Infants born small for gestational age (SGA) or preterm have increased rates of perinatal morbidity and mortality. Stressful events have been suggested as potential contributors to preterm birth (PB) and low birth weight (LBW). We studied the effect of the 2008 economic collapse in Iceland on the risks of adverse birth outcomes.st 2006 to December 31st 2009. LBW infants were defined as those weighing <2500 grams at birth, PB infants as those born before 37 weeks of gestation and SGA as those with a birth weight for gestational age more than 2 standard deviations (SD's) below the mean according to the Swedish fetal growth curve. We used logistic regression analysis to estimate odds ratios [OR] and corresponding 95 percent confidence intervals [95% CI] of adverse birth outcomes by exposure to calendar time of the economic collapse, i.e. after October 6th 2008.The study population constituted all Icelandic women giving birth to live-born singletons from January 1Compared to the preceding period, we observed an increased adjusted odds in LBW-deliveries following the collapse , particularly among infants born to mothers younger than 25 years  and not working mothers . Similarly, we found a tendency towards higher incidence of SGA-births  particularly among children born to mothers younger than 25 years  and not working mothers . No change in risk of PB was observed. The increase of LBW was most distinct 6–9 months after the collapse.The results suggest an increase in risk of LBW shortly after the collapse of the Icelandic national economy. The increase in LBW seems to be driven by reduced fetal growth rate rather than shorter gestation. Infants born small for gestational age or preterm have increased risks of perinatal morbidity and mortality It is widely believed that a woman's emotional and psychological environment during the prenatal period can affect fetal development. Numerous studies have examined this hypothesis by obtaining associations between emotional and stressful life events during the prenatal period and adverse birth outcomes. However, results of these studies are inconsistent, with some studies reporting that adverse life events increase risks of poor pregnancy outcomes Whether economic conditions during the prenatal period have adverse effects on infant health has been less investigated. Deheeja and Llers-Muney reported a reduced incidence of adverse birth outcomes during periods of high unemployment th 2008 the Icelandic prime minister informed the nation of an unusually swift and severe economic collapse in a dramatic manner and the government took over its three largest banks. The largely unforeseen collapse of the Icelandic economy with its associated rapid rise in unemployment and increase in household debt represents a potentially powerful stressor that may have adversely affected birth outcomes. Using the nationwide Medical Birth Registry, we examined the effect of the 2008 economic collapse in Iceland on infant health, as measured by low birth weight, preterm birth and small-for-gestational age birth.On October 6st 2006 to December 31st 2009  were considered. We excluded women with multiple pregnancies (n = 298) and stillbirths (n = 47), leaving a total of 16,271 eligible women in the study.All Icelandic women registered in the National Icelandic Birth Registry from January 1st week of gestation. In 7 pregnancies, gestational age could be estimated on the basis of last menstrual period. It could not be determined for 8 cases. Small-for-gestational age (SGA), a proxy for intrauterine growth restriction, was defined as infants with birth weight more than 2 standard deviations (SD) below the mean for gestational age according to the sex-specific Swedish fetal growth curve Information on birth weight in grams and gestational length in days was obtained from the Birth Registry. Low birth weight (LBW) was defined as less than 2,500 grams at birth and preterm birth (PB) as a delivery before 37 completed gestational weeks (259 days of gestation). For 16,228 births (>99.9%), length of gestation was based on ultrasound measurement before the 21st 2006 to October 5th 2008, and post-crisis period (“exposed”), spanning from October 6th 2008 to December 31st 2009. The pre- and post-crisis groups will hereafter be referred to as the unexposed (reference group) and the exposed group, respectively.The study period was dichotomized with pre-crisis period (“unexposed”), spanning from January 1Information on covariates was obtained from the National Medical Birth Registry. Maternal characteristics obtained from the registry were: place of delivery; maternal age at delivery; parity ; relationship status (mother cohabitating with father or not); employment status (employed or not employed (student/housewife/unemployed/on disablement benefit)); residence . Maternal and infants' diseases were classified according to the International Classification of Diseases, tenth revision (ICD-10). Pregnancy-related diseases known to influence fetal growth included essential hypertension (ICD-10 code O10-O11), gestational hypertension and preeclampsia (ICD-10 codes O12-O15) and pre-gestational and gestational diabetes mellitus (ICD-10 codes O24.0-O24.2 and O24.4). Obstetric information obtained was: mode of delivery , infants' sex, Apgar score at 5 minutes, vaginal induction of delivery (ICD-10 code O83.8), congenital malformations and chromosomal abnormalities (ICD-codes Q00-99) and early neonatal death (defined as death of a live-born infant within 7 days from birth). In order to account for seasonal variation of birth weight, the years were divided into four seasons and births occurring in the same season were grouped together.We calculated descriptive statistics for all maternal and obstetric characteristics as well as for the outcome variables, contrasting frequencies before and after the economic collapse. Differences in characteristics by exposure groups were explored using the Chi-square test for categorical variables and independent sample t-test was used for maternal age. Linear regression analysis was used for the continuous outcome variables gestational length and birth weight, adjusting for maternal age, parity and seasonality. One-way ANOVA tests with post-hoc Tukey's test were conducted to assess the homogeneity of birth weight and gestational length between seasons.Logistic regression analyses were used to calculate adjusted odds ratios (aOR) and their 95% confidence intervals [CI's] for LBW, PB and SGA in the exposed period. In model I, adjustments were made for variables assessed as possible confounders: maternal age, parity and seasonality. In models II and III, we explored whether possible increased risks of adverse birth outcomes were mediated by other maternal factors or diseases during pregnancy all which, in fact, may have been influenced by the crisis. In model II, we therefore also adjusted for: hypertension and diabetes, and in model III we added relationship status, residence, employment status into the model. Analysis involving LBW and PB were also adjusted for infant's sex in models II and III. We used linear regression models to estimate changes in the fetal growth rate index across exposure categories. In order to explore further the risk of adverse birth outcomes among certain subgroups, we performed logistic regression analyses where we stratified for each of the following maternal characteristics: age, parity, relationship status, place of residence and employment status. The model used in the analyses was also adjusted for age (continuous), parity and seasonal variations (model I).To further explore whether associations between PB, SGA and LBW differed depending on, when in gestation the collapse hit, we divided the study period into intervals of three months and compared those giving birth in a particular intervals in 2008 and 2009 with those giving birth in the same time intervals in 2006 and 2007. Each time interval in 2008 and 2009 averaged 1,050 births. In the comparison groups, the corresponding time intervals in 2006 and 2007 averaged 1,974 births.In order to refine our exploration of potential crisis effects, we also used date of conception (instead of date of birth) to sort pregnancies according to exposure to the economic crisis. For example, women who conceived in the time period January – March 2008 (exposed to the crisis in the 3rd trimester) were grouped together and compared to women who became pregnant January – March 2005, 2006 and 2007 (unexposed) etc.Further, in an attempt to detect a possible time-trend in LBW, SGA and PB that might falsely lead to measured exposure effects, we used linear regression analysis to calculate the monthly trend of each birth outcome in the pre-crisis period. This model was adjusted for maternal age and parity.th 2008. Women, pregnant on October 6th 2006 and 2007, were considered unexposed. Similar analysis was carried out to examine the effect of the crisis on women who became pregnant during the post-crisis period and gave birth in the last 7 months of 2009. The reference group consisted of women who became pregnant after October 6th 2006 and gave birth the following year.Additional analysis was conducted to examine the effect of the shock on fetuses that were in utero on the day of the collapse. The exposed group consisted only of those women who were pregnant on October 6The study was approved by the Icelandic National Bioethics Committee (VSNb2010050014/03.7), the Data Protection Authority (2010050499LSL/–) and the Directorate of Health (2010050296/5.6.1/HBS/hbs).Among all 16,271 infants; 11,111 (68%) were in the unexposed group and 5,160 (32%) were in the exposed group. The infants born in the period of the economic crisis weighed, on average, 28 grams less than infants in the reference group . There wThe rates of infants born with low birth weight  before and after the collapse were 2.5% and 3.0%, respectively. β =  −0.004; p = 0.032). This decrease was particularly distinct for women giving birth in the time period April – June 2009 .Additional analysis was conducted to estimate the change in fetal growth rate index between pre- and post-crisis groups. Compared to the reference group, infants born in time of crisis, had a decreased fetal growth rate (st– October 5th 2008) and 5 intervals after the collapse (October 6th 2008– December 31st 2009), using identical calendar times from 2006 and 2007 (combined) as reference periods. The first three comparisons are thus between before collapse time periods and can be viewed partly as falsification tests, for which we do not expect to see statistically significant results. After the economic collapse, we observed a statistically significant increased odds of LBW  among women who were in their 1st trimester when the crisis began, giving birth in the time interval April – June 2009, which is 6–9 months after the beginning of the crisis , SGA  and PB  in the pre-crisis period.Finally, our linear regression analysis indicated no time-trends in LBW  births occur in hospitals or at local health clinics, resulting in accurate measurement of birth weight. The richness of information in the Medical Birth Registry allows us to control for most major confounding factors and our time trend analysis also indicates a somewhat stable rate of LBW before the economic collapse. Thus, we finally decided that changes occurring in most covariates  may actually be a consequence of the economic collapse and therefore in the causal chain between stress and LBW/SGA.This study leverages the National Medical Birth Registry to accomplish a population-based cohort study of all pregnant Icelandic women giving birth in Iceland in a four year time period. A multitude of information on the mother and child has been systematically collected to the registry since 1973, and this data collection is independent of exposure level, i.e. time of economic recession. Several measures were taken in order to further enhance the internal validity of this study. In order to make the cohort homogenous with regard to birth weight and length of gestation, we excluded all stillbirths and multiple gestations. Furthermore, our sample included only Icelandic women, as the literature indicates that risks of IUGR and PB may differ by ethnicity. Practically all pregnant women undertook ultrasound scanning around the 20A limitation of this study is the lack of information on maternal smoking, alcohol, and nutritional habits during pregnancy. Smoking during pregnancy is causally associated with risk of LBW and IUGR st trimester of pregnancy. The increase in LBW seemed to be driven by fetal growth restriction rather than by shortened gestation. The crisis appeared to have the largest effect on younger women (<25 years) and women who were not employed.The results of this study add important knowledge on how birth outcomes are affected when mothers are exposed to significant economic shocks such as the economic collapse that occurred practically overnight in Iceland. Our results suggest that the economic meltdown was an important stressor that increased the risk of LBW deliveries, especially for women in the 1These findings suggest that the effect of the crisis on LBW was short lived, as women who were exposed during later periods of their pregnancy or who completed the pregnancy in the post-crisis period were relatively unaffected. However, further studies with longer follow-up are needed for definite conclusion, particularly to observe whether the effect for young and vulnerable women is persistent. The findings have implications for public health practice and clinical management of pregnant women, particularly young women and women in a vulnerable situation on the labor market.Appendix S1Odds ratios and 95% CI for (a) low birth weight, (b) small-for-gestational age and (c) preterm birth infants, born to Icelandic women in time of economic collapse. Women are grouped together by their date of conception into 5 three-months intervals; each period is contrasted with the combined time-intervals from the previous years.(TIF)Click here for additional data file.Appendix S2a) Table 1– The effect of covariates on the odds ratio of low birth weight, small for gestational age and preterm birth among women who were pregnant on October 6th 2008 (n = 3130) compared with women who were pregnant on October 6th in the two previous years (n = 6083). b) Table 2– The effect of covariates on the odds ratio of low birth weight, small for gestational age and preterm birth among women who became pregnant after October 6th 2008 and gave birth in the last 6 months of 2009 (n = 2030) compared with women who became pregnant after October 6th 2006and gave birth in the last 6 months of 2007 (n = 1898).(DOCX)Click here for additional data file.


