Among them, 10,544 women who had live born or stillborn infants with gestational age ≥28 weeks between 2008 and 2009 were interviewed using a structured questionnaire designed to collect information about periconceptional risk factor exposure, health care service utilization, and micronutrient supplements. Logistic regression was performed to assess the risk factors associated with birth defects and adjustments were made for imbalanced social-demographic characteristics between case and control groups.The prevalence of congenital birth defect in Shaanxi province was 14.3/1000 births. The environment risk factors associated with birth defects include unhealthy lifestyle : 3.60, 95% confidence interval (CI) 1.64−7.91; Smoking, OR: 1.32, 95% CI: 0.99−1.75; Drink strong tea, OR: 1.81, 95% CI: 1.27−2.59), exposure to heavy pollution , maternal diseases , drug use , maternal chemical pesticide exposure , and adverse pregnancy history . Periconceptional folic acid or multiple micronutrients including folic acid supplementation, was associated with a reduced rate of birth defects .Health care service utilization, unhealthy lifestyle factors, and environment risk factors seem to be associated with birth defects in Shaanxi province. Governmental agencies should focus on effective primary preventative methods, such as the delivery of periconceptional health education for minimizing potential risk factor exposures, periconceptional folic acid or micronutrient supplementation, environment monitoring, and assessment of factories with high levels of pollution. Birth defects are a global problem, but their impact on infant and childhood death and disability is particularly severe in low- and middle-income countries. Serious birth defects can be lethal. For those who survive early childhood with birth defects, they can experience lifelong mental, physical, auditory, and visual disabilities that exact harsh human and economic tolls on them, their families, and their communities. Up to 70% of birth defects could either be prevented or, with proper care, cured or ameliorated As the largest developing country in the world, a hospital-based surveillance system for monitoring birth defects was established in China in 1986 A population-based cross-sectional survey on birth defect prevalence rates and types was conducted in Shaanxi Province in Western China in 2009–2010 using a stratified, multistage cluster random sampling technique. Information on live births or stillbirths with complete gestational age ≥28 weeks born in the previous 2 years was gathered from parents or caregivers during household interviews.PPS) sampling. Households were selected with a two-stage sampling procedure. The 16 counties/districts in Shaanxi Province were selected during the first stage by PPS sampling. There were 125 births in each township averagely during 2008–2009 according to the data from Provincial Maternal and Child Healthcare center, so eight townships in each selected county/district were chosen during the second stage for ensure that 1000 eligible household would be covered in the survey. All of the households that met the inclusion criteria were interviewed in 128 selected townships.A sample of 13,347 household was estimated to be sufficient to detect a 1.4% birth defect rate and 20% acceptable variability in live born or stillborn infants, given assumption of α = 0.05, β = 0.20, and design effect = 2.0. The sample size was expanded to 16,016 households to account for a 20% non-response rate. Prior to fieldwork, the research team conducted village, township, and county listing operations to prepare multi-stage probability proportion to size . The project was also approved by the Population and Family Planning Committee in Shaanxi Province, China. Prior to the interview, informed written consent to participate in the study was obtained from main respondents of the household and was witnessed by the village doctor.The household questionnaires were used to collect information on the women and their most recent pregnancies in surveyed households where the women were the main respondent. The questionnaire consisted of two sections. The first was a cross-sectional survey designed to estimate the prevalence rates of birth defects in Shaanxi Province and covered the following topics: (1) respondent socio-demographic characteristics , (2) husband’s background, (3) family economic level, (4) antenatal and delivery care of the most recent pregnancy, and (5) birth outcomes of the most recent pregnancy. The second section was a case-control study that focused on the women’s reproductive history, periconceptional exposure to risk factors associated with birth defects in the most recent pregnancy, and the use of folic acid and other micronutrient supplementations. Periconceptional was defined as 3 months before pregnancy through the first 3 months of pregnancy. All the households completed the first section of the questionnaire, and the second section was completed when the mother was available to interview. One village was randomly selected in each county/district for re-interviewing within one week after the first visiting to assess the self-reporting accuracy.Training courses for field staff were carried out in two locations. The first was conducted at Xi’an Jiaotong University College of Medicine, and the second course was given in Chang’an County in Shaanxi Province. Both courses consisted of an introduction to interviewing skills and fieldwork procedures, how to complete the questionnaire, interview simulations in households outside the sample area. Data collection was carried out by interviewing teams, each of which was responsible for four counties and consisted of one team leader, eight field interviewers, one Maternal and Children Health (MCH) staff member, one officer from the county health bureau, one local driver, and one interpreter if needed. Data collection took place between August 2009 and April 2010.The data were self-checked by the field interviewers immediately after each interview and cross-checked by the team leaders for completeness and consistency of all items in the questionnaires before setting out for next village. The completed questionnaires were taken to the Center of Epidemiology and Biostatistics in Xi’an Jiaotong University College of Medicine and double entered through double data verification. The kappa statistics were used to evaluate consistency of categorical variables.All live- and stillborn infants with birth defects were selected as case subjects . Information on infants with birth defects were cross checked with birth outcome records at the local Family Planning Station to ensure that the information was collected correctly. The control subjects were live born infants without birth defects and their mothers were available to interview.Information on maternal illness and drug use, use of periconceptional multiple micronutrient supplements, and risk factor exposures A logistic regression model was used to estimate odds ratios (OR) of risk factors and 95% confidence intervals (CIs) adjusting for imbalanced demographic characteristics between case and control groups as potential confounders, including maternal education, maternal occupation, paternal education, family income, and residence type. We used Stata version 9.2  for all analyses.We conducted interviews in 16,541 households in Shaanxi Province with live born or stillborn infants during 2008–2009 . Among tThe overall participation rate in the Shaanxi Province Birth Defects Case-Control Study was 64.6%  for mothers of control infants and 93.2% (221/237) for mothers of infants with birth defects. Most demographic characteristics were balanced between the two groups. Households with case infants were more likely to live in rural areas and have lower family incomes and parental education levels compared with control infants .Compared with the control group, infants whose mothers drank alcohol, smoked or were exposed to secondhand smoke, and drank strong tea during pregnancy were at increased risk for birth defects . These data are summarized in Infants born to mothers with any kind of disease, including infectious disease, diabetes, anemia, sexually transmitted disease, hepatitis, thyroid disease, acute fatty liver, gestational intrahepatic cholestasis, and pregnancy-induced hypertension were at higher risk for birth defects . The risk was greater for infants whose mothers received drug therapy, including antibiotic, anti-cancer drugs, anti-TB drugs, anti-thyroid drugs, hormones (including sex hormones), anti-diabetic drugs, anti-epileptic drugs, salicylic acid drugs, anti-hypertensive drugs, anti- trichomonas fungal drugs, serum products, toxoid products, and vaccines during pregnancy  .Maternal exposure to chemical pesticides ; households near heavy pollution factories, such as coal mines, paper mills, cement plants, and coal-fired power plants ; and maternal adverse pregnancy history  were significantly associated with birth defects .This study showed that there was low utilization of antenatal care check in Shaanxi Province, but the difference of proportions of antenatal care check with frequency ≥6 times and the initial antenatal care check at first trimester between the case (28.5%) and control (33.3%) groups was not statistically significant. The percentages of infants whose mothers consulted the doctor about pre- and postnatal care were 24.2% in the case group and 26.5% in the control group. Just 28.5% of infants in the case group and 33.0% of infants in the control group were brought in for at least 6 antenatal care checks, with the initial visit in the first trimester .The proportion of women who reported periconceptional micronutrient supplements was very low; just 11.2% of women took folic acid or multiple micronutrients supplements that included folic acid from 3 months before pregnancy through the first 3 months after pregnancy (consumption amount ≥60 tablets). We found that there was a significant impact of periconceptional folic acid intake on birth defects compared with the control group  .The prevalence of congenital birth defects in Shaanxi province was 14.3/1000 births, which was slightly higher than the data (13.5/1000 births) compiled by the Birth Defects Surveillance System Network Estimations of birth defect prevalence in China have been derived from hospital monitoring systems since the 1980s. Hospital-based birth defect surveillance has been a useful approach for monitoring distribution and changes in birth defect incidence rates. Surveillance data provides information for epidemiological studies and support for health policy decisions, health service planning, and preventative programs Compared with 20 years ago, the rank of disease of birth defects in Shaanxi Province has changed, and there has been no significant reduction in the overall prevalence of birth defects. The four most common birth defects in 1996–2000 in Shaanxi Province were congenital malformations of central nervous system and neural tube defects, cleft lip and/or cleft palate, limb deformities, and congenital heart disease In this study, we found that maternal periconceptional exposure to general risk factors, including alcohol use, drugs, chemical pesticides, and maternal illnesses, were significantly associated with birth defects, which is consistent with findings from other studies Just 5% of pregnant women reported taking iron or multiple micronutrient supplements in Shaanxi province, despite high rates of anemia (>35%) and inadequate or deficient folate levels (>60%) among women of childbearing age, mainly due to low dietary intake of nutrients This study highlighted health care service underutilization, which merits urgent attention. Just one in four women received counseling about “Good Child Rearing,” which was the main approach to provide health education regarding preventing birth defects. One in three women had ≥6 antenatal care visits and an initial antenatal care check in first trimester, which is an important critical period for embryonic development.Health care service utilization, unhealthy lifestyle, and environmental risk factors seem to be associated with birth defects in Shaanxi province. Governmental agencies should focus on implementing a series of effective primary prevention methods, such as providing periconceptional health education for controlling for potential risk factor exposures, periconceptional folic acid or micronutrient supplementation, and environmental monitoring.


