Prematurity affects approximately 10% of all children, resulting in drastically altered antigen exposure due to premature confrontation with microbes, nutritional antigens, and other environmental factors. During the last trimester of pregnancy, the fetal immune system adapts to tolerate maternal and self-antigens, while also preparing for postnatal immune defense by acquiring passive immunity from the mother. Since the perinatal period is regarded as the most important “window of opportunity” for imprinting metabolism and immunity, preterm birth may have long-term consequences for the development of immune-mediated diseases. Intriguingly, preterm neonates appear to develop bronchial asthma more frequently, but atopic dermatitis less frequently in comparison to term neonates. The longitudinal study of preterm neonates could offer important insights into the process of imprinting for immune-mediated diseases. On the one hand, preterm birth may interrupt influences of the intrauterine environment on the fetus that increase or decrease the risk of later immune disease , whereas on the other hand, it may lead to the premature exposure to protective or harmful extrauterine factors such as microbiota and nutritional antigen. Solving this puzzle may help unravel new preventive and therapeutic approaches for immune diseases. In. In16). Fetal antibody production is supplemented by transmission of maternal antibodies during the last trimester. It is still under debate whether maternal antibodies confer passive immunity exclusively or whether they elicit an idiotypic network among B cell receptors and/or T cell receptors . In VLBWThe development of antibody repertoires parallels the diversification of T cell receptors during ontogeny  and the Stress contributes to preterm birth, and preterm birth is associated with postnatal stress. Based on this reciprocal interaction, we hypothesize that stress has consequences on the developing immune system of preterm infants and their long-term risk of developing immune-mediated diseases. This hypothesis is derived from several aspects.Intrauterine stress conditions  contribute to preterm birth , 29. StrThe association between intrauterine stress, programming fetal responses, and postnatal immunity is well established , 33.The largest longitudinal human prospective study used a natural disaster—the Quebec ice storm, which left three million people without electricity for 45 days—to explore the effects of stress on the offspring of 224 women who were pregnant during the crisis. The ICESTORM project found higher rates of preterm birth in relation to the objective hardship of maternal stress (days without electricity). Notably, immunological dysregulations were found in the offspring at 13 years of age, i.e., reduced proportions of CD4+ cells and increased levels of pro-inflammatory cytokines  and Th2 cytokines such as IL-4 and IL-13 .Preterm infants need medical support, which itself is associated with stress. The improved survival of extremely preterm infants is at the cost of over 100 invasive procedures during their hospital stay and exposure to disturbing influences such as tactile stimulation, light, and noise. The preterm infant responds to such exposures with observed changes in vital and behavioral parameters and increased metabolic demands. Early-life stress and trauma may lead to a long-term dysregulation of immune responses, i.e., sustained inflammation in adulthood , 35. IntThe premature exposure to extrauterine antigens, such as microbiota, nutrition, and medication, represents a non-physiological stimulation of all the senses, including taste and the chemosensory system. Chemosensation is a recently discovered mechanism of bacterial pathogen recognition in mammals that is conferred by classical taste receptors (T2R). Originally discovered in tongue taste buds , 42, T2RThe developmental trajectory of chemosensory cells in the respiratory tract and other tissues is unknown . The numIt is currently unclear how the normal, “healthy” microbiota influence the development and function of the chemosensory system in the respiratory tract. Many medications commonly given to preterm neonates, e.g., antibiotics, alter the classical chemosenses, taste, and smell , 54. In A meta-analysis of 31 birth cohorts showed that preterm birth is associated with an increased risk of wheezing  and school-age asthma  . The cliPreterm neonates are exposed to multiple risk factors for asthma development, for example, cesarean delivery (CD), antibiotic use, and viral infections. Long-term studies are necessary to disentangle the impact of prematurity and the multiple postnatal factors on the risk of asthma development.There has been a global rise in CD rates from 6.7% in 1990 to 19.1% in 2014 . CD signCesarean delivery is associated with asthma later in life. A meta-analysis of 23 studies revealed that children born by CD had a 20% higher risk of developing asthma compared with those born vaginally . This asn = 22.068 individuals, 22.3% CD), planned CD was associated with an increased risk of obesity   . PathophLactobacilli and a higher flora/microbiological diversity  had a higher probability of wheezing and a higher frequency of rhinovirus and respiratory-syncytial virus infections in the first 3 years of life, relative to preterm (32–37 weeks) or full-term (>37 weeks) children . MoreoveAtopic dermatitis affects 20% of all children in industrialized countries . The risAfter birth, transepidermal water loss, stratum corneum hydration, and skin-pH are differentially regulated in various anatomical regions based on the environmental surroundings, which differ from the relatively constant intrauterine exposure to amniotic fluid . MoreoveIn addition, systemic factors such as nutrition may influence the risk of atopic dermatitis. Many preterm neonates are not exclusively breast-fed. Prolonged exclusive breast feeding is associated with a higher incidence of atopic dermatitis –83. It rIn summary, preterm birth and early weaning from breast milk are both factors that increase the exposure to a greater variety of antigens, thus reducing the risk of developing atopic dermatitis. Possibly, the premature exposure to a skin microbiome, which differs from mature-born infants, can trigger local immune reactions in preterm neonates that prevent the later development of atopic dermatitis in conjunction with systemic factors.Due to care under highly controlled conditions, preterm neonates are a distinct group of patients that can be used as a model to discern (epi-) genetic factors from environmental changes and from maturation-dependent changes in the immune system. Short-term and long-term influences of preterm birth can be measured by comparison to term born children. The influence of preterm birth on the developing immune system is poorly understood but may imprint the risk for immune-mediated diseases later in life . Future It remains unclear why preterm neonates have a reduced risk of atopic dermatitis and atopy defined as elevated serum IgE, specific IgE, and skin prick test . However(1)Which factors are responsible for the epidemiological differences between asthma and atopic dermatitis in preterm children? In addition to thorough clinical phenotyping and lung function testing, it is essential to include objective analyses for sensitization such as serum IgE, specific IgE, and a skin prick test.(2)How are the various asthma and atopic dermatitis phenotypes distributed in preterm children?(3)Is the incidence of autoimmune disease altered in individuals that were born prematurely?(4)What effect do the microbiome, epigenetics, and other mechanisms have in imprinting the immune system of preterm neonates?The following questions should be addressed in future studies:These studies could provide important insights into the mechanisms of immunological imprinting and potential therapeutic interventions to lower the risk of immune-mediated diseases not just in preterm neonates but in the wider population.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To investigate the effect of anemia on perinatal outcomes as preterm delivery (PTD) and low birth weight (LBW) in the different stages of pregnancy.Medical records of 39,587 Turkish pregnant women who delivered between January 2011 and September 2014 were reviewed. Anemia during pregnancy was defined as hemoglobin (Hb)< 11 g/dl, low birth weight was defined as birth weight <2500 gr and PTD was defined as <37 weeks. The pregnant women were divided into three groups . Perinatal outcomes were compared between these anemic and non-anemic groups.The anemia prevalence in our study was 25.1%. In the first and second trimester of Hb<10g/dl group LBW ratio was significantly higher . In the second and third trimesters of Hb<10 g/dl group PTD ratio was significantly higher . In the first trimester Hb<10 g/dl group cesarean section rate was significantly higher .LBW infants and preterm birth rate was higher in Hb <10 gr/dl group than non-anemic in the first, second and third trimester. Hb <10 gr/dl group had higher cesarean rate in first trimester. The mean birth weight was significantly lower in anemic pregnant women in the second trimester. Preterm birth and cesarean section rate, in the group of anemic throughout pregnancy was higher than those of non-anemic in the whole pregnancy period. Anemia is seen in different populations, with different etiology, incidence and severity and the most common medical disorder in pregnancy.9Different results in the studies depend on variables such as the study design, different diagnostic criterias, demographic characteristics in different societies. In many societies anemic women have other features (such as low socio-economic status) which may cause low birth weight and preterm birth. Therefore, as noted in several studies in the literature, it is difficult to eliminate these differences between anemic and non-anemic pregnant women and design an independent study.12The aim of this study was to investigate the impact of anemia on pregnancy outcomes in different stages of pregnancy. Correlation between anemia and pregnancy outcomes in pregnancy may provide guidance as to whether is required iron supplementation.This retrospective study covers 39,587 women performed follow-ups during pregnancy and gave birth in our hospital between January 2011 and September 2014. Individuals who didn’t come to regular antenatal care, had multiple pregnancies or congenital malformations, and pregnant women with systemic diseases  were excluded from the study.Hemoglobin levels of first, second and third trimester and Hb levels of the patients admitted to the delivery room for birth were obtained from a tertiary hospital centers with our computerized medical records system. The women were divided into three groups according to their hemoglobin levels . Hb values are measured by Coulter® LH 780 Hematology Analyzer  and cyanmethaemoglobin method in our hospital.In our study infants born <2500 g was considered as LBW and <37 weeks of gestation was considered as preterm birth. Iron supplementation was prescribed regularly to all pregnant women in our hospital. 