age from birth at testing and thus, age from conception at BSID assessment did not account for study findings.Correlations, t-tests, and Analysis of Variance (ANOVA) were used when appropriate to identify socio-demographic , pregnancy-related , and infant  variables that might influence infant cognitive or motor development. Race/ethnicity, cohabitation status, maternal education, household income obstetric risk, birth order, birth weight percentile and infant sex were included as covariates in the model if they were associated with infant development. The factors associated with infant development (BSID scores) with a Hierarchical Linear Regression analyses were conducted to identify the association between gestational length and postnatal cognitive and motor development at 3, 6, and 12 months after adjusting for covariates. Covariates were entered in the first step, and GAB was entered second into the model.In addition to continuous analyses, we applied the American Medical Association Workgroup for Defining Term Pregnancy criteria  and evaluated the associations with mental and psychomotor development using Univariate Analysis of Variance with Covariates (ANCOVAs). The same covariates, described above, were used for both the Hierarchical Linear Regression and the ANCOVA models.F = 3.95, p<.001, 2R = .14), 6 months  = 2.45, p<.05, 2R = .11), and 12 months  = 2.84, p<.01, 2R = .12). Gestational length also is associated with elevated PDI scores at 3 months  = 3.03, p<.05, 2R = .06), 6 months  = 5.47, p<.001, 2R = .12), and 12 months  = 3.36, p<.05, 2R = .08).Hierarchical regression analyses reveal that longer gestational length is associated with higher mental and psychomotor development at each infant age beyond the effects of the covariates see . Among iF = 7.15, p<.001) and 6 months  = 7.23, p<.001), with a trend at 12 months  = 2.87, p = .06). As presented in F = 4.01, p<.05) = 6.69, p<.01) and 12  = 5.32, p<.01) months of age. Term infants had lower psychomotor development scores than late term infants at 12 months.Using the Working Group for Defining Term Pregnancy revised categories 27% of our sample was early term, 56% term, and 6.6% late term. ANCOVAs reveal that group differences in mental development are evident at 3 months . Early tintrauterine experiences, such as exposure to stress, that affect both fetal maturation and timing of delivery The Fetal Programming hypothesis posits that in utero experiences exert consequences for health and development that persist across the lifespan. Gestational length is affected by Accumulating evidence documents the importance of gestational length among term infants on a range of outcomes. The American Medical Association Workgroup for Defining Term Pregnancy recently has argued the importance of redefining term delivery based on evidence that both morbidity and mortality are increased among infants who are born at 37–38 gestational weeks compared to infants born at 39–41 gestational weeks. Their report suggests that the consequences of gestational length be considered among term as well as preterm infants. We report that the benefits of longer gestation for full term infants extend beyond physical health outcomes to include significant neurodevelopmental benefits. This association was significant when gestational age was analyzed continuously or categorically using the proposed redefinition of term delivery. Further, associations remained after considering socio-demographic factors, and obstetric factors known to be associated with neurodevelopment, as well as chronological age from conception at time of assessment.These present findings complement a recent and important study Rapid changes in the development and organization of the fetal brain occur throughout the entire course of gestation extending into the term period It is plausible that the associations between gestational age at birth and child neurodevelopment reported here are due to prenatal influences on processes that mature the last few weeks of pregnancy. Our findings in this low-risk healthy sample suggest that prenatal experiences  benefit fetal brain development Strengths of this investigation include the prospective longitudinal design and the precise assessment of gestational length. Infants in this sample are healthy, and have not experienced complications that pre-term infants often do, such as mechanical ventilation, intraventricular hemorrhage, or periventricular leukomalacia. The effects of gestational length are present after considering potential confounds of obstetric risk, ethnicity, maternal age at delivery, breastfeeding, and parity. A limitation of the present study is that infants were assessed only through one year of age and thus, it is not known if this association persists into childhood. In the present study, global measures of mental and motor development were implemented. Future research might evaluate specific functions that may be more or less susceptible to shortened gestation. Further, this study does not identify the mechanisms underlying the association between shortened gestation and developmental outcomes.These data support the redefinition of term delivery as proposed by the American Medical Association Workgroup for Defining Term Pregnancy. The implications for clinical practice are clear and argue against the relatively common practice of elective inductions or cesarean sections prior to 39 gestational weeks. Early term inductions occurred in 8% of births in the United States in 2006 Developmental processes occurring during the fetal period shape the development of physiological systems with consequences for birth outcomes as well as physical and mental health across the life span. Consistent with the Fetal Programming hypothesis, we show with a prospective design that longer gestation benefits cognitive and motor development among healthy full term infants. These findings have clear implications for clinical decisions.


Focus on the late preterm birth (LPB) and critical congenital heart defects (CCHD)Data on outcomes of CCHD specifically in late preterm infants are exceedingly scarce.The preterm newborn with associated complex CHD presents many intricate problems to clinicians who take care . Therapies used for the preterm neonate without heart disease frequently need to be altered in the presence of heart disease and those needed for management of heart disease may need to be altered because of prematurity.The population of newborn born preterm is at higher risk for postoperative death and short and long term complications than term newborn with the same CHD and the causes of this are multifactorial. Technical issue related to small cardiac structure, immaturity of other organ systems, decreased nutritional and cardiac reserve, increased risks of bleeding, abnormal chest wall mechanics after sternotomy can all together account for this epidemiologic data. In past years these findings were related in particular to low-birth weight infants and conventional management was oriented to await a threshold weight in order to reduce bypass-related morbidities. From 1990 rates of LPB have risen and now account for 75% of all preterm births. Whether late preterm infants with CHD, who may be only marginally more immature than their term counterparts, remain at risk for adverse outcome in unclear. Some recent papers do demonstrate the independent effect of LPB on mortality and morbidity if a CHD is present and this issue emerge as an important factor for a correct counseling. Natarajan have observed that the weight at surgical intervention was significantly lower and age higher in the late preterm infants compared to those delivered at term. Late preterm infants had significantly higher rates of NEC and seizures, with a greater risk of supplemental oxygen and tube feeding at discharge. Costello have examined mortality and morbidity stratified by gestational age, reporting for LPB group with CHD an hospital mortality rate of 16.4% compared to 2.6-8% in the term group. The exact mechanism of this vulnerability remains unclear although functional immaturity of the lung and the brain are plausible aetiologies. Altered intrinsic cardiac mechanism could play a role in adverse outcome of late preterm with CHD. Gestational age at delivery can be a risk factor over which clinicians might have some control. Before birth the challenge is planning the time and the place for the delivery of a foetus with CHD. After birth the challenge is not waiting for obtain an arbitrary correct weight for surgery but working in a complex team to discuss each case in order to maximize outcome.Domande inerenti la relazione del Dott. Stefano FiocchiUna cardiopatia congenita critica è:a) Quasi sempre mortaleb) se esiste una ostruzione “critica” agli efflussi ventricolaric) se richiede l’uso delle prostaglandinese richiede intervento chirurgico nel primo mese di vitad) Qual’è il peso ottimale per la correzione chirurgica di una cardiopatia congenita critica?Non esiste un peso “ottimale”a) b) > 2000 grc) > 2500 grd) > 3000 grIl rischio di mortalità neonatale nel late preterm affetto da cardiopatia congenita critica è:a) 8%b) < 5%c) 25-30%15-20%d) La aumentata vulnerabilità del late preterm con cardiopatia congenita si associa a:a) Ventilazione prolungatab) Prolungato uso delle prostaglandinec) Presenza di altre malformazioni associateTutte le precedentid)