Birth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects.This retrospective, statewide, population-based, cohort study was conducted in three US states . A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state’s births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold  in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus.Children with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research. An estimated 3% of babies are born with major birth defects The health burden associated with birth defects is significant; in the United States and many other countries, birth defects are the leading cause of infant death and a major contributor to disability and pediatric hospitalizations Research has uncovered the basis for a few associations between birth defects and cancer, mostly related to genes involved in growth homeostasis However, such studies are challenging: they require large population-based samples, longitudinal follow-up, detailed and validated information on clinical phenotype, and appropriate reference populations. In this study, we evaluated a large population-based cohort of U.S. children and young adolescents with birth defects to quantify and qualify their risk of cancer prior to age 15 years.The Institutional Review Board (IRB) in each of the three states  approved the study. These IRBs waived the requirement to obtain informed consent because the study used existing data collected under public health surveillance statutes as reportable conditions and required no patient contact.The three states partnered to increase the available study population. This partnership was facilitated by the presence of similar population-based surveillance programs of birth defects and of cancer  with accThe primary data sources were the birth surveillance programs, to select the birth defect cohort, and vital records databases, to select the reference cohort and to obtain death abstracts. These initial cohorts were reviewed  for inclBecause of early lethality, we also excluded infants with anencephaly and babies weighing less than 400g at birth or less than 20 weeks of gestational age. Clinical case review by a board-certified clinical geneticist and a pediatric oncologist led to the exclusion of secondary conditions (19 in the birth defect cohort) misclassified as primary birth defects  in the trisomy 21 group. We classified children with other chromosomal anomalies  who had a major birth defect  in “other chromosomal anomalies.” We grouped cancers using the International Classification of Childhood Cancers We restricted the analysis of individual structural birth defects to non-chromosomal cases. We analyzed chromosomal cases separately, by chromosomal diagnosis. To identify cases of cancer, we linked both cohorts to each state’s cancer surveillance program. To identify deaths, we also linked these cohorts by name, birth date, and sex to administrative databases . Linkages used a combined probabilistic and deterministic approach, followed by manual review of individual record matches Using these data we computed person-time as the duration from birth to cancer diagnosis prior to age 15 years, death, or to the end of follow-up period , whichever came first. Age-specific cancer incidence was based on the number of cases per 100,000 PY of follow-up through that age. To appropriately account for censored data, we used the Kaplan-Meier method to estimate cancer-free survival and cumulative cancer incidence. We used Cox proportional hazards models to adjust for potential confounders, including preterm birth, birth weight, sex, and maternal race/ethnicity, age, education, and state. Missing data were not imputed. Due to confidentiality agreements, the number of cases of cancer is not specified if it is fewer than five. Sample size of the cohort with birth defects was determined based on the largest number available from the three birth defect surveillance programs. Statistical analyses were done with SAS 9.1 .Baseline characteristics of the cohort with birth defects and the reference cohort are shown in Compared to the reference cohort, cancer risk was increased two-fold among children with non-chromosomal birth defects. No case of cancer was reported among 615 children with trisomy 13 or 18 . Among cThe “other chromosomal anomalies” group had a 7-fold increased risk compared to the reference cohort. The recorded cancers included lymphocytic lymphoma, nephroblastoma, and pilocytic astrocytoma, in children with Wolf-Hirschhorn/4p- syndrome, Cri-du-chat/5p- syndrome, and Turner syndrome.Because of earlier reports of increased cancer risk in children with hydrocephalus or heart defects, we evaluated these associations before and after clinical case review. Before clinical case review we had identified 15 cancer diagnoses in children with hydrocephalus, suggesting a 10-fold increased cancer risk . However, with clinical case review, all but one of the hydrocephalus diagnoses were found to be secondary to a brain tumor obstructing cerebrospinal flow or to intraventricular hemorrhage in a preterm baby (1 case). After excluding these cases, the excess cancer risk disappeared IRR 0.9, . SimilarThe cancer-free survival curves of the index and reference cohorts diverged significantly (p<0.001) soon after birth, markedly in the group with chromosomal anomalies , microcephaly, and cleft palate . These aWith regard to cancer type, the excess cancer risk in children with non-chromosomal birth defects appeared to be driven mainly by tumors other than leukemias and lymphomas; such “embryonal” tumors, which include neuroblastoma, hepatoblastoma, and nephroblastoma, were temporally restricted to childhood and exceedingly rare later in life. Biologically, these tumors could represent the endpoint of mis-programmed organ development rather than the result of early exposure to carcinogens, and unlike typical cancers of the adult, may share pathophysiologic features with birth defects. To date, evidence of causal or mechanistic commonalities between birth defects and cancer has been scarce. Aside from a few Mendelian conditions , pyloric stenosis, and hydrocephalus. This is at variance with some prior findings For Down syndrome, prior studies Compared to the studies reported to date, the current study adds information on specific birth defect groups that are clinically relevant and more precise than groupings based exclusively on the ICD coding conventions In studies of birth defects, ascertainment is a significant challenge. In this study, which is based on liveborn infants followed over time, the rates of individual birth defects were consistent with prevalence rates in livebirths reported in high quality surveillance programs in the United States An ascertainment bias of cancer in children with birth defects is unlikely, for several reasons. Children with birth defects are not monitored more closely for cancer than other children, and because cancer often develops years after a diagnosis of a major birth defect is made, the diagnostic evaluation for birth defects would not uncover cases of cancer. The converse, however, is probably a greater concern; finding previously undiagnosed birth defects during the diagnostic evaluation of a child with cancer. Factors that we think make such bias unlikely in this study include the focus on major birth defects, rather than minor anomalies that are more likely to have been missed early in life, and the clinical case review that examined the timing of diagnosis (to ensure that the birth defect diagnosis preceded that of the cancer). The case review also specifically mitigated another potential bias, that is, the miscoding as a birth defect of a structural finding that was a consequence of the cancer: one example of such miscoding is “hydrocephalus” secondary to a brain tumor impeding the circulation of cerebrospinal fluid.We used population-based cohorts and population-based cancer and death registries to minimize selection and follow-up biases. Because no single cancer registry exists country wide, people who moved from the state of birth to another state and there developed cancer would not have been identified in the study. If this occurred differentially in the two cohorts, bias could have arisen. If similar in the different cohorts, such inaccuracies would tend to dilute the estimates of cancer risk towards the null. This study also had limited power to detect weak cancer risks associated with rare defects, a limitation common to many cohort studies. A meta-analysis of similar studies could strengthen the quantification of risk associated with rare defects. Several birth defect subgroups were small with few cancer events  and the Finally, the study focused on childhood cancer, defined as cancer occurring prior to age 15 years. Whether children with birth defects are at increased risk for cancer at a later age is an important question that can be answered with longer follow-up.We found a modest but significant increased risk for cancer for specific non-chromosomal birth defects, including microcephaly, congenital cataract, microphthalmia, cleft palate, renal hypoplasia, obstructive renal defects, and selected heart defects. Conversely, for many common birth defects, the risk was not significantly increased. In a clinical setting, focusing on overall risk estimates would be inaccurate and potentially misleading, and may produce unnecessary concern in many families with affected children while potentially failing to properly consider cancer risk in children with specific clinical phenotypes. In some of these clinical presentations associated with increased cancer risk, in-depth genetic consultation could be indicated, with the goal of identifying recognized cancer-predisposing conditions. Furthermore, with the increasing power of molecular evaluation, such clinical research could lead to discovering new conditions that could shed further light on the origin and development of cancers among children and adolescents.Table S1Adjusted Relative Risk for cancer by major class of birth defects, UTAZIA study.(DOCX)Click here for additional data file.Table S2Hazard rate with 95% confidence interval (95%CI) for cancer, by age, in children with non-chromosomal birth defects and in reference cohort of children without birth defects, UTAZIA study. Hazard rate is by 100,000 person-years.(DOCX)Click here for additional data file.