30 mg/day of elemental iron to non-anemics while 30-120mg/day of elemental iron to anemics was provided. The study has been conducted in accordance with the Declaration of Helsinki.2) test for statistical significance. All analyzes were performed using SPSS 20.0 statistical package.In this study to compare categorical  variables, Fisher’s exact test was used, where appropriate. For the comparison of quantitative (continuous) variables, t-test was used. The percentage difference between groups is calculated with Chi-square  (p:0.01). LBW infants ratio was 13.5% in the same group and also considerably higher than in non-anemic women (%9.8) (p:0.03). The mean birth weight was 3120 grams in the anemic group. In the non-anemic group it was 3187 grams (p:0.06). p-values =0,1 were considered statistically significant. Particularly we can state that although it is very close to cut off value, birth weight in anemic group was lower than in non-anemic group .LBW rates in the second trimester were 22.7% and 17.4% in the groups of Hb <10 gr/dl, Hb 10-11 gr/dl, respectively, LBW (14.7%) was significantly higher in non-anemic women (p<0.01). In second trimester groups of Hb <10 gr/dl, Hb 10-11 gr/dl the preterm birth rates were 29.1%, 23.2%, respectively and according to the preterm birth rate they were significantly higher compared to non-anemic group (19%) (p<0.01). Average birth weights were 2862 gr, 3002 gr in the Hb <10 gr/dl, Hb 10-11 gr/dl groups, respectively, they were notably lower compared to non-anemic mothers (3068 gr) (p< 0.01vs p: 0.005). The average birth weight increased while Hb values increased.In the third trimester Hb <10 gr/dl group’s LBW infant rate was 12.6%, also significantly higher than in non-anemic women (11.5%)(p:0.1). Hb <10 gr/dl group preterm birth rate was 17.7% and considerably higher when compared non-anemic group (15.4%) (p:0.02).Comparing the trimesters of anemic pregnant women, in the first trimester Hb <10 gr/dl group cesarean rate was 65.2%, significantly higher than in 2nd and 3rd trimester caesarean section rate (58.1%) which carried same hemoglobin value (p<0.01) . Hb <10 In second and third trimester preterm birth rates were 21.4%, 18.8% in Hb <10 gr/dl, Hb 10-11 gr/dl groups, respectively, they were significantly higher than the group which carried the same hemoglobin levels in the first semester  (p:0.03). 2nd and 3rd trimester anemia was more dangerous than in the first trimester for preterm birth .The anemic mothers’, throughout the pregnancy from the early stage of pregnancy (first trimester) until the end of pregnancy (end of the third trimester), cesarean rate was (62.4%) significantly higher than in the non-anemic group (43%) (p<0.01). Preterm birth rate in anemic mothers during pregnancy was 19.1%, considerably higher than the rate of preterm birth in non-anemic group (15.5%) (p<0.01) .The World Health Organization (WHO) defined the hemoglobin levels of anemia in pregnancy as <11 gr/dl in 2001.12 In our study, the prevalence of anemia in pregnancy has been reported as 25%.12 The estimated prevalence of anaemia in pregnancy differs widely, 58% in China, 50% in South Asia, 40% in Istanbul.Traditionally, anemia is associated with suboptimal pregnancy outcomes such as low birth weight and preterm birth.Anemia during pregnancy is more common in patients with high parity. In literature, the importance of the multi birth and the frequent birth has been reported in the etiology of anemia.20What is interesting in the case of pregnancy is, high hemoglobin levels are not always with positive perinatal outcomes. There is U shape relationship between maternal hemoglobin levels and perinatal outcomes. Thus, both high and low hemoglobin levels are associated with adverse perinatal outcomes.21Despite the increase in the total number of erythrocytes, hemoglobin concentration decreased because of plasma volume during pregnancy were estimated to increase by more than the total erythrocyte mass. So placental perfusion become more favorable for maternal -fetal gas and nutrient exchange with reduced blood viscosity.22Increased viscosity secondary to high maternal hemoglobin levels can create placental infarcts. Large placental infarction has been reported to lead to intrauterine growth retardation and perinatal death.24Critical point in the iron treatment is to assess the actual iron requirement for each pregnancy accurately. Because iron results in production of free radicals and placental oxidative stress.25Difficulty in planning independent study by eliminating differences with additional features that may lead to negative perinatal outcomes  in most anemic pregnant; Not questioning the usage although given routine iron supplementation to all pregnant women as hospital policy; Not investigating the relationship between birth weights and physical properties of parents. The strengths of our study is that it is quite adequate and homogeneous in terms of demographic statistical inferences number of patients. Moreover, several studies in the literature have investigated the effects of anemia in pregnancy by certain period, but in our study perinatal effects of anemia was investigated in all three trimesters of pregnancy.LBW infants and preterm birth rate was higher in Hb <10 gr/dl group than non-anemic in the first, second and third trimester. Hb <10 gr/dl group had higher cesarean rate in first trimester. The mean birth weight was significantly lower in anemic pregnant women in the second trimester. Hb <10 gr/dl group’s preterm birth rate was higher in 2nd and 3rd trimester than the group with the same hemoglobin levels in the first trimester. Namely, with <10 gr/dl hemoglobin levels, preterm delivery risk was higher in 2nd and 3rd trimester than in the first trimester. Preterm birth and cesarean section rate, in the group of anemic throughout pregnancy was higher than those of non-anemic in the whole pregnancy period.


In a Perspective, Jane Norman and Phillip Bennett argue that it is time to explore alternatives to progesterone for preventing preterm birth. PLOS Medicine, Crowther and colleagues publish the results of the PROGRESS Study, which examined the effect of maternal vaginal progesterone on the risk of respiratory distress syndrome in the baby [In this week’s the baby . Women aAlthough vaginal progesterone is not licensed for prevention of preterm birth, it has been widely adopted by clinicians around the world for this purpose. Progesterone for preterm birth prevention in high-risk women is endorsed by expert guideline groups , includiOstensibly, there is biological plausibility behind the administration of progesterone for prevention of preterm birth. Progesterone can inhibit contractions of the myometrium in vitro , and antIn evaluating progesterone to prevent preterm birth, the Cochrane analysis groups evidence by maternal risk factor for preterm birth rather than by route of administration or type of progesterone , even thEven if progesterone is found to reduce preterm birth rates in women with either a previous preterm birth or a short cervix, it is increasingly evident that alternatives are needed because the impact on preterm birth rates overall are small. Modelling of the impact of progesterone to prevent preterm birth in women with a previous preterm birth (but without a short cervix), and assuming a 20% reduction in preterm birth before 37 weeks, suggests an absolute reduction of 0.01% in preterm birth rates . It has There has been huge renewed excitement amongst clinicians and the pharmaceutical industry for the use of progestogens to prevent preterm birth in the 21st century. A PubMed search shows 792 publications on this topic since 2000. The PROGRESS Study adds to a body of evidence suggesting that the role of progesterone may be more limited than previously thought. Preterm birth remains the single biggest cause of neonatal mortality and morbidity worldwide, and effective therapeutic interventions are desperately needed. It is time to start exploring alternatives, and to progress beyond progesterone for the prevention of preterm birth.


Ferromagnetic resonance showed that the in-plane magnetic easy axis of the Co film was shifted sharply with electric field E = 10 kV/cm, which indicates that the in-plane uniaxial magnetic anisotropy of the Co film can be inverted via the application of an electric field. These results demonstrated that converse magnetoelectric effect in the FM/FE heterostructure was indeed a feasible method to control magnetization orientation in technologically relevant ferromagnetic thin films at room temperature.Herein, we demonstrated an apparent electric field control of magnetization reorientation at room temperature, through a strain-mediated magnetoelectric coupling in ferromagnetic/ferroelectric (FM/FE) multiferroic heterostructure. As the applied electric field increased, the magnetization tended to deviate from the original direction, which was induced by nonlinear strain  The μ' and μ" represent the real and imaginary part of complex permeability, respectively. Figure E = 10 kV/cm. This result can be explained by following reason: with E = 0 kV/cm, the orientation of the magnetization was perpendicular to the direction of microwave magnetic field, resulted to the magnetization precession, which was detected a resonance peak. While for E = 10 kV/cm, according to the results of VSM and FMR, the magnetization deviated from the original position due to applying an electric and was along microwave magnetic field, which resulted to magnetization precession disappear. This finding has a promising potential for the electric controlling of microwave devices, especially phase shift device, anti-electromagnetic interference etc.Usually, the influences of magnetic interactions could be much more salient in the high-frequency magnetization dynamics and the magnetization rotation can also be well understood by means of vector network analyzer measurement. Figure The static and dynamic magnetic properties of Co/PMN-PT films with applying electric field have been investigated. Butterfly-shaped remanence versus electric field loops were obtained for the Co/PMN–PT thin films, which essentially tracks the strain loop in the single PMN–PT film. Ferromagnetic resonance shows that the magnetic easy axis in the Co film plane is rotated dramatically with applying an electric field, which indicated that the in-plane uniaxial magnetic anisotropy of the Co film can be inverted via the application of an electric field. The competition between the as-deposited magnetic anisotropy and stress anisotropy from FE substrate resulted to reorientation of magnetization. In particularly, electric field tuning the disappearance of resonance peak has crucial application in microwave devices, such as microwave absorption, etc.