Delivery of hydatid cysts, especially large ones, without rupture is very important and there is still no 100 % successful method.After the hydatid cyst was reached, starting near the surface working around the cyst toward the base, a Foley probe was advanced and, in the region of desired dissection, the balloon of the Foley probe was inflated, and adhesion bands were freed to allow dissection.We believe our balloon-aided dissection technique is a method that increases the chances of delivering hydatid cysts, with no calcification and secondary infection, without rupture.The online version of this article (doi:10.1007/s00701-015-2449-x) contains supplementary material, which is available to authorised users. It is very important to remove cerebral hydatid cysts without rupture, especially those of large size. Wide scalp flap and dissection of the atrophic cortex, lowering the head of the operating table to benefit from gravity and the use of warm saline between the hydatid cyst and brain parenchyma to deliver the hydatid cyst is the most frequently used method, known as Dowling’s technique , with anThis study evaluates the balloon-assisted dissection technique we developed in the removal of four large hydatid cysts in three patients Figs. , 2 and 3As the hydatid cyst can form in any anatomical region within the cranium or brain, a standard surgical anatomy description was not completed.On preoperative radiological tests, more complicated adhesions that may ease cyst rupture, such as local calcification of the cyst wall or vascularisation in the cleavage plane, may be suspected. It is recommended that the Foley probe be inflated a little away from these areas, accompanied by intraoperative ultrasound. In this way it may be possible for the cyst wall to be passively removed from the adhesion bands.The new surgical method we developed is applied during classic wide craniotomy for hydatid cyst surgery or standard surgical interventions like wide dura opening Fig. . It was see ESM 1 movie).Firstly a number 12 Foley probe was advanced between the cyst and brain, the balloon was inflated with saline and the hydatid cyst was freed from the brain tissue. When the cleavage line was formed, to ease delivery the Foley probe was increased to numbers 14 and 16. To start delivery of the cyst, the balloon was inflated with water in stages and the balloon was pulled slightly outward and released to support the initiation of the cyst removal. During each inflation, we patiently waited for the balloon to push the cyst slightly outward, allowing gravity and, if necessary, a finger on the surface of the cyst to slowly roll the cyst outward and ease removal. This method was used without requiring irrigation with hypertonic saline to remove four large hydatid cysts in three cases without damaging the cyst wall, allowing dissection and delivery without rupture We believe the balloon-assisted hydatid cyst removal method may be used to remove large cerebral hydatid cysts exceeding the cortex or located more deeply without rupture.We believe this method is not appropriate for hydatid cysts with calcified walls or infection. If the most distal tip of the balloon of the Foley probe penetrates brain parenchyma and the balloon is inflated, brain damage may occur. Dowling’s method has similar risks. In fact, if the irrigation probe penetrates the parenchyma and is not noticed, uncontrolled administration of fluid may cause more harmful unwanted complications. Technically, if the balloon of the Foley probe is used, a balloon apparatus that is easier to use and more effective, which also allows irrigation, may be developed. To determine the true success rate of the technique, there is a need to increase the number of cases.Echinococcus infection and cyst wall calcification. The number, location, distance to surface and most appropriate intervention location of the hydatid cysts should be determined. Wide craniotomy and dura opening allow both easy removal of the cyst and the possibility to access different intervention locations. The most significant complication of cerebral hydatid cyst surgery is rupture of the cyst. In case of a situation with cyst rupture, hypertonic saline should be prepared and ready to wash the interior of the cyst and surrounding tissue. We believe that patient application of this method may prevent development of this complication.To deliver hydatid cysts successfully and easily, preoperative radiological examination should be completed to evaluate alveolar type, Additionally, the slow inflation of the balloon in stages both eases dissection and exposes the cerebral parenchyma to less pressure.The most important factors are careful dissection, slow inflation of the balloon in stages and patient waiting for the hydatid cyst to deliver, changing table position to gain more benefit from gravity and the valsalva manoeuvre to remove the cyst without rupture.To see that the Foley probe is advancing correctly, to identify the areas of intense adhesion, to determine anatomical relations and to monitor the inflating balloon, the use of intraoperative ultrasound can provide significant contribution to preventing possible complications.This method has been improved from Dowling’s method. We use a balloon instead of saline irrigation. Patients can be informed that potential risks do not differ from the standard Dowling method.Hydatid cyst cases with no complications should be chosenSurgical planning should be completed together with preoperative careful radiological and clinical evaluationWide craniotomy and dura opening should be performedPrimarily the cyst should be reached by the shortest route with least neural damage and the initial dissection should not weaken the cyst wallAfter initial dissection, taking care that the distal tip of the Foley probe does not penetrate the brain parenchyma, the balloon should be slowly inflated. Advancing step by step, the dissection and delivery process should begin.The area where the cyst comes out of the cortex should be used as the delivery window and the delivery process should be patiently allowed to proceed slowly; if necessary, the process can be supported by gently rolling it out with a fingerThough not necessary in our cases, if required it is possible to benefit from the dissection effect of physiological serum and waterDue to the risk of rupture of the cyst wall, hypertonic saline should be prepared and the area should be washed with hypertonic salineTo benefit more from gravity, if necessary the table position should be changedThe dura should be tightly closed and postoperative radiological checks and infectious disease monitoring should be providedESM 1(M4V 73779 kb)


