Epidemiological studies have clearly demonstrated a strong association between low birth weight and long-term renal disease. A potential mediator of this long-term risk is a reduction in nephron endowment in the low birth weight infant at the beginning of life. Importantly, nephrons are only formed early in life; during normal gestation, nephrogenesis is complete by about 32–36 weeks, with no new nephrons formed after this time during the lifetime of the individual. Hence, given that a loss of a critical number of nephrons is the hallmark of renal disease, an increased severity and acceleration of renal disease is likely when the number of nephrons is already reduced prior to disease onset. Low birth weight can result from intrauterine growth restriction (IUGR) or preterm birth; a high proportion of babies born prematurely also exhibit IUGR. In this paper, we describe how IUGR and preterm birth adversely impact on nephrogenesis and how a subsequent reduced nephron endowment at the beginning of life may lead to long-term risk of renal disease, but not necessarily hypertension. Low birth weight infants are at increased risk of renal disease. A reduced complement of nephrons at the beginning of life in infants that are intrauterine growth restricted (IUGR) and/or born preterm may be the cause of their long-term risk of renal disease. A reduced nephron endowment in low birth weight infants may also lead to vulnerability to hypertension in adulthood; however, experimental evidence suggests that they are not causally linked. In this paper we discuss how IUGR and preterm birth adversely impact on nephron endowment and how this has the potential to lead to deleterious effects on renal health.The novelty of this paper is the emphasis on both preterm birth and IUGR leading to low birth weight; the effects of preterm birth on the kidney have only recently been described, and many of these studies have been undertaken in our laboratory. In this regard, much of the information reported in this paper has been derived from studies over the last decade in our laboratory.Low birth weight is defined as a birth weight of an infant less than 2500 grams at full term . It can The diagnosis of IUGR is assigned to infants with a birth weight and/or birth length below the 10th percentile for gestational age . IUGR isPreterm birth is defined as birth prior to 37 completed weeks of gestation ; it can The proportion of preterm births is different for each gestational age category, with the majority of preterm births being near term; approximately 60% of preterm births are at 34–36 weeks gestation, 20% at 32-33 weeks, 15% at 28–31 weeks, and just 5% of preterm births are at less than 28 weeks gestation . The incThe majority of preterm births (approximately 40%) occur due to spontaneous preterm labour, 25% occur following premature prelabour rupture of membranes, and 35% are clinically indicated . The cauin utero and in preterm infants, this occurs in the early neonatal period  arises from the lower limb of the S-shaped body through a process of glomerulogenesis. Firstly, the inner cells of the lower cleft of the S-shaped body differentiate into the glomerular  podocytes, while the outer cells form the parietal podocytes which line the Bowman's capsule , 23, 26.Importantly, nephrogenesis is normally completed by 32–36 weeks gestation, with no new nephrons formed for the lifetime of the individual after this time , 28. TheA number of autopsy studies have reported a significant reduction in nephron number as a result of IUGR , 40, 41.It has been proposed in previous studies that preterm birth leads to a reduced nephron endowment; Rodríguez et al.  found thPreterm birth occurs at a time when nephrogenesis is often ongoing in the kidney of the infant. In our laboratory, we have clearly demonstrated in both baboon and human kidneys that nephrogenesis continues after preterm birth , 59; obsOf particular concern, many of the glomeruli in the outer cortex appeared markedly abnormal in some of the preterm kidneys; the number of abnormal glomeruli varied widely, from less than 1% to as high as 13% of glomeruli in the preterm human kidney  and 22% ex utero as that in utero [Our findings thus strongly suggest that it is the glomeruli formed postnatally in the extrauterine environment that are vulnerable to abnormalities. The abnormal glomerular morphology is characteristic of atubular glomeruli , 62, andin utero , 64. ThiInterestingly, we have shown a marked increase in the size of the preterm kidneys in the neonatal period which is not proportional to body size , 59. In In addition to accelerated maturation, there was also evidence of glomerular hypertrophy, probably due to the increased functional demands on the kidney after birth and/or an increase in renal blood flow. If this hypertrophy persists into later life, it is likely to lead to deleterious effects on renal function given that glomerular hypertrophy is linked to renal pathology in adulthood , 65. Index utero. Overall, the haemodynamic adaptations of the fetal kidney to extrauterine life involve transformation from a high vascular resistance fetal organ with low blood flow (primary blood flow to the inner cortex), into a high blood flow, low vascular resistance organ with primary blood supply to the outer renal cortex [The glomerular hypertrophy and accelerated renal maturation in preterm infants are not surprising, given the marked change in hemodynamics at the time of birth and the increased functional demands on the kidney l cortex . Blood fl cortex –71. Aftel cortex .Importantly, studies in animal models with ongoing postnatal nephrogenesis have shown that after birth there initially remains a low blood flow to the outer renal cortex which is likely a protective mechanism to protect developing, immature glomeruli in this region of the kidney . It is uThere are a number of studies both in humans and experimental models showing a link between low birth weight and long-term increases in blood pressure and susceptibility to the development of renal disease.A systematic review of eighty studies, that had investigated the relationship between levels of blood pressure and birth weight, showed that in the majority of studies  blood pressure fell with increasing birth weight; there was an approximately 2 mmHg decrease in blood pressure for each increase in 1 kg of birth weight . AlthougIn addition to long-term effects on blood pressure, there is substantial epidemiological data linking low birth weight with chronic kidney disease. In this regard, a recent meta-analysis of 31 relevant studies, conducted by White et al. , concludextremely LBW compared to children born VLBW. As discussed earlier, postnatal nutrition and weight gain may adversely impact on ongoing nephrogenesis and long-term renal function; in relation to this, Bacchetta et al. [Most of the studies used in the meta-analyses described above have not separated low birth weight due to IUGR and preterm birth. Importantly, in this regard, there is now mounting epidemiological evidence linking preterm birth with the induction of hypertension in adults –84 and ea et al.  have dema et al.  have demThe mechanisms leading to the increased risk of developing elevated blood pressure and vulnerability to long-term renal disease in low birth weight infants are currently unknown; a reduced nephron endowment at the beginning of life are postulated to play a role.Convincing evidence from renal cross-transplantation studies directly implicates the kidney in the induction of essential/primary hypertension. For example, both human and experimental studies have shown that when the kidney from a hypertensive donor is transplanted into a normotensive recipient, it leads to the induction of hypertension in the recipient; the opposite occurs when the kidney from a normotensive donor is transplanted into a hypertensive recipient –100. FurIn the late 1980s, Brenner et al.  put forwImportantly, in our laboratory, we have conducted a number of studies which have addressed the Brenner hypothesis , 115. InHence, overall the experimental evidence now clearly indicates that a reduced nephron endowment at the beginning of life does not necessarily lead to hypertension. However, it is conceivable that when the functional reserve of nephrons is severely reduced, the glomeruli will eventually reach the limits of physiological compensatory hypertrophy and pathological mechanisms will come into play; elevations in blood pressure may then also ensue. Indeed, prolonged hyperfiltration of hypertrophied glomeruli can ultimately lead to glomerulosclerosis and eventual glomerular loss , 117. SiThis paper has shown how IUGR and preterm birth can adversely impact on the number of nephrons in the kidney and lead to glomerular hypertrophy; this in turn can lead to the induction of pathological processes within the kidney when the glomeruli reach their limits of compensation. A reduced nephron endowment does not necessarily lead to hypertension but renders the kidney vulnerable to long-term renal disease. Since IUGR is often a comorbidity of preterm birth, it is likely that individuals who were born IUGR and preterm will be particularly vulnerable to secondary renal insults.