Preterm birth  poses a risk of poorer neurocognitive functioning. Faster growth after preterm birth predicts better cognitive abilities and can be promoted through adequate nutrition, but it remains unknown whether variations in nutrient intakes translate into long-term benefits for neurodevelopment.In 86 participants of the Helsinki Study of Very Low Birth Weight Adults (birthweight <1500g), we examined if higher intakes of energy, macronutrients, and human milk during the first nine weeks after preterm birth predict performance in tests of cognitive ability at 25.1 years of age (SD = 2.1).10 kcal/kg/day higher total energy intake at 3 to 6 weeks of age was associated with 0.21 SD higher adult IQ . Higher carbohydrate and fat intake at 3–6 weeks, and higher energy intake from human milk at 3–6 and at 6–9 weeks were also associated with higher adult IQ: these effect sizes ranged from 0.09 SD (95% CI 0.01–0.18) to 0.34 SD (0.14–0.54) higher IQ, per one gram/kg/day more carbohydrate and fat, and per 10 kcal/kg/day more energy from human milk. Adjustment for neonatal complications attenuated the associations: intraventricular hemorrhage, in particular, was associated with both poorer nutrition and poorer IQ.In preterm neonates with very low birth weight, higher energy and human milk intake predict better neurocognitive abilities in adulthood. To understand the determinants of these infants' neurocognitive outcome, it seems important to take into account the role of postnatal nutrition, not just as an isolated exposure, but as a potential mediator between neonatal illness and long-term neurodevelopment. Preterm birth  poses a risk of poorer neurocognitive functioning. This risk is highest for those born very preterm (<32 weeks) or at very low birth weight VLBW; <1500g), and effects span beyond childhood. 500g, and ExplainiIn preterm children, higher neonatal energy intake predicts better neurodevelopment, but neonatal illness may underlie this association.  We know In our cohort of adults born preterm at VLBW, we examined whether intakes of energy, carbohydrates, protein, fats, and human milk during the first nine weeks of life predict general intelligence, memory, attention, and executive functioning at 25 years of age, when taking into account important pregnancy-related and neonatal factors.Helsinki Study of Very Low Birth Weight Adults has been previously described. [The scribed. ,3 We invscribed. ,13–15 WeWe compared the analytic sample (n = 86) with those who could not be included because of non-participation or missing data , and found no differences in gestational age, sex, birth weight standard deviation score (SDS), parental education, maternal smoking during pregnancy, preeclampsia, neonatal complications, nutrition in infancy, age at follow-up, or neurocognitive outcomes . We excluded all those with blindness (n = 2), cerebral palsy (n = 16), or intellectual developmental disability (n = 6) from these comparisons. The number of drop-outs whom we could include in each of the comparisons varied .total energy intakes and energy intakes from protein, fat, and carbohydrates from all enteral and parenteral nutrition, and energy intake from human milk, including donated and mother's own milk, per kilogram bodyweight. The macronutrient content of the mother's own milk was estimated based on the nutritional composition data published by Anderson et al. [Nutritional data during the initial hospital stay came from hospital records and was available for the first 9 weeks of life . As previously described in more detail,  we dividn et al. , who foln et al. ,19, who st-2nd day of life. Milk intake was increased to a maximum of 200ml/kg/day according to individual tolerance, and maintained at this level until discharge. All milk was pasteurized. During the 9-week period, 59 participants (69%) received mother's own milk, 81 (94%) received pooled donor milk, and 19 (22%) received formula. If targeted enteral feeding was not possible, intravenous fluids with glucose were initiated, and amino acids and lipids were gradually introduced from the 2nd-3rd day.Enteral feeding was initiated through a nasogastric tube with human milk on 1full-scale, verbal, and performance intelligence quotient . As measures of executive functioning, attention, and visual memory, we used Phonetic (words beginning with letters S and P) and Categorical  Verbal Fluency [Verbal flexibility (higher scores reflected better Fluency and Stroop scores), Visual flexibility (better Trail Making Test scores), Visual memory , and Impulsivity (faster Conners’ Continuous Performance Test reaction times and more commission errors)  .sex, date of birth for calculating age at adulthood follow-up, self-reported maternal smoking during pregnancy (no/yes), preeclampsia , and birth weight for calculating birth weight SDS according to Finnish standards. [highest education of either parent (basic/secondary/lower tertiary/upper tertiary), as proxy of parental neurocognitive abilities and socio-economic status. As neonatal complications, collected from medical records, we included septicemia , bronchopulmonary dysplasia , blood exchange transfusion due to hyperbilirubinemia (no/yes), duration of ventilator treatment (no/0-7/8-14/15-28/>28 days), and intraventricular hemorrhage (IVH) (no/grade I-II/grade III-IV). No participant was diagnosed with necrotizing enterocolitis. Neonatal cerebral ultrasound was being introduced during the study period, [From medical and birth records, we collected criteria ) gestatiandards.  During tcriteria ), patent period,  and despWe used linear regression models to test, first, if total energy intake and energy intake from human milk from birth to 3, 3 to 6, and 6 to 9 weeks of age predicted IQ, PIQ, VIQ, Verbal flexibility, Visual flexibility, Visual memory, and Impulsivity. Moreover, we tested associations between protein, fat and carbohydrate intake (g/kg/day) during the same three-week periods, and IQ. We square-transformed IQ and PIQ to improve linear model fitting, and standardized the outcomes within the sample  to facilitate comparison of effect sizes.In Model I, we adjusted for gestational age, sex, birth weight SDS, and age at follow-up. In Model II, we adjusted for Model I factors, parental education, maternal smoking during pregnancy, and preeclampsia. In Model III, we adjusted for Model I factors and the neonatal complications described above. We also tested if associations varied by sex or by birth weight SDS, by including a product term (‘sex x nutrition’ or ‘birth weight SDS x nutrition’) into the regression equation accompanied by main effects and other Model I covariates. Further, we tested whether total energy intakes, energy intakes from human milk, and IQ differed between those with versus those without each neonatal complication, and whether IQ differed between those who received mother's own milk versus those who did not: we used analysis of variance for duration of ventilation treatment and t-tests for dichotomized complications and for feeding with mother's own milk. We used IBM SPSS Statistics 24 for statistical analyses and considered two-tailed p-values<0.05 statistically significant.Characteristics, nutritional intakes in infancy, and neurocognitive test scores in adulthood are presented in Associations remained similar after further adjustment for parental education, maternal smoking during pregnancy, and preeclampsia (Model II), but adjustment for neonatal complications attenuated them, rendering them non-significant (Model III) Figs  and 2.Higher carbohydrate intakes at 3–6 weeks were associated with higher IQ and VIQ; higher protein intakes from birth to 3 weeks with higher PIQ, and higher fat intakes between birth and 6 weeks with higher IQ, VIQ and PIQ in Model I  . Only thIn an additional analysis, we compared those who received mother's own milk (n = 59) against those who did not (n = 27): no statistically significant differences in IQ, VIQ, or PIQ between the two groups were observed (p>0.07).Better Visual memory was predicted by higher total energy intake from birth to 3 weeks  and at 3–6 weeks , and higher energy intake from human milk from birth to 3 weeks . We found no other statistically significant associations between total energy intake or energy intake from human milk, and Visual memory, Verbal or Visual flexibility, or Impulsivity .As most associations attenuated after adjustment for neonatal complications, we specified their effects by testing associations between neonatal complications, nutrient intakes, and IQ. Those with IVH had lower total energy intake, lower energy intake from human milk, and lower IQ  . Those wAssociations between total energy/human milk/carbohydrate/protein/fat intakes and IQ did not vary according to birth weight SDS or to sex .In this well-characterized cohort of 86 VLBW individuals, we show that higher energy and human milk intakes during the initial hospital stay were associated with better cognitive functioning in adulthood. The effect sizes of these associations are quite consistent with earlier reports of childhood outcomes : 10 kcalThe associations we found between energy, human milk, carbohydrate, protein, and fat intakes and neurodevelopment were independent of sex, gestational age, intrauterine growth, maternal smoking, preeclampsia, and parental socio-economic status. Neither were they explained by manifest developmental disability nor neurosensory impairment.Interestingly, when a range of neonatal complications were taken into account, no independent associations between nutrition and adult IQ remained, as demonstrated by the reduced effect sizes. IVH, which seemed to be the main down-driver of the effect sizes, was associated with both lower nutritional intakes and poorer IQ. These findings may suggest that nutritional differences reflected, or possibly mediated, the severity of neonatal illness and its effect on neurodevelopment.Our adult findings are in line with previous observational studies in ELBW ,30 / VLBThe most compelling evidence exists for breast milk, which predicts better neurodevelopmental outcomes in preterm children at 2–11 years –43–effecWe are aware of only a handful of studies on nutrition after preterm birth which have spanned beyond childhood. In agreement with our results, energy intake during the first 10 days of life was not associated with IQ at 23 years in 46 small-for-gestational-age individuals born with VLBW in 1967–1975.  In that Our study strengths include the long follow-up of VLBW individuals to adulthood, validated and extensive outcome data, and detailed pre- and postnatal data. The neonatal nutrition data recorded by medical staff is exceptional for such a long follow-up. In an era when neonatal cerebral ultrasound was just being introduced, 64 of our 86 study participants underwent the scan: a strength for an adult follow-up, yet a limitation in comparison to modern-day cohorts where cerebral ultrasound has widely become routine practice.Our main study limitation is attrition: 113 VLBW individuals participated in the clinical visit (71% of those invited), and after excluding those with neurosensory impairments and missing nutritional data, we had an analytic sample of 86 individuals. Although those whom we could not include because of missing data did not differ from the analytic sample, loss of follow-up may cause selection bias and impact the generalizability of the results, especially into less healthy groups. We have refrained from post-hoc power calculations,  but noteAnother limitation of our study is that although the volumes of mother's own milk were recorded in detail, we did not have data available on any inter-individual or intra-individual variation in milk composition, and thus estimated the nutrient content of maternal milk based on previous research on lactating mothers of preterm infants. Further,Our study suggests that the intake of macronutrients during the initial hospitalization period after preterm birth may be linked with benefits for long-term neurodevelopment. However, these intakes, which in our cohort fall below current recommendations, may not act so much as an independent exposure, but rather mediate or reflect the severity of neonatal illness. Future long-term studies in cohorts who have received higher nutrient intakes in line with current guidelines are warranted to either confirm or refute this conclusion.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.