The aim of this study was to evaluate the association among birth weight, intrauterine growth, and nutritional status in childhood with grip strength in young adults from the 1982 Pelotas (Brazil) birth cohort.z-score for gestational age according to Williams (1982) curve. Weight-for-age, weight-for-length/height, and length/height-for-age at 2 and 4 y were analyzed in z-scores according to 2006 World Health Organization Child Growth Standards. Lean mass at 30 y was included as possible mediator using the g-computation formula.In 1982, the hospital live births of Pelotas were followed. In 2012, grip strength was evaluated using a hand dynamometer and the best of the six measurements was used. Birth weight was analyzed as z-score in birth weight was associated with an increase of 1.5 kg in grip strength in males . Positive effect of birth weight on grip strength was found in females. Grip strength was greater in individuals who were born with appropriate size for gestational age and positively associated with weight- and length/height-for-age z-score at 2 and 4 y of age. A positive association between birth weight and grip strength was only partially mediated by adult lean mass , whereas direct effect of weight at 2 y was found only in males.In 2012, 3701 (68.1%) individuals were interviewed and 3470 were included in the present analyses. An increase of 1 It is suggested that good nutrition in prenatal and early postnatal life has a positive influence on adult muscle strength. The results from birth weight were suggestive of fetal programming on grip strength measurement. •Newborns from southern Brazil were followed for 30 y.•Birth weight and nutritional status in childhood were prospectively measured.•Grip strength was positively related to birth weight and early nutritional status.•Coefficients of the association between birth weight and grip strength were higher in males.•Birth weight was associated with adult grip strength independent of current lean mass. Grip strength has been associated with several outcomes. In the clinical environment, low hand-grip strength is associated with postoperative complications, hospital length of stay, and short-term survival, whereas in epidemiological studies, grip strength is inversely related to all-cause mortality, disability, and risk for fracture but is positively related to functional status and bone mass phenotypic plasticityWhile it has long been known that lifestyle conditions affect physical capacity as well as health status, the fetal origins of adult disease hypothesis, also known as the Barker hypothesis, provides additional insights based on a biological programming theory in which conditions in the womb determine susceptibility to diseases in later life Evidence suggests that birth weight may be related to muscle strength in adulthood. Results from a meta-analysis observed a pooled effect of 0.86 kg  increase in muscle strength  per additional kg of birth weight, which is maintained across the life span Most of the studies on the long-term consequences of birth weight on muscular strength come from high-income countries Additionally, previous studies have not, to our knowledge, explored the mediating effect of the amount of lean mass in the relationship between early nutritional exposures and grip strength, especially regarding the use of adequate statistical tools. Recognizing these relationships may increase understanding of the underlying mechanisms that may explain the biological plausibility of this association. Moreover, the existing relationship between nutrition in infancy and childhood and later grip strength is not well established in the literature and this study may help in the construction of the body of evidence of studies analyzing the long-term consequences of early nutrition.This study was aimed at assessing the role of birth weight, intrauterine growth restriction, and nutritional status in childhood on grip strength in young adults from the 1982 Pelotas (Brazil) birth cohort.In 1982, all maternity hospitals in the city were visited daily and the 5914 live births whose families lived in the urban area of the city were examined and their mothers interviewed. These individuals have been followed often throughout the years The study was approved by the Ethics Committee of the Medicine School of the Federal University of Pelotas. Written informed consent was obtained during the 2012–2013 follow-up before the interviews and physical evaluations.Maternity hospital staff used pediatric scales  to record birth weight. The scales were calibrated weekly. Gestational age was obtained by asking mothers the date of their last menstrual period. Term birth was defined as gestational age ≥37 wk. Information on prepregnancy weight was referred by the mother and was confirmed on the antenatal care register card. The research team measured maternal height soon after the women were admitted to the maternity hospital in 1982.In 1984, a census was carried out in the urban area of the city in search of the cohort members; 4934 children were identified, which added to the 227 deaths representing a follow-up rate of 87.2%. Mean age at follow-up was 19.4 mo. In 1986, approximately 84.2% of the cohort children were located. In these visits, children were weighed using a portable spring scale with an accuracy of ±100 g  and had their supine length (1984) or standing height (1986) measured using boards manufactured locally according to international specifications .z-scores of weight, as well as the length/height at the 1984 and 1986 follow-ups, for age and sex using the 2006 World Health Organization growth standards z-score according to the same growth standard. Birth weight was transformed to z-score according to gestational age, using the reference population developed previously. Small-for-gestational-age was defined as a birth weight below the 10th percentile for gestational age and sex of the Williams' curve The weights in childhood were transformed to ® scale with a precision of 0.01 kg. Body mass index (BMI) was calculated as weight in kg divided by the square of height in m.From June 2012 to February 2013, the cohort members were invited to visit the Epidemiologic Research Center, and 3701 individuals  were examined and interviewed. Standing height was measured to the nearest 1 mm with barefooted participants using a wooden stadiometer. Weight was assessed using a BodPodGrip strength was obtained using the Jamar hand dynamometer . The assessment occurred with the participants in the sitting position in a chair with legs, back support, and fixed arms, with their shoulders adducted, their elbows flexed 90°, and their forearms in neutral, as recommended by the American Society of Hand therapists ®, Germany). Due to disparities between the sums of bone, fat, and lean mass measured by DXA and body weight measured by the previously described scale, the lean mass obtained by DXA was corrected according to body weight. Physical activity during commuting and leisure-time was measured in min/wk using the commuting section of the International Physical Activity Questionnaire and also a list of activities with frequency and duration of each activity, respectively.In 2012, lean mass was measured using the method of dual-energy x-ray absorptiometry  were considered possible confounders and the relationship of these variables with outcome was showed. Birth weight was used in the models that included nutritional status at the 1984 and 1986 follow-ups. Nutritional status at age 2 was included in the models using nutritional variables at the 1986 follow-up. A mediation analysis, using lean mass as a mediator, was carried out using the g-computation formula The analyses were performed using Stata 12 software . All analyses were stratified by sex and statistical interaction in the association between the exposures and grip strength according to sex was formally tested. The association between exposures and grip strength was evaluated using linear regression models. Wald test was used to test the significance and In the 2012–2013 visit, grip strength was measured in 3470 participants from the cohort . Percentage of data from males and females was similar. Characteristics of individuals with grip strength measurements are shown in z-score and nutritional status at 2 and 4 y in both males and females. Maternal smoking during pregnancy was associated with lower birth weight (P < 0.001), lower weight at age 2, and lower length for age z-score at 2 and 4 y in both sexes.P = 0.005). Females whose mothers achieved ≥12 y of schooling had lower adult grip strength than their counterparts. Non-white females had ∼2 kg more strength than white females  higher grip strength than males with birth weight <−2 z-score. Additionally, positive association was observed among males whose birth weight was between −2 and −1.1 z-score. Grip strength was also positively associated with all nutritional status variables at 2 y. Males with weight- and length-for-age and weight-for-length >1.1 z-score at 2 y had higher grip strength than males whose these nutritional status variables were <−2 z-score. Weight- and height-for-age z-score at 4 y were positively related to males' grip strength in young adulthood.P < 0.001). Those females whose birth weight was appropriate for the gestational age had 1.2 kg higher strength than females who were born small for the gestational age. Regarding association between grip strength and nutritional status at 2 y, females whose weight-for-age was >1.1 z-scores had 2 kg  higher grip strength than females whose weight-for-age was more than 2 SD below the mean of the reference population. Weight-for-length z-score at 2 y was not associated with grip strength, whereas females with length-for-age >1.1 had higher grip strength than females with length-for-age <−2 z-scores. Similar