Background. The objective was to examine the association between prepregnancy physical exercise and offspring birth weight and to assess the combined association of pre-pregnancy body mass index (BMI) and physical exercise on birth weight. Methods. The study included 2,026 women aged 20–39 years participating in the Norwegian HUNT study and linked with the Medical Birth Registry. We calculated mean differences in birth weight and odds ratios (ORs) for a macrosomic infant  using linear and logistic regression analysis. Results. There was no clear association between leisure time physical exercise and mean birth weight. Women who reported no exercise had reduced risk of a macrosomic infant , 0.4–0.9) compared to women with a high exercise level. Overweight (BMI ≥ 25.0 kg/m2) was associated with an OR of 1.9  for a macrosomic infant among women who reported low exercise levels, whereas the OR was 1.2  among women with higher exercise levels. Conclusion. There was some evidence that women who reported no exercise before pregnancy had lower risk for a macrosomic infant than women who exercised. Pre-pregnancy BMI was positively associated with birth weight and risk of macrosomia but only among the least active women. The proportion of women giving birth to large infants has increased around the world , 2, mostPrevious studies have reported that physical activity in pregnancy is related to foetal growth rate and birth weight , 16, andIn this prospective study in Norway, we have utilized data on women participating in a population-based health study linked with information from the Medical Birth Registry to study the association between maternal pre-pregnancy physical exercise and offspring birth weight. Additionally, we explored the combined association of pre-pregnancy body mass index and physical exercise on birth weight.The Nord-Trøndelag health study (The HUNT study) is a large population-based health study conducted in the county of Nord-Trøndelag, Norway. The HUNT study is a collaboration between HUNT Research Centre , Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. It constitutes three consecutive cross-sectional waves; the first was conducted in 1984–1986 (HUNT 1), the second in 1995–1997 (HUNT 2), and the third in 2006–2008 (HUNT 3). For the purpose of the present study, we have used information from the first wave (HUNT 1). In HUNT 1, 87,285 persons aged ≥ 20 years were invited to participate, and 77,216 (88.5%) accepted the invitation, filled in questionnaires, and attended a clinical examination . A more detailed description of participation, method, and procedures of the HUNT study can be found elsewhere [ For the purpose of the current study, we first selected all 3,739 women aged 20–39 years at participation in HUNT 1 (1984–1986) who gave birth to at least one child during a five year period after participation. Of these 3,739 women, we excluded 232 women due to pre- (<37 weeks) or postterm (>44 weeks) delivery, 32 women with multiple births, 10 women with gestational diabetes, 118 women with preeclampsia, 831 women without information of physical activity, body mass index, or gestational age, and 490 women who gave birth within 10 months after participation . This left 2,026 women available for statistical analysis.Information on the offspring was obtained by a linkage to the Medical Birth Registry of Norway. These data were obtained for the first child born during five years after participation in HUNT. The main outcome variable was newborn birth weight, measured in grams (g), first analyzed as a continuous variable and then as a dichotomized variable using 4,000 g as cutoff. Macrosomia was defined as birth weight at or above 4,000 g .  Leisure time physical exercise was assessed using three questions. In the first question, the participants were asked to report how many exercise sessions  they usually had during a week, with five response options . If the participants reported exercising at least once a week, they were also asked to report the average duration  and intensity  of the activity. Among participants who reported exercising at least once a week, a summary score of frequency, duration, and intensity was calculated according to the following equation: 1/5  ∗  frequency + 1/4  ∗  duration + 1/3  ∗  intensity. This procedure intended to give equal weight to each component of physical activity and resulted in a maximum score of 1.0 for each of the three components of the summary score. The median score value of 1.97  was then used as a cut-off to classify women into two categories of score values (±median). This information was used to construct a variable of total physical exercise with four unique categories: (1) no activity, (2) low activity (<1 session per week), (3) medium activity , and (4) high activity  [2) and categorized into two groups: BMI < 25.0 kg/m2 and BMI ≥ 25.0 kg/m2  [ Body mass index (BMI) was computed from standardized measures as weight divided by the squared value of height (kg/mr obese) . We used linear regression to analyze the association between measures of leisure time physical exercise and mean birth weight. We also calculated odds ratios (OR) for having a macrosomic infant  in different categories of leisure time physical exercise using logistic regression. Precision of the estimated associations was assessed by a 95% confidence interval (CI). Women who reported the highest activity level were used as the reference category in all analysis. The following variables were considered as potential confounders in the analysis; age , smoking , frequency of alcohol consumption during the past 2 weeks , education , marital status , and parity . Covariates were removed from the model if there was no meaningful difference between adjusted and unadjusted estimates. All estimates were adjusted for maternal age, smoking, and parity. Tests for trend across categories of leisure time physical exercise were conducted by treating the categories as an ordinal variable in the regression model. 2) and exercise level (no or low activity versus medium or high activity) to assess possible interaction between the two variables and as well as stratified the analyses of physical exercise on the two BMI groups.Since maternal BMI could be both an effect modifier and on the causal pathway between exercise and birth weight, BMI was not included as a confounder in the primary analyses. However, additional analysis was conducted for the combined associations of prepregnancy BMI and total leisure time physical exercise in relation to birth weight, using linear and logistic regression as described earlier. We also included a product term of BMI  nor in relation to total amount of exercise . Correspondingly, results from logistic regression presented in 2) before pregnancy and reported no or low leisure time physical exercise gave birth to infants with significantly higher mean birth weight  and had a higher risk for a macrosomic infant , compared to women with BMI < 25.0 kg/m2 who had a medium or high exercise level. In additional analysis stratified by body mass index, overweight women (BMI ≥ 25.0 kg/m2) who reported no or low exercise levels had significantly higher offspring birth weight  and higher odds ratio for a macrosomic infant  than women who reported a medium or high exercise level (data not shown). However, there was no statistically significant interaction between BMI and total exercise level (P = 0.08). The combined association of pre-pregnancy BMI and leisure time physical exercise in relation to birth weight is shown in 2 gave birth to infants with significantly higher birth weight than women with a BMI < 25.0 kg/m2, but only if they also reported no or low levels of physical exercise. This could suggest that physical exercise to some extent reduces the effect of maternal adiposity on offspring birth weight.In this large prospective study of Norwegian women, we found no clear association between reported leisure time physical exercise level before pregnancy and offspring birth weight. There was some evidence that inactive women had a slightly lower likelihood of giving birth to a child with excessive birth weight than more physically active women, but the small numbers of inactive women call for a cautious interpretation. Analysis of the combined association of BMI and exercise on birth weight showed that women with a BMI ≥ 25.0 kg/m The suggestive evidence that women who were inactive before pregnancy had lower risk for delivering a macrosomic infant is contradictory to some previous studies. Voldner et al.  reportedUnlike the present study, some previous studies have shown inverse associations between maternal pre-pregnancy exercise behaviors and offspring birth weight or risk of having excess weight , 18, alt There is growing evidence that overweight or obesity before pregnancy is a risk factor for macrosomia , 35, 36. The strengths of the present study include the prospective design, the large sample size of women reporting physical activity before pregnancy, and the standardized measures of size at birth obtained from the Medical Birth Registry of Norway. However, some of the categories of physical exercise  suffered from small samples size, and this could result in chance findings. Moreover, as in any observational study, residual confounding due to unmeasured  or unknown factors cannot be ruled out. Since the information on physical activity was self-reported, it could be subject to misclassification, although a validation study has shown acceptable agreement with objective measures . AlthougThere was no clear association between maternal prepregnancy leisure time physical exercise and offspring birth weight. However, the result may indicate that inactive women gave birth to infants with lower birth weight and had lower risk for delivering an infant with macrosomia. The results also show that high maternal pre-pregnancy BMI was associated with higher mean birth weight and increased risk of macrosomia in offspring of physically inactive women, whereas pre-pregnancy BMI was not associated with birth weight and risk of macrosomia among more active women.


Overweight is among the major challenging health risk factors. It has been claimed that birth weight, being a critical indicator of prenatal developmental conditions, is related to long-term overweight risk. In order to check this important assumption of developmental and preventive medicine, we performed a systematic review and comprehensive meta-analysis.p<0.001). Low birth weight  was found to be followed by a decreased risk of overweight (odds ratio (OR) = 0.67; 95% confidence interval (CI) 0.59–0.76). High birth weight  was associated with increased risk of overweight . Results did not change significantly by using normal birth weight  as reference category . Subgroup- and influence-analyses revealed no indication for bias/confounding. Adjusted estimates indicate a doubling of long-term overweight risk in high as compared to normal birth weight subjects .Relevant studies published up to January 2011 that investigated the relation between birth weight and later risk of overweight were identified through literature searches using MEDLINE and EMBASE. For meta-analysis, 66 studies from 26 countries and five continents were identified to be eligible, including 643,902 persons aged 1 to 75 years. We constructed random-effects and fixed-effects models, performed subgroup-analyses, influence-analyses, assessed heterogeneity and publication bias, performed meta-regression analysis as well as analysis of confounder adjusted data. Meta-regression revealed a linear positive relationship between birth weight and later overweight risk (in-utero overnutrition, e.g., by avoiding maternal overnutrition, overweight and/or diabetes during pregnancy, might therefore be a promising strategy of genuine overweight prevention, globally.Findings demonstrate that low birth weight is followed by a decreased long-term risk of overweight, while high birth weight predisposes for later overweight. Preventing  All studies which reported the proportion of overweight or obese subjects in at least one age at follow up were included. We did not restrict to a particular definition of overweight/obesity as studies may have been published before currently accepted definitions were introduced To be eligible for meta-analysis, a study had to fulfill the following criteria, defined From all eligible studies, data were abstracted in duplicate, using a standardized form. An independent reviewer confirmed all data entries.vs. below the respective cutoff value across all studies.We extracted data on numbers of subjects with and without overweight above or below the cutoff value and calculated corresponding crude odds ratios and 95% confidence intervals. We constructed fixed-effects as well as random-effects models to estimate the pooled odds ratios for risk of overweight above 2 according to Higgins et al 2 is a direct measure of inconsistency of study results in a meta-analysis, with 0% indicating no inconsistency.By calculating the IRobustness of the pooled estimates was checked by influence analyses. Each of the studies was individually omitted from the data set, followed in each case by recalculation of the pooled estimate of the remaining studies.2). To assess the impact of parental socioeconomic status (SES), we stratified by the extent by which low SES was present in the study samples.To identify potential sources of heterogeneity and sources of bias, studies were stratified by study design and source of birth weight data to assess potential recall bias. Additionally, studies were stratified by publication language. To examine participation/selection bias, we stratified by extent of lost to follow-up. Further stratifications were made by geographic origin, age, overweight classification criterion, source of overweight data, gender distribution, gestational age and parental overweight  as real-valued vector of fractional power from a predefined set To explore the shape of the continuous relation between birth weight and later overweight risk, meta-regression technique was applied vs. >2,500 g and >4,000 g vs. <4,000 g, respectively. To make pooled adjusted and unadjusted odds ratios more comparable, we therefore additionally calculated in all studies which provided adjusted data an unadjusted odds ratio that considered the reference category as used self-chosen by the authors for the adjusted odds ratios in the respective studies .An ethics statement was not required for this work.Course of the systematic review is illustrated in a flow diagram according to the PRISMA statement . From a In the systematic review, 94 of the 108 studies (87%) reported a positive relation between birth weight and later risk of overweight. In 7 studies (6.5%), no relation between birth weight and later risk of overweight was observed, while in 6 studies (5.6%) a U-shaped relation was found. Only one study (0.9%) reported an inverse relation between birth weight and later overweight risk.e.g., distribution of geographic origin, age at follow up, assessment of overweight etc. Moreover, the observed relations between birth weight and later outcome did generally not differ from those observed in studies which could be included in the meta-analysis. Of the 42 excluded studies, 35 (83.4%) reported a positive relation between birth weight and later risk of overweight. In 3 studies (7.1%), no relation between birth weight and risk of later overweight was observed. A U-shaped relation was reported in 3 studies (7.1%) and only one study (2.4%) reported an inverse relation between birth weight and later overweight risk. These percentages were very similar to those observed in the studies which could be included into meta-analysis (see below).For methodological reasons, 42 studies could not be included in the meta-analysis. Reasons for exclusion were firstly, data were insufficiently reported for quantitative analysis (n = 20). Secondly, birth weight was reported as z-score or centiles without units (n = 9) and thirdly, birth weight was dichotomized at unjustified cut points (n = 13) see . HoweverFor meta-analysis, 66 studies were identified to be eligible, including 58 cohort studies and eight studies with case-control-design Of the 66 studies eligible for meta-analysis 59 studies (89.4%) reported a positive relation between birth weight and later risk of overweight. In 4 studies (6.1%), no relation between birth weight and later risk of overweight was observed, whereas in 3 studies (4.5%) a U-shaped relation was detected. None of the studies reported an inverse relation between birth weight and later overweight risk.Low birth weight  was found to be associated with a decreased risk of overweight in the random-effects model  as well as in the fixed-effects model  was associated with increased risk of overweight in the random-effects model  as well as in the fixed-effects model  as reference category for all studies that gave data on both ends of the birth weight spectrum. The pooled estimate for low birth weight was 0.73 (95% CI: 0.63–0.84) and those for high birth weight was 1.60 .Influence analysis showed that the pooled estimates were robust. Omission of individual studies revealed that no single study had a particular influence on the pooled estimates, detected by pooled odds ratios ranging from 0.65 (95% CI: 0.57–0.73) to 0.68 (95% CI: 0.60–0.77) for low birth weight, and 1.64 (95% CI: 1.54–1.75) to 1.68 (95% CI: 1.58–1.78) for high birth weight.22 = 93%) and high birth weight (I2 = 81%). To identify possible sources of heterogeneity and bias, we performed sensitivity/subgroup analyses  and Egger's tests .Neither for the relation between low birth weight and risk of overweight nor for that between high birth weight and later overweight risk evidence for publication bias was found, as indicated by visual inspection of funnel plots, proven by nonsignificant Begg's tests (low birth weight: −3 (0.28−0.40×10−3); p<0.001). To further explore the shape of the association, fractional polynomial regression was used. 1 = 14.13 (9.27–19.00); b2 = −20.34 (−26.58−(−14.09)); p1 = −1; p2 = −0.5; p<0.001; inverse variance weighted). Over nearly the entire birth weight spectrum, birth weight was found to be linearly positively related to overweight risk. Risk does not further decrease below a birth weight of 1,500 g. Comparison of model fitness parameters showed that a linear regression model performed as good as the fractional polynomial model (p = 0.17 for comparison of deviance between both models).In a first step, we fitted a linear meta-regression model to the data, which revealed a significant positive linear relation between birth weight and subsequent overweight risk (b = 0.34×101 = 16.59 (9.55–23.64); b2 = −24.11 (−33.06 (−15.16)); p1 = −1; p2 = −0.5; p<0.001; inverse variance weighted).Whereas only one study gave an adjusted estimate for low birth weight, in 16 studies confounder-adjusted estimates for risk of overweight after high birth weight were reported. Number and types of adjustments varied across the studies . The pooOver several years, increasing attention is given on early developmental origins of long-term diabetic, adipogenic, and cardiovascular disorders in terms of the metabolic syndrome i.e., including western, westernized as well as developing countries in Northern- and South America, Europe, Asia and Australia. Our analysis shows with high consistency that an increased birth weight  may lead to a doubling of the long-term overweight risk, irrespective of geographic/ethnic origin, sex, socio-economic status, parental weight status etc.The data set and meta-analysis provided here is by far the largest one analyzed to date on this topic and the first to address the whole lifespan, provide confounder-adjusted estimates and incorporate global data i.e., one of the most critical cardiometabolic risk determinants In the context of the ‘small baby syndrome’ and the respective ‘fetal origins’ hypotheses General concerns on our data and their interpretation might arise regarding the suitability of investigated parameters and/or the consideration of bias and/or confounding variables. For instance, it has increasingly been proposed that the effect of low birth weight on later health risks might rather result from increased (‘rapid’) neonatal weight gain/catch up growth e.g., geographic origin/ethnicity, gestational age, age at follow-up, parental weight etc.) were not considered and confounder adjusted estimates were not provided. Nevertheless, the observed trend in the relation under investigation was similar to those ascertained and described in our study. This appears to underline the global impact and reproducibility of the observed relationship and indicates that it is even relevant for Asian populations, characterized by a high frequency of relatively ‘low birth weight’ subjects but, simultaneously, continuous increase of ‘diabesity’ prevalence Recently, Yu et al. i.e., in adulthood , especially the materno-fetal food supply Birth weight is essentially determined by the e.g., type 2 diabetes, hypertension, childhood primary brain tumors and breast cancer Accordingly, prenatal life appears to be a ‘critical period’ in-utero overnutrition, especially by avoiding and/or adequately managing maternal overweight, overnutrition, increased weight gain and/or diabetes during pregnancy, appears to be a promising strategy to lower overweight risk for the long term, globally.Taken together, increased birth weight is reproducibly and independently linked to increased overweight risk later on, suggesting prenatal overfeeding as important risk factor which ‘programms’ a long-term obesity predisposition. In conclusion, avoiding Checklist S1PRISMA checklist.(DOC)Click here for additional data file.Protocol S1Study protocol for systematic review and meta-analysis to determine the relation between birth weight and long-term overweight risk.(DOC)Click here for additional data file.Table S1Characteristics of 108 studies included in the systematic review of birth weight and subsequent risk of overweight, 1966–January 2011.(DOC)Click here for additional data file.Table S2Studies that adjusted for confounders in the meta-analysis on birth weight and subsequent risk of overweight, 1966-January 2011.(DOC)Click here for additional data file.Table S3Studies that reported data on neonatal weight gain or infant growth in the meta-analysis on birth weight and subsequent risk of overweight, 1966-January 2011.(DOC)Click here for additional data file.


Antenatal care is defined as the care given to mothers and their fetus during pregnancy. There are many aspects of antenatal care that need to be emphasized to ensure good delivery outcome. One important outcome is low birth weight which has been defined by the World Health Organization (WHO) as weight at birth of less than 2.500 grams  irrespective of gestational age. This paper aims to show the association between antenatal care and birth weight.A cross-sectional study involving 225 newborns recruited randomly from four General Hospitals in different areas of Baghdad were carried out in 2009. Mothers of these infants were interviewed within 24 hours after delivery. Severely ill mothers, preterm deliveries and congenital malformation babies were excluded from the study.The percentage of low birth weight babies was 21.3%. The minimum number of antenatal care visit was one, while the maximum number of antenatal care visits was 9; the mean was 3.95 ± 1.70. The percentage of mothers who attended and registered their first antenatal care during first trimester was 73.8%, as compared to 26% who registered their first visit after first trimester. There was no significant relationship between number of antenatal care visit and low birth weight babies (p = 0.89). However, time of booking and place of first antenatal visit were significantly associated  with low birth weight.Antenatal care of the pregnant mothers is one of the important risk factors contributing to low birth weight babies. Even though the average number of antenatal visits was satisfactory, early booking at a health centre need to be properly advocated to mothers to avoid poor birth outcome such as low birth weight.


The Australian Private Health Insurance Incentive (PHII) policy reforms implemented in 1997–2000 increased PHI membership in Australia by 50%. Given the higher rate of obstetric interventions in privately insured patients, the reforms may have led to an increase in surgical deliveries and deliveries with longer hospital stays. We aimed to investigate the effect of the PHII policy introduction on birth characteristics in Western Australia (WA).All 230,276 birth admissions from January 1995 to March 2004 were identified from administrative birth and hospital data-systems held by the WA Department of Health. Average quarterly birth rates after the PHII introduction were estimated and compared with expected rates had the reforms not occurred. Rate and percentage differences  were estimated separately for public and private patients, by mode of delivery, and by length of stay in hospital following birth. The PHII policy introduction was associated with a 20% (−21.4 to −19.3) decrease in public birth rates, a 51% (45.1 to 56.4) increase in private birth rates, a 5% (−5.3 to −5.1) and 8% (−8.9 to −7.9) decrease in unassisted and assisted vaginal deliveries respectively, a 5% (−5.3 to −5.1) increase in caesarean sections with labour and 10% (8.0 to 11.7) increase in caesarean sections without labour. Similarly, birth rates where the infant stayed 0–3 days in hospital following birth decreased by 20% (−21.5 to −18.5), but rates of births with >3 days in hospital increased by 15% (12.2 to 17.1).Following the PHII policy implementation in Australia, births in privately insured patients, caesarean deliveries and births with longer infant hospital stays increased. The reforms may not have been beneficial for quality obstetric care in Australia or the burden of Australian hospitals. The Australian health care system has features of British and American systems; residents can access free treatment in public hospitals covered by national health insurance (public patients), or choose to be treated as private patients at either private or public hospitals at their own expense or at a subsidised cost through Private Health Insurance (PHI) Considering that the PHII policy reforms were particularly targeted at younger people Our objective was therefore to estimate average quarterly birth rates in Western Australia (WA) after the introduction of the PHIIs and compare it with rates that would have been expected had the policy not occurred. We calculated rate and percentage differences separately for public and private patients, by mode of delivery, and according to length of stay in hospital following birth.The use of de-identified, administrative health data for this study without patient consent was approved by the Human Research Ethics Committee of the WA Department of Health. This study was performed in accordance with the Declaration of Helsinki.This study used routinely-collected, administrative health data from the WA Midwives Notification System (MNS) and the WA Hospital Morbidity Data Collection (HMDC), linked by the Data Linkage Branch at the WA Department of Health. The MNS data provided pregnancy and delivery details for all infants born in WA during 1995–2004 and the HMDC data provided hospital separation information for each birth that occurred in WA hospitals during 1995–2004.Information from the MNS provided the basis for selection of the study cohort. The MNS is a statutory data collection which records information on all live or stillborn infants in WA of at least 20 weeks gestation or with a birth weight of at least 400 g. Multiple births (e.g. twins) were counted as one birth admission for this study, with the information on length of hospital stay for the first born infant being used. Also, births to both live-born and stillborn infants were included. Length of stay was categorized into 0–3 days and 4+ days following birth since most mothers and babies stay less than 4 days in hospital following an uncomplicated vaginal birth. The data did not have information on maternity services in WA and we were thus unable to assess the effect of the PHII reforms on access to services.In addition to pregnancy and delivery details, the MNS provided information on the Index of Relative Socio-Economic (SE) Disadvantage (IRSD) based on maternal residence around the time of birth. The IRSD values are based on information on household income, educational attainment and occupation from the Australian census conducted every five years. The values were divided into quintiles for all analyses, with high scores reflecting low SE disadvantage in an area.The information from the MNS on infant delivery details was linked with mothers’ hospital admission information from the HMDC to provide information on the funding source of the mother at the time of each hospital birth. Patient funding source was categorized to reflect two types of patients; those treated as public patients and those treated as private patients at time of delivery. Private patients were defined as those funded with PHI or who were self-funded, whereas public patients included those insured under the Australian national Medicare scheme.We used logistic regression models to assess the difference in characteristics before and after the introduction of the PHII policy reforms and simple Chi square tests of independence for assessing the distribution of maternal age according to patient status, mode of delivery and length of hospital stay. The birth data was then analysed through interrupted time-series analyses using quarterly birth rates as main outcomes. Birth rates were estimated from the quarterly birth counts in our data (numerators) and the annual population figures for 12–50 year old females in WA (denominators) based on 5-yearly census data published by the Australian Bureau of Statistics (ABS) Segmented regression analyses assuming the outcome rates followed Poisson distributions were used to measure the impact of the LHC We used the segmented regression models to estimate the post-PHII average quarterly rates and compared them with the expected rates, calculated from the model as the projection of pre-PHII trends under the assumption that no intervention occurred We included 230,276 birth admissions in this study that occurred from January 1995 to March 2004 in WA. In Given that private patients are generally older and that caesarean sections without labour and longer hospitals stays are more common on older mothers , we addiOur results show the association between the introduction of the Australian PHII policy reforms and changes in birth rates in WA during 1995–2004. Following the introduction of the PHIIs, birth rates in public patients decreased while birth rates in private patients increased, possibly as a result of a shift from public to private care. Our results also showed that vaginal deliveries decreased, caesarean deliveries increased and rates where the infant stayed longer than three days in hospital increased in the period following the PHII implementation. These associations did not appear to be due to increased birth rates in older mothers.This study draws on the wealth of birth and hospital inpatient information routinely collected by the WA Department of Health. The MNS and HMDC are both statutory data collections and for the time period under study, we were able to study almost the complete birth information in WA since we received de-identified data from the WA Department of Health for 99.998% of all births recorded in the MNS for the entire state of WA. Despite the obvious strengths of using population based data such as this, we cannot be absolutely certain that our findings were caused by the PHII policy reforms. However, the increase in PHI uptake following the introduction of the government’s tax-incentives in 1997–2000 has been attributed primarily to the introduction of the LHC alone Our results indicated that following the PHII introduction, more women gave birth as private patients and more caesarean sections, particularly caesarean sections without labour, were performed, possibly as a result of this shift from public to private obstetric care. Our findings support previous research showing that privately insured women are more likely to have obstetric interventions than women treated in the public health system In Australia, caesarean section rates rose from 18% in 1991 Previous studies have found that length of hospital stay following childbirth is generally shorter in public hospitals than private hospitals in Australia In conclusion, this study assessed the impact of the PHII policy initiatives in 1997–2000 on birth rates in WA during 1995–2004. The results of our study reflect a shift away from public care (with greater midwifery input) towards obstetrician-led modes of care. The shift resulted in an increased rate of caesarean sections, particularly caesarean sections without labour, and in increased rate of births with longer hospital stays. The results indicate that the PHII implementation may not have been beneficial for obstetric care in Australia or the burden of Australian hospitals. Our findings are important for health care planning and policy, not only in Australia, but also in other countries where both public and private health insurance is available. The results illustrate the unforeseen and sometimes serious consequences that can occur following health care policy implementation in any country aiming to increase private health insurance membership. The lessons learnt in Australia can guide health care policy makers elsewhere in the world.


Many epidemiological studies have linked small size at birth to adverse adult health outcomes but the relative influence of environmental exposures is less well established.The authors investigated the impact of prenatal environmental exposure by comparing 2750 participants born before (1925–1929) and during (1930–1934) the Great Depression in Reykjavik, Iceland. Calendar year served as proxy for environmental effects. Anthropometric measurements at birth and school-age (8–13 years) were collected from national registries. Participants were medically examined as adults (33–65 years).2, 95% CI: 0.2, 1.1), higher fasting blood glucose levels  and greater odds of being obese 1.43  compared to unexposed counterparts. Non-significant associations were observed in men.Mean birth weight, adjusted for maternal age and parity, decreased by 97 g : 39, 156) for men and 70 g  for women from 1925 to 1934; growth at school-age was significantly reduced for participants growing during the Depression. As adults, women prenatally exposed to the Depression had higher body mass index (Δ0.6 kg/mReduction in birth weight due to rapid shifts in the economic environment appears to have a modest but significant association with later obesity for women while male offspring appear to be less affected by these conditions. There is strong evidence suggesting risk of some metabolic disorders is set early in life and that these risks can be further heightened by factors in the external environment The association between low birth weight and adverse adult health outcomes has been observed in well-nourished as well as famine exposed populations The environment that humans live in can change swiftly and birth weight provides a snapshot of the intrauterine environment. Stressful events have been linked to adverse birth outcomes, particularly low birth weight. In the 1920s Iceland's economy was expanding until the onset of the Depression which affected the country drastically due to heavy reliance on exports The rapid occurrence of the Depression in Iceland makes this time period relevant for investigating sudden environmental shifts and their impact on birth size under non-famine like conditions. The aim of this study was to identify the association between size at birth and later health prior to and after the onset of the Great Depression in a cohort of 2750 Icelanders born between 1925 and 1934. We hypothesized that those exposed to the Depression in utero would be of lower birth weight and have greater risk of disorders associated with smaller size at birth, specifically obesity and cardiometabolic risk factors.The study protocol was granted approval by the Icelandic National Bioethics Committee and the Data Protection Commission and written informed consent was obtained from all study participants.The source population for this study consists of 4601 subjects, aged 33–65 years, who were born in Reykjavik 1914–1935 and resided there when recruited into the longitudinal Reykjavik Study at the Icelandic Heart Association from 1967–1991. Methods regarding data collection have previously been described To evaluate the impact of the Great Depression which began affecting Iceland in 1930, five year periods were combined (1925–1929 and 1930–1934) prior to and after the onset of the Depression as a proxy for environmental exposure. These two birth year groups, totaling 2750 participants or 60% of the source population, covers a span of ten years allowing the analysis of the immediate consequences of the Great Depression; subjects born greater than ten years apart will reflect other factors such as economic recovery, public health initiatives, medical advances as opposed to the specific influence of the Depression.3×100. Yearly growth measures from ages 8 to 13 years including weight, height, and date of measurement were recorded by a school nurse and gathered from school health records.Information on infant sex, birth weight to the nearest 50 grams (g), and birth length from crown to heel in centimeters (cm) was gathered from midwives' birth records in the National Archives of Iceland. Mean birth weight in Iceland is one of the highest in the world Data on childhood growth was available for a total of 1500 individuals, representing 55% of participants in the current study. Despite this attrition, previous analysis has shown that anthropometric measures at birth and adult age do not differ markedly between subjects with and without growth data 2. Fasting blood glucose, serum triglycerides, and total cholesterol were measured after an overnight fast The longitudinal Reykjavik Study collected information on health and anthropometric measures at adult age. Body weight was measured to the nearest 100 g without shoes and height was measured with accuracy of ±0.5 cm. Subcutaneous skinfolds were measured with calibrated calipers to the nearest 1.0 mm The mean and standard error of the mean for birth weight and ponderal index were calculated separately by sex and yearly from 1925 to 1934. The mean and standard deviation (SD) or percentages were used to describe the cohort.Linear regression analysis was performed for each outcome variable with birth year exposure to the Depression being a predictor and separately by sex. Maternal age and parity were included in all linear regression models as independent covariates. Participant age at examination was also included as a covariate when analyzing outcome variables collected in adulthood.P<0.05, 2 sided.Logistic regression was used to estimate odds ratio (OR) of obesity, impaired fasting glucose, and dyslipidemia with the same covariates used in the linear regression models. Outcomes were adjusted for sex (when appropriate) however, women and men were also analyzed separately. Analyses included in the tables were not adjusted for participant's current or previous smoking habits as it post-dates birth year, however, data on percentage of current and previous smokers was obtained and is reported for descriptive purposes. Further modeling was performed to test for a recruitment effect by narrowing of study recruitment years and age range of participants, as well as addition of smoking variables although this data is not presented. All statistical analyses were carried out using SPSS 20.0 . Significance was defined as 3 for both sexes.3, a cut-off used for describing thinness in infants Lower birth weight (<3.0 kg) was more common in infants with birth year exposure to the Depression compared to unexposed participants , Panel A2, 95% CI 0.2, 1.1) and fasting blood glucose  compared to women born pre-Depression. Triceps and subscapular skinfold measures were also significantly higher among Depression-born women. Men born during the Depression had greater subscapular skinfold measures, yet, differences in BMI among men were negligible. Total cholesterol levels were slightly decreased among Depression-born men and women while triglycerides levels were slightly higher.Childhood growth characteristics , Panel Bth percentile while the BMI of Depression-born children was closer to the 50th percentile. Growth differences based on birth year exposure were more pronounced among girls from ages 9 to 13 than among boys.Mean BMI from ages 8 to 13 stratified by birth year exposure to the Depression are shown in In In order to further examine whether participant age influenced outcomes due to a recruitment effect we narrowed the age range of participants from 33–65 years to 45–55 years as well as recruitment year from 1967–1991 to 1974–1983. Adjusted combined OR for obesity remained significant 1.59 , with a stronger association among women 2.16  while the combined odds ratios for impaired fasting glucose and dyslipidemia remained non-significant (data not shown).In this Icelandic cohort we investigated the impact of the Great Depression on size at birth and adult obesity, impaired fasting glucose, and dyslipidemia in 2750 Icelanders living in Reykjavik. We found that infants with birth year exposure to the Depression were of lower birth weight. In adulthood, Depression-born females had a higher mean BMI and greater odds of being obese but this effect was not observed in males.With regards to size at birth, there was a significant decline in birth weight and ponderal index from 1925 to 1934 indicative of infants being born thinner as the economic impact of Depression progressed. Although birth weight still remained relatively high, the decreasing ponderal index is suggestive of increasing fetal undernutrition along with economic and environmental influences as there is a distinct and consistent drop after the initial onset of the Depression in Iceland in 1930.The 1920s and 1930s in Iceland were characterized by increased migration into Reykjavik and changes in birth weight may also be a consequence of overcrowding which can negatively affect birth size In addition to birth size, studies have suggested accelerated postnatal growth in thin infants may contribute to later disease It should be noted that the environment during which these participants were growing was quite different. Children born between 1925 and 1929 were growing-up during the Depression where access to food was more difficult and costly In adulthood, we observed higher fasting glucose levels and increased obesity only among women with birth year exposure to the Depression. We observed virtually no difference in BMI or odds of obesity among men. There is evidence that increasing glucose intolerance and obesity can coincide with transition to an environment of better nutrition We did not find the odds of impaired fasting glucose or dyslipidemia for either sex to be linked to birth year exposure to the Depression. The relatively high birth weight in Icelandic infants has been proposed to have a protective effect with respect to diseases  related to small size at birth While the findings of greater cardiometabolic risk factors primarily among women corroborate those from other epidemiological cohorts Although the participants were recruited at various ages (33–65 years), our findings do not appear to be influenced by a recruitment effect. In addition, Vilbergsson et al This cohort represents a population that was undergoing both economic and environmental changes during development in utero and early childhood In this current paper, we have presented that birth year exposure to the Great Depression was associated with offspring who were lighter at birth and Depression-born women had a greater likelihood of being obese in adulthood. With the increasing frequency of obesity-related diseases, the ability to identify environmental triggers that may negatively impact birth size in offspring and continue to affect weight status in later life is becoming critical. Pregnancy during periods of economic downfalls may inadvertently stress the fetus initiating a pathway favoring obesity development. Our findings contribute to the existing literature on environmental influences on size at birth and disease in middle-aged adults and emphasize the importance of accounting for both prenatal and postnatal environmental influences when exploring these associations.


The long term consequences of low birth weight (LBW), preterm birth, small-for-gestational age , and early newborn morbidity on functional outcomes are not well described in low income settings.In rural Nepal, we conducted neurocognitive assessment of children (n = 1927) at 7–9 y of age, for whom birth condition exposures were available. At follow-up they were tested on aspects of intellectual, executive, and motor function.The prevalence of LBW (39.6%), preterm birth (21.2%), and SGA (55.4%) was high, whereas symptoms of birth asphyxia and sepsis were reported in 6.7% and 9.1% of children. In multivariable regression analyses, adjusted for confounders, LBW was strongly associated with scores on the Universal Nonverbal Intelligence Test (UNIT), tests of executive function, and the Movement Assessment Battery for Children (MABC). Preterm was not associated with any of the test scores. Conversely, SGA was significantly  associated with lower UNIT scores (−2.04 SE = 0.39); higher proportion failure on Stroop test ; and lower scores on the backward digit span test , MABC , and finger tapping test  after adjusting for confounders. Head circumference at birth was strongly and significantly associated with all test scores. Neither birth asphyxia nor sepsis symptoms were significantly associated with scores on cognitive or motor tests.In this rural South Asian setting, intrauterine growth restriction is high and, may have a negative impact on long term cognitive, executive and motor function. Neonatal conditions including intrauterine growth and gestational age at birth are strongly linked with neonatal and infant mortality. Worldwide there is a strong focus on reducing neonatal mortality through early life interventions to achieve the Millennium Development Goals in 2015 . Using tIn rural Nepal in 2007–2009 we conducted a longitudinal follow-up of children to examine prenatal and postnatal supplementation with micronutrients on school age neurocognitive function -10. In tThe population-based studies described below were all conducted as part of the Nepal Nutrition Intervention Project - Sarlahi (NNIPS) in rural southern plains (sea level) of Nepal where 90% of births occurred at home and only 2-3% assisted by skilled birth attendants. Children born to women who participated in a double-blind randomized controlled trial (RCT) of micronutrient supplementation during pregnancy (1999–2001)  and who Details of the follow-up assessments and long term effects of prenatal and postnatal micronutrient supplementation have been published previously ,9. By deA battery of psychometric tests was administered in a central clinic by trained and certified psychological testers. General intelligence was assessed with the Universal Nonverbal Intelligence Test (UNIT) . A  defined as birth weight less than the 10th percentile for a given gestational age and sex using the Alexander US-fetal growth reference . Sepsis T scores, and the Stroop test was expressed as a proportion of failures (i.e. those who failed the practice test). The MABC test is scored based on failures and thus higher scores reflect worse instead of better performance. Raw scores on each task were converted to scaled scores. For the backward digit span, the longest number of digits remembered correctly was used.Bivariate analyses were done to examine the relationship between exposures and outcomes across each of the psychometric tests. Similarly, household, environmental and maternal factors were examined for their association with the outcomes to identify potential confounders. A simple socioeconomic index was created by summing up household asset ownership which ranged from 0–11. Child age, sex, asset score, HOME score, child schooling, previous 7-d intake of different food groups, and history of diarrhea/dysentery, lower respiratory infection, maternal literacy, Raven's score, and household salt iodine ≥15 ppm were examined as potential confounders due to their association with the outcomes. The raw UNIT test scores were converted to Multivariable linear regression models were run to adjust for confounders using a backward stepwise selection procedure with a significance level for removal from the model of 0.1. All exposure variables were locked into the models. Once the significant variables were identified we then applied the generalized estimating equations approach to the multivariable linear regression models to adjust for geographic clustering. The final models only retained those confounders that were significant at p < 0.05. Stata version 11.0  and SAS version 9.2  were used to analyze data.Ethical approval for the study was provided by the institutional review boards at the Institute of Medicine, Tribhuvan University in Nepal and Johns Hopkins School of Public Health and The Pennsylvania State University in the US.T score on the UNIT of 0.44 and an improved performance on the tests of executive function . Preterm birth, sepsis and birth asphyxia were not significantly associated with any of the test scores. In the adjusted analysis SGA and LBW were associated with a higher (worse) score on the MABC of 0.98 and l.29 (p < 0.001) , families having moved out of study area or not met upon repeated visits (n = 75), and child death (n = 3). The prevalence of low birth weight, preterm birth and SGA in this sample of children was 39.6%, 21.2%, and 55.4%, respectively . We found that SGA was strongly associated with negative consequences for outcomes of general intelligence and executive and motor function in this environment. Preterm birth which also contributes to LBW was not associated with cognitive and functional impairments. Neither symptoms of sepsis nor birth asphyxia were linked to the outcomes except in the case of motor scores, which were modestly although significantly worse among children who had experienced symptoms of birth asphyxia.Preterm birth is the second largest direct cause of under 5 child mortality and it is estimated that 14.9 million babies were born preterm worldwide in 2010 . In a reHypoxic ischemic encephalopathy and sepsis have previously been each associated with a 30% higher cognitive or learning difficulties or developmental delay . In our Small-for-gestational age at birth is not a perfect measure of intrauterine growth restriction (IUGR). However, our findings are similar to a recent study in which true IUGR was assessed using abnormal umbilical artery blood flow using Doppler velocimetry . This stStrengths of the study include a large sample size, assessment of a range of tests of functional outcomes, and high follow-up rates. We also adjusted for a large number of potential confounders and factors that influence childhood cognitive function. Limitations include lack of data on postnatal growth, morbidity and diet including breastfeeding practices. Additionally, the analysis suffered from survival bias.Our analysis reveal the adverse consequences of poor fetal growth on outcomes of cognitive, motor and executive function in a low income setting in South Asia. Our findings reveal that the central nervous system and its development may be susceptible to fetal life nutritional deprivation. Although intrauterine insults leading to poor fetal growth may result in only modest increases in the risk of immediate mortality, the long term consequences on cognitive function may have substantial public health implications for the health of future generations and should be assessed in future studies in low and middle income settings. Nutritional interventions for women of reproductive age before and during pregnancy as well as psychosocial interventions targeted to low birth weight or small-for-gestational age infants may be important public health strategies for ameliorating the long term adverse consequences of intrauterine growth restriction in under resourced countries.BMI: Body mass index; CNS: Central nervous system; IUGR: Intrauterine growth restriction; LBW: Low birth weight; MABC: Movement Assessment Battery for Children; SGA: Small-for-gestational age; UNIT: Universal Non-verbal intelligence test.The authors declare that have no competing interests.PC was the principal investigator and was involved with the study concept and design, and analysis and writing and editing the manuscript. LEMK was involved with study concept and design, acquisition of data, analysis and interpretation of data, obtaining funding, administrative/technical/material support and edited the manuscript. JMT was involved with study concept and design, interpretation of data, and revision of manuscript. JK was involved with study concept and design, statistical analysis and revision of manuscript. SLC was involved in review of manuscript, administrative/technical/material support, and study supervision. SKK was involved with administrative/technical/material support, acquisition of data, and review of manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/14/58/prepub


Concern regarding the biological effects of climate change has led to a recent surge in research to understand the consequences of phenological change for species interactions. This rapidly expanding research program is centered on three lines of inquiry: (1) how the phenological overlap of interacting species is changing, (2) why the phenological overlap of interacting species is changing, and (3) how the phenological overlap of interacting species will change under future climate scenarios. We synthesize the widely disparate approaches currently being used to investigate these questions: (1) interpretation of long-term phenological data, (2) field observations, (3) experimental manipulations, (4) simulations and nonmechanistic models, and (5) mechanistic models. We present a conceptual framework for selecting approaches that are best matched to the question of interest. We weigh the merits and limitations of each approach, survey the recent literature from diverse systems to quantify their use, and characterize the types of interactions being studied by each of them. We highlight the value of combining approaches and the importance of long-term data for establishing a baseline of phenological synchrony. Future work that scales up from pairwise species interactions to communities and ecosystems, emphasizing the use of predictive approaches, will be particularly valuable for reaching a broader understanding of the complex effects of climate change on the phenological overlap of interacting species. It will also be important to study a broader range of interactions: to date, most of the research on climate-induced phenological shifts has focused on terrestrial pairwise resource–consumer interactions, especially those between plants and insects. Shifts in the timing of life-history events are among the strongest biological signals of anthropogenic climate change  as a result of climate change? Second, why is the phenological overlap of interacting species changing in a mechanistic sense? Finally, how will the phenological overlap of interacting species change in the future, given assumptions about the trajectory of climatic changes and the plasticity of interspecific interactions?Spanning much of the research in this field is one central question: We can identify five approaches for studying climate-driven phenological shifts and species interactions: (1) interpretation of long-term phenological data, which relies on time series of adequate duration to allow comparisons between past and present phenologies; (2) field observations, which take advantage of phenological variation over shorter timescales; (3) experimental manipulations, which enable researchers to directly measure the consequences of altering the phenologies of study organisms; (4) simulations and nonmechanistic models, which generate predictions under future climate change scenarios; and (5) mechanistic models, which shed light on the cues and triggers that shape phenologies. Variables quantified with these approaches include extent of temporal overlap of interacting species, ideally measured in terms that are biologically meaningful for the species of interest  general category of interaction , (2) specific type of interaction , and (3) habitat . As Table  general Long-term phenological data on life-history events such as leaf budburst, flowering, insect emergence, egg laying, and plankton blooms were used in the study of nearly 60% of the interactions in our survey Table . For thiLong-term data have been used to address phenological shifts in a wide variety of interactions, both terrestrial and aquatic, and both mutualistic and antagonistic Table  and S1. With long-term records, it is possible to determine whether different species show similar responses to changing environmental cues, regardless of what those cues may be. Assuming that the data are reliable, this approach is likely the most accurate at capturing shifts in the timing of life-history events, especially if preclimate change data can be obtained that establish the prior phenological overlap of interacting species. If many years of data are available, then it is also possible to detect the trajectory of the phenological response to climate change, which may be nonlinear Inouye . Such inInherent in the use of long-term data is the assumption that records are of adequate duration to detect phenological shifts or to capture the true preclimate change baseline of phenological synchrony  that provide a way to test whether interacting species will respond similarly to climatic changes. These approaches by themselves can be used to address only the third question in Figure Clematis socialis was visited by different insect pollinators depending on whether flowering occurred early in an unusually warm year or late in an especially cool year. Thus, the pollinators did not respond in the same way as the plant to springtime temperature fluctuations in this natural experiment, addressing the question: How will the timing of interactions change? Because the primary pollinator in the warm year made fewer visits to C. socialis and tended to be less effective, the reproductive output of the plant was likely lower, addressing the consequences of altered phenology. Using short-term observations of natural variation in flowering time within individuals of Mertensia fusiformis to address these same questions, Forrest and Thomson . Therefore, their responses should provide accurate information about whether the same abiotic factors will affect their phenologies similarly. By taking advantage of opportunistic events, we might also gain information on how interactions will be affected by increased variability in climatic conditions. Increased variance in temperature and precipitation might have stronger effects on ecological systems than a slowly shifting mean  phenology was used as a proxy for other insect pollinators of Prunus tree species based on evidence that they would respond similarly to changing climatic cues , have been initiated in recent years whereby the public can submit phenological observations, and many facilities, such as arboretums and botanical gardens, are collecting phenological data (Primack and Miller-Rushing As the sole approach that can establish a baseline of interannual variation in the phenological overlap of interacting species, interpretation of long-term data is valuable for understanding both the ecological and evolutionary implications of phenological change. This baseline may be one of relative synchrony or asynchrony (Singer and Parmesan To better understand how ecological interactions are likely to be reshaped by phenological shifts, we need to expand our focus in several ways. Again, although long-term data can provide unique insight into how the phenological overlap of interacting species is changing, they must be combined with other approaches to project those changes into the future Fig. . We advoThe consequences of phenological shifts can extend beyond interacting pairs of species to influence community- and ecosystem-level processes. Although ecological network theory and simulations can yield general predictions, we have very little empirical data about how phenological shifts will shape interspecific interactions at the community level (Diez et al. Finally, phenological shifts are interacting with many other factors, including range shifts and landscape modification, to shape species interactions and community dynamics. There is concern that all these pressures together could cause a state shift on a global scale (Barnosky et al.


A seasonality of low birth weight (LBW) and preterm birth (PTB) has been described for most regions and there is evidence that this pattern is caused by ambient outdoor temperature. However, the association as such, the direction of effect and the critical time of exposure remain controversial.Logistic, time-series regression was performed on nearly 300,000 births from two German states to study the association between season and daily mean temperature and changes in daily proportions of term LBW (tLBW) or PTB. Analyses were adjusted for time-varying factors. Temperature exposures were examined during different periods of pregnancy.Weak evidence for an association between season of conception, season of birth or ambient outdoor temperature and tLBW or PTB was found. Results of analyses of temperature were not consistent between the two states. Different sources of bias which would have artificially led to stronger findings were detected and are described.No clear evidence for an association between season of conception, season of birth or temperature and tLBW or PTB was found. In the study of pregnancy outcome different sources of bias can be identified which can potentially explain heterogeneous findings of the past. Low birth weight (LBW) and preterm birth (PTB) are major contributors to short- and long-term morbidity High temperature was associated with both conditions: A birth cohort study in Scotland described reduced birth weight when exposure to high temperature occurred early in pregnancy Also cold has been associated with reduced weight at birth when exposure occurred during mid-pregnancy Evidence from animal studies supports the hypothesis of an association between temperature and birth weight How temperature might act on the foetus remains relatively unclear. Reduced body size was seen as adaption to heat through a high surface-to-volume ratio The overall aim of this study was to examine a potential seasonal rhythm of adverse pregnancy outcome in two German populations and to add to the quantification of current and possible future health impacts of temperature. The main research hypothesis was that tLBW and PTB show seasonal patterns which can be explained by differences in temperature.Approval of this study was granted by the Research Ethics Committee of the London School of Hygiene and Tropical Medicine. As all potential identifiers were removed from the data, no written informed consent from the participants of the study was necessary.Two datasets with daily birth records were obtained from the Departments of Quality Management of the State Chambers of Physicians of Brandenburg (years 2002 to 2010) and Saxony (2005 to 2009). The data was originally collected for the German “Perinatalerhebung” which contains all reported hospital births from these two states.Only singletons with a gestational age between 20 and 44 weeks and a birth weight greater than 200 g were included. Gestational age was counted from first day of last menstrual period. Gestational weeks are stated in completed weeks. Date of conception was defined as 14 days after date of last menstrual period.LBW, defined as birth weight below 2500 g, can result both from PTB and intrauterine growth restriction PTB was defined as birth before 37 gestational weeks. As done before Time-series data on daily mean temperature for eight weather monitoring stations in Brandenburg (five stations) and Saxony (four stations) was obtained from the German Meteorological Service. The temperature data from these stations was highly correlated by state  and mean temperature was very similar (mean temperature ranged in Brandenburg between 9.1 and 9.6°C and in Saxony between 9.0 and 9.7°C). Therefore we chose one weather monitoring station for each state (Potsdam and Dresden).Logistic time-series regression was used to examine both seasonality and the relationship between daily mean temperature and daily proportions of tLBW and PTB.To examine seasonality, indicator terms for seasons  and for individual months adjusted for calendar year were used. Sensitivity analysis was performed with Fourier (trigonometric) terms with one sine-cosine pattern with annual periodicity To examine temperature and to allow for both acute and delayed effects, a constrained distributed lag model was used, whereby temperature was averaged over different time periods of pregnancy Temperature effects on health might follow a linear or, more likely, a non-linear, U- or V-shaped relationship with increased effects at both low and high values When pregnancy data is collected by date of birth but analysed by date of conception, longer pregnancies will dominate at the start and shorter pregnancies at the end of data collection. This phenomenon has been described before th to 36th week of gestation. This takes into account that after the 36th week a pregnancy belongs no longer to this risk-set. This is necessary because the number of pregnancies at-risk and also their distribution of gestational ages show a seasonal pattern because the number of births and conceptions varies regularly throughout the year For analyses by date of conception, the numerator of the estimated proportions included all tLBW- or preterm births resulting from conceptions on each day and the denominator included all conceptions on that day. For analyses of tLBW by date of birth, the numerator included all tLBW births on each day and the denominator all term births on that day. For analyses of PTB by date of birth a pregnancies-at-risk approach Information on maternal age was only available for Saxony. As it was described before that maternal characteristics that show seasonal patterns can confound an association between season and adverse pregnancy outcome and as maternal age showed such a pattern in our dataset, we re-analysed the Saxony data with the inclusion of maternal age . Analyses were performed using Stata 11 software .Baseline data for both states is shown in In both states more babies were born between July and September and more babies conceived between October and December.A weak seasonal pattern was also observed for tLBW in Brandenburg . The risThe analysis of an association between temperature and tLBW or PTB showed at most weak associations that differed considerably between states  and 4 orThe model deviance residuals were plotted over time and showed no obvious pattern. No temporal autocorrelation of the exposure effect or over-dispersion of the data was apparent.The described analyses involved substantial potential for biased results in terms of artificial associations with temperature or spurious seasonal patterns. In the following paragraphs we will compare those results, describe their developments and how to avoid them. Distortions of effects were consistently stronger in Saxony, mainly due to a shorter observation period. Because of this and for ease of understanding, comparisons are shown for Saxony only. However, those biases were also apparent for Brandenburg.For analyses by date of conception, data needed to be restricted at the beginning of the observation period to avoid preponderance of longer and at the end to avoid preponderance of shorter pregnancies To examine PTB by date of birth only pregnancies at-risk to be born preterm on that day were considered. If, as in analyses for tLBW, number of births had been taken instead, evidence for a stronger seasonality with peaks of PTB in May and December would have been observed for Saxony after adjusting for year, gestational age in weeks and day of the week  would have resulted otherwise . No assoWeak evidence for a seasonal pattern with an increased risk for conceptions in spring and births in winter was observed for both conditions. However, the level of evidence differed considerably between the two states. An even weaker and inconsistent association between temperature and tLBW or PTB was detected.However, many prior studies described significant seasonal variations of (t)LBW or PTB with remarkable differences between regions Some limitations of our study can be identified. The data was routinely collected and may therefore contain errors A constrained lag model was used to investigate temperature. We considered temperature averaged over different time periods of pregnancy , to allow for both acute and variously delayed effects.Season was examined as smooth splines, Fourier or indicator terms. Indicator terms have advantages in interpretability but apply simplifying assumptions like a consistent effect across and the same length for each month No adjustment was made for air pollution, hypertensive disorders of pregnancy or infections. We did not have data on these factors, but if we did it is not clear whether they should be adjusted for. Air pollution and preeclampsia have been shown to be associated with both adverse pregnancy outcome and temperature The strengths of this analysis include a large sample size, a long time-span and the possibility for comparisons between two states. An important advantage of the time-series design is the inherent control for non-time-varying individual risk factors, even unknown or unrecorded As already highlighted, in analyses of adverse pregnancy outcome artificial seasonal patterns might occur e.g. a truncation bias This study might have implications for similar studies on environmental exposures on pregnancy outcome as sources for spurious seasonal patterns are discussed and appropriate approaches demonstrated.


GSTT1 gene was previously reported to affect birth outcomes in smokers. In this study, we dissect the associations among SMK, birth outcomes, and copy number variations (CNVs) in the GSTT1/GSTT2 region. A preterm birth case-control dataset of 1937 mothers was part of the GENEVA preterm birth study, which included genome-wide genotyping used to identify CNVs. We examined the association of SMK with birth outcomes, detected CNVs within the GSTT1/GSTT2 region using PennCNV, and examined associations of the identified CNVs with preterm birth and with birth weight (BW) in full term birth controls, including interactions with SMK. Finally, we tested the association of CNVs in GSTT1/GSTT2 with SMK. We confirmed the association of smoking with low BW and PTD. We identified 2 CNVs in GSTT2 (GSTT2a and GSTT2b), 1 CNV in GSTTP1 and 2 CNVs in GSTT1 (GSTT1a and GSTT1b). The GSTT2a deletion was associated with reduced BW  in smokers, and was more common in smokers . We found that the size of the reported common deletion CNV in GSTT1 was larger than previously shown. The GSTTP1 and GSTT1b null genotypes were in high linkage disequilibrium (LD) (D′ = 0.89) and less common in smokers . These two deletions were in partial LD with GSTT2a and GSTT2b duplications. All 5 CNVs seem to be associated with increased risk of preterm birth before 35 completed weeks. CNVs in the GSTTT1/GSTT2 region appear associated with low BW and PTD outcomes, but LD complicated these CNVs in GSTT1/GSTT2. In genetic association studies of BW, multiple CNVs in this region need to be investigated instead of a single polymorphism.Preterm delivery (PTD) is an adverse birth outcome associated with increased infant mortality and negative lifelong health consequences. PTD may be the result of interactions between genetics and maternal/fetal environmental factors including smoking exposure (SMK). A common deletion in the  Low birth weight (LBW) refers to the weight of a newborn being less than 2500 g Kramer,  and occuGSTT1 (Glutathione S-transferase theta 1), which belongs to the theta class of GSTs. The class members, GSTT1 and GSTT2, are located on human chromosome 22. The genes are approximately 50 kb away from each other, with a GSTT pseudo gene (GSTTP1) located between them. GSTT1 and GSTT2 share 55% amino acid sequence identity and have detoxification roles  in the region. A null genotype (homozygous deletion) of GSTT1 modifies the effect of maternal smoking on birth outcomes. Smokers have infants with lower mean birth weight compared to non-smokers; however, the reduction varies according to the GSTT1 copy number. Mean birth weight decreases dramatically in smokers with the GSTT1 null genotype compared to smokers with the GSTT1 wild-type genotype . This study is part of dbGAP (http://www.ncbi.nlm.nih.gov/gap)  preterm birth study (https://www.genevastudy.org/sites/www/content/files/datacleaning/data_cleaning_reports/Preterm_Birth_DN_Murray_DCR_9-3-2010.pdf). The genotyping quality was extremely high. For this CNV study, SNPs were not filtered by minor allele frequency or Hardy-Weinberg equilibrium testing, as those filters tend to remove precisely the SNPs in CNV regions.Complete genotyping and data cleaning reports for the GENEVA preterm birth study are available in dbGAP   only. The relationship between CNVs and PTD stratified by smoking status was examined using logistic regression. The association between CNVs and smoking adjusted for preterm birth state was assessed using logistic regression.CN) < 2] and duplication CNVs (CN > 2) were coded as dummy variables and compared to normal copy number (CN = 2), for two separate comparisons. For common deletions  in GSTT1 and GSTTP1, we compared the homozygous deletions CN = 0 vs. CN > 0 as a single dichotomous comparison. We adjusted for infant sex and maternal BMI in all regression models. All calculations were completed in R (version 2.15.1)  of two CNVs was measured by D′.In regression analysis, deletion CNVs  were all independently associated or borderline associated with birth <35 weeks in non-smokers (Table GSTTP1 and GSTT1b are common and the homozygous deletion (null genotypes) frequencies are 15.5 and 15.8% respectively. The duplication of GSTT2b when combined with the effect of smoking was similar to the CNV's effect among non-smokers (Table p = 0.05). The deletion of GSTT1b was associated with increased risk of birth before 35 weeks  in non-smokers and when combined with smoking had comparable effect but was not statistically significant as joint risk factors (Table p = 0.22). The marginal effect in smokers was not significant either (Table p = 0.80). The odds ratio for the effect of the GSTTP1 deletion on birth before 35 weeks was similar  to that of the GSTT1b deletion.We then analyzed the association of CNVs with preterm birth  and with birth <35 gestational weeks Table . None ofGSTT1/GSTT2 CNVs while adjusting for birth weight indicated that the duplication CNVs were not significantly associated with smoking. However, the deletion CNV in GSTT2a was significantly associated with smoking (Table p = 0.04). This same deletion and smoking were jointly associated with decreased birth weight (Table p = 2.50 × 10E-07), but the deletion alone accounted for less than half of the decreased weight (Table p = 0.07) in smokers. Smokers were also less likely to have the deletions in GSTTP1 and GSTT1b (Table p = 0.02) and 0.73 (p = 0.06), respectively). These deletions tend to increase birth weight in controls, although not significantly , GSTTP1 deletion and GSTT1b deletion are in partial LD  in infants of non-smoking mothers and is more common in non-smokers (Table p = 0.20), but again the weight change was of borderline statistical significance. Interestingly, neither of the GSTT2 deletions was associated with preterm birth or “very preterm” birth (<35 weeks)  (D′ = 0.89) and in moderate LD with two duplications in GSTT2 (D′ = 0.62). We did not observe significant effects of GSTTP1 and GSTT1b deletions on birth weight in full term controls, but they were associated with increased risk of birth before 35 weeks in both non-smokers and smokers, with the odds ratio slightly higher when the deletions were considered jointly with smokers. This suggests that GSTTP1 and GSTT1b deletions are associated with reduced birth weight through very preterm birth, but the effect on birth weight was not detected when including full term infants. We also found that GSTTP1 and GSTT1b deletions were less likely to occur in smokers. Smoking could be a proxy for some other linked yet unknown behavior or may be independently associated with these deletion CNVs.The deletions in GSTT1 and GSTT2 with published findings for the previously described GSTT1 CNV, which was reported to modify the effect of smoking on birth weight  was not covered by the HumanHap660 chip resulting in a marker gap between 22,697,104, and 22,713,954 bp in our arrays. However, our GSTT1b deletion encompasses the reported GSTT1 null genotype region. It is notable that the frequency of the homozygous GSTT1b deletion CNV in our data was highly consistent with the previously reported frequency of the GSTT1 null genotype in Denmark (15%)  in p-values do suggest a prioritization of findings to pursue in future studies.There are several epidemiologic limitations in our study. Smoking was recorded as any smoking present during pregnancy, which did not consider the influence of smoking in different trimesters. Secondly, regressions were adjusted for some demographic factors, but excluded adjustments for psychosocial factors. Statistical evaluations were not corrected for multiple testing which tempers the conclusions that can be drawn about associations, but the uncorrected GSTT1b homozygous deletion was an almost perfect match to the frequency reported in this population for the known deletion was very reassuring. We did not compare our PennCNV CNV calls to any other algorithm in this study, although we did so previously in a more explicit algorithm comparison (Zheng et al., In addition to the epidemiological issues, CNV calls are notoriously error-prone. It is not feasible to validate specific CNV calls within the context of a large-scale association study. However, for any given CNV with calling error rates independent of phenotype, those errors should only reduce power and not cause bias in the association measure (Zheng et al., GSTT1/GSTT2 and identification of five CNVs that appear to be associated with birth weight and/or birth before 35 weeks is novel. The distribution and LD pattern of these CNVs are more complicated than expected, which may impact our understanding of the relationship between the GSTT1 deletion and adverse birth outcomes. Follow-up genetic association studies of birth weight need to include multiple CNVs in this region instead of single polymorphisms. Additional studies including molecular evidence will be needed to validate the detected CNVs and replicate these results.Despite these limitations, our study is able to shed light on CNVs in smoking-associated adverse birth outcomes. Our candidate gene analysis in 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.