Low birth weight is the leading cause of infant and child mortality and contributes to several poor health outcomes. Proper knowledge of risk factors of low birth weight is important for identifying those mothers at risk and thereby for planning and taking appropriate actions. This study investigates factors predicting occurrence of low birth weight among deliveries at Debreberhan Referral Hospital. Facility-based unmatched case-control study was conducted among deliveries that took place at Debreberhan Referral Hospital. Birth records and mothers' ANC files were reviewed from April to June 2016. The study participants were selected by consecutive sampling technique. Data analysis was performed by SPSS version 20. Binary logistic regression analysis was performed to identify predictors of low birth weight. A total of 147 birth records of babies with low birth weight (cases) and 294 birth records of babies with normal birth weight (controls) were reviewed. The birth weight of low birth weight babies (cases) ranged from 1000 grams to 2400 grams with median (±IQR) of 2200 grams (±300 grams), whereas it ranged from 2500 grams to 4500 grams with median (±IQR) of 3100 grams (±525 grams) among controls. Preterm birth , history of any physical trauma experienced during pregnancy , and history of any pregnancy complication  were predictors of low birth weight. On the other hand, cesarean delivery  and instrumental  modes of delivery as well as maternal history of chronic diabetes  had preventive effect of low birth weight. Preterm birth, history of experiencing any physical trauma during pregnancy, and history of any pregnancy complication were predictors of low birth weight, whereas cesarean and instrumental delivery had positive effect to preventing low birth weight. Birth weight or size at birth is an important indicator of the child's vulnerability to the risk of childhood illnesses and to predict the child's future health, development, and the chances of survival . Low birGlobally, more than 20 million infants, representing 15.5% of all births, are born with low birth weight; 95.6% of them lived in developing countries, accounting for 17% of all births in developing countries . An epidHaving proper knowledge of risk factors for low birth weight is important to identification and giving appropriate attention to those mothers at risk. Despite few studies available to show factors associated with low birth weight across the country, it is not investigated in the study area. Therefore, this study investigates factors related to low birth weight particularly among deliveries at Debreberhan Referral Hospital. Findings from this study add to the current knowledge of risk factors of low birth weight particularly regarding mode of delivery, maternal chronic diabetes, pregnancy complication, and physical trauma during pregnancy which has not been well explained by other studies. This will have great relevance in identifying mothers and children at risk, designing appropriate measures, and undertaking timely interventions.Facility-based unmatched case-control study was conducted from April to June 2016 among deliveries that were performed at Debreberhan Referral Hospital. The hospital is found in Debreberhan town, located 130 kilometers to the North East of Addis Ababa. It is one of the most popular health facilities in the town rendering a range of medical, maternal, and child health services including delivery services, and various inpatient and outpatient healthcare services for a catchment population of over 95 thousand coming from the town as well as surrounding rural areas. Deliveries that take place at Debreberhan hospital were the source population. A case (low birth weight) was defined as a live birth baby born with birth weight of <2500 grams; and a control was defined as a live birth baby born with birth weight of ≥2500 grams.Assuming odds ratio of 2 desired to detect, 95% confidence level, 80% power, and control to case ratio of 2, the sample size was calculated by Open Epi version 2.3 using the formula for unmatched case control and found to be 441, 147 cases and 294 controls. Birth records were selected by consecutive sampling technique. For each low birth weight (birth weight < 2500 grams), the next two delivery cases with birth weight ≥ 2500 grams were considered as controls.p value ≤ 0.05 were used to claim statistical significance.Data were collected by review of birth records and mothers' ANC files. Relevant data were extracted from the birth records as well as corresponding mothers' ANC files using a structured checklist. Sociodemographic as well as maternal and obstetric variables were extracted from birth records, while gestational age of the fetus and data about history of pregnancy complications were obtained from the mothers' ANC files. Data processing and analysis were performed by using Statistical Package for Social Sciences (SPSS) version 20. Having the average age and the relative proportion of mothers in each age category under consideration as well as other literatures for comparison purpose, age of the mothers was categorized into three as 15–24 years, 25–34 years, and 35 years or above. Birth weight was categorized into two as low birth weight (birth weight < 2500 grams), considered as cases, and normal birth weight (birth weight ≥ 2500 grams), considered as controls or the reference birth weight. Multicollinearity diagnostics was performed to check for collinearity among independent variables and evaluated that each of the independent variables in the multiple analysis had tolerance value >0.1 against every other independent variable. Multiple binary logistic regression analysis was performed to identify independent predictors of low birth weight. Adjusted odds ratio (AOR) with 95% confidence interval (CI) and A total of 147 birth records of babies with low birth weight (cases) and 294 birth records of babies with normal birth weight (controls) were reviewed in this study. The age of mothers ranged from 15 to 42 years with mean (±SD) of 25.37 (±4.99) years. Overall, majority of the mothers were in the age group of 15–24 years, followed by 25–34 years, accounting for 203 (46.0%) and 202 (45.8%), respectively. The median (±IQR) age of mothers was 24 (±7) years among cases, while it was 25 (±6) among controls. Among cases, 77 (52.4%) of mothers were in the age group of 15–24 years, while 146 (49.7%) of maternal age among controls were found in the age group of 25–34 years. The proportion of mothers aged 35 years and above were relatively small both in cases and in controls: 14 (9.5%) and 22 (7.5%), respectively. Maternal gravidity ranged from 1 to 6 with primigravida accounting for the larger proportion of mothers both in cases and in controls: 86 (58.5%) and 156 (53.1%), respectively. Maternal parity ranged from 0 to 5 with primipara accounting for the larger proportion of mothers both in cases and in controls: 90 (61.2%) and 172 (58.5%), respectively. ANC follow-up status of mothers was almost similar among cases and controls. Among cases, 54 (36.7%) of mothers had ANC visit, while the remaining 93 (63.3%) had no ANC visit. Among controls, 107 (36.4%) of mothers had ANC visit, while 187 (63.6%) had no ANC visit. The hemoglobin level of mothers ranged from 6.9 g/dl to 19.3 g/dl among cases with mean (±SD) of 13.6 g/dl (±1.93 g/dl), whereas in controls it ranged from 6.0 g/dl to 41.0 g/dl with mean (±SD) of 13.8 g/dl (±2.58 g/dl). The proportion of mothers who ever experienced any physical trauma during pregnancy was relatively higher among cases. Among cases, 5 (3.4%) of mothers had ever experienced any physical trauma during pregnancy, while the proportion was only 2 (0.7%) among controls. Among cases, 76 (51.7%) of mothers experienced any one or more signs of pregnancy complications  during pregnancy, whereas among controls, 106 (36.1%) of mothers had any sign of pregnancy complications during pregnancy .The birth weight of babies ranged from 1000 grams to 2400 grams among cases with median (±IQR) of 2200 grams (±300 grams), whereas in controls it ranged from 2500 grams to 4500 grams with median (±IQR) of 3100 grams (±525 grams). Male age accounted for the larger proportion of cases, 78 (53.1%), while female age accounted for the larger proportion of controls, 158 (53.7%). Regarding gestational age at birth, 82 (55.8%) of cases were delivered at their full term, while 47 (32.0%) were delivered preterm or premature. Among controls, 231 (78.6%) of deliveries were full term, while 25 (8.5%) were preterm or premature. With regard to mode of delivery, the proportion of spontaneous vaginal delivery (SVD) was higher among cases as compared to controls. Among cases, 106 (72.1%) of the mode of delivery was SVD, whereas SVD accounted for 172 (58.5%) of the mode of delivery among controls. In contrast, the proportion of cesarean section (CS) and other instrumental deliveries were lower among cases as compared to controls .t-test showed that there is no significant difference in the mean hemoglobin level of mothers between cases and controls (p = 0.349). Both maternal gravidity and parity in its continuous scale as birth order as well as the categorized forms had no significant association with low birth weight , mode of delivery, maternal history of chronic diabetes mellitus, experience of any physical trauma during pregnancy, and experience of any sign of pregnancy complications  were found to be independent predictors of low birth weight. Babies who were born preterm (premature babies) were five times more likely to have low birth weight as compared to those born at their full term . With regard to mode of delivery, babies born via cesarean delivery were 58% less likely to have low birth weight  and babies born via instrumental delivery  were 43% less likely to have low birth weight  when compared to babies born via spontaneous vaginal delivery. On the other hand, babies born to mothers who had history of any physical trauma experienced during pregnancy were about fourteen times more likely to have low birth weight as compared to babies born to mothers who did not have such history . And similarly, babies born to mothers who had history of any sign of pregnancy complications  were about three times more likely to have low birth weight as compared to babies born to mothers who did not have such history . Maternal history of chronic diabetes was found to have negative relationship with low birth weight. In this regard, babies born to mothers having history of chronic diabetes mellitus were 72% less likely to have low birth weight as compared to those born to mothers with no history of chronic diabetes mellitus . The variables such as sex of the newborn, maternal age category, maternal parity (birth order), ANC visit, and maternal hemoglobin level had no significant association with low birth weight .This study investigated some maternal and pregnancy related factors associated with low birth weight. Preterm birth was found to be a risk factor for low birth weight; babies born preterm were more likely to be of low birth weight when compared to their full term counterparts. This is supported by a study from Ardabil, Iran, in which preterm birth was reported to be a risk factor of low birth weight  and a stIn the current study, mode of delivery was found to be associated with low birth weight. It was observed that babies born via cesarean section as well as instrumental deliveries  were less likely to be of low birth weight when compared