Epidemiological studies on the association between maternal exposure to persistent organic pollutants (POPs) and fetal growth alteration report inconsistent findings which weights in favor of additional studies.Blood samples were collected from interviewed pregnant women in Greenland (572), Kharkiv (611) and Warsaw (258) and were analyzed for CB-153 and p,p'-DDE by gas chromatography-mass spectrometry. Data on birth weight, gestational age and preterm birth were obtained for 1322 singleton live births. We examined the association between natural log-transformed serum POPs concentration and birth weight and gestational age using multiple linear regression and the association with prematurity using logistic regression controlling for potential confounding factors.The median serum concentrations of CB-153 and p,p'-DDE were for Inuit mothers 105.6 and 298.9, for Kharkiv mothers 27.0 and 645.4 and for Warsaw mothers 10.7 and 365.2 ng/g lipids, respectively. Increase in CB-153 concentration by one unit on the log scale in Inuit mothers serum was associated with significant decrease in infant birth weight of -59 g and gestational age by -0.2 week. Decreases observed in the cohorts in Kharkiv (-10 g and -0.1 week) and in Warsaw (-49 g and -0.2 week) were not statistically significant. Increase in p,p'-DDE concentration by one unit on the log scale was associated with a statistically significant decrease in infant birth weight of -39.4 g and -104.3 g and shortening of gestational age of -0.2 week and -0.6 week in the Inuit and Warsaw cohorts, respectively. In the Kharkiv cohort decrease in birth weight (-30.5 g) was not significant, however a shortening of gestational age of -0.2 week per increase in p,p'-DDE concentration by one unit on the log scale was of the borderline significance. There was no significant association between CB-153 and p,p'-DDE concentrations and risk of preterm birth however, in all cohorts the odds ratio was above 1.In utero exposure to POPs may reduce birth weight and gestational age of newborns however, new insights as to why results vary across studies were not apparent. Persistent Organic Pollutants (POPs) are chemicals that persist in the environment, accumulate in high concentrations in fatty tissues and are bio-magnified through the food-chain. They constitute a potential environmental hazard causing possible long-term risks to human health. They are border-crossing substances transported long distance, predominately by air and critical concentrations have been reached in some regions, even in places where they have never been produced or used. POPs have been detected in human blood, adipose tissue and breast milk all over the world. Chlorinated hydrocarbon pesticides are not presently recommended for the use in agriculture, and in public health programs only a few persistent chlorinated hydrocarbon pesticides are still being used in a few countries, especially DDT, in vector disease control. Similarly, PCBs widely used by the industry in the past and now ultimately banned for at least two decades are still transported through different environmental media.p-chlorophenyl)-ethylene  and birth weight and length of gestation [Although there has been a growing concern about the effect of POPs on human fetal development and birth outcomes, variation in results across studies remains unexplained. Epidemiological findings regarding association of POPs such as polychlorinated biphenyls (PCBs) and pesticides such as DDT with human fetal growth alteration are inconsistent -4. Thereestation ,15,16.http://www.inuendo.dk) aiming to enlighten the impact of dietary POPs on human reproductive function in an epidemiological setting of varying POPs exposure. The Inuendo project study population has been established in three European countries - Sweden, Poland (Warsaw) and Ukraine (Kharkiv) together with a population of Inuits from Greenland. Since we were able to follow-up most of the participating pregnant women from Greenland, Warsaw and Kharkiv till pregnancy termination it gave us an opportunity to analyze some characteristics of the newborns as an additional measurements of POPs impact on human reproduction. We have chosen to use the PCB congener, 2,2', 4,4'5,5'-hexachlorobiphenyl (CB-153) in serum as a biomarker for POPs exposure because of its very high correlations with the total PCB concentration [The present study stems from a collaborative research project funded by EU  and Warsaw (Poland) for interviews and blood sampling. A general criterion for eligibility was that the participants were born in the country of study and were at least 18 years of age. A detailed description of the recruitment process, population characteristics and data collection has been given elsewhere . In brieThe Inuit and Ukrainian women were earlier in their pregnancies at the time of interview and blood sample collection (on average 24 weeks pregnant) than the Polish women (33 weeks pregnant). Through the interview we obtained information on the maternal demographic and social factors and time varying characteristics such as weight, smoking, alcohol drinking and occupational exposures were obtained for the period of attempt to conceive  birth weight (in grams) analyzed only for full-term birth - 37 and more weeks of completed gestation; 2) gestational age (in weeks) defined as the duration between a self-reported date of the last menstrual period and the date of birth; and 3) preterm birth, before 37 week of gestation. The information from singleton live births were taken into account only. Of 1322 births 52 (3.9%) were born preterm while only 19 full term newborns had low birth weight (less than 2500 g) therefore we did not analyze this outcome variable. The mothers who were interviewed but were not included in the birth outcome analysis  did not differ significantly from the analyzed group taking into account the socio-demographic variables that were considered as potential confounding factors.We examined the association between CB-153 and p,p'-DDE serum concentrations and birth weight and gestational age, respectively, using linear regression models and relation to prematurity using logistic regression models built for each country independently.2 in the case of ordinary regression and in terms of a generalized R2 (computed as a ratio of deviance of the model to null deviance) in the case of logistic regression. Since values of the compared statistics were similar, we report estimates from the logarithmic model for easier comparability of the results. The effect point estimates are presented together with a 95% confidence interval (95% C.I.). Because analyzed concentrations of CB-153 and p,p'-DDE were log-transformed linear regression coefficients presented in the tables represent changes in the outcome variables  associated with increase in chemical concentration by one unit on the log scale. In the logistic regression analysis that we applied to premature birth, the effects of concentrations are presented as odds ratios associated with their twofold increase. In the case of natural-log transformed independent variable "x" odds ratio associated with change of this dependent variable from its value x1 to x2 is given by formula 1 is a regression coefficient. To show results in a generalized way, we applied common approach in such a situation and calculated odds ratio for the case when x1/x2 = 2 which is denoted as odds ratio associated with twofold increase of untransformed concentration.We assessed the shape of the relationship between POPs concentrations and outcome variables using generalized additive models with integrated smoothness estimation and derived number of the effective degrees of freedom (EDF) . If the To control for the confounding of the exposure-outcome association by other factors we built multivariate models taking into account such covariates as maternal age, body mass index (BMI) before pregnancy, education, marital status, smoking status, alcohol drinking, occupational exposure , parity and also the newborn's sex. Covariates were included in the models in a stepwise forward fashion if the addition of each variable to the model changed the regression coefficient of the chemical serum concentration by at least 10% . In the The analyses were done using the S-PLUS 2000  and R 2.There were differences in the mean birth weight of singleton, live, full term newborns among the study cohorts Table . The heaOverall, we found statistically significant relations between maternal serum concentration of CB-153 and birth weight and length of gestation only in the Inuit population  made impossible to disentangle the independent effect of each of them. In Warsaw and Kharkiv the weaker correlation (rS = 0.55 and 0.49 respectively) allowed us to run models for birth weight and gestational age with both compounds. Only the association between p,p'-DDE and gestational age in the Warsaw cohort remained statistically significant .A very high correlation between the two POP biomarkers in the Inuit study group .Our study found no significant effect of CB-153 and p,p'-DDE on the risk of prematurity however, in all cohorts the OR was above one (in Poland at the borderline of significance). It should be stressed, that small numbers of preterm births, 12 in each of the Warsaw and Kharkiv cohorts and 28 in the Inuit cohort, definitely limited statistical power of our analysis.As could be expected serum concentrations of CB-153 were much higher in the Inuit mothers as compared with Warsaw and Kharkiv mothers, whereas p,p'-DDE concentrations were highest in the Kharkiv mothers and were rather similar in the Inuit and Warsaw mothers. The exposure pattern in the Kharkiv mothers is in accordance with a previous analysis of maternal milk from Ukraine in which the median p,p'-DDE concentration (2457 ng/g lipid) was one order of magnitude higher than the median CB-153 concentration (149 ng/g lipid) . ConcentThe possible explanation why the association of CB-153 with birth weight and gestational age was found only among the Inuits may be a much higher exposure level in the Inuit cohort than in the other two. In previous studies, where significant association was observed, the exposure levels due to dietary intakes had been similar or higher than in our Inuit cohort ,13 or weAssociation of maternal DDE exposure with the decrease of birth weight that we observed in the Inuit and Warsaw cohorts corroborates earlier findings in a Great Lakes population study , in the To take into account the differences in the level of CB-153 as well as p,p'-DDE in the study cohorts we calculated changes in the outcome variables associated with the interquartile change of both POP biomarkers in each study cohort. Such a change is a good measure of the public health importance of the variation in population exposure. An interquartile increase in concentration of CB-153 was associated with the reduction of birth weight by 74.5 g, 8.1 g and 49.4 g, the reduction of gestational age by 0.3, 0.1 and 0.2 weeks and the increase of odds of prematurity by 2.01, 2.26 and 2.85 times in the Inuit, Kharkiv and Warsaw cohorts, respectively. An interquartile increase in concentration of p,p'-DDE was associated with the reduction of birth weight by 47.6 g, 22.9 g and 80.0 g, the reduction of gestational age by 0.3, 0.2 and 0.5 weeks and the increase of odds of prematurity by 1.39, 4.35 and 17.39 times in the Inuit, Kharkiv and Warsaw cohorts, respectively.The results from the Inuit cohort in Greenland speak in favor of an inverse association between POPs exposure and birth weight and gestational age. However, the high correlation between CB-153 and p,p'-DDE concentrations in serum made it impossible to disentangle independent effects from these compounds. It should also be noted that both CB-153 and p,p'-DDE act as index biomarkers, and other POP compounds could be the ones which affect fetal growth. However, it is of interest to note, that a significant association between p,p'-DDE and a reduction in birth weight and gestational age, was found also in the Warsaw cohort, in which the correlation