Obesity in pregnant women is a major problem affecting both the mother and her offspring. Literature on the effect of obesity on preterm birth is inconsistent and few studies have investigated the influence of weight gain during pregnancy. This study examined the effect of maternal pre-pregnancy BMI and weight gain during pregnancy on preterm birth.Data from the Collaborative Perinatal Project (CPP) on 45,824 pregnant women with singleton, live-born infants with no sever congenital anomalies was analyzed. Primary outcome variables included preterm (< 37 weeks of gestation), categorized into spontaneous preterm with and without premature rupture of membrane (PROM) and indicated preterm. Maternal BMI was categorized into underweight (BMI < 18.50), normal weight (BMI =1 8.50 – 24.99), overweight (BMI = 25.00 – 29.99), and obese (BMI ≥ 30.00). Multinomial regression analysis was conducted and OR and 95% CI were calculated.The rate of spontaneous preterm birth with PROM among overweight women decreased with increasing weight gain but increased among women who had excessive weight gain. Similarly, a U-shaped rate of spontaneous preterm birth with and without PROM was observed in obese women. Gaining less weight was protective of spontaneous preterm with and without PROM among overweight and obese women compared to normal weight women. Among underweight women, gaining < 7 kg or 9.5-12.7 kg was associated with increased odds of indicated preterm birth. Appreciable differences were also observed in the association between pre-pregnancy BMI, gestational weight gain and the subtypes of preterm births among African Americans and Caucasian Americans.Reduced weight gain during pregnancy among overweight and obese women is associated with reduced spontaneous preterm birth with and without PROM. Health care professionals and public health workers should be aware of this risk and adhere to the 2009 IOM guideline that recommended reduced weight gain during pregnancy for obese and overweight women. The rate of obesity was highest among non-Hispanic blacks at 50% [Obesity is a major public health problem in the United States . Accordis at 50% ,3. Maters at 50% -10. Howes at 50% -6,11-18.s at 50% .In general, preterm birth is classified into spontaneous with premature rupture of membrane (PROM), spontaneous without PROM and indicated preterm birth. The latter is usually performed due to maternal or fetal problems. The etiology and risk factors of preterm births differ by the type of preterm birth ,21. Pre-Another factor that plays a significant role in the association between pre-pregnancy weight and preterm birth is race. A study from Florida that analyzed 540,981 birth cohorts reported that African American women were disproportionately affected by obesity and preterm births. While the odds of preterm births were 71% higher in African American women, the odds were only 15% higher in Caucasian obese women compared to normal weight women . Unlike The Institute of Medicine (IOM) and the public health community has been concerned with the increased trends of obesity . In 2009Data for this analysis were drawn from the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) Collaborative Perinatal Project (CPP). The study methodology including, setting, population and recruitment has been described in detail elsewhere . BrieflyData was downloaded via File Transfer Protocol (FTP) from the Johns Hopkins University Bloomberg School of Public Health . The datThe dataset included information on reproductive history including gravidity, parity, previous abortions, diabetes, preeclampsia, chronic hypertension, previous pregnancy outcomes, number of prenatal visits and prior history of low birth weight and preterm births. Current pregnancy history including delivery method, child’s sex, APGAR score, birth weight, gestational age, congenital anomalies, preeclampsia, gestational diabetes and hypertension, anemia and other pregnancy outcomes were collected. It also included data on previous medical history including history of diabetes, chronic hypertension, heart, kidney, liver and other chronic and acute diseases. Additionally, the dataset included lifestyle factors such as cigarette smoking, substance use during pregnancy and demographic information such as mother’s age, marital status, education, race, and socio-economic index.The main outcome variable, gestational age, was provided in the dataset; and was calculated by subtracting the last menstrual period from the date of delivery. Gestational age was dichotomized into preterm birth (<37 weeks of gestation) and full term birth  spontaneous with premature rupture of membranes, b) spontaneous without PROM, and c) indicated. In accordance to the literature, preterm was further categorized as: a) spontaneous with premature rupture of membranes, b) spontaneous without PROM, and c) indicated (induced). These subtypes of preterm birth were created using two variables, ‘labor onset type’ and ‘rupture of membrane reason’. ‘Labor onset type’ was categorized in the data as “spontaneous”, “induced”, or “none”. The ‘rupture of membrane reason’ was dichotomized as “spontaneous”, and “non-spontaneous”. The spontaneous preterm birth with PROM was coded ‘yes’, if the response for ‘Labor onset’ is ‘spontaneous’, ‘the rupture of membrane’ variable was coded ‘spontaneous’ and the gestational age at birth was <37 weeks. Conversely, the spontaneous preterm birth without PROM was coded ‘yes’, if the response for ‘Labor onset’ was ‘spontaneous’ and the rupture of membrane variable was coded ‘non-spontaneous’ and the gestational age at birth was <37 weeks. Finally, if the response to ‘Labor onset’ was ‘induced’ and the gestational age at birth was <37 weeks, this group was categorized as indicated preterm births.Maternal BMI was calculated using self-reported pre-pregnancy weight and height. Pre-pregnancy BMI was categorized according to the World Health Organization’s definition into four groups: underweight (BMI < 18.50), normal weight (18.50 – 24.99), overweight (25.00 – 29.99), and obese (BMI ≥ 30.00) . PregnanMaternal hypertension was defined as hypertension documented by evidence occurring during any part of the pregnancy (including before 24 weeks) or a diagnosis of chronic hypertension. Preeclampsia was categorized as “yes” if mild or severe preeclampsia or eclampsia was indicated in the dataset . Prior and current medical conditions and pregnancy outcomes were categorized as ‘yes’ and ‘no’. Lastly, the number of prenatal visits was examined and categorized as ‘1-5’, ‘6-10’,’11-14’ and’15 or more’. Due to insufficient data, the Kotelchuck index for adequacy of pregnancy was not calculated.Cigarette smoking and other substance use during pregnancy, were coded as ‘yes’ or ‘no’. Maternal race was collapsed into three categories: White, Black, and Other. The ‘other’ category included “Asian”, “Puerto Rican”, and “Other”. Maternal education was categorized as less than high school, high school, or greater than high school attainment. Socio-economic index, a computed variable that was provided in the data set was examined. The variable was calculated by averaging the component scores for education, occupation, and family income. A lower score indicates lower affluence and conversely, higher indices indicate greater affluence (possible range of 0.0 to 10.0) .Data were examined using descriptive statistics, including frequencies, means and standard deviations, chi-square and t-tests. Multinomial logistic regression was conducted to investigate the association between pre-pregnancy BMI and the different sub-types of preterm categories stratifying by weight gain during pregnancy and to control for the effect of confounders. Odds ratios and 95% confidence intervals were calculated and the most efficient model was determined using 10% change in the estimate. Statistical analyses were performed with the SAS software .The average age of the study sample was 24.1 years (standard deviation (SD) = 6.0 years)  had increased odds of spontaneous preterm birth with and without PROM, regardless of their race Table . ConversThe adjusted model, controlling for study sites, maternal education, and race is shown in Table Underweight women who gained less than 7.0 kg or between 9.5 and 12.7 kg during pregnancy had significantly increased odds of spontaneous preterm birth with PROM  and without PROM  compared to normal weight women. Similarly, the odds of spontaneous preterm birth with PROM  was higher among underweight women gaining 9.5-12.7 kg.Among overweight and obese women, gaining less than 7.0 kg during pregnancy was statistically significantly associated with decreased odds of spontaneous preterm birth with and without PROM, compared to normal weight women. Further, gaining less weight (<7.0 kg) among overweight women was significantly associated with indicated  compared to normal weight women.Overweight and obese women who gained 7.0 to 9.4 kg during pregnancy had decreased odds of spontaneous preterm birth with or without PROM compared to normal weight women. Among overweight women, this weight gain was associated with nearly 30% decreased odds of spontaneous preterm birth with PROM  and over 40% decreased risk of spontaneous preterm birth without PROM . Obese women who gained 7.0 to 9.4 kg were also significantly less likely to have a spontaneous preterm birth with PROM  and spontaneous preterm birth without PROM  than normal weight women Further, obese women who gained 9.5-12.7 kg during pregnancy had lower odds of spontaneous preterm birth without PROM compared to normal weight women . Additionally, obese women who gained 9.5-12.7 kg were 2.7 times more likely to have an indicated preterm birth compared to normal weight women .This study identified weight gain during pregnancy and pre-pregnancy overweight and obesity to have differential effects on spontaneous preterm birth with and without PROM and indicated preterm birth. While gaining less than 7.0 kg was found to be a risk factor for preterm birth with and without PROM among underweight women, it was a protective factor for women who were overweight and obese. Additionally, gaining 7.0-9.5 kg was associated with lower odds of spontaneous preterm birth with and without PROM. While gaining less than 7.0 kg was found to be protective among overweight women, gaining 9.5-12.7 kg was found to be a risk factor for indicated preterm births in obese women. Consistent to this analysis, several studies have found a positive relationship between obesity and preterm birth -6,14-17.Although African American race is a known risk factor, racial differences in the association between gestational weight gain, obesity and preterm birth is not accentuated in this study. While gaining 7.0 kg was protective for preterm births with and without PROM, among both races, weight gain as high as 9.4 kg and 12.7 kg were found to be protective of preterm birth without PROM only in overweight and obese African American women, respectively. Few studies have also examined the racial differences between obesity and preterm birth ,25. HoweDespite the inconsistencies in the literature, this study reported that, among obese women, gaining less weight is protective of spontaneous preterm birth with and without PROM. On the other hand, gaining excessive weight is a risk for indicated preterm birth. There is some evidence to suggest inflammatory reaction and infection related to obesity may be the biological mechanism that is responsible for the reported association between obesity and preterm birth ,39,40. APrior studies had clearly established the relationship between obesity and fetal macrosomia ,43. FurtThe ability to utilize a large multisite data with over 45,000, ethnically diverse women is one of the major strengths of this study. Additionally, this dataset provided data on pre-pregnancy weight. Most available datasets do not provide data on pre-pregnancy weight and this dataset provided a unique opportunity to assess this association. This data allowed the evaluation of multiple confounding factors that may influence this association. However, other than race, maternal education, and study site, no other factors examined in this analysis showed a statistically significant confounding effect. Considering the data for this analysis was collected over 40 years ago, it is important to consider contextual differences such as advances in health care that could not be assessed in this analysis. Although obesity was not a major problem 40 years ago, this study has reported a significant association between obesity and preterm birth and the interaction between pre-pregnancy BMI and weight gain during pregnancy. Further analysis with more recent data, including an examination of the adherence to the current IOM guidelines, is warranted.Despite its strengths, there were some limitations to this analysis. First, gestational weight gain was calculated by subtracting weight at first prenatal care from weight at delivery. This computation, did not take into account the duration of pregnancy. Calculating the weekly weight gain rate to adjust for the length of pregnancy was not possible due to insufficient data on the timing of the first prenatal care. Although calculating weight gain rate is a preferred method, it also ignores the normal pattern of weight gain during pregnancy, assuming a steadily constant weight gain throughout the pregnancy. Secondly, pre-pregnancy weight was self-reported and may be subject to recall bias. Third, gestational age was calculated by subtracting the last menstrual period from the date of delivery and may also be subject to recall bias. Fourth, the data had overrepresented inner city African American population which is not representative of the US population.In conclusion, this study reported that gaining less weight is protective of spontaneous preterm with and without PROM among obese and overweight women. Excessive weight gain during pregnancy among obese women is associated with indicated preterm birth. Health care professionals and public health workers should be aware of this risk and adhere to the 2009 IOM guideline.Pre-pregnancy overweight and Obesity coupled with excessive weight gain is a risk factor for early preterm birth.The authors declare that they have no competing interests.SWM guided the analysis, wrote a significant portion of the manuscript. DLB participated in the data analysis, wrote a portion of the manuscript. MM participated in the analysis of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/13/120/prepub


This data has implications for future strategies of disease prevention.There is general consensus that season of birth influences the risk of developing psychiatric conditions later in life. We aimed to investigate whether the risk of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depressive disorder (RDD) is influenced by month of birth in England to a similar extent as other countries using the largest cohort of English patients collected to date . When cases were compared to the general English population  all diseases showed a seasonal distribution of births (SC  Seasonality dominates many features of the global environment and that this will impact human health appears inevitable. Seasonal factors can potentially act even before birth, when according to the “fetal origin of adult disease hypothesis“ environmental influences leading to changes in embryonic/fetal tissue structure and function can influence the risk of adult physiological and pathological conditions The concept of a season of birth study is simple and involves comparing the season or month of birth of individuals with a condition and comparing them to controls. However, performing the study with scientific rigour is more complicated. For example, since the size effect reported by such studies is often very small a large number of patients is required for statistical power. Furthermore, pooling data from different countries represents another potential source of bias since general population birth trends can substantially differ between countries.We aimed to further confirm the association of psychiatric disease with season of birth using three new large and recently collected cohorts of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depression disorder (RDD) patients in a single country (England). To our knowledge this is the largest study performed to investigate this hypothesis within England.http://www.hesonline.nhs.uk/). In particular we gathered information on English resident outpatients seen by a doctor between 2003 and 2011 across England and suffering from SC , BAD  and RDD . As an additional non psychiatric control we also collected month of birth data from 3,545 Parkinson's disease (ICD-10=G20) patients. To avoid counting the same patient more than once with the same condition, counts were based on the unique patient identifier (HESID) which is based on date of birth, postcode, sex, local patient identifier and NHS number. Patients were compared to 29,183,034 English general population births between 1950 and 1990 from the Office for National Statistics (http://www.ons.gov.uk/). We used the Walter and Elwood seasonality test to estimate within year fluctuations with a 12 month periodicity  Data on month of birth was collected for 57,971 patients from the English Hospital Episode Statistics . No difference was observed between patients suffering from Parkinson's disease and the general population (p=0.48).The birth distribution of controls, SC, BAD and RDD patients is presented in p<0.0001) and a significant trough exactly six months later in July . Peak to trough ratio showed a 17% increased risk for January vs July born individuals . Similarly to SC, BAD patients were more likely to be born than expected in January  and less in August and September . The January vs September ratio also indicated a 17% increased risk . In RDD an almost significant May peak  and a significant November deficit  were observed. Odds ratios with 95% CI are presented in When monthly ORs were calculated, SC had a statistically significant peak in January  and autumn (trough). Not many studies have assessed the seasonality of births in patients with depression. However, our results are consistent with those of Torrey et al who reported a spring excess of births in a large cohort of American patients a priori evidence for a season of birth effect in psychiatric conditions makes the data unlikely to be a chance finding. It could be that parents of psychiatric patients have an unusual pattern of conception and it would have been interesting to investigate whether the birth distribution of unaffected siblings of these psychiatric patients also follows a seasonal trend. Unfortunately data on siblings were not available to us, but other studies have tried to answer this question (in particular in SC) and overall the season of birth bias appears present in SC patients but not in their unaffected siblings This study has limitations. Information on sex and ethnicity was not available and this represents a potential source of bias. However the large sample size , and the strong Despite researchers' efforts, the causative factor/s behind this association remains unknown. A key factor which needs to be considered is that the risk is not only higher in certain months of the year vs others but also follows a seasonal distribution. This suggests a seasonal nature of the environmental causative factor. Seasonality dominates global environment, influencing effects of changing climate, sunlight, diet and infection. Interestingly, several lines of evidence now support a role for vitamin D deficiency in the pathogenesis of psychiatric conditions, in particular schizophrenia To conclude, season of birth influences the risk of SC, BAD and RDD in England to a similar extent as other countries and suggests that at least a proportion of psychiatric disease could be prevented by ameliorating the risk factor/s responsible for these intriguing epidemiological observations. It is now paramount to identify the seasonal factors that underlie the associations uncovered.


Conventional soybean lipid emulsions contain no docosahexaenoic acid (DHA) or arachidonic acid (AA). We investigated the relationship between blood DHA and AA status in 27 very-low-birth-weight (VLBW) infants with or without parenteral lipid emulsion.Sixteen infants received parenteral lipid emulsion, and 11 infants were control group. The fatty acid composition of the erythrocyte membrane was analysed at birth and at 2 weeks of age.No significant difference in AA levels was observed in the lipid emulsion group between the two time points, whereas the AA levels at 2 weeks were significantly lower than at birth in the control group. The DHA levels in both groups at 2 weeks were significantly lower than at birth, but no group differences were observed at both time points.The use of parenteral soybean oil lipid emulsions in VLBW infants in the postnatal period may prevent the decline in the AA level but does not appear to influence the DHA level. Preterm infants, especially very-low-birth-weight (VLBW) infants, often require parenteral lipid emulsion if an adequate energy and lipid intake cannot be achieved by enteral feeding because their polyunsaturated fatty acids (PUFAs) body stores are very low, whereas their metabolic requirements are high. Therefore, a PUFA supply is of critical importance .The conventional lipid emulsion for preterm infants is prepared from long-chain triacylglycerols, mostly soybean oil. The adequacy of soybean lipid emulsions has been questioned, primarily in view of the very high concentrations of linoleic acids  and α-linolenic acids  in most commercial preparations. Both of these PUFAs are metabolized to long-chain PUFA (LCPUFA) by desaturation and adding extra double bonds to the carboxyl group end of the molecule.Docosahexaenoic acid DHA; 22:6n-3) and arachidonic acid  are the major LCPUFA components of membrane lipids in the brain and retina , and the type of feeding depended on the mother’s willingness or ability to provide breast milk. When breast milk was unavailable, infants received a cow’s milk-based premature formula  containing LCPUFA. Parenteral nutrition (PN) with dextrose, amino acids  and vitamins was started at birth in all infants. Parenteral lipid emulsion was started from 72 h of age if the infant could not tolerate a sufficient amount  of feeding.The infants were divided retrospectively into two groups according to the use of a parenteral lipid infusion. The lipid emulsion group  received the parenteral lipid infusion, and the control group  did not receive parenteral lipid emulsion because all infants received sufficient  of feeding before 5 days after birth.In the lipid emulsion group, the administration of 0.60 ± 0.17 g/kg per day  was started from 3 to 8 days (mean 5.1 ± 2.3 days) after birth and continued until the intake of enteral feeding was over 50% of the total water intake for 4 to 18 days (mean 6.9 ± 3.6 days) with the emulsion level being increased to 2.0 g/kg. The composition of the soybean oil lipid emulsion is shown in All mothers had similar educational backgrounds and were between 25 and 38 years of age. The characteristics of the sampled mothers are presented in g for 10 min. The erythrocyte pellet was washed twice with 0.9% NaCl and stored at −80°C until analysis.Venous blood samples (approximately 600 μL) were collected in EDTA-containing tubes at birth and 2 weeks of age. The samples were centrifuged at 3000 The following biochemical blood variables were assessed at birth and 2 weeks of age by routine laboratory techniques: aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil), direct bilirubin (D-bil) and C-reactive protein (CRP).Erythrocyte lipids were extracted using chloroform and 2-propanol (7:11), according to the method described by Rose and Oklander . ErythroU-test. Differences between the two time points within groups were analysed using paired t-tests. p Value less than 0.05 was considered statistically significant. All statistical analyses were performed using StatView 5.0 software .The results are presented as the mean ± standard deviation (SD). Differences between groups were analysed using the Mann–Whitney Samples from 27 VLBWIs were analysed, and the patient characteristics are summarized in At 2 weeks of age, the LA levels were significantly higher in both groups than at birth. No significant differences were observed between the groups at the two time points. The ARA levels in the lipid emulsion group remained unchanged throughout the study, whereas the ARA level in the control group was significantly lower at 2 weeks of age compared to at birth. Furthermore, the AA levels in the control group at 2 weeks were significantly lower than in the lipid emulsion group. No significant differences were found in the eicosapentaenoic acid  levels between the time points or groups. At 2 weeks of age, the DHA levels were significantly lower in both groups than at birth. No significant differences were observed between the two groups at the two time points. The n-6/n-3 ratio in both groups at 2 weeks was significantly higher than that at birth, but no between-group differences were found at both time points .No significant differences were observed between the groups in the incidence of intracranial haemorrhage (IVH), necrotizing enterocolitis (NEC), period of ventilation, or the levels of transaminases, bilirubin and C-reactive protein at 2 weeks .Very-low-birth-weight infants are usually treated routinely with total PN containing dextrose, amino acids, lipid emulsions, vitamins and minerals to maintain their nutritional status with the aim of matching normal intrauterine growth during the first few weeks of life.Lipids are necessary in neonates receiving PN because of their high caloric value, low osmolarity and essential fatty acid (EFA) content . HoweverSimmer and Rao  reviewedHowever, concerns have been raised about the early administration of lipid emulsions because of potential adverse effects including chronic lung disease, increases in pulmonary vascular resistance, impaired pulmonary gas exchange, bilirubin toxicity, sepsis and free radical stress . Lipid eIn this study, we evaluated the incidence of NEC, ROP, respiratory morbidity, and markers of liver dysfunction, jaundice and sepsis. We did not see any deleterious effect of early lipid emulsion. Furthermore, we previously compared the oxidative stress levels in 23 premature infants by measuring urinary 8-hydroxdeoxyguanosine  and found no significant differences in the urinary 8-OHdG excretion levels between the lipid-infused and not-infused groups at 2, 7 and 14 days of age .As with previous studies ,21, we fOur results indicate that parenteral lipid emulsion first administered to VLBW infants around 5 days after birth prevented the decline in the AA level but did not influence the DHA level or n-6/n-3 ratio during the early postnatal period or the short-term clinical outcome. Therefore, we conclude that under the conditions studied, the administration of lipid emulsion to VLBW infants appears safe. Further research is needed to evaluate the long-term outcomes on growth, respiratory morbidity and neurodevelopment.


Prenatal exposure to persistent organic pollutants, e.g. polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) has been suggested to negatively affect birth weight although epidemiological evidence is still inconclusive. We investigated if prenatal exposure to PCBs and PBDEs is related to birth weight in a Swedish population with background exposure.ortho PCBs  and tetra- to hexa- brominated PBDEs . Simple and multiple linear regression models were used to investigate associations between lipid-adjusted, ln-transformed PCB and PBDE concentrations, and birth weight. Covariates included in the multivariate regression model were PCB and PBDE exposure, maternal age, pre-pregnancy BMI, weight gain during pregnancy, education, smoking, gender of the infant and gestational length. The effect of including fish consumption was also investigated.Breast milk was sampled during the third week after delivery from first-time mothers in Uppsala county, Sweden 1996–2010 (POPUP cohort) (N = 413). Samples were analysed for di-ortho PCBs was significantly associated with increased birth weight . The result did not change when gestational length was added to the model. An inverse association between PBDE(4)  and birth weight was observed in the multivariate model including gestational length . Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders of the association between di-ortho PCBs and birth weight. The associations were not alleviated after adjustment for fish consumption, a major source of PCB and PBDE exposure. The observed associations were stronger for boys than for girls.In the multivariate model, prenatal exposure to di-ortho PCBs and PBDE(4) may influence birth weight in different directions, i.e. PCB exposure was associated with higher birth weight and PBDE exposure with lower birth weight. Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders that may hide positive association between di-ortho PCB exposure and birth weight if they are not included in the statistical model. We speculate that even small PCB- and PBDE-induced shifts in the distribution of birth weight may influence future public health in populations with background exposure.Our results indicate that prenatal exposure to di- Among other potential effects, PCBs and PCDD/Fs are suggested to cause reduced birth weight [Toxic persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), polychlorinated dibenzo-h weight -4 and thh weight ,5,6. Amoh weight ,8. Both h weight -11 and ch weight ,13. Possortho PCBs and tetra- to hexa brominated PBDEs are related to birth weight in a Swedish population of first-time mothers with background exposure. The level of di-ortho PCBs is a good marker for dioxin-like PCBs and PCDD/Fs in Sweden [The aim of this study was to investigate if prenatal exposures to di-n Sweden , and then Sweden . Fish con Sweden , and at n Sweden -19. Furtn Sweden -22.ortho PCBs and tetra- to hexa brominated PBDE and birth weight in a cohort of Swedish first-time mothers. Prenatal exposure was estimated by levels in breast milk sampled three weeks after delivery.In this article we report crude and adjusted associations between prenatal exposure to di-The POPUP study  started in 1996, and up to 2010 we recruited 526 first-time mothers born in Nordic countries and living in Uppsala County. In 1996 to 1999, participants were randomly recruited in late pregnancy and donated a blood sample in gestational week 32–34 (N = 316) . 203 of Data on maternal and child characteristics were obtained from questionnaires or from the Swedish Medical Birth Register at the National Board of Health and Welfare ,23. 118 ortho substituted PCB congeners PCB 138, PCB 153 and PCB 180 (N = 413), and a randomly selected number of samples (N = 364) for four PBDE-congeners . The analyses were performed at the Swedish National Food Agency (NFA), and have been described earlier [ortho PCBs were analysed by gas chromatography coupled to high-resolution mass spectrometry [All breast milk samples were analysed for the di- earlier . After etrometry . To comptrometry . PBDEs wtrometry . The totortho PCBs and PBDEs were used to estimate prenatal exposure since these levels give a good estimate of the maternal body burden during pregnancy, and consequently the exposure of the fetus during pregnancy [Lipid-adjusted breast milk levels of di-regnancy ,27. For Correlation analysis (Pearson) and one-way analysis of variance (ANOVA) were used to investigate univariate associations between birth weight and individual characteristics of the mothers.ortho PCBs  and PBDE(4)  and birth weight. Logarithmically transformed exposure data were used since the distribution of data closely followed a log-normal distribution. Birth weight was normally distributed in the study population.We used simple and multiple linear regression models  to analyse associations between prenatal exposure to di-ortho PCBs or PBDE(4) and birth weight were investigated in separate models. In the adjusted model, di-ortho PCBs and PBDE(4) were included simultaneously. In addition, covariates included in the adjusted model were maternal age, pre-pregnancy BMI, weight gain during pregnancy, education, smoking during pregnancy and sex of the child. These variables have all been associated with birth weight [In the crude analyses, the associations between di-h weight -33. Covah weight  to the sCharacteristics of the participating women and children are presented in Table ortho PCBs and PBDEs among the women recruited in 1996–2010 are presented in Table ortho PCB data was available for all study participants (N = 413) and PBDEs in samples from 364 randomly selected participants from 1996 to 2010. PCB 153 was the di-ortho PCB congener with the highest mean concentration and the highest mean level among the PBDEs was shown for BDE-47. The levels of di-ortho PCBs were about thirty times higher than the levels of PBDE(4).Data on breast milk levels of di-ortho PCB exposure and birth weight (Table ortho PCB concentration. This corresponds to a mean difference in birth weight between the 25th (64 ng/g lipid) and 75th (132 ng/g lipid) percentile of di-ortho PCB exposure of approximately 100 g. When the analysis was restricted to individuals with data on gestational length, the p-value increased to 0.08, but the β-coefficient was essentially unchanged  and birth weight became stronger when fish consumption was included in the multivariate model, β decreased with 29% from −106 to −137 (p = 0.01). When female and male infants were studied separately, the multivariate models showed significant inverse associations between PBDE(4) and birth weight in male infants, but not in females  and birth weight was inverse in the unadjusted as well as in the multivariate model Table . When th and birtortho PCBs and birth weight. A shift towards higher birth weights at higher PCB exposures may be non-beneficial since positive associations between birth weight and risk of obesity later in life have been demonstrated [ortho PCBs on birth weight and a negative effect at higher exposure levels. For endocrine disrupting chemicals, different effects at low and high doses are currently discussed [Our study showed a weak but significant positive association between background prenatal exposure to di-nstrated ,35. In cnstrated ,36. Amonnstrated ,37-41, wnstrated -48. One nstrated  is unceriscussed .ortho PCB exposure and birth weight in the multivariate model was observed only after adjustment for maternal pre-pregnancy BMI, weight gain during pregnancy and concurrent exposure to PBDE(4). Increased pre-pregnancy BMI and weight gain are both associated with increased birth weight as well as with decreased levels of PCBs in breast milk and maternal blood [In our study, the positive association between di-al blood ,23, and Many studies like ours adjust their results for maternal pre-pregnancy BMI, but among studies showing inverse associations or no associations between birth weight and PCB exposure, Lopez-Espinosa et al.  is the oortho PCB exposure and birth weight. It could be speculated that PCBs and PBDEs influences birth weight via biochemical pathways in such way that exposure to PBDE(4) may to some extent mask the association between di-ortho PCBs and birth weight and vice versa. When the multivariate regression analysis was restricted to individuals with data on gestational length, the association did not change, although it became non-significant most probably because of a decreased statistical power  was an important covariate in the analysis of associations between di-er Table . Adding er Table , indicatortho PCBs, if causal. Maternal estrogen levels during pregnancy have been linked to increased birth weight [in vitro and in vivo bioassays [ortho PCBs alone are not responsible for the positive association with birth weight. In addition to di-ortho PCBs and PBDEs, a selected number of breast milk samples from the POPUP cohort have previously been analysed for non-ortho PCB congeners, 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) and for p,p’-DDE (N = 242-383) [ortho PCB levels and the levels of non-ortho PCB TEQs , PCDD/F TEQs and p,p’-DDE were strong (Pearson correlation coefficients 0.7-0.9), showing that di-ortho PCB is a good marker for exposure to the other compounds. Consequently, it is difficult to separate the influence of different chlorinated compounds on birth weight from each other, and it is possible that di-ortho PCB exposure is a proxy for exposure to the total mixture (‘cocktail’).We can only speculate about a possible mechanism responsible for the observed positive association between birth weight and di-h weight ,52, and ioassays -56. It i-DDE N = 2-383 [24ortho PCB exposure and gestational length as covariates. A β-coefficient of −106 corresponds to a mean difference in birth weight between the 25th (1.6 ng/g lipid) and 75th (3.5 ng/g lipid) percentile of PBDE(4) exposure of approximately −80 g. The association was similarly significant in the multivariate model , when the analysis was restricted to individuals with data on gestational length  and birth weight. The association was significant in the multivariate regression model including di- and birtThere are few other studies on associations between PBDEs and birth weight, and these studies report no ,58 or inortho PCBs. Consequently, our results strongly suggest that it is important to control for concurrent exposure to different contaminants, such as PCBs and PBDEs, in studies of POPs and birth weight. Including several pollutants in the same model may however introduce over-adjustment bias if the pollutants are strongly correlated. In our study, the correlation between levels of di-ortho PCBs and PBDE(4) was weak (Pearson correlation coefficient 0.19) and collinearity did not bias the associations. The weak correlation between di-ortho PCBs and PBDE(4) is probably due to differences in exposure pathways. Food is the main source of human exposure to di-ortho PCBs, while both diet and indoor dust may be important sources of PBDEs [Despite considerably lower exposure levels in the POPUP cohort than in the studies by Foster et al.  and Harlof PBDEs .Possible mechanisms responsible for the observed negative association between PBDE(4) exposure and birth weight are unknown but could involve effects on endocrine systems. For example, animal as well as epidemiological studies have shown that PBDEs can alter thyroid hormone levels -66, whicortho PCBs as well as PBDEs may be a proxy for fish consumption since fish is the major contributor to the dietary intake of these substances in the Swedish population [ortho PCBs exposure and birth weight was not appreciably changed when fish consumption during pregnancy was added to the regression model, thus indicating that omega-3 fatty acids in fish are not responsible for the observed association for di-ortho PCB. However, the inverse association between PBDE(4) and birth weight became stronger when fish consumption was added to the regression model. Fish consumption may consequently confound this association because of its positive association with both PBDE exposure and birth weight.Exposure to di-pulation . Maternapulation . Long-chpulation ,18,67. IWhen female and male infants were studied separately, the observed associations were only significant in males Table . The obsortho PCBs and PBDEs. This made it possible to adjust associations for concurrent exposure. The study is also relatively large in comparison to previously published studies, although statistical power is a problem in the analyses of e.g. sex differences. The long recruitment period could have influenced the results since the breast milk levels of PCBs and PBDEs have decreased in the POPUP cohort over the years [ortho PCBs became stronger . Available data on several life-style factors, including dietary habits, enabled us to evaluate several possible confounders. Some of the variables included in the final regression model were self-reported which adds uncertainty to the results, although a strong correlation between register and self-reported data was found for some variables. Data on gestational length was only available for 71% of the participants, and it is therefore difficult to conclude whether the observed effects on birth weight are related to gestational length  or fetal growth .An important strength of our study is the exposure assessment including chemical analysis of both di-he years . Howeverortho PCBs and PBDE(4) indicates that these substances may influence birth weight in different directions, especially in boys. Exposure to di-ortho PCBs tended to be associated with higher birth weight while the association between PBDE(4) and birth weight was inverse. Importantly, we were able to adjust for maternal weight gain during pregnancy, a factor that should be consider in future studies since failure to control for this may result in false negative associations between di-ortho PCB exposure and birth weight. The observed associations may be causal, but it is also possible that some unmeasured or unknown confounding factors have influenced the results. The differences in birth weight associated with an increase in exposure from the 25th to the 75th percentile of exposure were relatively small (+100 and −80 g for di-ortho PCBs and PBDE(4) respectively). This can be compared with a difference in birth weight between non-smoking and smoking mothers of about 200 g [Our relatively large study of background prenatal exposure to di-ut 200 g ,70. Bothut 200 g . We specp-dioxin; PCDF: Polychlorinated dibenzofuran; POP: Persistent organic pollutant; POPUP: Persistent Organic Pollutants in Uppsala Primiparas; SD: Standard deviation; SE: Standard error; PBDE(4): sum of BDE-47, BDE-99, BDE-100, BDE-153; TEQ: Toxic equivalent; VIF: Variance inflation factor.ANOVA: Analysis of variance; BMI: Body mass index; LOD: Limit of detection; LOQ: Limit of quantification; NFA: Swedish National Food Agency; PBDE: Polybrominated diphenyl ether; PCB: Polychlorinated biphenyl; PCDD: Polychlorinated dibenzo-The authors declare that they have no competing interests.All authors have read the final version of the manuscript and are in agreement that the work is ready for submission to a journal. SL took part in the planning of the study and the acquisition of data, conducted the statistical analyses and did most of the writing. AG planned and designed the study, helped interpreting the results and took part in the preparation and reviewing of the manuscript. MA was responsible for the chemical analyses, for the quality control of analytical results and for the reviewing of the parts of the manuscript involving chemical analyses. POD planned the study and helped interpreting results and critically revise the manuscript. AH helped interpreting the results in a toxicology context and revised the manuscript. SCL helped planning the statistical analyses, interpreting the results and revised the statistical parts of the manuscript.


Severe acute malnutrition in childhood manifests as oedematous  and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity.We reviewed the records of all children admitted with severe acute malnutrition to the Tropical Metabolism Research Unit Ward of the University Hospital of the West Indies, Kingston, Jamaica during 1962–1992. We used Wellcome criteria to establish the diagnoses of kwashiorkor (n = 391), marasmus (n = 383), and marasmic-kwashiorkor (n = 375). We recorded participants' birth weights, as determined from maternal recall at the time of admission. Those who developed kwashiorkor had 333 g  higher mean birthweight than those who developed marasmus.in utero induce potential marasmics to develop with a metabolic physiology more able to adapt to postnatal undernutrition than those of higher birthweight. Given the different mortality risks of these different syndromes, this observation is supportive of the predictive adaptive response hypothesis and is the first empirical demonstration of the advantageous effects of such a response in humans. The study has implications for understanding pathways to obesity and its cardio-metabolic co-morbidities in poor countries and for famine intervention programs.These data are consistent with a model suggesting that plastic mechanisms operative  Each year nine million children under age five years die: malnutrition contributes to one-third of these deaths Kwashiorkor and marasmic patients also display different patterns of intermediary metabolism in utero that induce developmentally plastic responses that match the fetus' metabolism to the anticipated postnatal environment These fundamental differences in acute and post-recovery metabolism led us to hypothesize that kwashiorkor and marasmus represent differential responses to the same nutritional insult based on pre-existing metabolic differences We reviewed the admission records for all patients who had been admitted to the Tropical Metabolism Research Unit, University of the West Indies, Kingston, Jamaica with severe acute malnutrition between 1963 and 1993. We abstracted clinical , anthropometric (weight and height at admission), and survival data as well as recalled birth weight. Birth weights that were recalled by the mother at the time of admission have been shown to be highly correlated with recorded birthweight We used the Wellcome criteria to make the diagnosis: weight for age <60% without oedema for marasmus, and weight for age 60–80% with oedema for kwashiorkor. Marasmic-kwashiorkor had weight for age of <60% but had oedema. Children who were 60–80% weight for age without oedema were classified as undernourished.The study was approved by the Faculty of Medical Sciences Ethics Committee, University of the West Indies.We used linear regression analysis to estimate the difference in birth weight by diagnosis, controlling for sex.1,336 patients were admitted to the Tropical Metabolism Research Unit Ward with severe acute malnutrition. Details of their clinical and anthropometric data, survival and birth weights are shown in Controlling for sex, the mean birth weight of children with kwashiorkor was 333 g  more than those with marasmus. The equivalent figures for males and females were 307 (155 to 458) and 371 (188 to 553) respectively. Birth weights for children with marasmic-kwashiorkor were intermediate . Adjusti27 males and 20 females died (4.1%). The odds ratio of death was 3.7  for kwashiorkor compared to marasmus. Survival was not associated with birth weight; nor did the difference between birth weights of patients with marasmus and kwashiorkor differ according to whether they died during that hospital admission or not.This study shows that children who experience severe acute malnutrition and develop kwashiorkor, marasmic-kwashiorkor or marasmus have pre-existing developmental differences at birth, as reflected by substantial differences in birth weight. This observation was consistent over the 30 years in the population under study.in uteroThis finding provides a developmental explanation for the disparate syndromes of severe malnutrition. It implies that underlying developmental attributes play a role in determining which syndrome is expressed when children are exposed to severe undernutrition. We propose that the developmental environment induces plastic changes affecting the development of metabolic control that can manifest as distinctly different phenotypes under extreme conditions. In the rodent, very different metabolic phenotypes with associated epigenetic changes can be induced by different prenatal nutritional conditions and these offspring respond very differently to postnatal manipulations such as leptin administration It has been suggested that developmental plasticity is maintained in mammals to allow the fetus and infant to adjust their development to anticipated future nutritional and other environments. Two classes of developmentally plastic response have been described in utero.The differences in metabolic and clinical attributes between marasmus and kwashiorkor provide a clear demonstration of the pre-pubertal fitness advantage of a predictive adaptive response induced by poor transplacental nutrition, as indicated by lower birthweight. The children born with lower birthweight had a metabolic response to severe undernutrition that aided survival, resulting in the more benign syndrome of marasmus. This finding provides the first direct evidence in humans in support of the fitness-enhancing effects in childhood of anticipatory responses Nineteen million children worldwide every year become severely wasted As this was a retrospective cohort there is a danger of misclassification. However, we sought to reduce this bias by reviewing all admission clinical findings and derived independent diagnoses of kwashiorkor, marasmus and marasmic-kwashiorkor using the Wellcome Classification. Birthweight recall by mothers of the subjects when subjects had been admitted as children might have been inaccurate. However, the validity of such recall has been established in our setting (13). Errors of recall are likely to occur in a way that does not depend on diagnosis, and so are likely to blunt rather than generate birth weight differences between diagnoses. Because the syndromes use weight at admission in their definition, the observed association between syndrome and birth weight may result from a mixture of two effects – an in utero developmental effect and the tracking of weight as children age. However, using the presence of oedema alone as the basis of analysis gives a similar conclusion suggesting that the finding reported here is not due to any confounding effect of birthweight on later weight or height gain.


Background: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents.Objectives: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother–child study.Methods: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006–2010. Maternal diet was estimated through food-frequency questionnaires.Results: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was –132 g ; the corresponding difference for head circumference was –0.33 cm . Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight.in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women.Conclusions: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure  Occupational exposure and smoking were originally regarded as the main sources of exposure to acrylamide in humans (IARC 1994), but a decade ago it was unexpectedly discovered that acrylamide formed in a wide variety of carbohydrate-containing foods during frying or baking at high temperatures . Worldwiin utero .ex vivo placenta perfusion studies  as part of research exploring the impact of diet during pregnancy on child health (http://dx.doi.org/10.1289/ehp.1205327)]. Precise participation rates for the present analysis cannot be estimated because several filters were applied for inclusion of mothers in the NewGeneris study, such as giving birth during the periods of cord blood collection and processing, getting sufficient volume of cord blood, successful blood processing, and analyzing biomarkers.d health . PregnanQuestionnaire information on maternal characteristics and cord blood Hb adduct measurements was available for 1,151 mother–child pairs. We excluded 16 pairs of twins and 34 mother–child pairs with missing information on maternal smoking, gestational age, birth weight, and/or sex of the child, leaving 1,101 mother–child pairs for analysis. Information on birth weight, head circumference, gestational age, sex, and mode of delivery was obtained from maternity records.Gestational age for participants from Denmark, Greece, and Spain was estimated from the interval between last menstrual period and date of the delivery and was corrected by ultrasound measurement if there was a discordance of ≥ 7 days between both estimates. Ultrasound-based estimation was provided for most participants from England and Norway. We defined small-for-gestational-age (SGA) children as those who weighed less than the 10th percentile of the cohort-specific reference of fetal growth , stratified by completed week of gestation and sex.http://dx.doi.org/10.1289/ehp.1205327). Written informed consent for participation of the women and their children was obtained from all participating women.Ethical approval was obtained from the research ethics committee in each country: the Regional Ethical Review Board in Stockholm, Sweden; the Capital Region of Denmark; the Ethical Committee of the University Hospital in Heraklion, Crete, Greece; the Norwegian Regional Committee for Medical and Health Research Ethics; the Clinical Research Ethics Committee of Barcelona, Spain; and the Bradford Local Research Ethics Committee, Bradford, United Kingdom. Further details regarding ethics approval are provided in Acrylamide and glycidamide Hb adducts in cord and maternal blood. Cord blood was collected in heparin tubes from the placenta by umbilical puncture immediately after delivery, following a common protocol at each site. Erythrocytes were separated by centrifugation and stored at –20°C before and after shipment on dry ice. Hb adducts from acrylamide and glycidamide were simultaneously determined by the “adduct FIRE procedure” (fluorescein isothiocyanate R Edman) in 1,101 cord blood samples and 172 maternal blood samples  using the same methods .Maternal diet. Detailed information on maternal diet during pregnancy was obtained from the mothers using FFQs collected before or at the time of delivery (n = 146), those who smoked during the last 4 months of pregnancy (n = 129), and 25 women with a total energy estimate of < 500 or > 6,000 kcal/day  and calculated beta-coefficients and 95% confidence intervals (CIs). Logarithmic-binomial regression models were used to determine relative risks (RRs) and 95% CIs for SGA. Cord blood Hb adduct levels were modeled on a continuous scale (effect estimated per 10 pmol/g Hb increments) or categorized according to quartiles of the distribution. All models were adjusted for country of the child’s birth and gestational age (continuous in completed weeks). Additional adjustment for gestational age as a quadratic term (continuous completed weeks squared) gave nearly identical results (not shown). Further adjustment was based on a priori selection of potential risk factors for reduced birth weight including maternal smoking , passive smoking , sex, prepregnancy body mass index , parity , maternal age (years), maternal ethnicity , and maternal education  as a marker of socioeconomic position. In addition, models were adjusted for high or low maternal consumption during pregnancy (according to country-specific median intake) of fruit and vegetables (based on 20–61 questionnaire items), fish , and soft drinks  as markers of more versus less healthy dietary patterns.n = 1,101) and separately for children born to nonsmokers (n = 972).The average lifespan of erythrocytes is 4 months in adults . TherefoIn addition to estimating associations adjusted for country, we estimated country-specific associations between acrylamide Hb adducts and birth weight, and performed a meta-analysis to derive pooled estimates of effect. Only results from fixed-effects models are shown because heterogeneity of effects between centers were not statistically significant.Associations of maternal diet with acrylamide Hb adduct levels in cord blood, and with birth weight, were estimated using linear regression models that were adjusted as described above. Exposure–response curves were estimated using a generalized additive model with the dietary score modeled as a smoothed spline with 2 degrees of freedom, adjusted for country and gestational age. We used alpha levels of 5% as reference value for statistical significance and Stata S.E. version 10.0 for the statistical analyses .Levels of Hb adducts from acrylamide. Acrylamide and glycidamide Hb adducts in cord blood were detectable in all children . The median Hb adduct level from acrylamide was 14.4 pmol/g Hb  and for glycidamide was 10.8 pmol/g Hb . There was a statistically significant correlation between glycidamide and acrylamide adduct levels in cord blood . Median acrylamide adduct levels were higher in cord blood from children of mothers who smoked (n = 129) than in children of nonsmokers . Corresponding levels for glycidamide adducts were 20.7 versus 10.1 pmol/g Hb (p < 0.001), and for ethylene oxide adducts (as a marker of exposure to cigarette smoke) were 24.5 versus 8.9 pmol/g Hb, (p < 0.001).r = 0.95, p < 0.001, n = 171) and glycidamide Hb adducts . Among nonsmokers the highest median level of acrylamide adducts was detected in children from England (23.6 pmol/g Hb) and the lowest in children from Denmark (12.0 pmol/g Hb).The median acrylamide Hb adduct levels in cord blood were approximately half of the levels in paired maternal blood . Hb adduFactors associated with birth weight. The participating mothers were mainly white, nonsmoking, in their late 20s to early 30s with prepregnancy BMI in a range of 18.5–24.9 kg/m2 and already parous (p < 0.001).y parous . The prey parous . On averHb adduct levels and birth weight. Higher levels of acrylamide and glycidamide adducts in cord blood were associated with a significant decrease in birth weight (p = 0.074) for a 10-pmol/g Hb increase in acrylamide adducts when adjusted for gestational age and country of birth; the corresponding reduction in birth weight for glycidamide adducts was 65 g .h weight . The mean = 1,063), the difference in birth weight for children in the highest versus lowest quartile of acrylamide Hb adduct levels was –137 g ; a similar difference was observed for 939 term babies of nonsmokers .Birth weight decreased monotonically with increasing quartiles of exposure . The estn = 747) is smaller than the population in models adjusted only for country and gestational age . We also estimated associations adjusted for ethylene oxide Hb adduct levels in cord blood as a biomarker for active/passive smoking, in addition to the other covariates listed above. The difference in birth weight for infants of nonsmokers (n = 656) in the highest versus lowest quartile of acrylamide Hb adduct levels remained statistically significant after adjustment for ethylene oxide adducts , whereas the corresponding difference was borderline significant for glycidamide Hb adducts .Associations between Hb adducts and birth weight adjusted for country and gestational age were not substantially modified when further adjustments were made for other potential risk factors for reduced birth weight, including sex, prepregnancy BMI, parity, maternal age, ethnicity, education, passive smoking and smoking, and dietary variables that could be related with a healthy  eating pattern such as intakes of vegetables and fruits, fish, or soft drinks . The popNegative associations between acrylamide and glycidamide Hb adduct levels in cord blood and birth weight were observed for all countries . A meta-p = 0.51 and p = 0.46), although in England the association with birth weight was minimal .The pattern was also consistent among nonsmokers , with no significant heterogeneity between countries (Hb adduct levels and SGA. SGA (birth weight < 10th percentile for the cohort according to week of gestation and sex) was increased in association with a 10-pmol/g Hb increase in acrylamide adduct levels in the full population  and for infants of nonsmokers . The corresponding estimates for glycidamide were RR = 1.36  for all and RR = 1.42  for nonsmokers.Hb adduct levels and birth head circumference. The highest versus lowest quartile of acrylamide Hb adduct levels was associated with a significant reduction in head circumference of 0.33 cm  in the full population and among nonsmokers, with similar results observed for glycidamide  after adjustment for country and gestational age. Additional adjustment did not change this association (p = 0.72) among children of nonsmoking women with acrylamide food score data (n = 726).t levels  for acryociation . Higher This study provides strong evidence that higher prenatal exposure to acrylamide through maternal diet during pregnancy is associated with reduced birth weight and head circumference. Prenatal exposure to acrylamide was evaluated using Hb adducts, which are well-established biomarkers for acrylamide exposure . Birth win utero formation of Hb adducts and reduce potential biases through adjustment in a large subset of the study population.Prenatal exposure assessment using biomarkers is a key strength of the study. The measurement of Hb adduct levels in cord blood enabled a more accurate estimation of prenatal exposure to acrylamide compared with estimates based solely on dietary questionnaires or maternal Hb adduct levels. When cord blood Hb adduct levels are measured, variation related to transplacental exposure, uptake, and metabolism among children is taken into account. In line with our observation of higher Hb adduct levels in children from England compared with those of other study countries, higher levels have also been reported in nonsmoking British adults compared with other European adults . FurtherIn addition to dietary intake of acrylamide , it is pA limitation of exposure assessment based on dietary information is the difficulty of evaluating exposure to toxic agents, such as acrylamide, for which concentrations may vary substantially among similar foods, depending on manufacturing or preparation methods . QuantitDecreases in offspring body weight following maternal acrylamide exposure during gestation have been consistently observed in mice and rats . A U.S. in utero to maternal smoking , Barcelona, Spain; 3Epidemiology, Biostatistics, and Clinical Trials, National Cancer Research Institute, Genoa, Italy; 4Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands; 5Department of Food Safety and Nutrition, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway; 6Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany; 7Laboratory of Cell Genetics, Faculty of Science and Bio-engineering, Vrije Universiteit Brussel, Brussels, Belgium; 8Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Greece; 9Department of Environmental Immunology, Norwegian Institute of Public Health, Oslo, Norway; 10Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom; 11National School of Public Health, Athens, Greece.(647 KB) PDFClick here for additional data file.


There is concern that the rate of planned births (by pre-labour caesarean section or induction of labour) is increasing and that the gestation at which they are being conducted is decreasing. The aim of this study was to describe trends in the distribution of gestational age, and assess the contribution of planned birth to any such changes.We utilised the New South Wales (NSW) Perinatal Data Collection to undertake a population-based study of all births in NSW, Australia 1994–2009. Trends in gestational age were determined by year, labour onset and plurality of birth.From 1994–2009, there was a gradual and steady left-shift in overall distribution of gestational age at birth, with a decline in the modal gestational age from 40 to 39 weeks. For singletons, there was a steady but significant reduction in the proportion of spontaneous births. Labour inductions increased in the proportion performed, with a gradual and changing shift in the distribution from a majority at 40 weeks to an increase at both 37–39 weeks and 41 weeks gestation. The proportion of pre-labour caesareans also increased steadily at each gestational age and doubled since 1994, with most performed at 39 weeks in 2009 compared with 38 weeks up to 2001.Findings suggest a changing pattern towards births at earlier gestations, fewer births commencing spontaneously and increasing planned births. Factors associated with changing clinical practice and long-term implications on the health and well-being of mothers and babies should be assessed. Duration of pregnancy, which is reported as the number of completed weeks of gestation, is the leading perinatal predictor of health outcomes in babies. Gestational age at birth is conditional on either spontaneous onset of labour or a clinical decision that birth should occur. Planned  births, by induction of labour or pre-labour caesarean section follows a considered decision about continuing the pregnancy that balances the potential benefits and harms of early delivery for the mother and baby. The study population included all births of at least 20 weeks gestation in New South Wales (NSW), Australia from January 1994 to December 2009. Data were obtained from the NSW Perinatal Data Collection (PDC), a statutory population-based surveillance system covering all livebirths and stillbirths in NSW of at least 20 weeks gestation or 400 g birth weight. Information is recorded by either the midwife or medical practitioner attending the birth, and includes demographic, medical and obstetric information on the mother, as well as details of labour, delivery, and condition of the neonate. Only de-identified data were provided to researchers. The study was approved by the NSW Population and Health Services Research Ethics Committee.In the PDC, gestational age is reported as the number of completed weeks of pregnancy. It is determined by the best clinical estimate including early ultrasound (>97%) and the first day of last menstrual period. Onset of labour  and plurality of birth (singletons versus multiples) are reported by check-box. Other maternal characteristics and birth outcomes assessed were maternal age , parity (first versus subsequent births), maternal country of birth , giving birth in a public or private hospital, pregnancy complications , preterm birth , birthweight percentile Of 1,427,527 births, records missing a gestational age (n = 378), labour onset (n = 390), or plurality of birth (n = 58) were excluded, leaving 1,426,701 (99.9%) records available for analysis. Trends in maternal characteristics and birth outcomes were examined using Cochrane-Armitage test and review of relative changes over time. Changes in the onset of labour between 1994 and 2009 were investigated by assessing the percentage of spontaneous births, labour inductions, or pre-labour caesareans among all births occurring in each year. Onset of labour was examined separately for singleton and multiple pregnancies.th–90th birth weight percentile of the distribution for gestational age and infant sex. Annual distribution in gestational age throughout the study period were determined with the proportion of births in each week of gestation calculated . Analysis was also carried out for each category of labour onset and stratified by singletons and multiples (as denominators) to show the relative contribution of each group. As relatively small number of records of multiple pregnancies resulted in greater annual fluctuations, analysis was carried out by grouping data into four-year intervals. To account for changes in pregnancy risk factors over time, sensitivity analyses were conducted among low risk primiparae (women having a first birth), aged 20–34 years, without pregnancy complications (defined above), and with a liveborn singleton infant, born in cephalic presentation and of normal fetal growth at the 10From 1994 to 2009, the annual number of women giving birth in NSW increased by 10% . In paraAmong singleton pregnancies, a decreasing trend in spontaneous labour was offset by an increase in pre-labour caesareans and labour inductions . BetweenDuring the study period, a steady left-shift towards earlier gestations was observed in the overall distribution of gestational age at birth . ObserveA similar shift was observed when singleton births were investigated separately. However, different patterns were revealed when examined by labour onset . For sinAmong multiple births, the modal gestational age decreased from 38 weeks gestation in the 1990’s to 37 weeks from 2003 onwards (data not shown). Again the trend differed by labour onset . The modWe report a gradual decreasing trend in the gestational age of babies born in NSW, Australia, between 1994 and 2009. The most common gestational age has changed from 40 to 39 weeks, with early term births (37–38 weeks) becoming more frequent. The observed trends occurred among both singleton and multiple pregnancies, with findings revealing a steady and constant reduction in spontaneous births and increasing planned births, particularly pre-labour caesareans. Despite the rise in obstetric interventions over the study period, a corresponding reduction in fetal mortality has not been reported in our New South Wales population. Similar findings were reported by Davidoff et al, 2006 who identified a left shift in gestational age distribution in both spontaneous births and those associated with planned births among singleton births in the US from 1992 to 2002. Findings highlight that not only has the rate of planned births increased significantly, but the gestation at which they are being conducted is decreasing. By 2009, almost half of all births were iatrogenically timed and almost one in four singleton infants were delivered before the due delivery date, 13% by pre-labour caesarean and 10% by labour induction. Despite no change in the prevalence of multiple births between 1994 and 2009, there was a decrease in modal gestational age for multiples from 38 to 37 weeks’ with changes in the gestational age distribution larger and different to singleton births, especially by onset of labour. Of note, we identified a left shift in spontaneous births and pre-labour caesarean section, and inductions at 38 weeks or more decreased steadily. These changes, particularly among planned births have occurred since 2002, although there has been no change in the evidence regarding delivery management for twins; with two trials currently underway. The trend towards delivery at earlier gestational ages has been reported internationally. The strength of this study is the use of population-based, prospective and routinely collected data over a 16-year period. Coverage of all births in NSW, the most populous state of Australia, comprising over one third of the nation’s births, In summary, findings suggest a changing pattern towards births at earlier gestations, fewer births commencing spontaneously and increasing planned births. Factors associated with changing clinical practice and long-term implications on the health and well-being of mothers and babies should be assessed.


The objective was to estimate the heritability for height and weight during fetal life and early childhood in two independent studies, one including parent and singleton offsprings and one of mono- and dizygotic twins.nd and 3rd trimester (Generation R only). Height and weight were assessed at multiple time-points from birth to 36 months in both studies.This study was embedded in the Generation R Study  and the Netherlands Twin Register . For the heritability estimates in Generation R, regression models as proposed by Galton were used. In the Twin Register we used genetic structural equation modelling. Parental height and weight were measured and fetal growth characteristics  were measured by ultrasounds in 2nd to 3rd trimester from 13% to 28%. At birth, heritability estimates for length in singletons and twins were both 26% and 27%, respectively, and at 36 months, the estimates for height were 63% and 72%, respectively. Heritability estimates for fetal weight increased from 2nd to 3rd trimester from 17% to 27%. For birth weight, heritability estimates were 26% in singletons and 29% in twins. At 36 months, the estimate for twins was 71% and higher than for singletons (42%).Heritability estimates for length increased from 2Heritability estimates for height and weight increase from second trimester to infancy. This increase in heritability is observed in singletons and twins. Longer follow-up studies are needed to examine how the heritability develops in later childhood and puberty. Heritability is the proportion of variability of a phenotype that can be explained by polymorphic genes. Total adult body height is a highly heritable trait, with an estimated heritability of about 80 to 90% It has been questioned whether twin studies are suitable for estimating heritability of early growth, since early growth patterns in twins are quite different from singleton growth patterns We hypothesized that the heritability of weight and height would be relatively high during the first half of pregnancy, lower during third trimester or at birth and gradually increase throughout early childhood. We tested this hypothesis in the Generation R Study, a population-based prospective study from early fetal life onwards among 3407 Caucasian singletons and their parents, and the Netherlands Twin Register, a large twin cohort of the same population of 33694 individuals.This study was embedded in the Generation R Study and the Netherlands Twin Register. Generation R is a population-based prospective cohort study from early fetal life onwards based in Rotterdam, the Netherlands, designed to identify early determinants of growth, development and health from fetal life until young adulthood. The Twin Register was established around 1987 to examine the genetic and environmental contribution to health and disease. Newborn twins are registered at birth by their parents. Both studies have been described previously in detail Analyses were restricted to parent-child trio's of singleton pregnancies from Dutch or other European Caucasian ethnicity with parental height and weight data available (n = 3407). Due to miscarriage and prenatal loss to follow-up, data at birth were collected for 3370 newborns. The prenatal follow-up rate was 95%. For the postnatal analyses, 9% of the study population lived outside the study area, leaving 3084 subjects. The postnatal overall follow-up rate was 73%.Analyses were performed in 33694 twins (from 16848 twin pairs) with a least one measurement of weight or height. There were 4956 MZMale, 5626 DZMale, 5562 MZFemale, 5148 DZFemale, and 6328 DZ MF and 6076 DZ FM. Zygosity status was based on blood group/DNA group polymorphisms for 1563 same-sex pairs. For the remaining same-sex twin pairs zygosity was assessed using items about physical similarity and frequency of confusion of the twins by family and strangers 10 EFW = 1.5662−0.0108 (HC)+0.0468 (AC)+0.171 (FL)+0.00034 (HC)2−0.003685 (AC * FL)) Fetal ultrasound examinations were carried out at the research centers in each trimester of pregnancy In Generation R, maternal pre-pregnancy weight was obtained through questionnaire at the enrolment in the study. In addition, weight (during pregnancy) was assessed at the research centre. Correlation of pre-pregnancy weight obtained by questionnaire and weight measured at enrolment  was 0.97 (P<0.001). Maternal height and paternal weight and height were also measured at the research center using standardized procedures.Date of birth, birth anthropometrics (length and weight) and offspring sex were obtained from community midwife and hospital registries. Well-trained staff in community health centers obtained postnatal growth characteristics (length and weight) using standardized procedures No fetal growth were available in the Twin Register. Parents of twins reported on sex, gestational age, birth weight and birth length in survey-1, which is collected after parents register their twins (age <1 years). In survey-2 and 3, mailed out when the twins were respectively 2 and 3 years old, a parent was asked to report height and weight as measured by the routine health care program in the Netherlands . Based on this program, visits for these growth measurements were grouped similarly to those of Generation R 2) was determined using the method of Galton The creation of Standard Deviation Scores (SDS) for fetal growth in Generation R is described in the The genetic analyses of the twin data were carried out using genetic structural equation modeling in Mx, using maximum likelihood estimation The parental anthropometric characteristics in Generation R are shown in Regarding weight, the heritability had a similar pattern as fetal height increasing strongly from second to third trimester  to 27% ) in Generation R. After birth, the heritability for weight showed a slight decline followed by a gradual increase to a heritability of 42%  at 36 months. For the twins, the heritability estimates up to the age of 4 months were similar to those in Generation R, showing a marginal decline in the first 3 months. However, in the twins the heritability estimates were markedly higher after the age of six months, resulting in a heritability estimate of 71%  at the age of 36 months.The parental effects of each parent separately as measured in the Generation R Study are shown in nd trimester to 36 months from 13% to 63% and from 20% to 42%, respectively. A similar increase between birth and 36 months (27% to 72%) was found for height when analyzing data from MZ and DZ twins. For both birth length (26% in singletons and 27% in twins) and birth weight (26% in singletons and 29% in twins) the heritability estimates were remarkably similar in both studies. The only difference in heritability estimates between the twin and singleton sample is seen for weight at 36 months. Heritability estimates were higher (71%) in twins than in singletons (42%).In this study we estimated the heritability of body size from second trimester until the postnatal age of 36 months using data from two different studies among parental-child trios and twins. In singletons, the heritability estimates for height and weight increased from 2Prior to the study, we had hypothesized that the heritability of height and weight would be relatively high in the first half of pregnancy, lower in third trimester or birth and gradually increase throughout early childhood. However, we observed that the heritability estimates for height and weight were considerably lower in second trimester than third trimester. Previously, the heritability of weight at 25 weeks of gestation was estimated to be 52%, which is much higher than the 17% found in the current study For height the heritability estimates at birth was around 26–27% is both studies. In Generation R, the heritability estimates increased strongly during the first month postnatally. Studies have shown that children tend to catch-up or catch-down in the first years after birth, after which growth generally continues along the same percentile until the individual reaches the target height in adulthood Regarding weight, a previous study demonstrated that heritability of birth weight decreased between 25 and 42 weeks of gestation from 52% to 30% IGF2 gene might explain part of the difference in heritability estimates between the parents Some methodological issues need to be considered. In our study the postnatal follow-up rate was 73%. It is unlikely, however, that this loss to follow-up biased our results, since one can assume that the follow-up is independent of the heritability. To our knowledge, this is the first study that assessed the heritability of body size from fetal life onwards at several ages. In Generation R, the regression method from Galton Estimating heritability by either Galton's method that makes use of mid-parent – offspring data or the classical twin method that compares identical and fraternal twins both have their own strengths and shortcomings. Galton's method makes the strong assumption that the same genes affect parents' and offspring's phenotype In conclusion, the current study demonstrated that the heritability of height and weight increases from second trimester to infancy in two independent studies from the same population, using two different methods to estimate heritability. Longer follow-up studies are necessary to examine how the heritability develops in later childhood and puberty.File S1Creation of standard deviation scores in the Generation R Study.(DOCX)Click here for additional data file.