to those born via spontaneous vaginal delivery. This means that low birth weight is less common among cesarean as well as instrumental deliveries while it is more common among spontaneous vaginal deliveries. It could be due to the natural mechanism that cesarean and instrumental procedures are more likely to be indicated for larger sized babies , while relatively smaller sized babies with low birth weight are likely to be born spontaneously. Apart from this, the natural procedure in the case of spontaneous vaginal delivery could have impact on the birth weight of the baby. That is, series of physical compressions due to the labor process and the procedure during spontaneous vaginal delivery could have been resulting in significant weight loss to the baby during delivery. Although cesarean section and minor instrumental procedures like vacuum or forceps deliveries are applied for different reasons, they would have positive effect in maintaining birth weight of the baby. Those babies born via cesarean section and other instrumental procedures are prevented from potential compressions at birth and hence attributable weight loss during delivery, yet the association with mode of delivery needs further investigation.It was found in the current study that occurrence of any sign of pregnancy complications  was a risk factor for low birth weight. This is consistent with the finding from a study conducted in Ardabil, Iran, in which bleeding or spotting during pregnancy was reported to be a risk factor for low birth weight . It was It was observed that babies born to mothers who had experienced any physical trauma during pregnancy were more likely to be born with low birth weight. The physical trauma could have directly resulted from an accidental injury which occurred during pregnancy or it could have resulted from a forceful hard work performed indoor or outdoor during pregnancy. According to a study conducted at a tertiary care hospital in Uttar Pradesh, severe physical work was one of the significant determinants of low birth weight . In lineAccording to this study, babies born to mothers having history of chronic diabetes mellitus were less likely to be born with low birth weight when compared to those born to mothers with no history of chronic diabetes mellitus. This could be explained by the medical effect that such mothers are medically likely to give birth to “giant babies” or the observed association could be just incidental. However, it is in contrary to the finding from a hospital-based study in Tigray, northern Ethiopia, which reported that presence of any chronic medical illness increased the risk of low birth weight . The disGenerally, this study has identified risk factors of low birth weight particularly those pertaining to the study area and most of which has not been identified by other previous studies. Despite employing case-control design which we consider as the strength of this study, it is yet not without limitation. As variables related to maternal nutrition and biomedical or anthropometric variables of the mother such as height, weight, and body mass index might have effect on the birth weight of the pregnancy outcome, lack of these variables from secondary data is limitation of the study.Preterm birth, history of experiencing any physical trauma during pregnancy, and history of any pregnancy complication were predictors of low birth weight, whereas cesarean and instrumental modes of delivery had preventive effect of low birth weight. Prompt identification of causes and prevention of premature delivery, proper knowledge of signs and symptoms of pregnancy complications, and preventing any physical trauma or its potential causes are recommended during pregnancy to prevent low birth weight. Identification of high risk mothers and early detection and management of the risk factors would reduce incidence of low birth weight and related short-term and long-term consequences.


Polycystic ovary syndrome (PCOS), whose aetiology is unknown, is predominately a familial syndrome but confirmation of candidate genes has proved elusive. The developmental hypothesis for the origin of PCOS suggests that exposure of the fetus to excess androgens influences imprinting, leading to altered genetic expression in adult life. The aim of this pilot study was to examine whether the female fetus of a mother with PCOS is indeed exposed to excess androgens.n = 9) and non-PCOS controls (n = 12), with a female fetus, were recruited at 24 weeks pregnancy and serum testosterone estimated. Sebum was measured using Sebutape® for 30 and 60 min within 24 h of birth, at 1 week, 4–6 weeks and 6 months after birth in both mother and child. Sebum excretion was measured in mother and child in the same site at each time frame and consistently. All semi-quantitative sebum excretion estimations were compared (t-test) between the two groups and correlated with testosterone concentrations during pregnancy.Using sebum production in the newborn as a surrogate for exposure to excess androgens during pregnancy thisprospective case control studyexamined whether neonatal sebum excretion is greater in female infants born to PCOS mothers compared to non-PCOS. Women with known PCOS   and controls (n = 12). Mean testosterone was 6.2 nmol/L  in PCOS mothers and 2.75 nmol/L in controls at 24 weeks pregnancy. At all time frames, the results of sebum excretion at 30 and 60 min were consistent. The sebum excretion of mothers in both groups was fairly constant from birth throughout 6 months. All babies were born between 37 and 41 weeks gestational age. Six of nine newborns had detectable sebum excretion at birth in the PCOS mothers group compared to 1 of 12 in the controls (P = 0.01).These results suggest that women with PCOS could hyper-expose their fetus to androgens in-utero and that this may be detected using a simple novel test within 24 h of birth to predict development of PCOS in adult life and induce research to eliminate its symptoms.NCT 02654548.Clinical Trials UK.Retrospectively registered 11/1/16. Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women andthe commonest cause of anovulatory infertility. The aetiology is largely unknown. It has a high degree of heritability but the search for confirmed candidate genes has proved elusive. The developmental hypothesis for the origin of PCOS, based on the Barker hypothesis , suggestStudies on pregnant monkeys injected with testosterone , prevaleThe first step in proving the developmental hypothesis for the origin of PCOS is evidence that the susceptible fetus may indeed be exposed to a hyperandrogenic environment. Androgens influence the production of sebum by exerting an effect on sebaceous gland activity . At the The aim of this pilot study was to examine whether the female fetus of a mother with PCOS is indeed exposed to excess androgens.n = 9) and non-PCOS controls (n = 12), with a female fetus, were recruited at 24 weeks pregnancy and serum testosterone estimated. They were next seen in labour at a single University Hospital.This is a prospective case control study to discern whether neonatal sebum excretion is greater in female infants born to PCOS mothers compared to non-PCOS.Followinglocal ethical committee permission and signing of informed consent, women with known PCOS ,is a rectangular white adhesive tape containing micro-cavities to trap sebum. The surface is hydrophobic. As the sebum issues from the follicles it is trapped in the cavities and the tape becomes transparent. Sebum excretion can therefore be assessed and the number of active secreting sebaceous follicles over an 8x8mm area captured. The skin is pre-cleaned with an alcohol wipe to remove causal sebum and the contact time, pressure, temperature and humidity are standardised to give reliable, reproducible results Fig. . Once thSebum excretion was measured for 30 min and 60 min to ensure slow secreting follicles were captured. This was done within 24 h of birth, at 1 week, 4–6 weeks and 6 months after birth in both mother and child. Sebum excretion was measured at the same site at each time frame as the amount of sebum per unit skin surface is generally constant in an individal and on a given anatomical site. This was done consistently for mother and baby.All semi-quantitative sebum excretion estimations were compared (t-test) between the two groups and correlated with testosterone concentrations during pregnancy.As would be expected, women with PCOS had a significantly higher mean BMI and a higher mean serum total testosterone concentration at 24 weeks gestation compared with controls but the groups were otherwise demographically similar Table . Six of Results of sebum excretion measured at 30 min and 60 min were almost identical.Maternal sebum production was reasonably stable throughout from 24 weeks pregnancy to 6 months post natal. Any detectable neonatal sebum within 24 h of delivery was no longer evident 4 weeks later.P = 0.04)(Table P = 0.005). There was no difference in the gestational age at birth between the sebum positive and sebum negative newborn (38.4 vs 38.8 weeks respectively) nor in the mode of delivery although sebum positive newborn had a significantly higher birth weight (Table Serum testosterone in mothers with sebum positive newborn was 7.03 +/− 6.3 pmol/l compared with 2.77 +/− 1.4 in the remainder (Although animal studies laid the foundations of the developmental hypothesis for PCOS etiology, in humans this theory was doubtedfor many years. Although maternal testosterone concentrations are significantly higher in both serum and amniotic fluid compared to normal controls –13,the hThe hormonal alterations during pregnancy in PCOS women show that the uterine environment in PCOS is most probably hyper-androgenic.The results of initial autopsies of placentae from women with PCOS, showing macroscopic and microscopic alterations compared to healthy controls  were alsWhen placental tissues from women with PCOS and healthy women were compared, changes in the activities of important enzymes for steroid synthesis were noticed. Specifically higher 3β-HSD-1 activity and lower P450 aromatase activity were seen in placenta tissue of women with PCOS. These alterations could increase androgen production during pregnancy according to the authors, as these enzymes are principally linked to placental steroidogenesis . It seemThis pilot study has shown that a simple method for detecting fetal exposure to excess androgens is feasible. Clearly 30 min measuring was sufficient and the fact that sebum excretion was unmeasurable in the newborn one month after birth strongly suggests that the origin of the androgen hyper-exposure in PCOS is maternal and not fetal and that any effect of this androgen exposure originates during pregnancy rather than afterwards. Previous studies employing different methods of measuring sebum excretion, one very small  and one Following the results of this pilot study we are now proceeding with the use of more robust methods for sebum excretion measurement in order to confirm our original findings suggesting that women with PCOS hyper-expose their fetus to androgens.The higher sebum production in babies of PCOS mothers strongly suggests hyper-exposure of the fetus in-utero to androgens. Confirmation is required but in line with the developmental theory of PCOS, this simple novel method could potentially be used within 24 h of birth to predict development of PCOS in adult life and induce research to eliminate the symptoms of PCOS.