between CB-153 and p,p'-DDE was only moderate. Moreover, the association in Warsaw was stronger than in Greenland. In the case of gestational age this association retained its significance when we also controlled for CB-153. In Kharkiv both CB-153 and p,p'-DDE were non-significant when simultaneously included in the models. We have not identified a study that would demonstrate an inverse independent association of PCBs and DDE with birth weight or gestational age.Our results provide only limited evidence that increased CB-153 or p,p'-DDE levels are associated with an increased risk of preterm birth. In all three cohorts and for both chemicals the risks of prematurity were elevated but only for CB-153 concentration in the Warsaw cohort the association reached statistical significance at borderline level. As mentioned above small numbers of preterm births limited statistical power of our analysis. Results of other studies are inconsistent demonstrating presence of significant association ,15,39 asOur study has several strengths. In all participating countries the study was set-up and carried out according to an agreed uniform research protocol regarding measurement of exposure and pregnancy outcome. We used maternal serum CB-153 and p,p'-DDE concentrations as index biomarkers representing direct measurement of POPs as the indicator of intrauterine exposure. Determination of p,p'-DDE and CB-153 in maternal serum was performed for all samples in one specialized center.On the other hand our study has some limitations as well. The participation rate in the study varied considerably between the populations and while in Greenland we obtained full information from more than 80% of those invited, in Kharkiv the participation rate was only 25%. We have no reason to suspect that the mothers' decision to participate was associated with knowledge of POPs exposure or expected pregnancy outcome in Greenland or in Warsaw. In Kharkiv however, low risk of premature birth (2.1%) could be a result of collecting part of the data (about 12%) at maternity hospitals which were not taking care of mothers with previous preterm birth since such mothers received care at a specialized neonatal hospital. In a study of pregnancy outcome in two urban areas of Ukraine the rate of preterm delivery was 6.6% of singleton live births . This sein utero exposure to the POP biomarkers CB-153 and p,p'-DDE and reduction in birth weight and gestational age however, new insights as to why results vary across studies are not apparent. Because observed birth weight reduction was independent of gestational age our findings suggest detrimental effect of the exposure on intrauterine growth as well as on length of gestation.Our results provide some epidemiologic support for an association between p-chlorophenyl)-ethylene; DDT: dichlorodiphenyl trichloroetane; POP: persistent organic pollutant; EDF: effective degrees of freedom.BMI: body mass index; LOG: natural logarithm; PCB: polychlorinated biphenyls; CB-153: 2,2', 4,4'5,5'-hexachlorobiphenyl; p,p'-DDE: 1,1-dichloro-2,2-bis (The authors declare that they have no competing interests.JPB, LH designed and initiated Inuendo project. GT, HSP, JKL, KG, VZ and AL were responsible for collecting the blood samples and the interview data. BAGJ was responsible for the chemical analysis of the POP biomarkers. JPB and GT coordinated the execution of the Inuendo project. GT has main responsibility for creating Inuendo database. BJW initiated the newborn study. DR and BJW had main responsibility for creating newborn database. BJW and DR were responsible for statistical analysis and writing the draft version of manuscript. All authors commented on and approved the final manuscript.


Genetic factors and the prenatal environment contribute to birth weight. However, very few types of study design can disentangle their relative contribution.To examine maternal genetic and intrauterine contributions to offspring birth weight and head circumference. To compare the contribution of maternal and paternal genetic effects.Mothers and fathers were either genetically related or unrelated to their offspring who had been conceived by in vitro fertilization.423 singleton full term offspring, of whom 262 were conceived via homologous IVF (both parents related), 66 via sperm donation (mother only related) and 95 via egg donation (father only related).Maternal weight at antenatal booking, current weight and maternal height. Paternal current weight and height were all predictors. Infant birth weight and head circumference were outcomes.Genetic relatedness was the main contributing factor between measures of parental weight and offspring birth weight as correlations were only significant when the parent was related to the child. However, there was a contribution of the intrauterine environment to the association between maternal height and both infant birth weight and infant head circumference as these were significant even when mothers were unrelated to their child.Both maternal and paternal genes made contributions to infant birth weight. Maternal height appeared to index a contribution of the intrauterine environment to infant growth and gestational age. Results suggested a possible biological interaction between the intrauterine environment and maternal inherited characteristics which suppresses the influence of paternal genes. These adverse sequelae are thought to arise from early programming effects Differential maternal and paternal genetic contributions to infant birth weight may also be important. To date, the evidence suggests that the effect of maternally provided genes on infant birth weight is greater than that of paternally provided genes Here we used a novel approach to examine the contributions of maternally provided genetic influences, intrauterine influences and paternally provided genetic influences on infant birth weight by examining children who differ in their genetic relatedness to mother and father because of assisted reproductive technology .22.12.1.1The contribution of maternal genes to infant birth weight can be identified by comparing mother–offspring associations in the two groups where mother shares genes with their offspring (homologous and sperm donation groups) to the correlation in the egg donation group See .2.1.2The clearest indication of intrauterine factors is provided by the magnitude of mother–offspring correlation in the egg donation group since significant mother–offspring correlation in this group can only be due to intrauterine factors as mother and child do not share genes. Mother–offspring and father–offspring comparisons can also be informative as higher mother–offspring associations are consistent with prenatal effects .2.1.3Within conception group comparisons of the mother–offspring and father–offspring correlations are informative for identifying the relative contributions of maternal and paternal genetic contributions to infant size at birth. Within the homologous group, mother–offspring and father–offspring correlations should be similar to the extent that maternal and paternal genetic contributions to infant birth weight are similar. Within the sperm donation group, if genes contribute to birth weight the mother–offspring correlation should be larger than the father–offspring correlation. Within the egg donation group, if genes contribute the father–offspring correlation should be larger than the mother–offspring correlation.2.1.3.1Families who had a live birth between 1994 and 2002 (children aged 4 to 10 years) following successful IVF treatment from any of the three conception groups described were recruited from 19 UK clinics and 1 USA clinic. Gamete donors were unrelated to either parent. All initial contact was made through clinic staff. Data were collected through postal questionnaires and, where consent was provided, review of antenatal records. The majority of women agreed for their antenatal records to be reviewed (77%) although we did not request antenatal notes for participants recruited from the USA clinic. Wales Multi Centre Research Ethics Committee reviewed and approved the study. Mothers and fathers were sent a postal questionnaire that included scales to assess various aspects of the pregnancy and demographic characteristics. Mothers reported on pregnancy and obstetric complications using an adapted version of the Lewis and Murray scale 2.1.4N = 384), ICSI (intra cytoplasmic sperm injection) (N = 76) and GIFT  (N = 6) and excluded children born following intrauterine insemination (N = 58). Treatment details were missing for 5 cases. We also excluded prenatal smokers (N = 31) given the known effect of prenatal smoking on offspring birth weight N = 8) were excluded. Specifically, we excluded two women with diabetes, three women taking anti-epileptic medication throughout pregnancy and three women taking medication for hypertension throughout pregnancy. Finally, children with serious medical conditions that could have influenced prenatal growth (N = 3) were also excluded. These were three children with genetic syndromes . Following these exclusion criteria, questionnaire data from at least one parent was available for 423 families; 262 homologous IVF (parents own gametes used) , 66 IVF with sperm donation , and 95 IVF with oocyte donation . Data from antenatal records were available for 277 (65%) of these mothers .This report focuses on singleton births born at term (>=37 weeks gestation) from the three conception groups described given the strong influences of prematurity and multiple birth on birth weight 33.13.1.1r = .972, p = .001, n = 277; mean difference = − 15.82, sd = 112.69). We therefore used maternal reports which allowed us to use data from the full sample as opposed to the subsample for whom antenatal records were available. Agreement between maternal and antenatal reports for low birth weight <=2500 g was also very good .In accordance with our previous work 3.1.2Since birth weight is both a function of foetal growth and of gestational age we additionally calculated birth weight adjusted for weeks gestation. The unstandardised residuals were saved from a regression where gestation in weeks was the predictor and birth weight was the outcome.3.1.3This measure was available from antenatal records.3.23.2.1Mothers and fathers reported on their height. Responses were converted to metres. Maternal report of height in the questionnaire and information from antenatal records showed good agreement  indicating that on average mothers reported their height within 1 cm of their measured height.3.2.2Maternal weight at antenatal booking was available for 215 mothers (mean week of pregnancy weighed = 12.57) from antenatal records.3.2.3Although on average, children were aged 6 years at the time these data were collected, we also included maternal and paternal reports of current weight for two reasons. First, to examine whether the pattern of results obtained for maternal pregnancy weight could be replicated using this less stringent measurement variable of maternal weight. Second, to allow a direct comparison of the relative contributions of maternal and paternal weight to infant size. Mothers and fathers reported on their current weight. All responses were converted to kilograms. Current maternal weight was very similar to weight at antenatal booking . Thus, on average women currently weighed .07kg more than they weighed in pregnancy.3.3Mothers reported on their child's gender, whether the child was their first born child and maternal and paternal age when their child was born. Mothers reported their annual family income on a six point scale ranging from <£10,000 to >£60,000 and completed an adapted version of the Lewis and Murray antenatal complications scale 3.4t-tests or ANOVA tests as appropriate to examine the influence of a number of variables on infant birth weight. We also compared the frequency of the potential confounding factors described above between the three conception groups. Next, we examined the unadjusted correlations between maternal and paternal height and weight with infant birth weight separately in the three conception groups . We used linear regression to adjust for potential confounders in the association between parental height and weight with infant birth weight. Finally, we calculated maternal–offspring and paternal–offspring correlations using birth weight adjusted for gestational age as an outcome variable.We first analysed data from the whole sample and used correlations, 44.1χ2 = 3.038, df = 2, p = .219). The majority of mothers and fathers described their ethnic group as white British (96% of mothers and fathers). 