Although little is known about etiology of childhood rhabdomyosarcoma (RMS), early life factors are suspected in the etiology. We explored this hypothesis using linked data from the California Cancer Registry and the California birth rolls. Incident cases were 359 children <6-year-old  diagnosed in 1988–2008. Controls , frequency matched on birth year (1986–2007), were randomly selected from the birth rolls. We examined association of birth characteristics such as birth weight, size for gestational age, and timing of prenatal care with all-type RMS, embryonal, and alveolar subtypes. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. In contrast to a previous study, we observed statistically non-significant association for embryonal subtype among high birth weight (4000–5250 g) children for term births [OR (95% CI): 1.28 ] and all births adjusted for gestational age [OR (95% CI): 1.21 ]. On the other hand, statistically significant 1.7-fold increased risk of alveolar subtype  was observed among children with late or no prenatal care and a 1.3-fold increased risk of all RMS subtypes among children of fathers ≥35 years old at child birth , independent of all covariates. Our finding of positive association on male sex for all RMS types is consistent with previous studies. While we did not find a convincingly positive association between high birth weight and RMS, our findings on prenatal care supports the hypothesis that prenatal environment modifies risk for childhood RMS. TP53 tumor suppressor gene, translocation of chromosomes 2 and 13 or 1 and 13, and abnormalities on chromosome 11p15 where the IGF2 gene is located (IGF2). This can result from either loss of heterozygosity  due to the loss of the maternal allele and duplication of paternal allele, or loss of imprinting (LOI) via hypomethylation of the maternal IGF2 allele  is the most common type of soft-tissue sarcoma among 0- to 19-year-olds, with the incidence rate highest among children of ages 0–4 . Geneticde novo genetic and epigenetic alterations perhaps due to environmental factors, some cases (7–33%) have familial predisposition as observed in families with Li-Fraumeni syndrome (LFS) and neurofibromatosis  and RMS tumor cell growth and motility , and 2008 among children of ages 0–5 years. Using first name, last name, and date of birth, we were able to match 89% of these cancer cases to a California birth certificate (1986–2007). Controls, frequency matched on birth year, were randomly selected in 1:20 ratio for all California registered <6-year-old cancer cases from the California birth roll. We ensured that the controls were cancer free up to age six or at the age attained by 2008 if younger than 6 years. Cancer-related information including RMS diagnosis, histology, and year of diagnosis were obtained from the CCR, while prenatal and perinatal data including birth weight, gestational age, parental age, and demographic information were collected from birth registry records. Institutional review board approvals were obtained from the University of California Los Angeles, the California Committee for the Protection of Human Subjects, and the CCR.The RMS cases were those assigned site group of IXa in the International Classification of Childhood Cancer, third edition (ICCC-3) and the subtypes were based on the following histological codes from the International Classification of Disease for Oncology, third edition (ICD-O-3): 8900/3 – RMS (unspecified), 8901/3 – pleomorphic RMS, 8902/3 – mixed type RMS, 8910/3 – embryonal RMS, 8912/3 – spindle cell RMS, 8920/3 – alveolar RMS, and 8991/3 – embryonal sarcoma . Here, wWe started with a total of 364 RMS cases and 209,700 controls. After excluding 1,522 controls who died before age 6 years, 57 children with Down syndrome, and births with implausible or extreme birth weight or gestational age values , the final study population included 359 RMS cases and 205,173 controls.n = 10,134,074) allowed us to use Californian instead of US births as a standard; this standard is more likely to be relevant for our diverse study population. In order to study the role of socioeconomic status, we applied a census-based SES index which combines seven census-block group indicators from 2000 census data: education index, median household income, percent living 200% below poverty level, percent blue-collar workers, percent older than 16 years in workforce without job, median rent, and median housing value (The birth registry data included birth weight (grams), gestational age (days), sex of infant, date of birth, parental age at child birth, plurality , parity, maternal pregnancy history , prenatal care , and maternal race/ethnicity . Gestational age was calculated based on the interval from date of last menstrual period to birth. For children born in 2007, obstetric estimated gestational age was also available. Thus, for those without gestational age, the obstetric estimated gestational age was used where available. Size at gestation was assigned as small if birth weight was less than the 10th percentile and as large if greater than the 90th percentile of the birthweight standards for a given gestational age. The 10th and the 90th percentile values were obtained for each gestational week (20–45 weeks) by maternal race/ethnicity  and child’s sex based on the total singleton live births in California between 1988 and 2006 using the method described by Alexander et al. . The larng value .We used logistic regression to examine, in crude and adjusted models, associations between both birth weight and measures of fetal growth at a given gestational age  and the three outcomes of interest . In addition, we examined associations with the following perinatal and demographic characteristics: parental age at child birth, child’s sex, plurality, parity, timing of prenatal care, maternal race/ethnicity, gestational age, and census-based SES. We also conducted trend tests for birth weight, gestational age, and parental age at child birth. The following covariates, selected based on literature, DAGs (directed acyclic graphs), and initial analysis, were included in all adjusted models: birth year, child’s sex, plurality, parity, maternal age, maternal race/ethnicity, and prenatal care. The SES variable was excluded from the final analysis and the results presented since the effect estimate of interest changed by less than 1% when adding this variable in the model. All analyses were carried out using SAS version 9.2 .Among the 359 RMS cases, the majority – 218 (61%) – were embryonal RMS cases, 81 (23%) alveolar, and 60 (17%) other types or unspecified cases. Both case mothers and fathers were slightly older than control parents. Male children were over-represented among RMS cases overall (61%) as well as among embryonal and alveolar subtypes .Our adjusted point estimates suggested a small statistically non-significant increase in risk of embryonal RMS for high birth weight 4000–5250 g) infants who were born at term and in all infants when adjusting for gestational age [odds ratio (OR) (95% CI): 1.28  and 1.21  respectively], but not for alveolar RMS or all-type RMS cases , but not for embryonal and alveolar subtypes separately . As for maternal age, none of the outcomes showed a linear trend . In addition, our data suggest a possible 60% risk increase for multiple compared to single births for all-type RMS [OR (95% CI): 1.60 ]. Furthermore, delivery at late gestational ages (43–45 weeks) may increase embryonal RMS risk by as much as 56% [OR (95% CI): 1.56 ], but the 95% CIs included the null values for these estimates indicating statistically non-significant. In contrast, children of Hispanic mothers appeared to have about a 20% reduced risk for embryonal [OR (95% CI): 0.78 ], but not for alveolar RMS [OR (95% CI): 1.10 ]. However, the 95% CI for adjusted models included the null value : 1.52 1.23, 1.89), 1.60 , and 1.71  respectively] after adjusting for all covariates. We found a very small increase in risk for all-type RMS with each year increase in both maternal and paternal age at childbirth [OR (95% CI): 1.02  and 1.02  respectively]. Examining categorical variables, we observed a 32% increase in risk of all-type RMS for children with 35 years or older fathers [OR (95% CI): 1.32 ]. We also observed approximately 30% increase in risk in mothers 30 years or older and fathers 35 years or older for embryonal RMS cases, albeit statistically non-significant  risk increases, particularly for embryonal RMS, among children in the 4000–5250 g birth weight group. Positive associations were suggested for birth weight with all of the measures we employed and embryonal RMS. No associations were apparent for alveolar RMS and our measures of fetal size at birth. While statistically non-significant, our point estimates for embryonal RMS group are similar in direction to those reported by Ognjanovic et al. , the stuIGF2 pathway (such as IGF2 and IGFR1). Accelerated fetal growth, often measured as high birth weight for gestational age, can be a marker of such changes in DNA structure. However, many different factors determine birth weight including parental build, race/ethnicity, and diet. Therefore, the fetal growth measures based on birth weight and gestational age are at best imprecise markers of overgrowth disorders linked to aberrations in the IGF2 pathway and also implicated in RMS development. Thus, it is perhaps more important to either determine a precise marker or to examine factors that may trigger molecular changes of the genes in the IGF2 pathway leading to increased susceptibility for childhood RMS. Studies examining associations between environmental factors and epigenetic changes in IGF2 linked to various cancers are lacking. So far, only a few studies examined associations between preconceptional as well as pre- and early post-natal factors for RMS. These studies reported positive associations for X-ray exposure during pregnancy, parental preconceptional use of marijuana and cocaine, maternal antibiotic use during pregnancy, organ meat consumption by children, childhood infections, and childhood exposure to chemicals  or maternal race/ethnicity (p = 0.15). The positive association we observed with alveolar RMS remained even in the model adjusted for both maternal race/ethnicity and SES [OR (95% CI): 1.70 ]. Lack of early prenatal care may be associated with lack of important nutrients in the maternal diet, exposure to harmful agents, or risky lifestyle factors, all of which should be explored in future studies.Our findings on male sex and per year increase in parental age at child’s birth for all RMS types are consistent with previous studies , 24–26. 