to males, weight- and height-for-age z-score at 4 y were positively associated with adult grip strength in females. However, grip strength was positively associated with weight-for-length at 4 y (P = 0.019), since females with weight-for-height above p50 of the reference population had higher grip strength than females below the p50.P-values for the variables weight-for-age z-score at 2 and 4 y, weight-for-length at 2 y, length- and height-for-age at 2 and 4 y were <0.001.We observed an interaction between sex and most of the independent variables included in the analyses, the z-scores at 2 y in females were not showed in z-scores at 2 y had a positive direct effect on grip strength in males. The percentage of effect on grip strength mediated by lean mass was 59% and 57% when considered weight-for-age and weight-for-length z-scores at 2 y, respectively.To test the mediation of lean mass, we also stratified the mediation analyses . Resultsz-score at 2 y in males had part of its effect not mediated by lean mass.Results of the present study demonstrated an important relationship between intrauterine growth and nutritional status at 2 and 4 y and grip strength in young adults belonging to the 1982 Pelotas birth cohort. Gestational age, however, was not associated with grip strength. The effect of most exposures was mainly mediated by lean mass in adulthood. However, birth weight according to the gestational age and weight-for-age The main limitation of this study was the lack of data on birth length making it impossible to compare effects of birth weight and length. The present study, however, had the advantage of being population based and including several measurements at different ages. The high follow-up rate of the 1982 Pelotas birth cohort is another strength as it reduces the susceptibility to selection bias. Additionally, both exposures and outcomes were prospective and objectively measured.A recent systematic review and meta-analysis found strong and consistent evidence for a positive association between birth weight and muscle strength in men and women across the life course The regression coefficients of the present study showed higher strength of association and more pronounced dose–response relationship in males. Other studies also found differences between sex in the relationship between early growth variables and later grip strength so that some associations were not statistically significant in females 2) from biopsy of the vastus lateralis was significantly lower in individuals with decreased birth weight in elderly males The association between birth weight and later grip strength can be explained by influences of birth size on growth and development of muscle fibers The results indicated that both prenatal and postnatal period might play an important role on adult grip strength. A study in the United Kingdom found that grip strength in the elderly was positively associated with weight at 1 y The theory of phenotypic plasticity explains lifetime adaptation of the organism due to early nutrition. In the case of muscle strength, the satellite cells, formed during myogenesis, play an essential role in the processes of postnatal muscle growth, muscle regeneration, and muscle hypertrophy across the life course. In animal models, the postnatal growth, a process that is normally regulated by satellite cells, is related to a phenotype marked by reduction in skeletal muscle mass and fiber caliber thrifty phenotype hypothesis, which primarily reflects adaptation in growth of lean mass and competing organs In addition to the type of fiber, the amount of lean mass was important to mediate the association between early nutrition and later grip strength in our population. Several studies in diverse populations have supported the hypothesis that poor fetal growth, as measured by low birth weight, results in a smaller proportion of lean mass later in life The results pointed to no effect of gestational age on grip strength in adulthood, whereas birth weight according to gestational age, a proxy of intrauterine growth, was positively related to grip strength. It suggests that intrauterine growth is more important than duration of the gestation. Thus, more attention should be focused on the intrauterine environment, especially from 6 to 18 wk, when the primary muscle fibers are formed and after the formation of secondary fibers The results of this study suggested that good nutrition in prenatal and early postnatal life positively influences adult muscle strength, evaluated in this study as grip strength. The results reinforce that the first 1000 d (conception to the first year of life) is a critical period for human growth and development. The findings indicate that the relationship between early determinants and adult grip strength may be mediated not only by muscle mass but by other causes not yet elucidated. The association with intrauterine growth emphasizes the importance of early environment and nutrition on later life. This is relevant because muscle strength is a marker of muscle function, which is related to loss of functional capacity, sarcopenia, and unfavorable cardiometabolic conditions in later life.


Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina.th percentile) of average census tract metal levels and compared to the lowest category (≤50th percentile).A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category  or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5).These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects.The online version of this article (doi:10.1186/1471-2458-14-955) contains supplementary material, which is available to authorized users. Theseng fetus –7. Some ng fetus –15.Birth defects are a leading cause of infant mortality in the U.S. , 17, yetDiet and drinking water are common sources of metal exposure in non-occupationally exposed individuals. In North Carolina, 2.3 million residents use private wells for drinking water , and theIn the present study we examined private well water levels of arsenic, cadmium, manganese, and lead across North Carolina, and used a semi-ecologic study design to estimate the association between metal levels and specific birth defect phenotypes. As individual level data on maternal water consumption were not available, maternal drinking water metal levels were assigned based on geocoded residence within a census tract. The prevalence of twelve specific defect types or groups of defects was compared between census tracts with high versus low average metal levels. This work represents the first effort to assess the association between statewide levels of metals in North Carolina wells with birth defects.This study was reviewed by the UNC IRB (#11-0414) and was approved according to regulatory category 5 under the National Institutes of Health description on Research on Human Specimens (44 CFR 46.101(b)). A statewide semi-ecologic study was conducted from a baseline study population that included livebirths between January 2003 and December 2008 that comprised 24,704 infants with birth defects (cases) and 725,690 non-malformed controls in North Carolina. Infants from non-singleton births , without a geocoded residence at delivery , or case infants with known chromosomal abnormalities  were considered ineligible and excluded from this study.Individual-level data regarding maternal source of drinking water and frequency of consumption were not available. Thus, the census tract corresponding to maternal residence at delivery served as the unit of analysis in this semi-ecologic study. The analysis included 1,563 census tracts comprising 5,271 block groups across North Carolina. Private well water metal data were provided by the North Carolina Department of Health and Human Services (DHHS) within the Division of Public Health. The well water database contained metal concentrations collected from private wells across the state between 1998 and 2010 measured by inductively coupled plasma-mass spectrometry. This database contains historical records of well water samples collected by and analyzed at the State Laboratory of Public Health in Raleigh, North Carolina as we have previously summarized . State oCase infants with selected birth defects were identified by the North Carolina Birth Defects Monitoring Program (BDMP). The BDMP is a statewide active surveillance program covering all 100 North Carolina counties . Cases wThe following twelve structural defects or groups of defects were included in this study: (1) spina bifida without anencephaly (n = 218); (2) anotia and microtia (n = 94); (3) conotruncal heart defects including common