81% of mothers in the sample were primiparous and there was no difference in the proportion of primiparous women in the different conception groups . The mean birth weight for the sample was 3385 grams (sd = 502) which is consistent with UK population norms for singletons of White British ethnicity F  = 2.131, p = .12).Descriptive characteristics of the full sample have been described in detail elsewhere 4.2p = .441). Parity (primiparous and multiparous) did not significantly influence birth weight . There were no significant differences between the three conception groups in terms of maternal reported antenatal complications with the exception that women in the egg donation group reported higher levels of oedema/high blood pressure in pregnancy  and there was a trend for this to be associated with lower birth weight . Maternal age and paternal age at child birth were also not associated with infant birth weight  respectively. However, child gender and family income did influence birth weight: males were significantly heavier at birth than females  and families with an annual income under £10,000 per year (n = 14) had lower birth weight babies than the remainder of the sample .There was no significant difference between the three conception groups  on infant birth weight , 4.34.3.1r mother height = .174; r mother weight = .290) and sperm donation groups  than for the egg donation group . The squared difference in the correlation coefficients for the combined homologous and sperm donation groups  and the egg donation group gives an estimate of the proportion of variance attributable to maternally provided genetic effects  (.216–.174)2. effects . For mat4.3.2r = .023, p = .888) suggesting no intrauterine influences. However, although, the correlation is only approaching significance, it is in the expected direction and much larger for mother height–offspring birth weight  suggesting that intrauterine contributions may differ according to the measure of maternal stature used. The correlation in the egg donation group can only be due to intrauterine influences and suggests that approximately 3% of the covariance in birth weight and maternal height is due to intrauterine influences (.1772). r = .174, p = .006) than for fathers  which again, suggests intrauterine influences indexed by height but not weight.The correlation between mother weight–offspring birth weight in the egg donation group is near zero  compared to the father–offspring correlations for the homologous and egg donation groups (where fathers pass genes on to their children). The only exception is for paternal height and infant birth weight where the correlation is small and non significant in both the homologous group where the father passes on genes and in the sperm donation group where the father does not. In general however, the unadjusted correlations appear to vary primarily according to whether the father is genetically related to the child. The square of the average correlation for the combined homologous and sperm donation group gives an estimate of the proportion of covariation with infant birth weight attributable to paternal genetic effects. For paternal height, this is 1% (.1212) and for paternal weight this is 5% (.2182).The pattern of correlations in the sperm donation group suggests that paternal genetic factors are also important in the aetiology of birth weight in that the father–offspring correlations are smaller and non significant for the sperm donation group . However, this greater maternal genetic contribution is not observed when only one parent in a dyad passes genes on to the child; the magnitude of association for (related) mothers in the sperm donation group (r = .196) and (related) fathers in the egg donation group (r = .274) is similar and in fact slightly higher in the egg donation fathers. Thus, the results suggest genetic contributions from both mothers and fathers. The only exception concerns the egg donation group where the father and not the mother are related. There, the (related) paternal contribution is significant and larger than the paternal contribution in the (related) homologous group . That result thus highlights that intrauterine influences play a role in the association between maternal height and offspring birth weight. Height was measured in metres thus a 10 cm increase in maternal height is equivalent to an 18.7 g increase in infant birth weight (1871 × .1). Since the mother and offspring share no genes in common, this significant association must be attributed to the intrauterine environment provided by the mother.We next examined the pattern of mother–child and father–child association when controlling for the effect of potential confounding variables. The overall pattern of results was not altered when adjusting for the influences of child gender and family income see . We also4.6Since birth weight is both a function of foetal growth and gestational age, we examined whether the pattern of correlation differed when birth weight corrected for gestational age was an outcome variable in this sample of singletons born at term . In gene4.7r = .185, p = .01, n = 192) as well as the unrelated group . This pattern of results therefore suggested an intrauterine contribution to the relationship between maternal height and head circumference. Again, the pattern of results was different for maternal weight and there was evidence of a smaller but largely genetic contribution. Maternal weight at antenatal booking and head circumference were correlated in the related groups  but not the unrelated group .Information on infant head circumference was available for 239 cases from antenatal records . Head circumference showed a positive correlation between maternal height in the related groups  and offspring birth weight was in fact very similar to a large population-based study of the familial transmission of birth weight  Using this novel design, we found a different pattern of results depending on the measure of parental size examined. The contribution of parental weight to offspring birth weight was explained by genetic factors whereas intrauterine influences were apparent when maternal height was examined as a predictor variable. For parental weight, in both unadjusted correlations and adjusted multiple regression analysis, significant parent weight–offspring birth weight associations were only seen when the parent was genetically related to the child. Both maternal and paternal genetic factors made a contribution. Moreover, results were similar when using two assessments of maternal weight; one objective measure assessed at the time of pregnancy and one self report measure assessed some years after the birth of the child. In families where both parents passed genes on to the child (the homologous IVF group), there was evidence of a greater maternal than paternal genetic contribution to infant birth weight as has been observed in previous studies using standard family data One interesting observation was that the greater maternal genetic contribution that was seen when both parents were genetically related to the child was not observed when only a single parent in a pair passed genes on to the child: in fact mothers in the sperm donation group and fathers in the egg donation group showed very similar sized correlations with offspring birth weight. This raises the possibility of biological interactions between maternal and paternal genetic contributions. In fact, the contribution of paternal genetic factors to birth weight differed depending on whether the mother also contributed her genes. When examining paternal height, there was a difference in the magnitude of the contribution of paternal factors in the egg donation and the homologous groups. In both these groups, the father is genetically related to the child, although the correlation was significant only in the egg donation group. One interpretation of this finding is that competition between maternal and paternal genes could be influencing foetal growth The results that examined the association between birth weight and parent height—a measure of adult stature independent of obesity showed evidence of a contribution of the intrauterine environment in that significant mother–offspring correlation was observed in the egg donation group despite the fact that mother is not genetically related to the child . The association between maternal height and infant birth weight in the egg donation group is therefore attributable to intrauterine effects that are independent of the link between the foetal and maternal genomes. Although the numbers were small, a similar pattern of results was observed for head circumference. Taken together, this pattern of results suggests that maternal height is a more accurate estimate of the constraint that maternal size exerts on the growth of the foetus as opposed to maternal weight. These results are in line with a previous study that examined the contributions of egg donor and egg recipient height and weight to offspring birth weight The results of the analysis of birth weight corrected for gestational age illustrated that maternal height influenced length of gestation. When examining the association of maternal height with infant birth weight corrected for gestational age, the correlation did not reach significance in the egg donation group. Although we restricted our analysis to singletons born at term, birth weight is an index of both foetal growth and gestational age r = .261, p = .002). This association could be due to either assortative mating or to shared environmental contributions. However, since there was no evidence of a significant correlation in parental height , this suggests that the parent correlation in weight is due to shared environmental factors. A final limitation is that we cannot exclude the possibility of clinics matching gamete donors and recipients on height. However, this seems unlikely to account for our results for a number of reasons. Firstly, because we excluded related donors and secondly, because given the limited choice of donors available in the UK, close matching of physical characteristics between recipient and donor is impossible The research design employed included children conceived via IVF and allowed the comparison of paternal and maternally provided genetic influences as well as an examination of the contribution of the intrauterine environment independent of the link between the foetal and maternal genomes. However, the focus on offspring born following IVF means that there may be some concern about the representativeness of the sample and the generalizability of results. Studies have consistently shown that children conceived via assisted reproductive technologies do not differ from children conceived naturally in terms of psychological adjustment 6In summary, we find that genetic factors explain the association between parental weight and infant birth weight but that there is a contribution of the intrauterine environment on the association between maternal height, infant birth weight and head circumference. Presumably maternal stature as measured by height puts a physical constraint on the growth of the foetus. The intrauterine influence of maternal height on birth weight appears to work both through influences on foetal growth and on gestational age. There was also evidence that could be interpreted as suggesting a biological interaction between maternal inherited characteristics and the intrauterine environment that suppresses the contribution of paternal genes to birth weight.