Introduction. The developmental origins of health and disease hypothesis and season of birth have been linked to a wide variety of later life conditions including cancer. Whether any relationship between month and season of birth and colorectal cancer exists is unknown. Methods. A case-control study was performed with month of birth extracted from a dedicated colorectal cancer database. Age and gender matched patients were used as a control group. Generalised linear models were fitted with Poisson and negative binomial responses and logarithmic links. A forward stepwise approach was followed adding seasonal components with 6- and 12-month periods. Results. 1019 colorectal cancer patients and 1277 randomly selected age and gender matched controls were included. For both men and women there is an excess of colorectal cancer in those born in autumn and a corresponding reduction of risk among those born in spring (p = 0.026). For the identified September peak, the excess risk for colorectal cancer was 14.8% (95% CI 5.6–32.3%) larger than the spring trough. Conclusion. There is a seasonal effect in the monthly birth rates of people who are operated for colorectal cancer with a disproportionate excess of cancer in those born in September. Further large studies are required to validate these findings.  The developmental origins of health and disease hypothesis states that intrauterine and early life environmental conditions have a significant impact upon health and development that persists through into adult life . This coSeason or month of birth can result in differing early environmental exposure to a variety of stimuli such as sunlight, temperature, and infectious pathogens which could influence physiological and immunological development. Epidemiological studies have linked season of birth with a wide variety of conditions including lifespan and mortality risk –5, cardiProof of principle that season of birth can influence malignancy risk through long latency periods to adult onset cancer is suggested by available reports on skin , 16, breThe association between month of birth and the risk of developing colorectal cancer (CRC) has not been explored. Therefore, we aimed to investigate if there is a disproportional seasonality phenomenon in monthly birth rates of individuals who later develop CRC.A case-control study using an observational review of a dedicated, prospectively populated database of patients undergoing surgery for CRC at Yeovil District Hospital, UK, was performed. All data was prospectively collected and managed by a dedicated information analyst team. Study inclusion criteria were surgical resection, with curative intent, for histopathologically proven colorectal adenocarcinoma after resection between 2002 and 2015. All eligible patients were included with month of birth extracted. All patients entered a standard clinical, radiological, and endoscopic follow-up until five years after surgery or death. A control group of inpatients, with age and gender matching, managed at the same hospital over the same time period with any other diagnosis than colorectal cancer was selected at random from UK NHS Hospital Episode Statistics data . Control p value of <0.1 was considered significant.We fitted generalised linear models (GLM) with Poisson and negative binomial responses and logarithmic links. Overdispersion was formally assessed with a likelihood ratio test comparing Poisson and negative binomial models taking into consideration the problems of testing at boundary values. Trends by year of birth were adjusted using cubic splines with 3 effective degrees of freedom; this functional form was deemed complex enough to model these trends by comparing other possible spline models using Akaike's information criterion (AIC). Seasonal variation was modelled using at most three harmonic components in order to have enough flexibility to detect asymmetric seasonal variations which would be lost if only one symmetric, 12-month cycle had been fitted. The seasonal components used had 12 and 6 months; the first accounts for symmetric, yearly cycles, and the second was included in order to allow detecting semestral and quarterly patterns. The final models presented were selected by minimising the AIC and, as in all stepwise-type model selection procedures, correlation among the parameter estimates may produce misleading results—for instance entered variables can be proxies for others. The final models have a large number of parameters, and some of the effects, which appear to be significant when comparing the parameter estimates to their standard errors, may be spurious. All calculations were carried out using R version 2.8. The negative binomial GLM were fitted for male and female cases and controls using the MASS R-library. A2296 patients were included in this study. 1019 CRC patients  met inclusion criteria with 1277 randomly selected age matched controls .p = 0.026). For the peak at end of September, the excess risk for CRC was 14.8% (95% CI 5.6–32.3%) larger than that at the trough in spring. p = 0.06). The February peak in CRC birth which was not present in the Poisson model may have resulted from adjusting for overdispersion in the negative binomial model. Figures Generalised linear models for negative binomial responses with a logarithmic link function were fitted since there was significant overdispersion in the Poisson models. A forward stepwise approach was followed adding seasonal components with 12-month and 6-month periods, as well as interactions among them, the secular trend. We aimed to investigate any potential association between month of birth and undergoing surgery for colorectal cancer and observed a higher incidence among those born in the autumn months, particularly September, and a trough for those born in spring. This model supports the hypothesis of different seasonal phenomena by month of birth for both men and women who develop CRC. The higher birth rates in the autumn for people who later develop CRC suggest that seasonality of birth for CRC may exist. To our knowledge, this is the first report exploring this relationship and our findings need to be validated using larger datasets.The mechanism behind month and CRC risk is unknown and correlation should not be interpreted as a causative association. It is unclear how early life events could contribute to CRC given the very long latency which greatly exceeds that of the reports investigating cancer in children and adolescents. The list of potential candidate exposures is vast and likely to be multifactorial including infections, many of which vary seasonally, maternal diet, environmental toxins, sunlight, and the hormonal milieu. On the basis of the foetal origins hypothesis, it may be plausible to suggest that the “month of birth” factor in CRC may reflect the timing of an errant early cellular changes or differentiation process due to one or more of these exposures, resulting in epigenetic programming  or chronThis exploratory study is subject to a number of limitations. It is impossible to rule out entirely the effect of random fluctuations in birth rates of people who later develop CRC or other confounding influences that might explain the findings. Our results may have been influenced by including only those patients that were amenable and fit to receive curative surgery. In order to be absolutely sure about the diagnosis of colorectal cancer, only patients with positive tissue diagnosis after surgery were selected to remove the possibility of cohort heterogeneity. Our strict inclusion criteria allowed us to be certain about our case group and ensure the cohort was homogenous. Whilst our data on this group was complete, future large scale validation studies should incorporate all diagnoses of CRC in order to truly investigate if month of birth is a risk factor. Meaningful subgroup analysis by age groups or site of colorectal cancer was not possible due to low numbers.This study took place at one site and may not be generalisable to other geographical areas or populations particularly as patient ethnicity, place of birth, and time living in the UK were not included in this dataset. Seasonal environmental factors present in the childhood of included patients may not be applicable to children born today. Without previous data, it was not possible to perform a power calculation or calculate an effect size for the findings observed; therefore the inferential value of the study is undetermined.Our results support the hypotheses that there is a seasonal effect in the monthly birth rates of people who later undergo colorectal cancer resection. There is a disproportionate excess of colorectal cancer in those born in September compared with the other months. Larger studies are required to validate this finding.


Aim. Cord blood of intrauterine growth restricted (IUGR) neonates displays lipid changes towards atherosclerotic profiles. Apolipoprotein E (ApoE) and its isoforms  are involved in the regulation of lipid metabolism. Specifically, ApoE e4 has been associated with atherosclerotic diseases, while e2 has a favorable effect. We therefore hypothesized that ApoE e4 haplotype is frequently observed in IUGR neonates and contributes to impaired fetal growth and the association of IUGR with cardiovascular and metabolic diseases later in life. Methods. A cohort of 4885 preterm infants (≥22+0 and <32+0 weeks of gestation and birth weight below 1500 g) from the GNN study cohort was analyzed. Neonates were categorized into subgroups of <3rd, 3rd–10th, and >10th birth weight percentile. Analysis of the single nucleotides rs429358 and rs7412, identifying the ApoE genotype, was carried out using TaqMan® SNP genotyping assays. The proportional odds model was used to assess data. Results. No association was found between genotype and birth weight percentiles in each of the subgroups. Conclusion. ApoE genotype and low birth weight depict two distinct risk factors for cardiovascular disease without being directly associated. Inadequate birth weight, compared to population based standards, has a complex pathophysiology not yet entirely understood. Disrupted placentation and consequently insufficient placental vascular supply of nutrients and oxygen to the fetus, among other factors, are believed to be involved in intrauterine growth restriction (IUGR) and to result in small for gestational age (SGA) neonates , 2. As sApolipoprotein E (ApoE) is an important circulating serum protein involved in transporting lipids and cholesterol and regulating lipid levels. Its regulatory functions have been attributed to many biophysiological processes including neuronal growth and modulation of oxidant and inflammatory processes , 13. TheThe association of ApoE e4 with the development of dyslipidemia and cardiovascular disease has been described for the past two decades and is now well established , 17. RecGiven the significant impact of ApoE genotype on serum lipid levels and the association of IUGR with altered lipid metabolism, we hypothesized fetal ApoE genotype to be a modulator of fetal growth and severity of IUGR. A link between ApoE genotype and birth weight percentile would prove the role of the APOE gene as modulator of fetal growth and consequently provide an explanation for the fact that impaired fetal development depicts a cardiovascular risk factor. Hence, the aim of the present study was to identify ApoE genotypes in IUGR neonates. We took advantage of a nation-wide genomic study of the German Neonatal Network (GNN) including more than 18000 preterm neonates born before 32 weeks of gestation or with very low birth weight below 1500 g. The neonates were clustered according to birth weight percentiles with the lowest percentiles likely reflecting impaired fetal development. However, IUGR is not uniquely defined and neonates can be born small for their gestational age (SGA) by genetic determination and in the absence of a pathologic process . Hence, Subjects were enrolled in the GNN cohort between January 2009 and December 2015 by 54 currently participating neonatal intensive care units in Germany. Preterm infants with a birth weight below 1500 g and born <37+0 weeks of gestation were enrolled. The GNN study was approved by the local committee for research in human subjects of the University of Lübeck (Germany), as well as by all of the local committees of participating centers. Written informed consent was obtained from parents with neonates eligible for the research and publication of data. A predefined clinical data set form, containing obstetric and neonatal data, was filled out by the attending physician. Data were then sent to the GNN coordinating center in Lübeck. Parental refusal, early neonatal death, and parents not asked to participate were reasons for nonenrollment. A specialized neonatologist surveyed the data quality by annual visits to the participating centers. Obstetrical and neonatal data collected included maternal origin, maternal age, gestational age, birth weight, fetal sex, singleton versus multiple birth, fetal malformations, presence of pathologic Doppler/IUGR, presence of maternal pregnancy induced hypertension (PIH) or preeclampsia, and presence of HELLP syndrome. Birth weight percentiles were calculated according to Voigt et al. . UltrasoApoE genotyping was performed on buccal swabs and/or cord tissue transferred to the study center (University of Lübeck) together with the clinical data set form. DNA extraction was carried out by using commercial DNA purification kits . The samples underwent real-time PCR. Genotyping of the APOE rs429358 and rs7412 single nucleotide polymorphisms (SNP), defining the e2, e3, and e4 allele, was performed by using TaqMan SNP Genotyping Assays  according to the manufacturer's protocol. Genotyping of rs7412 and rs429358 was done in 10211 GNN-infants who were born between 2009 and 2014. Genotyping was successful in 93% of all patients for rs429358 and 96% of all patients for rs7412 (90% for both SNPs).n = 3921), 3rd–10th percentile (n = 625), and <3rd percentile (n = 339). Those groups were further divided into subgroups according to antenatal clinical diagnosis of one of the subsequent features indicating a placental involvement : (1) presence of maternal pregnancy induced hypertension (PIH including preeclampsia) and/or HELLP syndrome, (2) presence of IUGR and/or pathologic Doppler  with/without PIH/HELLP, or (3) absence of criteria (1) or (2) . It was assumed that the subgroup with birth weight percentile <3rd plus the clinical indication of IUGR/pathologic Doppler was most severely growth restricted while the subgroup of patients with birth weight percentile >10th in the absence of (1) or (2) served as the most “pure” control group  = the ApoE genotype not affecting the Voigt birth weight percentile in different subgroups of premature IUGR. The type I error level was set to 0.05. To correct for the multiple testing, nominal p values were adjusted according to the Bonferroni-Holm procedure. Hardy Weinberg equilibrium for three alleles was assessed by chi-square test.Data analysis was performed using the SPSS 20.0 data analysis package . In order to evaluate the effect of the ApoE genotype on the birth weight in different SGA subtypes the proportional odds model was used to assess ordinal data. The model analyzes the likelihood to reach a higher ordinal level in relation to other variables. An equal slopes assumption of the data must be met which is tested beforehand. Our null hypothesis was  on birth weight centiles have been estimated. As expected the groups PIH/HELLP and IUGR/pathological Doppler showed a statistically significant negative effect on birth weight percentile when compared to neonates born in absence of a placental syndrome . None ofTo further investigate a possible correlation between ApoE genotype and birth weight percentile, the ApoE genotypes were pooled in groups containing the haplotype e2 (e2/e2 and e2/e3), haplotype e3 only, and haplotype e4 (e3/e4 and e4/e4). Thus the compiled allele groups did not show a significant effect on the birth weight percentiles in any of the analyzed subgroups compared to the groups e2/e2 and e2/e3 (data not shown).To our knowledge, the data set used in this study was the largest analyzed to date. 4885 preterm neonates were included in the analysis with the aim of identifying the effect of the ApoE genotype on proper fetal development. However, we did not find any association of ApoE haplotypes with birth weight percentiles independently of whether or not pregnancy was further complicated by a placental disorder characterized by PIH or IUGR.n = 10) results into an even more statistically significant effect. This points to different pathomechanisms for specific IUGR/SGA subgroups [Three prior studies investigated the ApoE genotype in IUGR/low birth weight children. Our results are in accordance with Akisu et al. who also found no correlation between the ApoE genotype and IUGR born newborns . Howeverubgroups .n = 141 with 47 patients suffering on preeclampsia) with ApoE e4 not being normally distributed in their control group. Other authors did not find associations of ApoE genotype and the risk of preeclampsia when genotyping the mother [Though we did not primarily aim to analyze the association between ApoE genotype and the incidence of preeclampsia and the HELLP syndrome, our study does partly allow us to draw certain conclusions. Both of the aforementioned diseases are pathologically closely related to IUGR. No association between the clinical diagnosis of pregnancy being terminated in the presence of a hypertensive disorder like preeclampsia or the HELLP syndrome has been observed in this study. The present study therefore contradicts a recent publication by Procopciuc et al. in which the fetal Apo e4 genotype was found to be an independent risk factor for preeclampsia compared to the other ApoE genotypes . The dive mother –29 which APOE locus, either through its direct effects on the developing fetus, on the fetal lipoprotein metabolism, or through its effects on maternal cholesterol levels and the maternofetal lipoprotein metabolism. In IUGR fetal serum lipid levels resemble atherogenic profiles, with lower HDL-C concentrations and higher triglyceride levels as well as elevated ratios of oxidized LDL/LDL-C and LDL-C/HDL-C [Despite these findings, there is increasing evidence that ApoE plays a pivotal role in fetal development and lipid metabolism. ApoE is the only apolipoprotein in the fetal circulation in concentrations as high as the mother's . It is h-C/HDL-C , 10, 11.-C/HDL-C , 7.The physiologic effect of the ApoE genotype on lipoprotein levels and the development of atherosclerotic diseases are well established in humans. Though being born with low birth weight predisposes to cardiovascular disease later in life it is likely that the three haplotypes of the APOE gene and low birth weight depict two independent risk factors on cardiovascular disease, since our study does not suggest that the association between low birth weight and cardiovascular disease is due to ApoE genotype.Our study is limited by two main aspects. First, preterm birth per se is a pathological condition; hence, our study lacks a valid control group of uncomplicated pregnancies. However, the overall distribution of ApoE genotypes was within the expected range for the German population. Second, the study may be biased due to the vague definition of IUGR in the absence of precise antenatal recorded criteria. Neonates with birth weights less than the 10th percentile of a population are SGA. The term SGA is descriptive and refers not to fetal growth velocity but to the birth weight of an infant. It does not reflect the causes that lead to the low birth weight. Most SGA neonates are born small by constitution and have constant growth patterns , 22, 35.Genotyping our large cohort of 4885 preterm infants did not reveal an effect or dose-effect relationship of the fetal ApoE isoform on the birth weight percentile in all subgroups investigated. IUGR born infants display atherogenic blood lipid levels. Apolipoprotein E is known to regulate blood lipids and its three haplotypes are associated with distinct blood lipid patterns. Yet, the hypothesis of ApoE genotype affecting birth weight could be rejected since no direct effect was found. The stratification of maternal pathology in our large population size, that in earlier studies might have biased the results, could not alter this conclusion. Cholesterol levels and ApoE genotype depict major risk factors for CVD in later life. Our results, however, suggest that the ApoE genotype and low birth weight represent two synergistic factors exposing the fetus to an atherogenic environment and contributing to intrauterine programming without being directly associated to each other. The maternal genotype, known for affecting fetal blood lipids, could play a role and should be addressed in further studies.


In healthy controls (HCs), the visuospatial attentional network consists of fronto-parietal bundles distributed across both hemispheres, but the anatomical organization of this network remains largely unknown in patients with schizophrenia (SZPs). Using diffusion tensor imaging (DTI)-based tractography, we investigated both white matter integrity and the volume of visuospatial attentional pathways in the right and left hemispheres (RH and LH), as well as their structural asymmetry in SZPs and HCs and hypothesized that SZPs would have WM pathway alterations and abnormal structural asymmetry.This study included 34 SZPs and 69 HCs. Integrity parameters  and volume were calculated in each fasciculus of this network: the three branches of the superior longitudinal fasciculus (SLFI–III), the inferior longitudinal fasciculus, and the inferior fronto-occipital fasciculus in the RH and LH.In SLFII and SLFIII, compared to RH and LH values for SZPs, HCs presented increased FA and/or decreased RD/MD in RH and/or LH. Both SZPs and HCs presented increased FA and decreased RD/MD in the RH compared to the LH in the SLFIII, whereas only HCs had this pattern in the SLFII. Volumes did not differ between groups.To our knowledge, this study is the first to describe the structural hemispheric lateralization/organization of the visuospatial attentional network in SZPs. Our main findings are disrupted structural connectivity in the SLFII associated with abnormal anatomical asymmetry in patients, which could be a substrate of attentional deficits.


Coffee and tea are commonly consumed during pregnancy. While several of their components, like caffeine, have strong pharmacological effects, the effect on the unborn fetus remains unclear. Caffeine intake has been associated with abortion, preterm birth and fetal growth restriction, but a general consensus on caffeine restriction is still lacking. We aimed to investigate antenatal coffee, tea and caffeine consumption and the effect on birth weight and length, gestational age at birth and hypertensive disorders in pregnancy.A total of 936 healthy pregnancies from the WHISTLER birth cohort with data on coffee and tea consumption were included. Maternal and child characteristics as well as antenatal coffee and tea consumption were obtained through postpartum questionnaires. Reported consumption was validated using available preconceptional data. Caffeine intake was calculated from coffee and tea consumption. Linear and logistic regression was used to assess the association with birth outcome and hypertensive disorders.After adjustment for smoking and maternal age, a daily consumption of more than 300mg of caffeine compared to less than 100mg of caffeine was significantly associated with an increased gestational age . Tea consumption was significantly related to a higher risk of pregnancy induced hypertension . No associations concerning coffee consumption or birth weight and birth length were observed.Daily caffeine consumption of more than 300mg is possibly associated with an increase in gestational age at birth. A possible relation between high tea consumption and increased risk for pregnancy induced hypertension warrants further research. For most outcomes, we found no significant associations with coffee or tea intake. Pregnancy is a delicate equilibrium between the mother and her unborn fetus. While fully dependent on mother’s blood supply, chemicals that freely pass the placenta can pose a risk for the developing child. There is increasing evidence that maternal lifestyle influences fetal development and can increase the risk for pregnancy complications and disease later in life.–3 SeveraCoffee and tea are available worldwide and are commonly consumed during pregnancy. While anDespite the known biological mechanisms of caffeine, clinical research does not observe a clear association with adverse pregnancy outcomes in population studies. Studies monitoring caffeine intake during pregnancy reported an increased risk of spontaneous abortion,12, fetaSome studies suggest a possible effect of chemicals present in coffee and tea other than caffeine, for instance polyphenols, which contribute to adverse pregnancy outcomes including preterm delivery and pre-eclampsia.,14,18,35In this cohort study among 936 healthy Dutch pregnant women we aimed to investigate coffee, tea and caffeine intake during pregnancy and the effect on birth weight and length, gestational age at birth and hypertensive disorders in pregnancy.The dataset is part of the Wheezing-Illness-Study-LEidsche-Rijn (WHISTLER) study, an ongoing population-based birth cohort. This stuParticipants were recruited within 14 days after giving birth. The study was approved by the pediatric Medical Ethical Committee of the University Medical Center Utrecht. Written informed parental consent was obtained.When offspring was four weeks of age, participants visited the clinic and information regarding ante-, peri- and postnatal factors was obtained through a questionnaire. These included maternal characteristics  and child characteristics . Participants were asked about their average coffee, tea and alcohol consumption during pregnancy. Consumption was reported in cups per day, week, month or year. Coffee was specified as either caffeinated or decaffeinated. Due to later addition of the coffee and tea questions to the questionnaire, information about prenatal coffee or tea intake was available for only 936 of the 2500 participants, of which 887 reported information on both. Smoking was reported in number of cigarettes per day. Participants were asked if they suffered any specific disorders during pregnancy .Coffee (caffeinated and decaffeinated) and tea intake was converted to cups/day. Caffeine intake was calculated from daily caffeinated coffee and tea intake. According to the Dutch Nutrition Centre caffeine content for one average serving (125mL) of coffee and tea is considered 85mg and 30mg, respectively. Alcohol Ethnicity was based on western or non-western origin of the mother. Mothers were considered of western origin when born in Europe (excl Turkey), North America, Oceania, Indonesia or Japan.th percentile for gestational age at birth. SGA was calculated by comparing birth weight and gestational age at birth using reference charts from the Netherlands Perinatal Registry.[Birth weight was assessed by calculating internal Z-scores, adjusted for gestational age at birth, birth length and sex. Birth length was assessed by calculating internal Z-scores, adjusted for gestational age at birth, birth weight and sex. Small for gestational age (SGA) was considered a weight below the 10Registry.Linear regression was used to assess the relation between coffee, tea and caffeine consumption and continuous birth outcomes. Caffeine intake, tea intake and coffee intake were entered as independent variables in separate models. Birth weight, birth length and gestational age at birth were entered as dependent variables in separate linear models. Pregnancy hypertensive disorders and SGA were dichotomized and entered as dependent variables in separate binary logistic regression models. After univariable analysis, models were adjusted for smoking and age of mother as they were considered confounders. To assess a possible threshold effect, caffeine consumption was converted into categories and analyzed using dummy variables in linear regression. Since ethnicity data was available for 86.5% of the mothers, we checked in a separate model whether adjusting for ethnicity influenced the results. All statistical analyses were conducted using IBM SPSS (version 21 for Windows). Statistical significance was assumed for a two-sided P value <0.05.936 mothers and their children were included in the analysis. Baseline characteristics are presented in Tables There was a trend in association between intake of coffee, tea and caffeine and increased gestational age at birth . Associations between coffee, tea and total caffeine consumption and hypertensive pregnancy disorders are shown in This study demonstrates that birth weight and birth length are not associated with coffee or tea consumption or caffeine intake during pregnancy. A daily caffeine consumption of more than 300mg is possibly associated with an increase in gestational age at birth. A similar tendency was observed for coffee, tea and caffeine consumption as continuous variables, but none of these associations were statistically significant.The largest cohort study studying the effects of antenatal caffeine consumption and birth outcome (n = 59 123) Sengpiel et al (2013) in Norway, found total caffeine intake associated with decreased birth weight and higher risk for small for gestational age (SGA). Similar Our finding of a threshold effect with an intake of more than 300mg of caffeine a day is in agreement with findings from other studies and suggests that like many agents, caffeine may only be harmful in high doses.,40–42The only existing randomized controlled trial studied the effect of caffeine restriction and was performed by Bech et al (2007) in a Danish cohort of 1207 women. After raWe also found that tea consumption was associated with a statistically significant increase in the risk of pregnancy induced hypertension. A possible mechanism is through caffeine and polyphenol chlorogenic acid, both present in tea, that have been shown to increase homocysteine levels in humans.,44 ElevaCoffee and caffeine consumption were not associated with any hypertensive disorders, although with caffeine consumption a near significant increased risk for HELLP syndrome was observed. This observation could be due to chance since the prevalence of HELLP syndrome was very low in this cohort .Besides smoking habits, alcohol was considered a confounder, but due to the minimal alcohol consumption in this cohort, adjustment had a negligible effect on results and was omitted from the analysis.Strengths of this study comprise the separate analysis of coffee, tea and caffeine intake and the inclusion of hypertensive pregnancy disorders as outcome in a healthy group of unselected women. The mean birth weight, birth length and incidence of hypertensive disorders in our sample are comparable to national reports,48, whicSome limitations have to be taken into account. Firstly, beverage consumption was aggregated for overall pregnancy and not available per trimester, while consumption may not be constant during trimesters by which effects of intake may vary. However, large studies that incorporated trimester specific questionnaires showed no difference between trimesters.,18 SeconDespite our efforts to validate the accuracy of the reported intake, the retrospective design of this study makes our data subject to recall bias. Next, for only 86.5% of the mothers ethnicity was known. Therefore we chose to do a sensitivity analyses to investigate the effect of ethnicity on our results. Also, we could not adjust for total energy, specific nutrient intake or caffeine intake from other sources like chocolate, cola or energy drinks, due to lack of data.Finally, we cannot exclude the possibility of residual confounding.Our findings suggest a possible effect of caffeine in prolonged gestational age at birth and an association between tea consumption and pregnancy induced hypertension. This considered, we cannot rule out that caffeine, or tea and coffee use in general, is harmful for the developing fetus. Dutch national guidelines recommend a caffeine restriction of 300mg or less but do not advise active preconceptional counseling on caffeine.,33 OtherThe association between tea and pregnancy induced hypertension has been scarcely studied, while biological evidence suggests a potential mechanism. Moreover, possible adverse health effects of tea, the second-most consumed beverage worldwide, will have substantial global impact. More research on this subject is needed.In conclusion, a daily caffeine consumption of more than 300mg is possibly associated with a modest increase in gestational age at birth. There is no evidence that birth weight is associated with coffee or tea consumption or caffeine intake during pregnancy. A possible relation between high tea consumption and increased risk for pregnancy induced hypertension warrants further research.