truncus, Tetralogy of Fallot (TOF), and transposition of the great arteries (TGA) (n = 435); (4) atrioventricular septal defects (AVSD) and endocardial cushion defects (ECD) (n = 150); (5) hypoplastic left heart syndrome (HLHS) (n = 142); (6) cleft palate (CP) (n = 351); (7) cleft lip with or without CP (n = 516); (8) esophageal atresia (EA) and tracheo-esophageal fistula (TEF) (n = 140); (9) pyloric stenosis ; (10) reduction defects of the upper and lower limbs (n = 255); (11) gastroschisis (n = 215); and (12) hypospadias .TM 9.3 .Environmental metals of interest included arsenic, cadmium, manganese, and lead. As described above, more than 22,000 measurements of metal concentrations in private wells were collected by the North Carolina DHHS across the state between 1998 and 2010. Only private wells with a corresponding global positioning system (GPS) coordinate or with a complete geocoded address were considered in this study  to minimize the impact of geocoding error. GPS coordinates were standardized to a decimal degree format and private well locations were geocoded according to previously described methods . The numThe average level of each of the four metals  was calculated within each census tract across the state. The distributions of average metal levels were mapped using ArcGIS. Census tracts with fewer than ten well measures for each contaminant over the total time period were excluded from further analysis to reduce exposure misclassification in poorly sampled tracts. Approximately 50% of census tracts were excluded due to limited sampling.th and 90th percentiles of average concentration was calculated for each metal. Then, an exposure status was assigned to each census tract for each metal where residences were considered “exposed” if the average concentration of the metal within the corresponding tract was equal to or greater than the 90th percentile of metal concentration across all tracts combined. Likewise, tracts were considered “unexposed” if the average concentration of the metal within the corresponding tract was less than or equal to the 50th percentile of metal concentration across all tracts combined. Thus, the final dichotomous exposure contrast compared exposed census tracts  and unexposed census tracts. The 50th and 90th percentile of census tract average levels were as follows: 1.29 and 2.54 ppb for arsenic, 0.54 and 1.82 ppb for cadmium, 41.55 and 139.69 ppb for manganese, and 3.52 and 7.28 ppb for lead.Maternal residence at delivery for cases and controls was geocoded by the North Carolina State Center for Health Statistics. Cases and controls were assigned to census tracts in North Carolina based on geocoded maternal residence at delivery using ArcGIS. A dichotomous exposure contrast was developed to compare “exposed” and “unexposed” census tracts at delivery. First, the distribution of average metal concentrations across all tracts with at least ten well water measures was examined, and the 50a priori using a directed acyclical graph approach. The final set included in the statistical analysis were maternal age (continuous), race/ethnicity , and education .Maternal and infant characteristics were obtained for cases and controls from the North Carolina birth certificate. Covariates were selected Crude and adjusted estimates of the association between metal concentrations in drinking water and the prevalence of each birth defect within census tracts were calculated by log-linear regression using SAS 9.3 . Prevalence ratios (PRs) with 95% confidence intervals (CIs) were calculated to estimate the association between dichotomized metal exposure status for each metal and the prevalence of birth defects within census tracts, adjusted for maternal age at delivery, race/ethnicity and education status. Any subjects with missing data for one or more covariates were excluded from the adjusted statistical model. To account for multiple testing, Bonferroni-corrected PRs with 99.9% CI estimates  were also calculated.To examine potential inter-metal correlation, Spearman’s rank correlation was used to examine the relationship between each pairwise metal level averaged to the ecologic unit. Corresponding Spearman’s rank coefficients (r) and p-values were calculated.th percentile exposed category were compared to areas where both arsenic and manganese were less than or equal to the 50th percentile unexposed category. Crude and adjusted PRs and corresponding 95% CIs were calculated using log-linear regression as described above.Given the correlations observed between levels of arsenic and manganese, a multiplicative interaction effect was estimated for the association between residence in areas of both higher arsenic and manganese levels and the prevalence of each birth defect category. Specifically, the prevalence of birth defects among infants residing in census tracts where both arsenic and manganese levels were greater than or equal to the 90th and 90th percentiles of block group average levels were 1.24 and 2.75 ppb for arsenic, 0.50 and 1.90 ppb for cadmium, 41.85 and 163.00 ppb for manganese, and 3.32 and 7.55 ppb for lead. PRs and corresponding 95% CIs were calculated using log-linear regression as for the main analysis.A sensitivity analysis was conducted using the census block group as the ecologic unit of analysis to determine whether the pattern of findings observed at the tract level was robust. The analysis included 5,271 block groups across North Carolina. Although the smaller block group level as the unit of exposure resulted in a finer geographical exposure assessment, fewer study subjects  were included since a larger proportion of the block groups did not have adequate well sampling data (greater than 75%). Maternal residence at delivery and the private well locations were assigned to North Carolina block groups corresponding to the 2000 census. Exposure levels for each metal were calculated for each block group using the same methods as the tract level analysis. The resulting 50To further refine the exposure assessment, a secondary sensitivity analysis was conducted using a nested cohort of individuals residing outside of public water supply distribution areas. Using North Carolina public water supply area service data and the spatial overlay tool in ArcGIS, the nested analysis was limited to only those subjects with a geocoded maternal residence at delivery outside of a public water supply area. This selection restricted the analysis to individuals who are more likely to use private drinking water wells . PRs and corresponding 95% CIs were calculated identically to the main analysis using the tract and block group ecologic units.The final eligible study population for analysis included 20,151 case infants and 668,381 non-malformed control infants. Table From the well water database records collected between 1998 and 2010, the analysis included between 11,000 and 47,000 wells with geocoded locations . The patterns of these levels are represented in Figure To examine the spatial occurrence of each birth defect category within census tracts, a dichotomous exposure status was assigned based on 50Crude and adjusted PRs and 95% CIs were calculated to estimate the association between average concentration of each metal and the prevalence of birth defects within census tracts  compared to the unexposed category. An elevated PR was also observed for manganese-exposed versus unexposed categories and the prevalence of anotia/microtia (PR: 1.3 95% CI: 0.5-3.4) and AVSD/ECD (PR: 1.3 95% CI: 0.6-2.5), however the CIs were consistent with unity.The lead-exposed category was associated with an increased prevalence of HLHS (PR: 1.7 95% CI: 0.9-3.3), but the finding was not statistically significant. The cadmium-exposed group was associated with a significantly decreased prevalence of pyloric stenosis (PR: 0.4 95% CI: 0.3-0.7) compared to the unexposed group. The findings did not suggest patterns of association with cadmium-exposure and an increased prevalence of any birth defect analyzed in this study.To account for multiple comparisons, Bonferroni correction was applied and 99.9% CIs are reported  point estimates for the interaction effect of arsenic and manganese exposure with defect outcomes including anotia/microtia (PR: 2.7 95% CI: 0.7-10.2), conotruncal defects (PR: 1.6 95% CI: 0.8-3.2), AVSD/ECD (PR: 1.5 95% CI: 0.5-4.3) and cleft lip with or without cleft palate (PR: 1.4 95% CI: 0.8-2.6)  metal levels are elevated in private wells across the state and some metals such as arsenic and manganese co-occur, (ii) residence in manganese-exposed census tracts was statistically significantly associated with increased