Little is known about risk factors for childhood rhabdomyosarcoma (RMS) and the histology-specific details are rare.Case–control studies formed by linking cancer and birth registries of California, Minnesota, New York, Texas and Washington, which included 583 RMS cases  and 57 966 randomly selected control subjects, were analysed using logistic regression. The associations of RMS  with birth weight across five 500 g categories (from 2000 to 4500 g) were examined using normal birth weight (2500–3999 g) as a reference. Large (>90th percentile) and small (<10th percentile) size for gestational age were calculated based on birth weight distributions in controls and were similarly examined.High birth weight increased the risk of embryonal RMS and RMS overall. Each 500 g increase in birth weight increased the risk of embryonal RMS (odds ratio (OR)=1.27, 95% confidence interval (CI)=1.14–1.42) and RMS overall . Large size for gestational age also significantly increased the risk of embryonal RMS .in utero growth and embryonal RMS, but not alveolar RMS. These results warrant cautious interpretation owing to the small number of alveolar RMS cases.These data suggest a positive association between accelerated  Owing texposure , 2009, mexposure , advanceexposure  and stilexposure , 1969b ain utero growth, resulting in high birth weight would be more important in embryonal than in alveolar RMS.High birth weight has been associated with several childhood malignancies, and recent evidence suggests that accelerated intrauterine growth may increase RMS risk, although based on only 27 cases , Washington and Texas) with case–control data sets by having linked cancer and birth registries (n=100), but possibly not completely, because such reporting was not implemented in Texas before 1984 and in Washington before 1989.Institutional review board approvals were obtained from each participating institution and State department of health. The selection of cases and controls varied by state and has been previously described in detail . ControlThe information available for cases included RMS diagnoses and the age of onset. Cases were classified according to the International Classification of Childhood Cancer (ICCC-3), third edition , year of birth, parental age and race/ethnicity and maternal years of education. Gestational age clinical estimate was provided by each state, except California, which provided only the date of last menstrual period (LMP) that was used for gestational age calculation. Some states also provided the LMP information; therefore, a combined gestational age variable was developed that gave preference to the calculated estimate when available and used clinical estimate otherwise. Gestational ages less than 20 or more than 45 weeks were deemed implausible, as were birth weights less than 350 g, and were excluded from analyses. Maternal education was available from all states only after 1992 and was, therefore, included in secondary analysis. Using birth records data, we calculated size for gestational age based on the distribution observed in controls (described below). Separate distributions were used for males and females.vs multiple births. Birth order was categorised as first, second, third, fourth or higher order. Parental age categories consisted of <20, 20–24, 25–29, 30–34, and >35 years. Maternal education categories consisted of <12, 12, 13–16, >17 years.Birth weight categories were selected to distinguish very low birth weight (<2000 g), low birth weight (2000–2499 g), normal weight (2500–3999 g), high birth weight (4000–4499 g) and very high birth weight (>4500 g). The very low birth weight category was assigned higher than the standard cutoff at <1500 g, because only seven cases weighed less than 2000 g. Normal birth weight was used as a reference group for comparisons. Gestational age was categorised as 20–36 (preterm), 37–40 (term) and >40 weeks (post-term). Size for gestational age was analysed using an internal standard (the distribution in controls). The tenth and ninetieth percentiles were used as cut points for small for gestational age and large for gestational age (LGA), respectively. We used this internal standard rather than other published external standards because of the large number of controls available and the long span of the study. For plurality, we distinguished single All analyses were carried out using SAS version 9.1 . Unconditional logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) to examine the associations between perinatal characteristics and RMS and its two major subtypes. Individual matching in California was broken for the purpose of pooled analysis. Results of analyses in subgroups which had fewer than four  or two cases (for RMS subtypes) were not reported. Risk estimates were adjusted for available covariates. After adjustment for state/study centre, the choice of other variables evaluated as possible confounders included those known or suspected to be associated with inappropriate fetal growth  and for third-born child it was OR=0.70 (95%CI=0.54–0.91). This reduced risk reflects the significant associations with birth order observed for embryonal RMS, whereas no associations were observed for alveolar RMS .Higher birth weight, however, was associated with increased risk of RMS overall and embryonal RMS, with OR=1.19 (95% CI=1.09–1.29) and OR=1.27 (95% CI=1.14–1.42) per 500 g increase in birth weight, respectively. Despite the trend, none of the individual categories showed a significant association with these risks. Only two alveolar RMS cases had birth weights below normal (<2500 g); hence, we could only compare cases with normal birth weight (<4000 g) (reference) with those with high birth weight (4000–4500 g), and we observed no association. We observed no association with gestational age for RMS or either of its subtypes. The majority of cases born preterm were between 32 and 36 weeks gestation, and only two cases were born before 32 weeks.per se from that of accelerated fetal growth, we calculated size for gestational age as a surrogate measure for accelerated fetal growth .Children whose birth weight was high had an increased risk of RMS overall and of embryonal RMS in particular. Trend analysis showed that the birth weight increase per 500 g increment increased the odds of RMS and its embryonal subtype. The examination of size for gestational age showed that LGA babies had increased risk of developing embryonal RMS, whereas no associations between birth weight alone or birth weight for gestational age were observed for alveolar RMS. Our results support the hypothesis that the two major RMS subtypes, embryonal and alveolar RMS, have different aetiologies. The associations with RMS overall primarily reflected the associations observed for embryonal RMS, as the majority of cases belonged to this subtype.in utero growth, measured by higher than expected weight for gestational age, increases the risk of embryonal RMS. The only previous study of relevance suggested an increased risk with increasing birth weight and intrauterine growth (in utero. Our study supports the view that size for gestational age provides insight beyond that of birth weight per se (This is the first study to show that accelerated e growth , brain tTemporal trends in fetal growth show that the birth weight of term infants has increased over the last two decades of the previous century . Indeed,We also found that RMS cases were more likely to be first born, as increasing birth order was associated with progressively decreasing RMS risk owing to the embryonal subtype; no association was observed for alveolar RMS. The similar findings observed in childhood leukaemia prompted the suggestion that later exposures to infections, an established risk factor for leukaemia, may have been more frequent among the first-born children (We confirmed previously reported associations with increasing maternal age, and have shown that this is significant for embryonal histology only. In addition, we have observed that each 1-year increase in paternal age is associated with a slight, but significant, increase in RMS overall and embryonal RMS risk. Maternal education was not associated with RMS risk, overall or by subtype; however, this may be due to the limited availability of this variable.The main limitations of this study include multiple comparisons and potential measurement error in the birth certificate data. Although maternal age, birth weight, birth order and plurality have been shown to be accurate in validation studies , gestatiin utero growth may have an important role. However, caution is warranted in interpreting the results related to alveolar and other RMS histology subtypes, given their small numbers, and further studies are needed.Our study further supports the view that embryonal RMS may be associated with growth characteristics, suggesting that accelerated


To clarify the nature of the relationship between food deprivation/undernutrition during pre- and postnatal development and cardiovascular disease (CVD) in later life, this study examined the relationship between birth weight  and the incidence of hospital admissions for CVD from 1997–2005 amongst 873 Guernsey islanders (born in 1923–1937), 225 of whom had been exposed to food deprivation as children, adolescents or young adults  during the 1940–45 German occupation of the Channel Islands, and 648 of whom had left or been evacuated from the islands before the occupation began.Three sets of Cox regression models were used to investigate (A) the relationship between birth weight and CVD, (B) the relationship between postnatal exposure to the occupation and CVD and (C) any interaction between birth weight, postnatal exposure to the occupation and CVD. These models also tested for any interactions between birth weight and sex, and postnatal exposure to the occupation and parish of residence at birth (as a marker of parish residence during the occupation and related variation in the severity of food deprivation).The first set of models (A) found no relationship between birth weight and CVD even after adjustment for potential confounders (hazard ratio (HR) per kg increase in birth weight: 1.12; 95% confidence intervals (CI): 0.70 – 1.78), and there was no significant interaction between birth weight and sex (p = 0.60). The second set of models (B) found a significant relationship between postnatal exposure to the occupation and CVD after adjustment for potential confounders , as well as a significant interaction between postnatal exposure to the occupation and parish of residence at birth (p = 0.01), such that those born in urban parishes (where food deprivation was worst) had a greater HR for CVD than those born in rural parishes. The third model (C) found no interaction between birth weight and exposure to the occupation (p = 0.43).in utero prior to the occupation.These findings suggest that the levels of postnatal undernutrition experienced by children, adolescents and young adults exposed to food deprivation during the 1940–45 occupation of the Channel Islands were a more important determinant of CVD in later life than the levels of prenatal undernutrition experienced  Indeein utero . This rein utero ,6. Howevin utero , with puin utero . Indeed,periods' .Since it is difficult, expensive and time consuming to undertake prospective studies examining the relationship between living conditions in early life and health in later life, retrospective analyses of cohorts exposed to food deprivation during two 'natural experiments' – the 1944–45 Dutch famine and the 1941–44 Leningrad siege – have proved invaluable for clarifying this relationship. Although these analyses have primarily focused on the relationship between prenatal exposure to food deprivation and health in later life, they include some that have examined the potential impact of postnatal undernutrition during childhood, adolescence or early adulthood. These analyses have found a higher incidence of breast cancer ,11 – thoThe present study aimed to clarify the nature of the relationship between undernutrition during pre- and postnatal development and CVD in later life. This involved examining a cohort of Guernsey islanders (born between 1923 and 1937) for whom data on birth weight were available , some of whom had been exposed as children, adolescents or young adults to food deprivation  during the 1940–45 German occupation of the Channel Islands . The occand long-term effects on health. The analyses that follow therefore aim to compare the impact of birth weight and postnatal exposure to the occupation on CVD in later life.Previous studies examining the short-term consequences of the 1940–45 occupation on the health of Channel Islanders have found little evidence of any impact on self-reported birth weight  or on inThe cohort was based on 1673 live births delivered by a community midwife in the 10 parishes of Guernsey between February 1923 and August 1937. The midwife's records included data on birth weight, date and place of birth, sex of the baby and gestational age in weeks. These data were confidentially matched by hand to the Guernsey birth registers, which provided additional information on the occupation of the father and marital status of the mother, as well as confirmation of the parish of residence at birth. Paternal occupation at birth was classified as manual vs. non-manual and used as a marker of social class in the analyses which follow. It was also reclassified as 'agricultural' vs. 