24We conducted a population-based case-control study with controls selected at random from all California born children. Thus, our study is less likely to have been affected by bias in control selection. Furthermore, we were able to link our data to death records and exclude controls who died prior to the diagnosis of the frequency matched cases, reducing potential inaccuracy in estimates. RMS is a rare disease, but our data for a 20-year period made it possible not only to use a uniform case/control ascertainment and examine various risk factors for RMS, but also to distinguish the two most common histological subtypes. Embryonal and alveolar RMS have distinct genetic characterizations, age- and sex-specific distributions, and different prognoses  compared to most other variables including birth weight, which may introduce selection bias if the missing data are non-random. Higher proportions of missing or inaccurate gestational age data on birth records have been reported for women of lower SES status, receiving later prenatal care, and non-white mothers , 31. In 32In summary, our study provides some additional evidence in support of a weak association between accelerated fetal growth and childhood RMS. Furthermore, the estimated effect size reflects those from earlier reports for the embryonal subtype. However, sample size limitations preclude us from drawing conclusions except that the effect seems to be relatively weak. Given the sample size for the embryonal subtype and controls in this study, the smallest effect size the study can detect at 80% power is an OR of 1.40. Our findings on starting time of prenatal care and parental age at childbirth further support the notion that the early fetal/embryonic environment may be important for developing RMS in early childhood. However, further study with better measures of prenatal care is needed to explore and confirm this association. Given that the majority of RMS cases are sporadic in nature, environmental factors may play an important role in the genomic and epigenetic alterations causing these tumors. For example, diet and supplement intake during pregnancy may cause molecular alterations observed in RMS cases. Future studies should incorporate additional, accurate measures of early life and pregnancy exposures associated with birth weight or have more accurate fetal growth measure such as fundal height and additional predictors of birth weight  to improve our understanding of RMS etiology.Anshu Shrestha designed the study, analyzed and interpreted the data, and drafted the manuscript. Beate Ritz, Julia E Heck, and Michelle Wilhelm designed the study, provided critical input on each step of the study, guided analysis and interpretation of the data, and revised the manuscript. Simona Ognjanovic provided critical input in analysis of the data and revised the manuscript. Christina A. Lombardi contributed to data analysis and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Every year more than 20 million infants are born with low birth weight worldwide. About 3.6 million infants die during the neonatal period. More than one third of child deaths are thought to be attributable to maternal and child under nutrition.To systematically review the effect of supplementing various combinations and types of micronutrients on the course and outcomes of pregnancy.Electronic search of Medline, Pub Med, Health Internetwork access to Research Initiative, and Google Scholar databases was conducted. Outcomes of interest were birth weight, low birth weight, small size for gestational age, prenatal mortality and neonatal mortality. After exclusion of irrelevant /incomplete ones, 17 out of 115 articles were considered for the final analysis.Majority of the articles reviewed favored the supplementation of micronutrients to pregnant mother. Some studies suggested calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia. The remaining articles reviewed, showed significant benefit of Multiple Micronutrients supplementation during pregnancy in reducing low birth weight, small for Gestational Age births as compared to the usual iron-folate supplements.Supplying micronutrients, mainly multiple micronutrients have beneficial effect in reducing the risk of low birth weight and other complications. Further studies at various combination and doses of micronutrient supplements are recommended. Every year more than 20 million infants are born with low birth weight worldwide. About 3The World Health Organization (WHO) currently recommends iron and folic acid supplementation to reduce the risk of iron deficiency anemia among pregnant women. Since many developing countries already have systems in place for the delivery of iron and folic acid supplements, micronutrient supplements could be provided at little additional cost.Several systematic reviews of trials examining the effects of maternal multiple micronutrient supplementation have been conducted-10 but tIn addition, most of the studies and literature reviews dealing with maternal nutrition and birth outcomes have approached the issue by investigating single nutrients in isolation. On one level, this is necessary for an in-depth study of the complex issues involved. However, nutrient deficiencies are generally found in low-Socio-economic populations, where they are more likely to involve multiple rather than single deficiencies; and stuThe effects of maternal micronutrient supplementation on perinatal mortality and other pregnancy outcomes can differ depending on trial characteristics and study population. An updated systematic review is essential to provide the basis for future research and for a discussion of policy implications. Hence, this manuscript examines the effect of micronutrient supplements on the progress and outcomes of pregnancy by reviewing high quality literatures/articles.The published results from high-quality human observational and experimental studies which analyzed the effects of supplying Multiple Micro Nutrients (MMN) on the course of pregnancy and pregnancy outcomes were all included to this literature based analysis. Electronic search of Medline, Pub Med, Health Internetwork Access to Research Initiative (HINARI), and Google Scholar databases up to the end of 2011 was conducted. Search was done in keywords:  AND (“Micronutrients” OR “multiple micronutrient*” OR multivitamin OR micronutrient*) AND (supplement*) AND . A function extracting related articles as well as reference lists from research, reviews and editorials was used during the search process. The full version of the English-language analyzed articles and abstracts of most found papers were available during the selection process except for pubmed search.All literatures, including: observational studies, quasi-randomized trials and prospective randomized controlled trials (RCTs) evaluating multiple micronutrient supplementation in women during pregnancy, published in English language, were included. There were no limits on gestational age at the time of enrolment in the study and the duration of supplementation. Other than the assessment of Small for Gestational Age and neonatal mortality, we did not specifically evaluate minor adverse effects of the supplements such as nausea and vomiting among the mothers and newborns.In the primary search 115 records were found. After exclusion of studies/reviews which did not examine the effect of micronutrient supplements on pregnancy outcomes duplicated and outdated (published before 2005) data, 64 articles were selected. During the second selection we evaluated 17 of them as potentially relevant articles considering the effect of multiple micro nutrient supplementations on pregnancy and birth outcomes. Studies that failed to meet our criteria were not taken into consideration (FigureWe defined a “multiple micronutrient supplement” as a single tablet containing more than three different micronutrients; however micronutrient-fortified powders, foods and beverages were not included in the definition.We identified 115 potentially relevant articles for detailed review (FigureThough some degrees of variation by type and amount of micronutrients supplied are observed, the results of the final analysis of the most articles reviewed, favored the supplementation of micronutrients to pregnant mothers.The systematic review of clinical trials by Buppasiri P et al. from Thailand, with the objective of determining the effect of calcium supplementation on maternal, fetal and neonatal outcomes revealed that Calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia and improving mean infant birth weight. The same study also confirmed lack of additional benefits for calcium supplementation in prevention of preterm birth or low infant birth weight.Another study with a similar finding by Hofmeyr GJ et al. concluded that Calcium supplementation appears to almost halve the risk of pre-eclampsia, and to reduce the rare occurrence of the composite outcome ‘death or serious morbidity’, with no other clear benefits, or harms.The thesis based study by Melody B. on maternal vitamin D status during pregnancy as a predictor of offspring bone mass at three years of age shows that maternal vitamin D status during pregnancy did not predict for the child at 3 years of age. AnotherSimilarly, the study by Dror DK et al. shows the existence of recent evidence supporting the role of maternal vitamin D status, particularly early in pregnancy, in modulating the risk of pregnancy complications and in sustaining fetal growth, bone development, and immune maturation.On the other hand, according to the findings of the many of the final articles reviewed; though few disfavored the beneficial outcomes of supplementing MMN to pregnant mothers; majority of the others in one way or another supported the presence of significant association and benefit of MMN supplementation with at least one birth outcome.Among the studies against the added role of supplying MMN to pregnant mothers, the study by Parul Christian, which was about the Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal, revealed that Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight but MMN confer no additional benefit over folic acid-iron in reducing this risk,18. AnotConversely, the remaining RCT and observational studies reviewed from various parts of the world confer that oral supplementation of MMN for pregnant woman benefits the mother and the growing fetus as well as the newborn.In line with this, the reviews and RCT studies by Prakesh S., Zulfiqar A Bhutta, Michael B Zimmermann and other scholars across the globe unanimously reported that supplementing pregnant mothers with MMN immensely benefits both the mother and the