prevalence of conotruncal heart defects, and (iii) there is suggestive evidence of an interactive effect between residence in arsenic- and manganese-exposed census tracts and the prevalence of conotruncal heart defects.North Carolina is the fourth largest state population with approximately 2.3 million people relying on private wells for drinking water; the total number of individuals served is larger only in Pennsylvania, California, and Michigan as estimated by the USGS . ArsenicThe levels of metals in private wells is not currently regulated in North Carolina, and routine testing of private well water quality for contaminants is not required by state or federal regulations (state regulation requires a single test only when new wells are constructed). The MCL for arsenic levels in public water supplies is 10 μg/L, and 5 μg/L for cadmium . Lead isSpatial trends of private well metal contamination were identified across North Carolina. Here we find that manganese levels correlate spatially with arsenic levels in private wells. Levels of arsenic and manganese have been described in North Carolina groundwater –32; howeOur findings support a potential association between residence in manganese-exposed census tracts and the prevalence of conotruncal heart defects. The results of the sensitivity analyses showed similar positive trends and statistically significant associations that are suggestive of a potential association between manganese levels and conotruncal defects. To our knowledge, to date no studies have examined the relationship between drinking water manganese and birth defects in humans. A previous study reported that increased placental manganese levels were associated a higher risk of NTDs showed a statistically significant association with spina bifida . In animThe results suggest that residence within arsenic-exposed census tracts was modestly associated with a higher prevalence of cleft lip with or without cleft palate and EA/TEF defects at the census tract ecologic unit. Residence in arsenic-exposed tracts was also significantly associated with decreased prevalence of HLHS at the census tract ecologic unit, although the sensitivity analyses were consistent with a trend towards a null association. Previous population-based studies have shown associations between drinking water arsenic levels and CHDs –21, NTDsOur results show a potential interactive effect between arsenic and manganese on the association with spina bifida, conotruncal heart defects, AVSD heart defects, and cleft lip with or without cleft palate. Specifically, the estimates reveal that the prevalence of these defects among infants residing in census tracts that were considered both arsenic- and manganese-exposed compared to areas that were arsenic- and manganese-unexposed were increased compared to the PR estimates observed for either metal alone. The findings suggest a potential, but not statistically significant, joint effect in areas of arsenic and manganese co-occurrence. These analyses had limited power as reflected in the width of the reported CIs because the total sample size was considerably reduced. This association has not been previously examined in studies of environmental metal exposures and birth defects. There is previous evidence for potential drinking water co-exposure to both manganese and arsenic. In a study of US public wells, the combination of arsenic and manganese detected in the same water source was one of the most commonly occurring pairs of unique mixtures out of over 90 organic and inorganic contaminants that were tested .The results suggest some associations between residence in areas of the highest cadmium levels and reduced birth defects prevalence. A decreased prevalence in pyloric stenosis was associated with residence in areas of the highest cadmium exposure, a relationship that remained statistically significant after Bonferroni correction. There were no statistically significant positive relationships between birth defect prevalence and residence in areas of the highest cadmium or lead levels. At the time of this study, we are aware of only three studies that examined the relationship between drinking water levels of cadmium and/or lead and birth defects in humans , 22, 51.This study had several limitations that are important when interpreting the results. As individual-level environmental data were not available within the birth defects database, it was not possible to evaluate the relationship between personal water consumption patterns and the risk of defects. Data on individual use of well water were unavailable; therefore, any observed associations are limited to the ecologic unit of analysis and the findings are subject to the ecologic fallacy. However, in the absence of individual-level exposure data, ecologic approaches have previously been applied to examine associations between metals in private wells and other health outcomes , 63.Exposure assessment remains a challenge among epidemiological studies of birth defects , 65. ForIn this study the assigned exposures represent a census tract average over a period of 12 years and BDMP data represent the location of cases at delivery. It is possible that non-differential exposure misclassification was introduced by the databases including a potentially biased sample of tested wells, a large proportion of tracts with limited sampling, and the likelihood of maternal mobility during pregnancy . It is pThis study had several strengths including an active statewide case ascertainment program, which provided a large sample size of liveborn cases and controls representing six years of active birth defects surveillance in North Carolina. The semi-ecologic design enabled individual-level assessment of newborns with specific defects and covariate adjustment using data from birth certificates. The outcomes we investigated included specific phenotypes or groups of phenotypes based on similar etiologic mechanisms, which is advantageous over previous studies that have grouped multiple defect outcomes. The statewide surveillance program allowed exclusion of case infants born with chromosomal abnormalities, as this is a known risk factor for some structural defects . This stOverall, our findings suggest evidence at the ecologic level of possible relationships between elevated concentrations of arsenic, cadmium, manganese, and lead levels in drinking water and specific birth defects. Given that our results support previous evidence of an association between metal exposure and specific heart defects, these relationships should be prioritized for future studies. This is directly in line with ongoing research directed at understanding the biological mechanisms that underlie metal-birth defect associations using animal and cell culture models . FurtherTable S2. Spearman’s rank correlations and coefficient of variation for average (ppb) census tract metal levels and census block group metal levels (noted in parentheses). Table S3. Crude PRs and 95% CIs using the census tract ecologic unit and comparing individuals in the exposed (≥90th percentile) to unexposed (≤50th percentile) groups for average census tract metal levels. Table S4. Bonferroni corrected adjusted PRs and 99.9% CIs using the census tract ecologic unit and comparing individuals in the exposed (≥90th percentile) to unexposed (≤50th percentile) groups for average census tract metal levels. PRs were adjusted for maternal age, race, and education status. Table S5. Crude and adjusted PRs and 95% CIs estimate arsenic-by-manganese interaction using the tract level ecologic unit. PRs were adjusted for maternal age, race, and education status. Table S6. Adjusted PRs and 95% CIs using the census tract ecologic unit and excluding individuals living in public distribution areas. PRs were adjusted for maternal age, race, and education status. Table S7. Crude and adjusted PRs and 95% CIs using the block group ecologic unit and comparing individuals in the exposed (≥90th percentile) to unexposed (≤50th percentile) groups for average census block group metal levels. PRs were adjusted for maternal age, race, and education status. Table S8. Adjusted PRs and CIs at the block group level excluding individuals living in public distribution areas. PRs were adjusted for maternal age, race, and education status. (DOCX 35 KB)Additional file 1: Table S1: Number of geocoded wells for each metal as well as number of census tract and block groups with average metal levels above EPA drinking water standards for public distribution systems. Averages were calculated where more than ten wells were measured in the respected block group or tract.


It is well documented that maternal exposure to second-hand smoke (SHS) during pregnancy causes low birth weight (LBW), but its mechanism remains unknown. This study explored the potential pathways. We enrolled 195 pregnant women who delivered full-term LBW newborns, and 195 who delivered full-term normal birth weight newborns as the controls. After controlling for maternal age, education level, family income, pre-pregnant body mass index, newborn gender and gestational age, logistic regression analysis revealed that LBW was significantly and positively associated with maternal exposure to SHS during pregnancy, lower placental weight, TNF-α and IL-1β, and that SHS exposure was significantly associated with lower placental weight, TNF-α and IL-1β. Structural equation modelling identified two plausible pathways by which maternal exposure to SHS during pregnancy might cause LBW. First, SHS exposure induced the elevation of TNF-α, which might directly increase the risk of LBW by transmission across the placenta. Second, SHS exposure first increased maternal secretion of IL-1β and TNF-α, which then triggered the secretion of VCAM-1; both TNF-α and VCAM-1 were significantly associated with lower placental weight, thus increasing the risk of LBW. In conclusion, maternal exposure to SHS during pregnancy may lead to LBW through the potential pathways of maternal inflammation and lower placental weight. Low birth weight  may result from preterm birth or intrauterine growth restriction (IUGR), which can occur simultaneously in pregnancy35It is well documented that maternal exposure to second-hand smoke (SHS) is an important risk factor for LBW. A recent meta-analysis estimated that maternal exposure to SHS during pregnancy reduces mean birth weight by 31–60 grams and may increase the risk of LBW by 1.16–1.60 timesThe aforementioned hypothesis is suggested by the following strands of evidence. First, SHS exposure leads to abnormal levels of inflammatory markers in different populations81415To the best of our knowledge, there is no research that links the above evidence together to explore the plausible mechanisms. As such, this study aimed to explore the potential pathways that integrate maternal inflammation and the placenta, which might explain the mechanism by which maternal exposure to SHS during pregnancy leads to LBW.pr = 0.19), IL-6 and CRP (pr = 0.11), TNF-α and IL-1β (pr = 0.25), TNF-α and CRP (pr = 0.12), TNF-α and VCAM-1 (pr = 0.14), IL-1β and CRP (pr = 0.11) and CRP and VCAM-1 (pr = 0.12), whereas significant negative correlations were obtained between IL-6 and TNF-α (pr = −0.14), IL-6 and VCAM-1 (pr = −0.14).After controlling for potential confounders, significant positive correlations were observed between MCP-1 and IL-6 , lower placental weight  and increased maternal serum levels of TNF-α  and IL-1β The SEM results indicated a good fit to the model . The coefficients in the pathway diagrams indicated that maternal SHS exposure during pregnancy might induce full-term LBW indirectly . First, The effect of maternal SHS exposure on full-term LBW via each pathway was calculated, as shown in This study tested the hypothesis that maternal SHS exposure during pregnancy leads to full-term LBW through maternal inflammation and lower placental weight. The SEM results showed that maternal exposure to SHS during pregnancy initially induced maternal inflammation by increasing the secretion of IL-1β and TNF-α, which then triggered the secretion of IL-6, CRP and VCAM-1; both TNF-α and VCAM-1 caused a decrease in placental weight; and eventually, TNF-α and the damaged placenta increased the risk of full-term LBW.et al. found that healthy children exposed to SHS had lower serum concentrations of IL-1β than those without SHS exposureet al.22921229et al., has reported an insignificant association between them in adolescentset al. found that young healthy male smokers had slightly decreased serum MCP-1 levelsPrevious studies have reported inconsistent associations between SHS exposure and the six measured inflammatory markers in our study. For example, two studies of male workers reported that SHS exposure was significantly associated with elevated serum CRP98et al. indicated that maternal exposure to SHS in pregnancy could produce similar ultra-structural changes as maternal active smokinget al. observed no significant differences in placental surface area, volume and weight between pregnant women with and without SHS exposureThere is abundant evidence showing that maternal active smoking during pregnancy profoundly alters placental weight, morphology and function172829et al. found significantly elevated serum IL-1β levels in women who delivered with IUGRet al. reported the same result in women with LBW and complications with pre-eclampsiaet al. found that women with full-term IUGR had significantly higher serum IL-6 levels than women with babies appropriately grown for gestational age (AGA)et al. reported that maternal serum IL-6 levels during the first trimester were significantly associated with poor foetal growth in pregnant women with rheumatoid arthritis32et al. reported that an elevated maternal serum CRP level during the first trimester of pregnancy significantly increased the risk of delivering a growth-restricted baby41Although the association between LBW and inflammation has been explored, the results varied for the different kinds of inflammatory markers and with the period of pregnancy in which the specimens were collected. With regards to the association between maternal serum TNF-α level and LBW, three studies reported that pregnant women with LBW had significantly higher serum TNF-α levels before delivery than those with normal birth weight3233The association between placental weight and birth weight is well established. Previous studies provide consistent evidence that placental weight is much lower in LBW cases than in control groups with normal birth weight1415et al. found that placental weight mediated the effects of prenatal factors on foetal growthIn line with previous findingsAs a critical maternal inflammatory marker in our study, TNF-α is a pleiotropic pro-inflammatory cytokine, which may have direct effects on the placenta. Previous studies have suggested that an excessive level of TNF-α may damage the placenta by inhibiting the growth of the trophoblast, causing apoptosis of trophoblast cells, interfering with the development and invasion of placental spiral arteries and damaging the endothelium and decidual vasculature454649Our results revealed a noteworthy role of VCAM-1. As a marker of endothelial cell activation, VCAM-1 is a crucial adhesion molecule in both efficient placentation and adequate placental vasculature development54We explain the biological mechanisms of maternal exposure to SHS during pregnancy resulting in full-term LBW as follows. First, some of the components  in SHS may cause a maternal inflammatory response. Then, some inflammatory cytokines  may damage the placenta or affect placental development resulting in deficiencies in its size, structure and function; finally, the damaged or insufficiently developed placenta is unable to transfer sufficient nutrients and oxygen from the maternal body to the foetus, which may eventually lead to full-term LBW.Several limitations should be addressed. First, all of the subjects were sampled from women and children’s hospitals in this study, which might have caused a selection bias that would limit the generalisability of our findings. Second, maternal SHS exposure was retrospectively assessed using a questionnaire that might have introduced information bias and confused the association between maternal SHS exposure during pregnancy and full-term LBW. Third, we only measured placental weight, while other physical parameters of the placenta, such as the placental width and length and the cord placement, may also predict outcomes. Fourth, inflammation is an active process involving the release of an extensive array of inflammatory markers, yet this study only included six markers. Therefore, further research should take a ‘systematic biology’ approach to explore how disturbances in inflammatory networks may lead to full-term LBW. Fifth, we only obtained maternal serum at one time point, near parturition, which limited our ability to define the temporal changes in these cytokine profiles and weakened the clinical application value when attempting to predict adverse pregnancy outcomes early in gestation. Parturition may also increase the level of inflammatory cytokines such as IL-1β, and thus the association between inflammatory markers and full-term LBW may be more complicated than our simplified explanation. Although we controlled for gestational age as a potential confounder in this study, an elaborately designed study with measurement at different gestational weeks would be better able to explain the association between inflammatory markers and full-term LBW. Sixth, despite the indirect effect explaining 48.4% of the total effect, the mediating effect of placental weight and maternal inflammatory markers on the associations between maternal SHS exposure during pregnancy and full-term LBW is only partial, rather than complete. Moreover, in contradiction with the previous finding that TNF-α may not cross the placentaIn summary, to the best of our knowledge, this is the first study to explore the pathways through which maternal exposure to SHS during pregnancy causes full-term LBW via maternal inflammatory mediators and damage to the placenta. Our findings support the above hypothesis and thus extend our understanding of the mechanisms of full-term LBW and provide necessary insights for the development of novel, effective and targeted immunomodulatory therapies to improve pregnancy outcomes.The study population consisted of 390 pregnant women who gave birth to full-term (≥37 weeks) infants at the Maternity and Child Health Care Hospitals of Shenzhen and Foshan in Guangdong, China, from September 2009 to March 2010. Birth weight was measured on an electronic balance scale immediately after birth. Mothers whose infants weighed less than 2500 grams were categorised as full-term LBW cases. When a full-term LBW case was enrolled, a control was randomly selected from the mothers with newborns with a normal birth weight  and gestational age of ≥37 weeks who went into labour on an adjacent date (+/−3 days) in the same hospital. Overall, 195 LBW cases and 195 controls were recruited in this case-control study. The study was approved by the Ethics Committee of Sun Yat-sen University in Guangzhou, China, and it was carried out in accordance with the approved guidelines. All of the participants understood the study and gave their written informed consent.Mothers who had an infectious disease in the last trimester were excluded from the study to avoid bias in the measures of inflammation due to their infectious status. Women with the following characteristics or behaviour were not included: 1) actively smoked cigarettes during pregnancy; 2) had one or more pre-existing chronic renal diseases, lung disease, diabetes, hypertension, hyperthyroidism or anaemia; 3) had an induced or accidental abortion; 4) had multiple births or newborns with birth defects; 5) had one or more obstetric complications, such as pre-eclampsia, antepartum haemorrhage, placenta previa etc.; and 6) placenta calcification.In the postnatal face-to-face interview, each selected mother was asked to complete a structured questionnaire on her social-demographic information, medical history, reproductive history, health behaviour and pre-pregnancy weight and height.The medical records were reviewed to collect detailed gestational medical and obstetrical information including medication, last menstrual date, early ultrasound assessment, birth weight, infant gender, parity and placental weight.The information about maternal exposure to SHS during pregnancy was collected at the postpartum interview, as reported previouslyThe placenta, with membranes and large clots but with the cord trimmed, was weighed immediately after birth on an electronic balance scale in decagrams to the nearest 10 g. A lower placental weight was defined as below the median (500 g).Maternal blood samples were collected within 12 hours after the eligible mothers were admitted to the hospital for parturition, and they were not in active labour or membrane rupture. Two millilitres of maternal peripheral venous blood were collected in a serum separator tube and centrifuged at 3000 rounds/minute to obtain the serum. The serum specimens were immediately stored in a freezer at −80 °C until all of the samples were collected. Freezing and thawing cycles were avoided during the sample collection process.The maternal serum levels of six inflammatory markers, MCP-1 (monocyte chemotactic protein-1), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α), IL-1β (interleukin-1β), CRP (C-reactive protein) and VCAM-1 (soluble vascular cell adhesion molecule-1), were measured using flow cytometric (bead-based) multiplex assays with the Human Basic Kit Flow Cytomix  and Flow Cytomix  on a BD FACS Calibur instrument , in strict accordance with the manufacturer’s instructions. Data were obtained using Cell Quest software (BD Bioscience) and calculated using the Flow Cytomix program .According to the literature585960Means and standard deviations (SD) were used to describe continuous variables. Levels of serum inflammatory markers were logarithmically transformed and described as geometric means with 95 per cent confidence intervals (95% CIs). Proportions were used to describe the distributions of categorical variables.t tests or Satterthwaite t-tests were performed to test the differences in maternal age, gestational age, placental weight and log-transformed maternal serum levels of inflammatory markers between the full-term LBW group and the normal control group.First, Chi-square tests were used to examine the associations between full-term LBW and maternal social-demographic and clinical characteristics, and Student’s Second, logistic regression analysis was performed to test the associations between full-term LBW and maternal exposure to SHS during pregnancy, lower placental weight and maternal serum levels of inflammatory markers, with adjustment for potential confounders. Partial correlation analyses were conducted to examine the correlations between any two of the maternal inflammatory markers while controlling for the potential confounders.Third, SEM was conducted to explore the potential pathways of maternal inflammation and lower placental weight in the association between maternal exposure to SHS during pregnancy and full-term LBW, on the basis of the fit between our data and the hypothesised pathways5462P values were two-sided and statistical significance was set at P = 0.05. The structural equation model was calculated using AMOS version 17 , and all of the other statistical analyses were conducted with SPSS version 17.0 .All How to cite this article: Niu, Z. et al. Potential pathways by which maternal second-hand smoke exposure during pregnancy causes full-term low birth weight. Sci. Rep.6, 24987; doi: 10.1038/srep24987 (2016).