'non-agricultural' to explore the potential impact of paternal occupations with access to off-ration foodstuffs during the 1940–45 occupation. Likewise, parish of residence at birth was used as a marker of parish of residence during the occupation and was classified as 'urban' or 'rural' to reflect differences in the availability of off-ration foodstuffs in different parishes during the occupation ,27.The cohort was then confidentially matched, again by hand, to the 'occupation register' compiled by the German Army during the 1940–45 occupation, which comprised a complete list of all resident islanders. In this way it was possible to identify those cohort members who were resident in Guernsey during the occupation, and those who were not (i.e. those who had left the island or had been evacuated before the 1940–45 occupation began). Finally, cohort members were confidentially matched to the hospital episode statistics (HES) database at the island's only hospital. HES for 1997–2005 were then searched for any admissions for CVD events – defined as myocardial infarction, stroke or unstable angina using the ICD-10 coding system.Cox regression models were used to assess whether birth weight and/or exposure to the 1944–45 occupation might be associated with CVD in later life. Birth weight, which had been measured to the nearest 1/4 lb, was converted to kilograms (kg) and used as a continuous variable. The 'occupation register' compiled by the German army was used to identify those cohort members who had been exposed to the 1940–45 occupation (i.e. those resident in Guernsey) and those who had not (i.e. those who had left or had been evacuated from the island). The analyses that follow therefore provide hazard ratios for CVD-related hospital admissions corresponding to a 1 kg increase in birth weight, and to exposure to the 1940–45 occupation.To inform the design of the Cox regression models, an analytical framework was drawn up in the form of a causal path diagram  which suFrom Figure The first set of models (A: birth weight) included sex, gestational age at birth and paternal occupation at birth  and exposure to the 1940–45 occupation (as a competing exposure). The first set of models also tested for any interaction between birth weight and sex. The second set of models (B: exposure to the occupation) included gestational age at birth, birth weight, paternal occupation at birth and parish of residence at birth . The second set of models also tested for any interaction between exposure to the occupation and parish of residence at birth. Finally, the third model (C: birth weight × exposure to the occupation interaction) included sex, gestational age at birth, paternal occupation at birth and parish of residence at birth  and tested for any interaction between birth weight and exposure to the occupation. All of the temporal variables available for inclusion in the analyses  were found to be correlated with one another. For this reason, the temporal variable most strongly related to CVD in later life  was included as the core temporal variable in the Cox regression analyses.not experienced a CVD event. Meanwhile, although the sample size used in the analyses that follow was predetermined by the numbers of cohort members who could be matched to the HES database, it was possible to conduct power calculations based on the cumulative incidence of CVD over a 7-year period estimated from the literature, and these were then compared with the actual effect sizes found in the Cox regression models.Sensitivity analyses were conducted to assess the possibility of selection bias occurring due to selective loss to follow-up in the HES database. These analyses assumed that those lost to follow-up did not appear in the HES database because they had Formal ethical clearance for the study was granted by the States of Guernsey Board of Health's research ethics committee.Of the original 1673 live births included in the cohort, 113 (6.8%) had died before the age of 18, and were therefore excluded from these analyses of CVD in adults. Data on hospital admissions in the HES database were identified for 931 of the remaining 1560 cohort members  showed that although there was some evidence of a positive relationship between birth weight and CVD, this was not statistically significant either before or after adjustment for sex, paternal occupation at birth, gestational age at birth and exposure to the 1940–45 occupation (see Table The second set of models (B: exposure to the occupation) confirmed that there was a significant relationship between exposure to the occupation and CVD, such that those who had remained on the island during the occupation had more than twice the HR of hospital admission for CVD in later life (see Table The third model (C: interaction between birth weight and exposure to the occupation) divided the cohort into those who had been exposed to the occupation and those who had not and examined the relationship between birth weight and CVD in each of these groups to assess whether there was any evidence of an interaction . However, a comparison of cohort members included in the HES database with those who were not found few sociodemographic or clinical differences, although those included in the HES database were less likely to have died in Guernsey and more likely to have been exposed to the 1940–45 occupation. While such differences will affect the generalisability of the results, they may well be the result of population movement rather than pre-existing sociodemographic differences between those included in the analyses and those lost to follow-up. In this regard, the results of the sensitivity analyses were encouraging since these were not substantially different from the main analyses when all those lost to follow-up were assumed Finally, the power calculations indicated that the analyses in the first set of models (A: birth weight) are likely to have been underpowered. If so, it is possible that a significant relationship may have been found between birth weight and CVD had a larger sample been available for analysis. However, because the modest relationship between birth weight and CVD amongst men and women combined was positive rather than inverse, and was only inverse amongst men when the analysis was stratified by sex, it seems unlikely that a larger sample size would have generated the statistically significant inverse relationship between birth weight and CVD that has commonly been observed in previous studies .Notwithstanding these potential limitations, the lack of a significant inverse relationship between birth weight and CVD in this cohort runs contrary to the findings of numerous previous studies ,31-33. Tboth resident and evacuated islanders would have experienced some form of stress, whilst only those who remained on the island would have experienced the undernutrition and related deprivation associated with the 1940–45 occupation.Meanwhile, the results of both the first and second sets of models , which indicated that exposure to the occupation was more strongly associated with CVD amongst those born/living in urban parishes where there was less access to off-ration foodstuffs ,27. Authin utero) and CVD in later life, although these analyses were substantially underpowered. In better powered analyses, there was clear evidence that exposure to nutritional deprivation during the 1940–45 occupation of the Channel Islands in childhood, adolescence and young adulthood was associated with an increased risk of CVD in later life. These findings suggest that, in this cohort, postnatal undernutrition associated with exposure to the 1940–45 occupation may be a more important determinant of CVD in later life than the levels of undernutrition experienced in utero prior to the occupation.The present study aimed to explore the impact of undernutrition at various stages of early development on the subsequent risk of CVD in later life. In contrast to many previous studies, there was little evidence of an inverse relationship between birth weight (as a marker of nutrition The authors declare that they have no competing interests.RFH contributed to the design of the study, collection of data, analysis and interpretation, and also drafted and approved the manuscript. MSG contributed to the design of the study, analysis and interpretation, and also assisted with drafting the manuscript and approved the final version. AB contributed to the collection of data and approved the final manuscript. GTHE contributed to the conception and design of the study, collection of data, analysis and interpretation, and also assisted with drafting the manuscript and approved the final version.The pre-publication history for this paper can be accessed here:


It is unclear whether the high rates of low birth weight in South Asia are due to poor fetal growth or short pregnancy duration. Also, it is not known whether the traditional focus on preventing low birth weight has been successful. We addressed these and related issues by studying births in Kaniyambadi, South India, with births from Nova Scotia, Canada serving as a reference.Population-based data for 1986 to 2005 were obtained from the birth database of the Community Health and Development program in Kaniyambadi and from the Nova Scotia Atlee Perinatal Database. Menstrual dates were used to obtain comparable information on gestational age. Small-for-gestational age (SGA) live births were identified using both a recent Canadian and an older Indian fetal growth standard.The low birth weight and preterm birth rates were 17.0% versus 5.5% and 12.3% versus 6.9% in Kaniyambadi and Nova Scotia, respectively. SGA rates were 46.9% in Kaniyambadi and 7.5% in Nova Scotia when the Canadian fetal growth standard was used to define SGA and 6.7% in Kaniyambadi and < 1% in Nova Scotia when the Indian standard was used. In Kaniyambadi, low birth weight, preterm birth and perinatal mortality rates did not decrease between 1990 and 2005. SGA rates in Kaniyambadi declined significantly when SGA was based on the Indian standard but not when it was based on the Canadian standard. Maternal mortality rates fell by 85%  in Kaniyambadi between 1986–90 and 2001–05. Perinatal mortality rates were 11.7 and 2.6 per 1,000 total births and cesarean delivery rates were 6.0% and 20.9% among live births ≥ 2,500 g in Kaniyambadi and Nova Scotia, respectively.High rates of fetal growth restriction and relatively high rates of preterm birth are responsible for the high rates of low birth weight in South Asia. Increased emphasis is required on health services that address the