growing fetus in reducing maternal morbidity conditions and morbid neonatal birth outcomes-23.Similarly, the systematic review by Prakesh S. et al. also indicates that prenatal MMN supplementation is associated with a significantly reduced risk of low birth weight and with improved birth weight when compared with iron–folic acid supplementation. However, there was no significant effect of MMN supplementation on the risk of preterm birth or small-for-gestational-age infants,22.Additionally, the review by Zulfiqar A Bhutta et al. also provides evidence on significant benefit of MMN supplementation during pregnancy on reducing SGA births as compared to iron-folate, with no significant increase in the risk of neonatal mortality in populations where skilled birth care is available and majority of births take place in facilities.Furthermore, other review by Kosuke Kawai et al. discusses the safety, efficacy and effective delivery of maternal micronutrient supplementation requiring further research. The other study by Dr. Kathleen Abu-Saad on the other side, declares that maternal nutrition is a modifiable risk factor of public health importance that can be integrated into efforts to prevent adverse birth outcomes, particularly among economically developing/low-income populations,25.On the other hand, RCT by Philip N Baker et al. revealed that Poor micronutrient intake and status increases the risk of SGA births in pregnant adolescents and hence mothers should get prenatal micronutrient supplementation in addition to the customary iron folic acid supplementation.In addition, in a poor population, the effects of maternal MMN supplementation on the fetus persisted into childhood, with increases in both weight and body size. Maternal MMN supplementation might therefore be an important part of overall strengthening of prenatal-care programmes-28.Therefore, it is clear to see that given comparability of impacts on maternal anemia, the decision to replace iron-folate with MMN during pregnancy may be taken in the context of available services in health systems and birth outcomes monitored.It was possible to learn that almost all available studies of RCT and other observational studies conducted in various parts of the world revealed that it is beneficial for the mother and the neonate and even to childhood with supplementation of MMN than ordinarily iron folic acid supplementation; nonetheless, there are still some equivocal findings related to the effect of MMN supplementation on the risk of preterm birth, small-for-gestational-age infants and neonatal mortality. Therefore, further studies at various combination and doses of micronutrient supplements particularly in areas where there is high prevalence of malnutrition are recommended.The authors declare that they have no competing interests.TA developed the review parameters and secured support. He also undertook partial literature search, data extraction and analysis. HT made detailed and extensive literature search and involved in the write up and synthesis of the findings. He also reviewed and standardized the study. Both authors read and approved the final manuscript.


The first canonical correlation was 0.42 (P<0.001), demonstrating a moderate positive correlation mainly between the 5 birth size measurements and 5 maternal factors . A significant interaction between infant sex and preterm delivery on birth size was also revealed from the score plot. Thirteen percent of birth size variability was explained by the composite score of the maternal factors . Given an ability to accommodate numerous relationships and reduce complexities of multiple comparisons, CCA identified the 5 maternal variables able to predict birth size in this rural Bangladesh setting. CCA may offer an efficient, practical and inclusive approach to assessing the association between two sets of variables, addressing the innate complexity of interactions.This analysis was conducted to explore the association between 5 birth size measurements  as dependent variables and 10 maternal factors as independent variables using canonical correlation analysis (CCA). CCA considers simultaneously sets of dependent and independent variables and, thus, generates a substantially reduced type 1 error. Data were from women delivering a singleton live birth (n = 14506) while participating in a double-masked, cluster-randomized, placebo-controlled maternal vitamin A or  There is a growing interest among maternal and child health researchers in studying the relationship between birth size and maternal socio-demographic and health factors. It is universally recognized that birth size is a lagged indicator of fetal health and predictive of neonatal health and survival. Birth weight in particular is strongly associated with mortality and morbidity in infancy and early childhood Maternal nutritional status largely depends on socio-economic factors. Women from a higher socioeconomic status have increased access to and consumption of nutritious foods during or prior to gestation and more antenatal care (ANC) visits and nutrition supplementation during gestation. Small birth size is more common in resource poor settings or among more disadvantaged populations Birth weight is often the exclusive birth size measure used to evaluate fetal growth. However, other measurements like length and head, chest, and arm circumferences may be important in predicting long-term health and development outcomes The data reported in this analysis were collected during a field based double-masked, cluster randomized, placebo-controlled trial assessing the efficacy of maternal vitamin A or β-carotene supplementation on maternal and infant mortality through 6 months of age from January 2002 to July 2007. Details are available elsewhere On enrollment into the trial, mothers were interviewed about household socioeconomic conditions, education, demographic characteristics, previous pregnancy history, frequencies of dietary intake and morbidity in the previous 7 days and measured for mid-upper arm circumference (MUAC) Birth anthropometry was collected on infants of consenting mothers who took part in a placebo-controlled newborn vitamin A supplementation trial that was nested into the latter half of the above maternal trial Birth size measurements included weight, length, MUAC and head and chest circumferences. Birth weight was measured to the nearest 10 g using a Tanita BD-585 digital pediatric scale . Length was measured to the nearest 0.1 cm using an affixed headboard and movable footplate that had been fashioned for use with the Tanita scale. Circumferential measurements were made to the nearest 0.1 cm with a Ross insertion tape . All measurements, except for weight, were measured in triplicate with the median taken as the accepted value, as previously described The maternal characteristics included in the present analysis are: age at enrollment, parity, early pregnancy mid upper arm circumference , education (yrs), LSI, number of ANC visits, and maternal trial supplementation (Vitamin A or β-carotene). Additional infant characteristics included preterm (<37 week of gestation) delivery status and sex.The overall Jivita study protocol was reviewed and approved by both the Bangladesh Medical Research Council (BMRC) and the Institutional Review Board (IRB) of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. Documented consent was given by all participating women.2 statistic. We interpreted the most widely used test for significance of each function, the F statistic 2 statistic in multiple regressions. According to Sherry and Hensen CCA is a multivariate statistical model that facilitates the study of linear interrelationships between two sets of variables: one set of variables is referred to as independent and the other as dependent; a composite score is formed for each set. CCA develops a canonical function that maximizes the correlation between the two composite variables. Additionally, CCA develops as many functions as there are variables in the smaller variable set; each function is independent  from the others so that they represent different relationships among the sets of dependent and independent variables st variate on the horizontal axis and the 2nd variate on the vertical axis, of composite score also helped to find natural variable groupings in to the data set To determine the relative importance of each original variable in to each function three methods have been proposed (i) canonical weights (standardized coefficients), (ii) canonical loadings  and (iii) canonical cross-loadings. As the canonical weights, like regression weights, are vulnerable to multicollinearity, most of the literature suggest to use canonical loadings or crossing loadings Multiple linear regression was used to examine the relationship between birth size and maternal factors and to compare the performance of the model with important maternal variables derived from CCA and the model with all maternal variables. Five models, one for each infant's size variable, were fitted with (i) 10 maternal factors and (ii) with only that factors which had significant loadings (≥30) in the canonical correlation analysis.To support our CCA findings we stratified our samples by prematurity status and infant sex and investigated their interaction on birth size. We used mean and 95% CI of the 5 anthropometric measurements for 4 strata . Multivariate Analysis of Variance (MANOVA) was used to investigate interaction effects on infant's size at birth. All analyses were performed using statistical software R version 2.14.1. We used the CCA and yacca R packages.More than 50% of the infants were born small. That is they were born with weight <2.5 kg, MUAC<10 cm, head circumference<33 cm and chest circumference<30.5 cm. Twenty seven percent of infants were preterm. Half of the infants were male. Mean (SD) maternal age was 22.0 (5.9) years and MUAC was 23.0 (2.0) cm. Most of the women (74%) had not reported an ANC visit. Nearly half of the women (∼43%) were nulliparous and their mean (SD) parity was 1.2 (1.4). Half of the women were literate (52%) and their mean (SD) years of schooling was 3.8 (3.9) .P<0.05, F-test). However, the redundancy index for all functions except the first one was zero. Therefore, only the first function is noteworthy in the context of this study.The canonical correlation coefficients and the redundancy indices are presented in st canonical function are presented in The loadings and cross loadings of the variables for the 12 of the full models and the models with 5 variables varied from 0.01 to 0.02.Regression coefficients are presented in A of B of the We studied the association between birth size and maternal factors using canonical CCA. CCA was used instead of separate linear regression models for each birth size measurement because it simultaneously models effects of multiple independent variables on multiple dependent variables. As CCA uses information from all the variables in both the exposure and outcome variable sets and maximizes the estimation of the relationship between the two sets, CCA may offer a more efficient approach for assessing the effects of the maternal factors on infant size at birth than methods routinely used, such as multiple linear regression. CCA starts with simultaneous consideration of both exposure and outcome variables, limiting the inefficiencies that may accompany conventional multiple testing, and, thus, reducing type-1 error. Furthermore, in CCA the latent variable approach, as used, helped to avoid multicollinearity Because the birth size measurements are highly correlated, the combination of the indicators captures more information and, thus, as a composite variable may better predict future health outcomes more efficiently than use of a single birth size measure. For example, head circumference, as an indicator of brain volume WHO suggests that a population with a prevalence of low birth weight of 15% or more or a prevalence of chest circumference at birth <30 cm experiences a disproportionately elevated risk of infant mortality and morbidity and long-term adverse effects on childhood growth and performance P<0.05) (data not shown). Christian and colleagues Pearson's correlation coefficients showed that maternal factors, age, parity, MUAC in early pregnancy, LSI of socioeconomic well being, maternal education, number of ANC visits and infant sex were significantly positively associated with birth size whereas, expectedly, preterm delivery was strongly negatively associated with newborn size measures. The individual multiple linear regression analyses also depicted virtually identical results, i.e. in all 5 models, except vitamin A and β-carotene supplementation, all other predictors had significant β-coefficients (st and 2nd composite score of the independent variables. In this study, following the canonical correlation analysis, the multivariate analysis of variance indicated that infant sex and preterm delivery displayed a significant interaction effect on birth size. Infant size was bigger for the male term followed by female term, male preterm and female preterm. Many literature also found this kind of interaction effect on birth size The score plot of the composite scores can also identify the effect of interaction between factors on outcome of interest In conclusion, CCA was used to explore the significant association between infant's size at birth and maternal factors. The maternal factors affecting or not affecting infant size at birth, isolated through canonical correlation analysis, were consistent with evidence of these kinds of associations in the literature


Adult height is inversely associated with the risk of coronary heart disease (CHD), but it is still unknown which phase of the human growth period is critical for the formation of this association. We investigated the association between growth in height from 7 to 13 years of age and the risk of CHD in adulthood.The heights of almost all children born 1930 through 1976 who attended school in the Copenhagen municipality  were measured annually from 7 to 13 years of age. Birth weight data were available since 1936. Fatal and non-fatal CHD events were ascertained by register linkage until 2008 . Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression for height z-scores (standard deviation units) and change in height z-scores. Height z-scores were inversely related to the risk of CHD. The association was strongest at 7 years of age  and steadily weakened thereafter, yet it still remained at 13 years of age . The associations were not modified by birth weight. Independent of the age-specific risk, rapid growth was associated with an increased CHD risk, most pronounced between 9 and 11 years in girls  and between 11 and 13 years in boys  per unit increase in z-score. Adjustment for body mass index somewhat strengthened the associations of CHD risk with height and weakened the association with growth.Risk of CHD in adulthood is inversely related to height at ages 7 through 13 years, but strongest in the youngest, and, independently hereof, the risk increased by growth velocity. The association between the physical development of the child and the adult risk of coronary heart disease (CHD) assessed by CHD risk factor profiles as well as by the incidence of CHD in adulthood has long attracted scientific interest The intermediate period between infancy and adolescence, i.e. childhood, has however received little attention. The period of childhood growth and its associations with CHD risk are interesting both from scientific and public health point of views. First, childhood is characterized by slow growth and its associations with CHD risk may be different than the periods of very rapid growth during infancy and puberty. Second, childhood is a unique period of life from a public health point of view because it allows for school-based screening, monitoring and intervention. Thus we investigated how growth in height from 7 to 13 years of age is associated with risk of CHD throughout adulthood, and whether the association is dependent on birth weight in a large cohort of Danish children.The data are from the Copenhagen School Health Records Register described in detail elsewhere st, 2008, whichever came first. During the follow-up period, 25,214 new CHD events occurred, 67% of them in men, including 6623 fatal events. From all CHD cases, 41% were because of acute myocardial infarction (ICD-8 code 410 and ICD-10 code I21) and 39% because of angina pectoris . The median follow-up time was 28.9 years. Of all CHD cases, 58%  occurred before 60 years of age, and these were classified as early CHD cases in this study.Follow-up data were obtained from the National Cause of Death Register To allow the comparison of risks associated with height among boys and girls, at different ages and by year of birth, age-, sex- and birth cohort-specific standardized height values called height z-scores were computed, where one standard deviation of the sex, birth-cohort and age-specific distribution of height is the unit. Since standard deviations of height were very similar across birth cohorts in all ages and in boys and girls , one uni2-statistics according to degrees of freedom between models having all main and interaction effects with models that only included main effects.Hazard ratios (HR) and 95% confidence intervals (CI) for the risk of all CHD events  were first computed for height z-scores at each age from 7 to 13 years using Cox proportional hazards regression with age as the underlying time scale. Thus the Cox model estimates relative hazards for covariates, such as height z-score in these analyses, across the range of ages. Next we analyzed the association between growth in height and the risk of CHD by calculating differences in height z-scores between subsequent two year intervals and computed the HRs for this change with and without adjusting the baseline height z-score. Further we adjusted the results for baseline body mass index (BMI). Since the z-scores were either interpolated or extrapolated to exact ages, measures of adjacent ages are not necessarily based on separate measures, thus precluding the analysis of yearly changes. These analyses were also repeated using only fatal CHD cases and CHD cases before 60 years of age. Finally we analyzed potential non-linearity between growth in height and CHD risk; after dividing z-scores of birth weight and height at 7 and 13 years of age into quartiles, we estimated the HRs for different combinations of these quartiles. We tested the interactions between birth weight and the height quartiles using them as categorized variables. This was done by comparing χYear of birth was included as a continuous variable in all models to account for any linear association between year of birth and CHD risk within the five birth cohorts. Birth cohort was also used as a stratum variable in the models thus allowing different baseline hazards for each of them. Because growth is different in boys and girls, separate analyses were conducted by sex. The exception was the analyses of growth between birth weight and height at 7 and 13 years of age since the number of cases in some categories was too small for sex-specific analyses; in these analyses sex was used as a stratum variable. Stata statistical software, version 10.1, was used to conduct the analyses.Since the study is entirely based on register data, only an approval by the Danish Data Protection Agency was required, and it was obtained.Boys were nearly 1 cm taller than girls until age 11 at which age the difference in height disappeared and thereafter girls were slightly taller . Growth Height was inversely associated with CHD risk at all ages in boys and girls . When adRapid growth in height between 7 and 9 years of age, measured as change in relative height between these two ages, was associated with an increased CHD risk in boys and girls  . In boysNext, we analyzed whether the association between height z-score at age 7 and CHD risk varied according to birth weight z-score. The risk of CHD steadily increased from the tallest to the shortest quartile of height in all quartiles of birth weight . There wNext we conducted the same type of analysis between height z-scores at ages of 7 and 13 . This anWe finally tested the heterogeneity of the associations of height and growth with CHD incidence over the birth cohorts. Because we found that the HRs were slightly stronger for CHD cases before 60 years of age than for all CHD cases, we conducted these analyses only for CHD cases before 60 years of age to account for differences in follow-up time among the birth cohorts. We found that the interactions between birth cohort and height at different ages were not statistically significant . Growth In this large longitudinal cohort we found that shorter stature in children from age 7 to 13 years was associated with an increased risk of CHD in adulthood, and these associations were not modified by birth weight. Height z-scores predicted the later risk of CHD with approximately the same effect size as did BMI z-scores in these same data The association between short adult stature and increased CHD risk has been known since the 1980s Our results show that it is necessary to disentangle the effects of a generally slow growth trajectory leading to short stature in adults and a fast growth trajectory during late childhood; both are associated with increased risk of later CHD, and are therefore masking the effects of each other in the final stature. Thus the decreasing strength of the association between height and the risk of CHD across childhood probably reflects a mixture of opposing effects. The inverse association between childhood height and risk of CHD in adulthood may be diluted by the opposite effect of rapid growth that increases the CHD risk. The tallest boys and girls at 13 years of age thus appear to be a heterogeneous group with regard to CHD risk. Those who were taller-than-average at 7 years of age and remained tall had the lowest CHD risk. In contrast, those who were shorter-than-average at 7 years of age and then grew and became taller-than-average at 13 years of age had an increased CHD risk, which even exceeded the risk of the children who remained shorter-than-average between 7 and 13 years of age. Rapid growth was associated with higher BMI, but the association between rapid growth and CHD risk remained even when adjusting the results for baseline BMI.Interestingly, rapid growth between 11 and 13 years of age in boys and between 9 and 11 years of age in girls showed the strongest association with increased CHD risk. These ages closely coincide with the timing of puberty in the Danish population both measured as sexual maturation It is noteworthy that rapid growth and increased CHD risk was seen already between 7 and 9 years of age in both boys and girls thus well preceding the onset of puberty. A Finnish study found that participants diagnosed with hypertension at 63 years of age had a lower birth weight and had showed catch-up growth in height and weight until 11 years of age when compared to normotensive men and women. The individuals, however, who were newly diagnosed as hypertensive in the clinical examination showed a different growth pattern since they had low birth weight, but did not show catch-up growth We found no evidence supporting that only children with a low birth weight combined with later rapid growth in height have a higher CHD risk; the association between height in childhood and later CHD risk was largely independent of birth weight. This result is consistent with a previous Finnish study, which found no evidence of catch-up growth from 2 to 10 years of age in the persons who had had coronary event in adulthood The association between short stature-to-age in childhood and later CHD risk may at least partly reflect the role of socio-economic factors, since it is well known that low socioeconomic position in childhood is associated with shorter adult stature The biological pathways underlying the association of CHD incidence with growth are still largely unknown. In addition to the above mentioned hypotheses on the role of nutritional, metabolic, hormonal and socioeconomic factors as mediators of this association, there are also other possible explanations. It has been suggested that short stature might be a CHD risk factor itself since it correlates with narrow coronary arteries, which may further predispose to CHD Our study has several strengths, but also limitations. We used a very large population-based cohort with annual height measures from 7 through 13 years of age. The health examinations were performed at all public and private schools and thus cover virtually every schoolchild in the Copenhagen municipality born from 1930 to 1976. Our follow-up data cover also all study participants because of universal health care system in Denmark. Thus, it is very unlikely that any selection bias exists at baseline or during follow-up. In the present cohort, we lack information on conventional risk factors for CHD, and it will be a task for future studies to elaborate which metabolic or other biological factors may underlie the observed associations between childhood growth and further CHD risk. Further since we do not have any measurements of sexual maturation, such as age at the onset of menarche, and we cannot determinate peak growth velocity for late mature children our results on the associations between timing of puberty and further CHD incidence can be regarded only tentative. It is also noteworthy that our study population represents an ethnically homogeneous Caucasian population with tall average stature To summarize, we found that shorter stature in childhood was associated with increased CHD risk in adulthood, that it grew weaker with age, and that the association was independent of birth weight. Rapid pre-pubertal growth, but especially rapid growth close to puberty, was associated with increased CHD risk, demonstrating the importance of physical development of the child for the risk. Physical development in childhood thus captures important information on the childhood environment, such as socio-economic factors and nutrition, which are important for further cardio-vascular health. Thus our results support the importance of optimal living conditions in childhood for a future healthy life. Unraveling the biological pathways of this association and the exploration of the utility of the association in prevention of CHD are tasks for future research.Table S1Number of participants, means (cm) and standard deviations (SD) of height from 7 to 13 years of age by five birth cohorts.(DOC)Click here for additional data file.Table S2Hazard ratios (HRs) with 95% confidence intervals (CI) for early and fatal CHD incidence cases per 1 unit increase in z-scores of height from 7 to 13 years of age.(DOC)Click here for additional data file.Table S3Hazard ratios (HRs) with 95% confidence intervals (CI) of early and fatal CHD incidence cases for 1 unit change in z-scores between 7 and 13 years of age.(DOC)Click here for additional data file.Table S4Hazard ratios (HR) with 95% confidence intervals (CI) for CHD incidence before 60 years of age per 1 unit increase in z-scores of height from 7 to 13 years of age by birth cohort.(DOC)Click here for additional data file.Table S5Hazard ratios (HR) with 95% confidence intervals (CI) for CHD incidence before 60 years of age for 1 unit change in z-scores between 7 and 13 years of age by birth cohort.(DOC)Click here for additional data file.


Observational epidemiological studies and a systematic review have consistently shown an association between maternal exposure to biomass smoke and reduced birth weight. Our aim was to further test this hypothesis.We analysed the data from 47,139 most recent singleton births during preceding five years of 2005-06 India Demographic Health Survey (DHS). Information about birth weight from child health card and/or mothers' recall) was analysed. Since birth weight was not recorded for nearly 60% of the reported births, maternal self-report of child's size at birth was used as a proxy. Fuel type was classified as high pollution fuels , and low pollution fuels , natural gas and biogas). Univariate and multivariable logistic regression models were developed using SURVEYLOGISTIC procedure in SAS system. We used three logistic regression models in which child factors, maternal factors and demographic factors were added step-by-step to the main exposure variable. Adjusted Odds Ratios (AORs) and their 95% CI were calculated. A p-value less than 0.05 was considered as significant.Child's birth weight was available for only 19,270 (41%) births; 3113 from health card and 16,157 from mothers' recall. For available data, mean birth weight was 2846.5 grams (SD = 684.6). Children born in households using high pollution fuels were 73 grams lighter than those born in households using low pollution fuels . Use of biomass fuels was associated with size at birth. Unadjusted OR was 1.41 . Adjusted OR after controlling for child factors was 1.41 . AOR after controlling for both child and maternal factors was 1.21 . In final model AOR was 1.07  after controlling for child, maternal and demographic factors. Gender, birth order, mother's BMI, haemoglobin level and education were significant in all three models.Use of biomass fuels is associated with child size at birth. Future studies should investigate this association using more direct methods for measurement of exposure to smoke emitted from biomass fuels and birth weight. Each year about four million neonatal deaths occur worldwide. Nearly 98% of these neonatal deaths occur in developing countries . GloballRecently, there has been a growing interest about health effects of exposure to biomass smoke ,13. IndoThough the epidemiological studies mentioned above varied in their designs, they have shown consistent results. A systematic review about the effect of indoor air pollution on LBW has also concluded that the association is consistent despite the limited evidence from epidemiological studies . We aimeWe conducted a secondary data analysis of the most recent DHS of India. India DHS 2005-06  was carried out under scientific and administrative supervision of International Institute for Population Sciences (IPPS), Mumbai and Macro International during the time period November 2005 to August 2006. The survey collected information about demographic factors, socio-economic factors and health status from a nationally representative probability sample of households. The sample size was 109,041 households selected by two-stage probability proportional to size (PPS) method in rural areas and three stage PPS sampling in urban areas. In both urban and rural areas, primary sampling units were blocks/wards or villages. From each of the chosen sampling units (i.e. village/s or block) random household sampling was done. Within each selected household, all women aged 15 to 49 years were eligible to be respondents for the survey. As primary sampling unit was household, a national household weighing factor was used to maximise representativeness of the sample.Data were collected according to a standard protocol. Three core survey questionnaires i.e. the Household Questionnaire, the Woman's Questionnaire and the Man's Questionnaire were translated into 18 local languages and field tested. Subsequently, filled questionnaires were back-translated to English. These questionnaires were used in all 29 states of India. Questionnaires used in each state were bilingual, with questions in both principal languages of the state and English. To minimize language barriers, the survey was administered by trained interviewers either in English or principal language of the state or preferred language of the household. Further details of sampling design, training of survey team, survey management and quality control measures are separately documented in the country reports published by ORC (Opinion Research Corp.) Macro International . From a The Independent Review Boards (IRB) of IPPS and ORC Macro international had independently reviewed the DHS protocols, data collection tools and procedures and provided ethical approval. Approval was also taken from the IRBs of Melaka-Manipal Medical College, Malaysia and School of Public health, University of Alabama at Birmingham. The interviewers informed the participants that participation in the survey was voluntary and assured them that information provided will be kept confidential. Following this an informed consent was obtained from each participant.The main outcome measure used was child's birth weight. For each birth during the preceding five years, mothers were asked about birth weight. Mothers were asked, "Was your baby weighed at birth?" If the response was 'yes', they were further questioned, "How much did your baby weigh?" If mother possessed a health card, she was asked to show it and birth weight was recorded. For those mothers who did not possess a health card, birth weight was recorded according to mother's recall. Mothers were also asked to classify 'size of the baby' at birth into of following five categories: 'very large', 'larger than average', 'average',' smaller than average', and 'very small'. We pooled these categories to form a binary variable as 'greater than or equal to average size' and 'less than average size' at birth corresponding to normal birth weight (≥2500 grams) and low birth weight (birth weight < 2500 grams) respectively. Births with missing information about size at birth and multiple births (6.7%) were excluded from our analysis. In a similar study based on Zimbabwe DHS, the authors have acknowledged about bias arising from a disproportionately high number of babies from households using biomass fuels being not weighed at birth as compared to the households using cleaner fuel . We obseThe standard DHS used eleven fold classification of cooking fuels used in the house. The specific question asked was, "What type of fuel does your household mainly use?" For our analysis, the main cooking fuel used was grouped into one of the two categories. These two categories were namely; high pollution fuels , and low pollution fuels .The DHS also collected information about smoking habits of the individuals in households, and tested haemoglobin level for women. Mothers were asked, "Do you currently smoke cigarettes?" The effect of exposure to biomass fuels on birth weight may be confounded by factors like tobacco smoking and nutritional status of mother. Therefore, we adjusted for body mass index (BMI) as an indicator for nutritional status of mothers  and haemWe did an exploratory analysis of birth weight of the child obtained from health card and mother's recall. We compared the mean birth weight between two fuel type categories i.e. high pollution and low pollution fuels using independent samples t-test. To test the concordance between birth weight of child  and size at birth we used Somer's D test. The outcome variable was size at birth dichotomized into normal birth weight and low birth weight. For bivariate analysis of categorical variables we used chi square test. We carried out the analyses using SAS software . In addition to type of fuel used, other (independent) variables considered were child factors , maternal factors  and socio-demographic factors . We tested for the possibility of collinearity between predictor variables. In a correlation matrix, BMI versus haemoglobin level and wealth index versus type of cooking fuel were paired and Pearson's correlation coefficients were calculated to rule out multicollinearity. Multilevel modelling was done to adjust for cluster sampling (cluster as primary sampling unit used in DHS). Three multivariable regression analysis models were built using SURVEYLOGISTIC procedure in SAS system (version 8.02) . During A total of 124, 385 women participants reported 56, 438 births during the previous five years. The final sample analysed was 47,139 most recent singleton births. The main types of fuel used by the households were as follows: electricity , liquid petroleum gas , biogas, kerosene , coal & lignite , charcoal , wood , straw/shrubs/grass , agricultural crop , and animal dung . Birth weight of the child was available for only 19,270 (41%) births. Of these, birth weights for 3113 children were available from child health card (18.4% were LBW) and for 16,157 children from mother's recall (20.5% were LBW). Overall mean birth weight was 2846.5 grams (SD = 684.6). The children born in households using high pollution fuels were 73 grams lighter than the children born in households using low pollution fuels . This difference was statistically significant (p < 0.001). The adjusted  mean difference was 39.9 grams (SD = 13.4).The distribution of birth weights of most recent births according to type of fuel used in the households, mothers' education, and type of residence is shown in Table We used the test of association (Somer's D) for concordance between birth weight of child  and size at birth table . Out of The results of univariate analysis for type of fuel and other control variables with low birth weight i.e. the effect of cooking fuel, tobacco smoke, biological factors and other variables on low birth weight are shown in table We checked for collinearity between BMI and maternal haemoglobin level and there was no correlation (r = 0.04). A strong collinearity was present (r = 0.664) between wealth index and type of cooking fuel. Table The results from our analysis suggest that use of biomass cooking fuels is associated with child's birth weight and size at birth. The children born in households using high pollution fuels had significantly lower birth weight than those children born in households using low pollution fuels. The association between use of high pollution fuels and size at birth was independent of child's gender, birth order, mother's education and nutritional status, even after adjustment. The association did not remain significant after adding socio-economic factors in the final model.The results of our analysis about the association between type of cooking fuel and LBW are consistent with previous reports from rural Guatemala, Pakistan, Zimbabwe and Southern India -22. The 10 have also shown that these pollutants are associated with decreased birth weight [The study from Guatemala used a non-representative sample with predominantly hospital deliveries . The stuh weight -30. The h weight . Studiesh weight , cross th weight .Like any other epidemiological study, our study has certain strengths and limitations. The strength of our analysis was using a large nationally representative sample. Additionally, using size at birth as proxy for birth weight gave us a bigger sample and increase in statistical power for our results. We examined the effect of maternal smoking, maternal BMI and haemoglobin levels on size at birth. However, our results should be interpreted with caution against the inherent limitations of cross-sectional design and secondary data analysis. The main limitations are lack of temporality of association due to cross-sectional design, and possible misclassification of both exposure and outcome assessment. Due to cross-sectional design of DHS, it was not possible to ascertain if exposure (type of fuel use) occurred prior to the outcome (size of baby at birth) or vice versa. Another main limitation was misclassification bias of both exposure and outcome. For the information about type of fuel used, we relied on one question in the DHS questionnaire. Information about multiple fuel use, temporal changes (time trend) in fuel use, duration of fuel used were not assessed leading to exposure misclassification. Type of fuel used during pregnancy may have been different from that being used at the time of survey. The main outcome i.e. birth weight was not available for majority of births. The use of size of baby at birth as proxy to birth weight has lead to misclassification bias. Mothers were generally very good at identifying non-LBW babies. Only about half of the babies whose birth weight was reported or recorded as below 2500 grams were correctly classified as less than average size at birth (i.e. LBW). This low sensitivity of outcome measure may have lead to attenuation of association (effect size) in our final multivariable analysis. The use of actual birth weight as recorded from child health card and/or mother's recall as outcome measure would have led to selection bias (a large proportion of babies were not weighed in high pollution fuels compared to low pollution fuels i.e. 71% versus. 26.1%). Similarly, women from more affluent households, with better education were likely to have recorded birth weight. Use of birth weight as recorded from child health card may also lead to misclassification bias. This is because birth weight recording in developing country like India is usually imprecise except for hospital births. In India, where are high proportion of births are taking place at home, weight is measured at a convenient time. We did not have information about some important determinants of birth weight from the DHS data i.e. foods consumed and physical activity, and exposure to second hand smoke during pregnancy. We could not examine the effect of these variables on size at birth in multivariable analysis.We could not assign the households using combination of fuels into a different category since we did not have such information from DHS data. We lacked information about duration of exposure, and stage of pregnancy when exposure had occurred. The women exposed to biomass smoke may have had higher rates of still birth  and miscDespite these limitations, the consistency of the association from various studies and systematic reviews  providesUse of biomass fuels is associated with child size at birth. Our results are consistent with previous observational studies in different developing country settings. Future studies should investigate this association using robust study designs which use more direct methods for measuring level of exposure to smoke emitted from burning biomass fuels and clinical parameters like birth weight and other pregnancy outcomes.The authors declare that they have no competing interests.CTS conceptualised the study, wrote the project proposal and write the first draft of manuscript. RRS assisted in conceptualisation, carried out data analysis, interpretation of results and commented on draft manuscript. NS assisted in conceptualisation, assisted in data analysis and commented on draft manuscript. All the authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/403/prepub