morbidity and mortality in all birth weight categories. Several unique problems beset perinatal health in less industrialized countries including high rates of low birth weight  and infant death. According to UNICEF , low birThe substantial burden of illness notwithstanding, perinatal health in less industrialized countries has received inadequate attention in the medical literature ,3. For iAnother critical issue relates to public health policy for addressing perinatal morbidity and mortality in such settings. Whereas public health efforts have traditionally focused on preventing low birth weight -11, empiWe attempted to answer these questions using population-based data from Kaniyambadi, a rural area in South India, where a community-based maternal and child health program has operated for over 2 decades. We assessed temporal trends in low birth weight, preterm birth, small-for-gestational age (SGA) birth, and perinatal and maternal mortality from 1986 to 2005. To provide an industrialized country context for examining absolute rates and temporal trends, we also analyzed similar population-based data from Nova Scotia, Canada.Kaniyambadi comprises a mostly rural population of about 112,000 (2008) in 80 villages of Tamil Nadu, South India. In addition to the regular health care offered by the government, primary and secondary health care services for these villages have been provided by the Community Health and Development (CHAD) program of Christian Medical College, Vellore, for over 50 years ,16. BasiThe CHAD program in Kaniyambadi includes a health information system, initiated in 1986 and described in detail elsewhere . SurveilInformation on all births in Nova Scotia was obtained from the Nova Scotia Atlee Perinatal Database. This database contains detailed information on births to Nova Scotia residents and is abstracted from antenatal and medical charts by trained personnel using standardized forms. For the years 1986 and 1987, the database included information on all births in Halifax county and most but not all births in the rest of Nova Scotia. All births in Nova Scotia were included in the database from 1988 onwards.th percentile cut-off of a Canadian fetal growth standard [th percentile value assumed to be 1.28 standard deviations less than the mean birth weight for gestational age [Since the only estimates of gestational age in the Kaniyambadi database were those based on the date of the last menstrual period, menstrual dates were used to estimate gestational age in both Kaniyambadi and Nova Scotia. Analyses were restricted to live births and stillbirths with a calculated gestational age between 20 and 50 completed weeks or a birth weight ≥ 400 g. Rates of low birth weight (per 100 live births) and trends by 2-year period were examined; the rate in 2004–05 was contrasted with the rate in 1986–87 using percent declines and 95% confidence intervals, while the statistical significance of temporal trends was assessed using a Chi-square for linear trend in proportions. Rates of preterm birth (per 100 live births), small-for-gestational age (per 100 live births), stillbirth , early neonatal death , perinatal mortality  and maternal mortality  and temporal changes were assessed using the same methods. Small-for-gestational age live births were identified using the 10standard . We alsoonal age . Sensitional age . We alsoWe determined etiologic fractions  for polyThere were 49,806 total births in Kaniyambadi and 208,020 total births in Nova Scotia between 1986 and 2005. The proportion of births to mothers < 20 years of age was 18.8% in Kaniyambadi and 7.6% in Nova Scotia. Births to older mothers, previous cesarean delivery rates and multiple birth rates were higher and previous perinatal death rates were lower in Nova Scotia  did not substantially alter these indices . Regression analysis showed that adjustment for maternal age, parity, height and infant sex did not alter temporal trends in preterm birth and low birth weight. Preterm birth rates (2004–05 vs 1990–91) did not decline , while low birth weight rates showed a non-significant reduction  in the adjusted models. SGA rates, based on the Canadian fetal growth standard, did not decrease significantly , while SGA rates based on the Indian standard showed an attenuated, significant decline .The rates of low birth weight (5.5%), preterm birth (6.9%) and SGA (7.5%) were substantially lower in Nova Scotia; the rates of these outcomes in the restricted subgroup with more accurate data (77% of live births) were 5.0%, 6.8% and 7.5%, respectively. The SGA rate in Nova Scotia was < 1% when the Indian fetal growth standard was used to identify SGA live births. Low birth weight rates were stable, preterm birth rates increased and SGA rates decreased in Nova Scotia between 1986–87 and 2004–05 Table .The perinatal mortality rate in Kaniyambadi was 38.6 per 1,000 total births compared with 8.5 per 1,000 total births in Nova Scotia. Stillbirth rates in Kaniyambadi decreased by 15%  between 1986–87 and 2004–05; the linear trend between 1986–87 and 2004–05 was significant (P = 0.01) but that from 1990 onwards was not (P = 0.59). Early neonatal deaths decreased by 38% (95% CI 15–54%); the linear trend between 1986–87 and 2004–05 was significant (P = 0.002), although that from 1990–91 to 2004–05 was not (P = 0.66). Similarly, perinatal mortality rates declined by 26% (95% CI 10–40%) from 1986–87 to 2004–05; the linear trend over the entire study period was significant (P = 0.003), yet the trend from 1990 onwards was not (P = 0.49). Regression adjustment for maternal age, parity, height and infant sex did not change temporal trends in perinatal mortality rates; the adjusted odds ratio contrasting 2004–05 vs 1990–91 was 0.82 (95% CI 0.59–1.13). Rates of perinatal mortality in Nova Scotia declined by about 50%, with larger relative declines in early neonatal death rates  were high and cesarean delivery rates were low in Kaniyambadi relative to Nova Scotia, suggesting one potential avenue for reducing perinatal mortality . Birth rth percentile cut-off of the Indian standard  resulted in a SGA rate of 6.7% which was substantially lower than the low birth weight rate (17%). This suggests that the Indian standard [SGA rates were very high in Kaniyambadi under the Canadian fetal growth standard and low under the decades-old Indian fetal growth standard. The low 10standard  is perhastandard -36, resestandard , may proth percentile at 40 weeks was 2,315 g in the older Indian standard, and approximately 2,550 g for males and 2,450 g for females according to the South Indian standard [We could not use a more recent South Indian fetal growth standard  because standard ). Regresstandard ), thoughThe relatively high rate of preterm birth observed in Kaniyambadi also requires attention; preterm birth is increasingly being recognized as a primary contributor to perinatal death in less industrialized countries . The useInfant mortality rates in India and other less industrialized countries appear to show large reductions in recent years  represent a reporting artefact. The failure to reduce low birth weight, preterm birth and perinatal death rates in the 16 years after 1990 raises the question of health policy focus With nutritional supplementation having minimal efficacy in increasing gestational weight gain and birth weight  and no aThe above-mentioned need to reconsider the health policy focus  is also supported by the experience of immigrant Asian-Indians. Studies show that Asian-Indians in the United States have better socio-demographic risk profiles , higher rates of preterm birth, much higher rates of small-for-gestational age, higher rates of fetal death and the same (or modestly higher) neonatal and post-neonatal mortality rates as their white counterparts -45. ThesThe relatively high rates of perinatal death and the relatively low rates of cesarean delivery among births ≥ 2,500 g also support the need to enhance the availability and uptake of health care services over the medium and long term future. The absence of a change in preterm birth rates in Kaniyambadi also reflects a health service issue; iatrogenic preterm birth at 34–36 weeks gestational age has increased in industrialized settings and this has been associated with declines in perinatal death ,47. WherThe applicability of our study's findings to other parts of India and related environments deserves comment. Kaniyambadi has intensive community- and hospital-based health care services and other inputs that exceed those extant in other parts of rural and semi-rural India. Therefore some of the findings of our study may not directly apply to regions without such services. Nevertheless, we believe our study provides some important caveats for reducing perinatal mortality rates in India and similar countries. Intensive community-based and other inputs, although successful in reducing post-neonatal mortality, are unlikely to reduce rates of preterm birth, low birth weight and perinatal death in such populations. Therefore, a focus on reducing low birth weight may not be as productive as a focus on reducing perinatal morbidity and mortality across the birth weight range through investments in health care infrastructure and personnel.The strengths of our study include a longstanding, prospective collection of data through a closely monitored health information system. Data were collected by trained personnel who worked closely with village-resident health workers, thereby ensuring completeness and accuracy of the information. Although Kaniyambadi has a relatively small population, it is likely representative of other rural populations in south India. Our study has several limitations, however. Primary among these is the potential for data errors in various measurements including birth weight and menstrual-based gestational age. Menstrual-based estimates of gestational age suffer from a higher degree of error than gestational age confirmed by early ultrasound measurements ,50. HoweOur study showed high rates of low birth weight and relatively high rates of preterm birth in Kaniyambadi. The magnitude of the SGA rates was dependent on the fetal growth standard used to define SGA, with very high rates observed when the Canadian fetal growth standard was used and low rates observed when an older Indian standard was used. Secular declines in SGA were also dependent on the fetal growth standard used. No substantial declines were observed in low birth weight, preterm birth, or perinatal death over the previous 16 years, whereas maternal mortality rates declined dramatically. Overall, this picture suggests the need for a reexamination of the traditionally focus on preventing low birth weight and for increasing support for clinical infrastructure and trained personnel.The authors declare that they have no competing interests.This study was carried out by the Christian Medical College-Canada Collaborative Group, which includes all the listed authors. KSJ proposed the study. Methods and preliminary analyses were discussed by all the authors  and other staff at CHAD hospital. Additional analyses were carried and a manuscript was drafted by KSJ. This was revised for intellectual content based on comments from the authors and all authors approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:


Higher risks of preterm birth and small for gestational age babies have been reported in teenagers. The aim of this study was to investigate the relationship between first and second teenage pregnancies and preterm birth, birthweight and small for gestational age (SGA).th percentile), very SGA (VSGA< 3rd percentile). We compared these outcome measures in teenagers' first and second pregnancies with those of mothers aged 20 to 29 yrs.All women aged 14 to 29 yrs who gave birth to live singletons in the North Western Region of England between January 1st 2004 and December 31st 2006 were identified. Women were classified in three groups; 14-17 yrs, 18-19 yrs and 20-29 yrs (reference group). The outcome measures were preterm birth, very preterm birth, birthweight, SGA  and second  time mothers aged 14-17 yrs compared to the reference group. Birthweight was reduced in the first  and second  time mothers aged 14-17 yrs compared to the reference group. There was some evidence of a protective effect against VSGA in 14-17 yr old first time mothers .Teenage mothers are at increased risk of preterm birth compared to adult mothers and this risk is further increased in second time teen pregnancies. This study highlights the importance of ensuring pregnant teenagers have appropriate antenatal care. A first pregnancy may be the first and only time a pregnant teenager interacts with health services and this opportunity for health education and the promotion of contraception should not be overlooked. The United Kingdom is widely quoted as having the highest teenage pregnancy rate in Western Europe,2 and thThe association between young maternal age and adverse pregnancy outcome has been attributed to gynaecological immaturity and the growth and nutritional status of the mother. The redMost studies investigating teenage pregnancy compare outcomes in teenagers with outcomes in adult mothers. Many investigators were unable to control for the combination of adverse socioeconomic pressures,19. FurtThe North West of England is well placed to study the outcomes of teenage pregnancy. The North Western Perinatal Survey collects routine maternal, obstetric and neonatal information on all infants delivered in the region's 21 maternity hospitals. These hospitals cover a wide geographic area containing a mixture of urban and rural communities and provide for women from a variety of ethnic groups and socio-economic strata, including those residing in areas of considerable social deprivation.The aims of this study were to determine whether teenage pregnancy was associated with reduced infant birthweight and with increased rates of small for gestational age (SGA) and preterm birth, whether the association differed by parity, and whether any associations were independent of confounding factors.We performed a population based cohort study using a database generated from the North Western Perinatal Survey (NWPS), based at St Mary's Hospital, Manchester, UK. We identified all singleton live infants who were born between January 1, 2004 and December 31, 2006. The data were restricted to women aged between 14 and 29 yrs in their first or second pregnancies.We defined first births as the first pregnancy to result in a singleton live born infant and second births were defined as the second pregnancy to result in a singleton live born infant. Women were classified into 3 groups according to their age at the time of delivery; 14-17 yrs, 18-19 yrs and 20-29 yrs of age.th percentile and very SGA (VSGA) if their IBR was below the 3rd percentile.Birthweight records were considered invalid if they were less than 500 g or more than 5500 g. Preterm delivery was defined as birth ≥ 33 and < 37 gestation weeks and very preterm delivery was defined as birth ≥ 23 and < 33 weeks. We used individualised birthweight ratios (IBR) to generate a measure for SGA. IBR corrects birthweight for gestational age taking into account ethnic origin, infant sex, parity and maternal height and weight. The IBR provides a better indicator of perinatal mortality than birthweight for gestational age alone. Babies For the statistical analysis we used multiple regression models which allow us to control for the potential confounding effect of several variables on the association between teenage pregnancy and the outcome measures. Multiple logistic regression was used to estimate the odds ratio (OR) of preterm birth, very preterm birth, SGA and VSGA. All ORs were adjusted for maternal ethnicity, body mass index (BMI) and infant sex using the categories indicated in Table We used linear regression with robust estimation variance to estimate the difference in mean birthweight among teenage mother groups compared with adult women. The models were adjusted for social deprivation score, parity, BMI, ethnicity and gestational age. Since the relationship between birthweight and gestational is not linear, we used fractional polynomial regression to determine the best functional model which resulted in adding four fractional polynomial functions of gestational age to the model. The teenage group was divided into two groups: 14-17 and 18-19 yrs of age. We compared the outcome measures of women in each of the teenage groups with those of the adult women (reference group). All models were carried out separately for first and second births. All statistical analyses were performed using Stata Software 10.From 2007, additional information regarding maternal smoking at the first antenatal visit has been recorded by the NWPS. Thus we had access to data on all 2007 births from the NWPS in which to explore the potential confounding effect of maternal smoking on the association between young maternal age and preterm birth and birthweight. We carried out two sets of models; the first set were adjusted for social deprivation score, BMI, ethnicity and infant sex while the second set were adjusted for the same variables in addition to maternal smoking. These models were carried out separately for primiparous and multiparous patients.The present study used anonymised data and it is not possible to identify participants. The director of the NWPS gave permission to conduct this study. Thus ethical approval was neither required nor requested.The cohort consisted of mothers of 56,353 singleton live babies. Mothers of 3,636 babies were between 14-17 yrs of age at the time of birth, mothers of 7506 babies were 18-19 yrs and mothers of 45,211 babies were 20-29 yrs old. Table The adjusted analyses suggested that teenagers aged 14-17 had a significantly higher risk of preterm birth  and very preterm birth  compared to adult women  and very preterm birth  were increased significantly in second time mothers aged 14-17 yrs compared with second time adult mothers  but not preterm birth  Table . In addiThe estimates suggested that mean birthweight was reduced by 55 grams in second time mothers aged 18-19 yrs  compared with second time adult mothers and the result was similar when the analysis was restricted to term babies. These women were at significantly increased risk of SGA  and preterm birth  but not VSGA  and very preterm birth  compared with second time adult mothers  than for older teenagers (18-19 yrs) and in the 14-17 yrs old group the risk was greater in second pregnancies than in first. Our findings are in contrast to a recent Swedish longitudinal study which reported that teenagers were at a higher risk of preterm birth in their first as compared to their second births. Previou yrs thanAlthough we found a significant reduction in birthweight of babies born to teenage mothers compared to adult mothers, when individualised birthweight ratios (IBRs) were used, teenagers having their first baby did not have an increased risk of delivering either SGA and VSGA babies. In teenagers having their second baby, the risks of SGA and VSGA were not significantly increased apart from SGA in teenage women aged 18-19 yrs. These findings are in contrast to an American study which found that teenage birth was independently associated with risk of intrauterine growth restriction. HoweverAlthough our study was population-based, there were limitations. Firstly, there were missing data on the potential confounders, although the missing data appeared to be equally distributed across the maternal age groups. Therefore these missing data are unlikely to have affected our reported estimates. Secondly, the main cohort lacked information on maternal smoking. The 2007 data suggested that although maternal smoking had some effect on the association between young maternal age and birthweight, there was little if any confounding effect on the association between young maternal age and preterm birth. However, maternal smoking data are often subject to misclassification as a substantial proportion of pregnant smokers misreport their smoking status. Moreover many quitters are reported to smoke again during pregnancy,31. EnglIt is unlikely that the association between second teenage pregnancy and preterm birth can be explained by differences in the interval between pregnancies among teenage and older mothers since the associations observed were much greater than those previously reported for short intervals between pregnancies. It is pIn conclusion, our findings suggest an association between second teenage delivery and preterm birth and birthweight independent of maternal social deprivation, ethnicity, BMI and smoking. Teenagers have an increased risk of preterm and very preterm delivery and this risk is greatest for younger teenagers and those in their second pregnancy. In contrast to previous studies, there was little evidence for an association between teenage pregnancy and risk of delivering a small for gestational age infants. This study highlights the importance of ensuring pregnant teenagers have appropriate antenatal care. Moreover a vital component of this care is post-natal contraception to prevent a second teenage pregnancy with potentially higher risks of adverse outcomes. A first pregnancy may be the first and only time a pregnant teenager interacts with health services and this opportunity for health education and the promotion of contraception should not be overlooked.The authors declare that they have no competing interests.all co-authors contributed to the 1) conception and design or analysis and interpretation of the data; 2) drafting the article or revising it critically for important intellectual content; 3) all co-authors approved the submission of this version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/10/36/prepub


Ibadan, Nigeria, has a very high rate of complications of male circumcision. In a previous survey, redundant or excessive loss of foreskin, skin bridges and injury to the glans penis were the major types of complications identified. Epidermal inclusion cyst complicating neonatal male circumcision appears to be extremely rare, and an extensive search of all databases revealed no reports in the recent literature.In 1992, a 10-year-old boy was seen at the urology outpatients clinic presenting with a globular swelling in the penile skin located at the ventral surface proximal to the coronal sulcus. The histology of the excised mass revealed an epidermal inclusion cyst. Since then, he has remained healthy.Epidermal inclusion cyst complicating male neonatal circumcision is extremely rare. The diagnosis is easy and a simple total excision is curative. Neonatal circumcision is a common practice in Nigeria . HoweverA 10-year-old boy presented at the urology outpatients clinic in December 1992 with a 9-year history of a penile swelling. The swelling was located at the ventral aspect of the penis along the circumcision scar (Figure et al.[In a systematic review of the prevalence of complications of circumcision in anglophone Africa, Muula et al. did not The term 'epidermal inclusion cyst' has been used interchangeably with 'epidermal cyst' and 'epidermoid cyst' in the medical literature. These cysts result from the proliferation of epidermal cells within a circumscribed space of the dermis and appear as firm, round, mobile, subcutaneous nodules of variable size. A central pore or punctum that may tether the cyst to the overlying epidermis is an inconsistent finding.This was not present in this patient but his cyst was tethered to his circumcision scar. These cysts can occur in various parts of the body but are found most commonly in the vulva, especially in populations where female circumcision is practised ,6. In adEpidermal inclusion cyst complicating male neonatal circumcision is extremely rare. The diagnosis is easy and a simple total excision is curative.Written informed consent was obtained from the patient's next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The author declares that he has no competing interests.


A 32-year-old woman with a choledochal cyst (Todani type I) developed recurrent acute pancreatitisleading to calcific chronic pancreatitis. She had previously been treated with two cyst drainageprocedures and subtotal cyst excision. This association between choledochal cyst and chronic pancreatitishas not been previously reported. Severe continuing symptoms led to pylorus-preserving proximalpancreatoduodenectomy, which was undertaken to prevent future carcinoma in the cyst remnant andprogression of the chronic pancreatitis


Birth before the 37th week of gestation (preterm birth) is an important cause of infant and neonatal mortality, but has been little studied outside of wealthy nations. Chile is an urbanized Latin American nation classified as "middle-income" based on its annual income per capita of about $6000.We studied the relations between maternal social status and neighborhood social status on risk of preterm delivery in this setting using multilevel regression analyses of vital statistics data linked to geocoded decennial census data. The analytic data set included 56,970 births from 2004 in the metropolitan region of Santiago, which constitutes about 70% of all births in the study area and about 25% of all births in Chile that year. Dimensionality of census data was reduced using principal components analysis, with regression scoring to create a single index of community socioeconomic advantage. This was modeled along with years of maternal education in order to predict preterm birth and preterm low birthweight.Births in Santiago displayed an advantaged pattern of preterm risk, with only 6.4% of births delivering before 37 weeks. Associations were observed between risk of outcomes and individual and neighborhood factors, but the magnitudes of these associations were much more modest than reported in North America.While several potential explanations for this relatively flat social gradient might be considered, one possibility is that Chile's egalitarian approach to universal prenatal care may have reduced social inequalities in these reproductive outcomes. Birth before the 37th week of gestation (preterm birth) is an important cause of infant and neonatal mortality . NonetheChile is a Latin American nation with just over 16 million inhabitants, about 85% of which are urbanized, with about 40% of the population living in the capital district of Santiago. It is representative of a large number of nations outside of North America and Europe that are rapidly urbanizing, integrating women into the formal economy and experiencing an epidemiologic and demographic transition away from high levels of childhood mortality and toward an older population age structure and higher burden of chronic diseases. The World Bank currently includes 96 nations as "middle income" nations – gross national income (GNI) per capita of more than $875 but less than $10,726 – including Chile, which had a 2005 GNI of about $6000 . AlthougWe therefore set out to estimate the relation between maternal social status and neighborhood social status on risk of preterm delivery in an urbanized region of a middle income country, as well as the joint relations between these factors in multilevel regression analyses. We used maternal education as an indicator of individual social status and an index created from decennial census data as an indicator of neighborhood social status. By geocoding maternal addresses from birth certificates, we were able to assign exposure values to births as recorded in vital records data.We studied all births in the metropolitan region of Santiago de Chile  in the year 2004. Vital registration in Chile is virtually complete and quality of data is generally regarded as meeting high standards . There wIn addition to individual level information from the birth record on mother's age and number of years of education, we also extracted mother's address at the time of birth, and used this to geocode each mother to one of the 348 census districts within the study area. Census districts in the metropolitan region of Santiago contain an average of about 10,000 inhabitants, and therefore are somewhat larger than those used in North America. Geocoding of address information from the birth records had not previously been attempted in this setting, and the data required extensive revision due to spelling inconsistencies in addresses, inability of the software (Arcview V.3.3) to accommodate Spanish language characters such as "ñ", and a large number of small streets and passages with similar names. After careful hand-processing of many of the records that failed in the initial automated match, we were able to achieve a match rate of just above 70%. This is lower than typically reported for cities in Europe and North America, but one of the first attempts to apply this technology in an urban developing nation context. Therefore, 23,811 (29.0%) births were not assigned to a census district, and are not analyzed further, leaving an effective analytic sample size of 56,970 births. To allay potential concerns about selection bias due to differential geo-coding success, we conducted two-sided t-tests between geocoded and non-geocoded birth records, which demonstrated no significant differences in mean birthweight, birth length, or weeks of gestational age. Age of mother was significantly different between groups, but the mean values differed by only about 4 months, suggesting minimal potential for bias. Furthermore, it is important to note that the final analysis sample of geocoded births accounts for almost a quarter (24.7%) of all births in the entire nation of Chile during the study year.Census data from 2002 were assigned to each birth based on her census district of the mother's residence, but a data reduction strategy was required to avoid modeling a large number of highly correlated social indicators. Using a technique commonly applied to census data in the developed world ,14, we uinverse density (i.e. number of domiciles per capita in the district)percentage of homes connected to a sewer systemlogarithm of the average total valuation per square meterpercentage of the population that does not self-identify as indigenouspercent of the population with formal schoolingpercent of the population that is not currently unemployed and seeking workpercentage of the population that is classified as an owner or employerpercent of domiciles that have concrete pavingpercent of domiciles that have indoor plumbingthe percent of domiciles that have indoor heating.The average inter-item correlation for these 10 values is 0.62, with a scale reliability coefficient equal to 0.94. The first principal component, accounting for over 66% of the total variability in the items, is used as the index of socio-economic advantage. All 10 items load in the same direction on this factor, with loadings falling in a narrow range from roughly 0.25 to 0.35. The estimated score has good face validity as a measure of community SES as evidenced by a correlation of 0.47 with years of maternal education.We studied preterm delivery, which was defined as singleton gestational age less than 37 weeks, as estimated clinically by the attending health care provider . This assessment has proved more accurate than maternal reporting of last menstrual period alone, since it also may involve information from ultrasound , which iBecause of exposure information at the individual and the community level, the data have a multilevel structure. We therefore employed random effects logistic regression, allowing a district-specific intercept term to be estimated as a draw from a random distribution of intercepts, conditional on modeled covariates . ExponenBirths in Santiago during the study period demonstrate a relatively advantaged pattern of outcomes, with modest risks of low birth weight (4.9%) and preterm delivery (6.4%) in comparison with developed countries Table . For exaA relationship between individual maternal education and preterm delivery is observed in the data, but it is modest in magnitude Table . When adOur study of individual education and community SES in relation to preterm birth in a middle-income country demonstrated detectable effects that were nevertheless much more modest in magnitude than what is commonly observed in the US and Europe. Figure These results are also consistent with the pattern of adverse outcomes observed in previous studies for Hispanic migrants in the US ,22. RiskThe surprisingly healthy profile of birth risk in Chile compared to the US, despite being a much poorer country, may reflect substantial differences in the organization of medical services for pregnant woman. The current program for universal provision of prenatal care was developed by the Ministry of Health in the late 1970s. There are no official statistics for the actual coverage of this ostensibly obligatory prenatal care, due to the fact that many women who qualify for public health insurance (FONASA) choose to instead attend private health care providers during pregnancy. In 1983 an early estimate of national coverage showed that 91% of pregnant women had prenatal care throughout pregnancy . A laterThe Chilean prenatal care program prides itself on an integrated multidisciplinary perspective with the intention of providing for complete physical and mental health of the mother during pregnancy and the mother-child pair after parturition. The program includes at least 6 professional visits by clinical nurse midwifes and/or physicians, referral to tertiary health care facilities if needed, educational sessions, laboratory exams including blood and urine monitoring  as well as glucose tolerance testing, and screening for HIV, syphilis, Chagas disease, and cervical cancer. Women also receive three ultrasound examinations around gestational weeks 14, 24 and 34. Dietary supplements are also included and distributed according the nutritional status of the mother . All of The observed modest socioeconomic gradient in preterm birth in these data does not imply socioeconomic equality in health more generally. Chile remains a profoundly unequal society in many respects, with one of the highest gini coefficients in the world for income inequality  , p. 332]233]. DesWhile these data appear consistent with a more modest effect of social factors on preterm birth at the individual and community level, there are potential alternate explanations. One might question data quality, but this seems the least likely explanation for the findings, given the consistently observed advantage for Chilean pregnancies and the resources and attention devoted to data integrity in Chile. A more plausible concern is that our a priori decisions about relevant census variables may have failed to capture true social variation between communities . For exaWe conducted a study of maternal social status and neighborhood social status on risk of preterm delivery in a middle-income country, using vital statistics and geocoded decennial census data. Analysis of 56,970 births that occurred in 2004 in the metropolitan region of Santiago revealed a relatively advantaged pattern of preterm risk overall, with only 6.4% of births delivering before 37 weeks. Moreover, although associations were observed between risk of outcomes and individual and neighborhood factors, the magnitudes of these associations were much more modest than those reported in North America. This relatively flat socioeconomic gradient for adverse birth outcomes is similar, however, to that reported for Hispanic women in the United States, especially those that are born in other countries. We considered several potential explanations for the modest social gradient in risk observed in these data, including the potential impact of Chile's relatively egalitarian approach to universal prenatal care.The authors declare that they have no competing interests.JSK conceptualized and led the study, conducted the statistical analysis and led the writing of the manuscript. FTA assembled and managed the data sets, geocoded the data, assisted in analysis and interpretation, and collaborated in the writing of the paper. PP obtained the raw data, organized the research effort, consulted on all substantive and analytic questions, and collaborated in the writing of the paper.The pre-publication history for this paper can be accessed here: