According to life-history theory, paternal investment affects the well-being of offspring. We hypothesized that environmental stress caused by a lack of paternal investment may diminish maternal resource allocation during pregnancy, especially for women who already have dependent children. Our study was conducted on a representative group of more than 80,500 singleton, live-born, full-term infants born in Krakow, Poland in the period 1995–2009. Birth data were obtained from the birth registry. We found that missing data about fathers  was associated with higher probability of multiparous mothers giving birth to low-birth-weight infants , but this was not the case with primiparous mothers . The statistically significant synergistic effect between parity and paternal investment was found . These findings suggest that in situations of low paternal investment, multiparous mothers face trade-offs between investing in existing versus unborn children, therefore investment in the latter is lower. Such a strategy may benefit maternal fitness due to investment in older children, who have higher reproductive value. The concept of parental investment –2 suggesFurthermore, maternal parity (i.e. the number of previous births), viewed as a rough proxy of the costs of reproduction , 20, is The association between paternal investment and birth outcomes has been explored with the use of birth registry data. For example, establishment of paternity for children of unmarried mothers was used as a proxy for both high paternity confidence and male willingness to commit to paternal investment; it was also found to predict birth outcomes, including low birth weight . MissingAccording to Polish legislation, one way of determining paternity is to presume that the mother’s husband is her child’s father. Therefore, the name of the mother’s husband is listed on a child’s birth record. For unmarried parents, an unmarried father must sign an acknowledgment or have paternity established in court in order to have his data on the birth certificate . The preThe study group was restricted to singleton live-born infants to remove the effect of multiple gestations and stillbirths. We included infants born after gestations of 37 and 41 weeks from the 14-year period from October 1st, 1995 to December 2009 to mothers whose residence at the time of the infant’s birth was the city of Krakow. We obtained anonymized data from the birth registry . Data included month and year of birth, birth weight (in grams), infant’s sex, maternal age (in years), gestational age (in weeks), parity, maternal education , maternal employment status (employed vs. not employed) and maternal marital status . Paternal data, if present, included age (in years), education  and employment status (employed vs. not employed). Low birth weight (LBW) was defined as birth weight below 2,500 g; all infants with birth weight ≥ 2,500g were classified as having normal birth weight (NBW).Of 88,474 singleton births, we excluded N = 4,648 born before 37 weeks of gestation, N = 3,141 born later than 41 weeks of gestation, and N = 132 stillbirths. These exclusions left N = 80,553 eligible births, and among them N = 1615 (2.0%) LBW newborns.In order to identify potential confounders, the distribution of several known risk factors for LBW across different exposure categories was examined with simple logistic regression analyses. Women were divided into two categories according to parity (number of births): primiparous (reference category) and multiparous, i.e. women with two or more births. Maternal and paternal employment status was divided into two categories: employed vs. not employed. Maternal and paternal education was stratified into two levels: higher education  and lower education . Because employment status and education were strongly related, we calculated an Employment & Education indicator which allowed us to categorize mothers and fathers into four groups: “Not Employed–Poorly Educated”, “Not Employed–Highly Educated”, “Employed–Poorly Educated” and “Employed–Highly Educated”, with the last being the reference group.We also tested the distribution of characteristics of births among primiparous and multiparous mothers using a t-test for separate variance estimates of independent samples with normal distribution, and a Chi-square test for categorical variables. The distribution of birth characteristics among missing paternal data groups (yes vs. no) was also investigated with the same tests as mentioned above.After a descriptive analysis of the parental–infant characteristics and their distribution among LBW–NBW children among the strata of parity and among the missing paternal data groups, we performed simple and multiple logistic regression analyses to estimate the association between missing paternal data as a categorical variable and the odds ratio (OR) of LBW. Firstly, only the missing paternal data was entered as a predictor of LBW (crude effect). In the second stage, we built the full model by entering biological factors such as maternal age (continuous), sex of the child, parity, and social factors  and tested whether there was a significant change in the log odds of LBW after adding these factors to the simple model.Because the main research objective of our study was to determine if multiparous mothers are more susceptible than primiparous mothers to the effect of missing paternal data  on the risk of LBW, we conducted the same procedure after stratification for parity. The influence of parity on the observed association, i.e. effect modification by parity, was further tested by adding the product term  into the full logistic regression model. The statistical significance of this product term was verified with the Wald test. The interaction (effect modification) related to the state in which the effect of one exposure  on an outcome (LBW) differs across the strata of another exposure (primiparous and multiparous). The adjusted Synergy Factor  were derAmong the study group of 80 533 births, father's age, education and employment were recorded for N = 77 242 (95.9%), N = 77 071 (95.7%), N = 77 041 (95.6%) neonates (respectively), whilst for N = 3 257  all of the above three categories were left missing.The univariate analysis suggested that the odds ratio of LBW was significantly associated with paternal and maternal age, parity, sex of the offspring, maternal education, employment status and marital status .Mothers who had female newborns had a 63% higher odds for LBW than those who gave birth to males. Each year of paternal age was associated with an increasing OR for LBW by 1%. Unmarried women had a 95% higher odds for delivering an infant with LBW than married women. Among mothers, having a higher education level was associated with 52% lower odds of LBW in comparison to lower education levels, whilst being employed vs. unemployed decrease the odds by 38%. When analyzing maternal educational and employment status together, women who simultaneously had lower education and no employment, had almost three times higher OR for delivering a child with LBW than women with both higher educational level and employment. Similar patterns were seen for paternal education and employment. Taking these two paternal characteristics into account at once, fathers who simultaneously had lower education and no employment, had more than a twofold increase in OR in comparison to those with both higher educational level and employment. Mothers having two or more births in comparison to primiparous mothers had lower odds of LBW by 12% . The misThe strata of parity varied according to maternal and paternal age, maternal marital, employment and educational status, Employment & Education indicator calculated for mothers, sex of the child, paternal employment and educational status, and Employment & Education indicator calculated for fathers .The univariate analyses revealed that missing paternal data were associated with almost 2.5 times increased odds for LBW in comparison to paternal data present . After standardization to maternal-infant characteristics, this association was weaker, and marginally significant . After stratification for parity, elevated odds of LBW noted among primiparous mothers in crude analyses  did not reach the level of statistical significance after adjustment . However, among the strata of multiparous mothers, missing paternal data was associated with higher odds of LBW both before  and after adjustment for confounders . Strata specific estimates after standardized to confounders are presented in These different effects of missing paternal data across the subgroups of parity  were confirmed by the statistically significant product term in logistic regression model after standardizing to confounders .In the second step of our analysis of interaction we calculated four OR’s, that is those associated with each factor in the presence or absence of the other factor, with taking subjects with neither factor as the baseline . Thus, tWe showed that maternal reproductive effort during gestation, manifested in an infant’s birth weight, may be sensitive to environmental conditions such as lack of paternal investment and number of existing children. We found that a lack of paternal investment  was associated with higher odds of LBW. This relationship was statistically significant even after standardization to factors with a well-established impact on birth weight . Stratified analysis revealed that the effect of missing paternal data on the odds of LBW differed according to parity. On the basis of the stratum-specific estimates, missing paternal data was more strongly associated with LBW in multiparous than in primiparous mothers. After adjustment for confounders among the strata of multiparous mothers, missing paternal data was associated with higher odds of LBW , whilst the same association was not statistically significant among primiparous women (p = 0.24). The effect modification by parity was confirmed by the test for interaction on the multiplicative scale . The study has shown that missing paternal data and multiparity interact in evoking the low birth weight. We found that the combination of missing paternal data and being multiparous increased the odds of low birth weight in comparison to expected diminishing of risk from the product of the individual effects of these two exposures. Our results suggest that multiparous mothers may be more vulnerable to little or no paternal investment than primiparous mothers; therefore we propose treating parity as a potential modifier of the association between paternal investment and the risk of LBW.There are no empirical studies, to our knowledge, which show the association between a partner’s support and the risk of LBW with respect to parity. However, making reference to life history theory, it is likely that the decisions mothers face between investment in current vs. future reproduction may be affected by the number of dependent children they already have. High parity may serve as a proxy for high costs of reproduction , 20 and The unfavorable environment that exists when a father provides little or no support and previous children still require attention and care make women follow a reproductive strategy that results in lower investment in the current pregnancy, which is expressed in reduced fetal growth. Such a strategy may be viewed as a response to ecological circumstances, shaped through phenotypic plasticity. We assumed that physiological responses to little or no paternal investment may be guided by evolved mechanisms and can be predicted by evolutionary theories. Comparative studies indicate that human offspring are costly to produce, mature slowly, and reach nutritional independence late . These fThere are multiple routes by which paternal support may be linked to variation in the birth weight of offspring. A lack of paternal support may induce psychological stress in the mother, which can lead to altered fetal growth through neural and endocrine pathways . MaternaAnother mechanism through which parity can be linked to birth outcomes is related to maternal supply of nutrients to the fetus. The risk of folic acid deficiency  and loweLike other studies based on birth registries, our research has several limitations, one of which is that the type of paternal involvement and partner relationship quality cannot be examined in detail. In our study we used a proxy indicator of paternal investment; however, similar indicators were also used in other studies based on birth certificates –29,41. WAccording to Polish law, for married couples the husband of the child's mother is usually assumed to be the father of the child. Therefore, in our data there were no married mothers with missing paternal data. When a child's parents are not married, recognition (acknowledgment) of paternity by the father is required, therefore missing paternal data is noted only for unmarried mothers. Such an observation raised the problem of multicollinearity between marital status and missing paternal data. In order to verify this, we used the variance inflation factor (VIF). We found that VIF for missing paternal data equaled 1.4, which indicates a small correlation between this variable and all others in the model. The same value was found for marital status (VIF = 1.4). According to the literature, VIF should not exceed 10, while in logistic regression models, values above 2.5 may be a cause for concern . Thus, oWe added further support to the hypothesis that a low level of support from a partner may affect a woman’s trade-offs between investment in current vs. future reproduction , 12. We Further studies are needed to verify these predictions. Taking into account recent changes in family structure (an increasing number of children are born outside of marriage ) even in


Preterm birth is a health and social problem, considered the leading cause of neonatal mortality worldwide. It is associated with higher rates of neurodevelopmental morbidity, sensorineural impairments and other complications. The aim of the study was to describe the incidence and the major risk factors associated with preterm birth.We performed a single center, observational and retrospective Cohort study in the Division of Obstetrics and Gynaecology, University Hospital “G. Martino”, Messina. Clinical records of all pregnant women who delivered from 1st January 2010 to 31 of December 2016 were collected.p < 0.0001), and unmarried (p = 0.003) and underweight or obese patients (p < 0.0001). In addition, prematurity was associated with presence of uterine anomalies (p < 0.0001), vaginal/urinary infections (p = 0.02), poli/oligohydramnios (p < 0.0001), maternal diabetes (p = 0.004), hypertension (p < 0.0001), short cervical length (p < 0.0001).In the 7 years considered, a total of 7954 pregnant women were included in our study. The majority of all preterm births were due to infants born late preterm (71.83%), 26.45% were due to preterm and 1.72% to extremely preterm. The preterm cohort had a higher proportion of history of preterm delivery (We suggest prompt identification of all risk factors associated with preterm birth to apply immediate and appropriate specific interventions. Preterm birth (PTB) is a serious health and social problem, considered the leading cause of neonatal mortality worldwide , 2. It iAccording to World Health Organization (WHO), preterm birth is defined as any birth before 37 completed weeks of gestation  and repoThe research carried out and the preventive measures adopted in this field over the years have allowed a reduction of the incidence of PTB demonstrating the importance of identifying the risk factors associated with this condition .The aim of this study was to assess the trend of the incidence of preterm birth and the major risk factors, combining both maternal risk factors (RFs) and cervical length (CL) and with the inclusion in our cohort of women with a history of previous PTB.http://www.equatornetwork.org/).We performed a single center, observational and retrospective Cohort study in the Division of Obstetrics and Gynaecology, University Hospital “G. Martino”, Messina, Italy. As a standard protocol, each patient, on admission, signed an informed consent allowing data collection for research purposes. The study design was in accordance with the Helsinki Declaration and was approved by the Institutional Review Board of the University Hospital involved. All the design, analysis, interpretation of data, drafting and revisions followed the guidelines for reporting observational studies (STROBE) , availabClinical records of all pregnant women who delivered from 1st January 2010 to 31 of December 2016 were collected, while patients who underwent cerclage, pregnancies complicated by intrauterine fetal death or serious fetal malformation and multiple pregnancies have been excluded . Continuous variables are presented as mean (SD) or median (interquartile range), where appropriate, and categorical variables as frequencies and percentages. Differences between control and preterm cases were assessed using unpaired Student’s t-tests or Mann–Whitney U test, as appropriate. The chi-square test was used to compare frequencies. Bivariate associations were tested by Spearman correlation. A conservatively adjusted a priori alpha was set at A total of 8179 pregnant women were admitted to deliver in our Institution in the period considered [Fig. The rate of preterm birth in our Institution has shown a relatively stable or a slightly decreasing trend from 7.2 to 6.9% over the 7 year period Fig. b.n = 459), 26,45% (n = 169) were due to preterm and 1.72% (n = 11) to extremely preterm , unmarried women (p = 0.003) and underweight or obese patients (p < 0.0001). In addition, PTB was associated with presence of uterine anomalies (p < 0.0001), vaginal/urinary infections (p = 0.02), poli-oligodramnios (p < 0.0001), maternal diabetes (p = 0.004) and hypertension (p < 0.0001).The preterm cohort showed a higher proportion of history of a prior spontaneous PTB (p < 0.0001) , while no correlation was found among late preterm . Among PTB, cervical length correlated with older mothers . No other correlations were found.Among PTB, cervical length positively correlated with gestational age   should be performed in order to discover, at an early stage, asymptomatic women with a short cervix   and to aAlso the recent Italian guidelines of the Confalonieri Ragonese Foundation recommend performing a cervical measurement during the second trimester ultrasound screening (19–23.6 weeks) of all pregnant women and to administer 200 mg of Progesterone to those women with a cervix between 10 and 20 mm . This suWe also use to administrate vaginal progesterone in all the cases at risk for a short CL. This procedure has probably contributed, together with all other preventive measures, to the slight reduction of preterm birth over the years in our Hospital.Based on our results, we suggest prompt identification of all risk factors associated with preterm birth to apply immediate and appropriate specific interventions.We also recommend, confirming the evidence of other studies , 38–40, All these procedures could reduce the rate of PTB and the associated neonatal morbidity and mortality.


Adverse childhood experiences (ACE) are associated with an array of health consequences in later life, but few studies have examined the effects of ACEs on women’s birth outcomes.We analyzed data gathered from a sample of 1848 low-income women who received services from home visiting programs in Wisconsin. Archival program records from a public health database were used to create three birth outcomes reflecting each participant’s reproductive health history: any pregnancy loss; any preterm birth; any low birthweight. Multivariate logistic regressions were performed to test the linear and non-linear effects of ACEs on birth outcomes, controlling for age, race/ethnicity, and education.Descriptive analyses showed that 84.4% of women had at least one ACE, and that 68.2% reported multiple ACEs. Multivariate logistic regression analyses showed that cumulative ACE scores were associated with an increased likelihood of pregnancy loss , preterm birth , and low birthweight . Additional analyses revealed that the ACE-birthweight association deviated from a linear, dose-response pattern.Findings confirmed that high levels of childhood adversity are associated with poor birth outcomes. Alongside additive risk models, future ACE research should test interactive risk models and causal mechanisms through which childhood adversity compromises reproductive health. Adverse childhood experiences (ACEs) are a prevalent class of acute or recurring stressors that have long-lasting health consequences. Research in the U.S. has shown that most adults report at least one ACE, and that a higher number of ACEs increases the risk of various disorders and diseases in adulthood –6. Due tACEs like emotional neglect, physical abuse, and sexual abuse have been linked to an increased risk of poor birth outcomes such as pregnancy loss and preterm birth , 9. Yet,Another lingering question in the literature pertains to whether a higher number of ACEs incrementally increases the probability of negative consequences. Research has frequently uncovered a linear, or dose-response, association between the number of ACEs and the risk of poor health outcomes. However, some studies have found that the effects of maltreatment and other adversities follows a non-linear function –19. The The present study attempts to advance the literature by examining the effects of ACEs on reproductive health in a low-income sample of women. We hypothesized that our analyses would uncover a dose-response relationship between ACEs and three birth outcomes: (1) pregnancy loss, (2) preterm birth, and (3) low birthweight. In addition to testing linear associations, we explore whether the relationship between ACEs and birth outcomes is non-linear, the hypothesis being that effects are observable only once participants are exposed to a high number of ACEs.The present study is a secondary analysis of longitudinal data collected from low-income women with children in Wisconsin, United States. All participants received services within a statewide network of evidence-based home visiting programs that are supported by the federal Maternal Infant and Early Childhood Home Visiting Program . AgencieThis investigation uses child and caregiver data that are collected by home visiting personnel and entered into a state-administered public health database. During routine prenatal and postpartum assessments, home visitors routinely gather information about client ACEs, pregnancy history, and birth outcomes. The study sample is composed of 1848 women who received home visiting services between July 2015 and January 2018. Women were included in the sample if they (a) were at least 16 years old at program enrollment, (b) completed an assessment of ACEs with home visiting staff, and (c) had valid prenatal and postpartum assessment records. Access to participant records was granted by the Wisconsin Department of Children and Families pursuant to a data sharing agreement and approval by a university institutional review board.< 20 weeks gestation) or stillbirth . Premature birth indicates whether a participant ever gave birth prior to the 37th week of pregnancy. Low birthweight indicates whether a participant ever gave birth to an infant weighing less than 2500 g, or 5.5 pounds.We used archival program records to measure three dichotomous indicators of reproductive health: (1) any pregnancy loss, (2) any premature birth, and (c) any low birthweight infant. A measure of any pregnancy loss denotes whether a sample member ever had a miscarriage . The racial/ethnic composition of the sample was 41.1% Caucasian, 24.0% African American, 23.2% Hispanic, 7.1% American Indian, and 4.9% Other race/ethnicity. Approximately 29.7% of participants had completed some postsecondary education. On average, participants endorsed 3.2 ACEs (SD = 2.6); 84.4% of subjects reported at least one ACE, 68.2% reported two or more ACEs (not shown), and 29.8% reported 5 or more ACEs. Results showed that 27.3% participants had at least one pregnancy loss, 14.8% of women had given birth prematurely, and 12.0% had given birth to a low birthweight infant.Table Multivariate analyses presented in Table When we modeled ACEs as categorical indicators, results showed that there were no significant differences in birth outcomes between participants with 0 ACEs and participants with 1–2 ACEs or 3–4 ACEs. Having 5 or more ACEs was associated with an increase in the odds of pregnancy loss  while associations with preterm birth  and low birthweight  did not reach statistical significance.Figure Results from this study indicated that a large majority (84.4%) of low-income women receiving home visiting services had at least one ACE, and over two-thirds (68.2%) reported multiple ACEs. We also confirmed that elevated levels of childhood adversity undermine reproductive health, as higher ACE scores were associated with a greater likelihood of pregnancy loss, preterm birth, and low birthweight. Multivariate analyses showed that each additional ACE was associated with a 12% increase in the odds of pregnancy loss, a 7% increase in the odds of preterm birth, and an 8% increase in the odds of low birthweight. Taken at face value, the findings point to a dose-response relationship between the number of adverse childhood experiences and the risk of adverse birth outcomes.When ACEs were modeled as categorical groupings rather than as a cumulative index, however, a more nuanced pattern of association emerged. The observed relationship between ACE scores and pregnancy loss appeared to follow a largely continuous function, whereas associations between ACE scores and both preterm birth and low birthweight clustered at the most extreme levels of adversity. Multivariate analyses confirmed that the relationship between a total ACE score and low birthweight fit a quadratic model, denoting a significant deviation from linearity. The results suggest that ACEs are associated generally with poor birth outcomes, but that certain outcomes may only manifest once an individual has been exposed to profound adversity. Supporting this interpretation, a long line of research on cumulative risk has sometimes uncovered similar threshold effects , 23.A corollary to the above explanation is that outcomes may differ in sensitivity to less extreme gradations of adversity. One potential reason is that the relative proportion of variance explained by genetic and environmental causes differ across outcomes . A signiThe impact of ACEs also may vary by the developmental timing of the outcome. Other studies have documented robust associations between ACE scores and poor outcomes in later life, whereas we uncovered statistically significant, yet comparatively modest associations between a cumulative ACE index and reproductive health outcomes in early adulthood. It is possible that the effects of ACEs on physical health may increase over time due to the wear and tear of stress processes that are catalyzed by early adversity , 27. TheThe results also should be interpreted considering certain methodological features of the study, including the low-income sampling frame. Participants who were exposed to few ACEs still may have experienced poor birth outcomes due to their experiences of poverty and other associated risks , 30. As The current study adds to emerging evidence that ACEs are deleterious to reproductive health. Results showed that exposure to a greater number of ACEs increased the risk of pregnancy loss, preterm birth, and low birthweight. The relationship between ACEs and pregnancy loss largely followed a dose-response pattern, while the associations between ACEs and both preterm birth and low birthweight appeared to be at least partly non-linear. The latter findings signify potential threshold effects, meaning that some poor birth outcomes may emerge only when an individual is exposed to a critical level of adversity. The findings also justify further inquiry into non-additive and interactive effects of ACEs as well as the extent to which the timing, frequency, severity, and duration of adverse experiences yield differential outcomes.Our work also adds to a growing interest in applying a life course perspective to the study of maternal and child health , 33. A l


Preterm birth is a significant public health problem worldwide, leading to substantial mortality in the newborn period, and a considerable burden of complications longer term, for affected infants and their carers. The fact that it is so common, and rates vary between different populations, raising the question of whether in some circumstances it might be an adaptive trait. In this review, we outline some of the evolutionary explanations put forward for preterm birth. We specifically address the hypothesis of the predictive adaptive response, setting it in the context of the Developmental Origins of Health and Disease, and explore the predictions that this hypothesis makes for the potential causes and consequences of preterm birth. We describe how preterm birth can be triggered by a range of adverse environmental factors, including nutrition, stress and relative socioeconomic status. Examining the literature for any associated longer-term phenotypic changes, we find no strong evidence for a marked temporal shift in the reproductive life-history trajectory, but more persuasive evidence for a re-programming of the cardiovascular and endocrine system, and a range of effects on neurodevelopment. Distinguishing between preterm birth as a predictive, rather than immediate adaptive response will depend on the demonstration of a positive effect of these alterations in developmental trajectories on reproductive fitness.This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine'. In order to do so, we start by situating preterm birth in the context of low birthweight (LBW) and the Developmental Origins of Health and Disease (DOHaD) [in utero environment. We conclude by examining the limitations of the data, and ask whether prematurity should be best seen as an immediate, or predictive, adaptive response.In this review, we will outline the hypotheses that have been advanced that place the phenomenon of human preterm birth in an evolutionary context. After discussing these, we will focus specifically on addressing the hypothesis that preterm birth may, in some circumstances, be a  (DOHaD) . Followi2.The null hypothesis for preterm birth having any adaptive significance is that it represents a pathophysiological response to triggers such as systemic or intra-uterine infections, or the endothelial dysfunction associated with diseases such as pre-eclampsia. From this perspective, preterm birth could be seen as a pathological process that has no evolutionary context or implications.Another argument that has been put forward is that preterm birth has no adaptive advantage for the fetus, but that premature delivery, associated with a low chance of survival for the fetus, instead allows a mother to prioritize her own survival, and increase her chances of having a subsequent, more successful pregnancy .immediate adaptive advantage to either the fetus or the mother, but that the length of gestation is likely to represent the outcome of a trade-off, for both the fetus and mother, between the benefits and costs of continuing a pregnancy. It has long been recognized that for many sexually reproducing species, and in particular for non-human primates, at certain points during gestation and early life there is likely to be conflict between the interests of the mother and the fetus/infant, in relation to both the length and amount of parental investment [in utero conditions are more favourable than those after delivery. However, throughout gestation a mother's reproductive decisions are more likely to be influenced by a trade-off between the chance of a fetus surviving birth and thus transmitting maternal alleles, and the fitness costs of continuing a gestation beyond an optimal duration (for the mother), particularly during the final weeks, which are associated with the deposition of subcutaneous fat in the fetus and substantial energetic investment from the mother [A more nuanced alternative to this is that preterm delivery may provide an vestment . This idvestment , who arge mother .Thus, faced with adverse intra-uterine circumstances, a fetus may choose to trigger delivery (as is seen with intra-uterine infection or with growth restriction ) prematuex utero environment leads to changes in developmental trajectories appropriate to this environment.A final possibility, which we examine in detail in this paper, is that preterm birth may form one of a suite of predictive adaptive responses (PAR) to an adverse environment: the information provided by the maternal niche to the fetus about the 3.Daphnia pulex. If a predatory midge is present in the environment antenatally, the offspring develop a spiked helmet and long pointed tail, which provide protection against the midge, but are associated with reduced reproductive success if the predators disappear before reproductive age is attained. A PAR is also documented in voles (Microtus pennsylvanius), where pups born in the autumn have thicker coats than those born in spring; the cue to produce a thicker coat is provided by hormonal signals from the mother before birth, determined by day length [The PAR hypothesis refers to ‘a form of developmental plasticity in which cues received in early life influence the development of a phenotype that is normally adapted to the environmental conditions of later life’ , p. 2357y length .in utero-induced PAR appropriate to the low-nutritional conditions that had induced their birthweight [A possible example of a PAR in humans is seen in cases of kwashiorkor and marasmus, both forms of malnutrition, where the development of each disease was associated in Jamaican children with different birthweights. Those with marasmus had a lower birthweight than those with kwashiorkor, but were also less likely to die during an acute episode of malnutrition, suggesting a possible thweight ; these ithweight .4.in utero conditions as an adaptive developmental response. They hypothesize that the capacity to alter the trajectory of development, and thus the mature phenotype, in response to environmental influences, may lead to increased chances of survival and reproduction. These adaptive responses may be immediate—that is, challenges to which an individual must respond immediately—or predictive, where fitness is enhanced by matching the phenotype better to the anticipated environment [Placing LBW in evolutionary context, Gluckman and co-workers ,17 have ironment . The conironment , p. 88.In this theoretical framework, preterm birth forms part of a suite of potential developmental trajectories in response to a perceived deprived environment and a predicted uncertain life course . PretermTo examine whether preterm birth could be seen as a PAR, we first discuss initial findings showing that early life exposures correlate with later cardiometabolic outcomes, and the place of preterm birth within these cohorts. We then examine the data available from which to infer preterm birth rates in the pre-industrial context in which most of human evolution has taken place. Having outlined the evidence base available for the subsequent section, we move on to examine specific aspects of the PAR hypothesis in relation to preterm birth.5.It has been recognized since the first half of the twentieth century that early life exposures might have an influence on outcomes in later life ,20. HoweWhile in most contemporary settings gestational age is calculated using the date of the start of the last menstrual period (LMP), or in higher-income locations ultrasound measurements, birthweight was used throughout much of the twentieth century to identify infants born preterm. In 1919, prematurity was defined as a birthweight of less than 2500 g . This soIt is therefore likely that many of the cohorts used to analyse the long-term consequences of LBW comprise a heterogeneous population of preterm infants with and without growth restriction, and term infants with growth restriction  found evidence of a similar distribution of relative gestational ages in which live births occurred in a number of non-human primates . AnotherThe second key question is at what gestation infants are viable without any medical intervention. The importance of this intervention at extremely early gestations ; infection in itself may act as a trigger to preterm birth . HoweverRecent studies examining the relationship between maternal BMI and gestational duration show an association between lower pre-pregnancy maternal weight and a higher risk of giving birth prematurely after spontaneous onset of labour ,41. High8.et al. argue that ‘based on the principles of developmental plasticity it becomes an appropriate response to accelerate the tempo of maturation in expectation of a shorter life expectancy’ [We discuss above how spontaneous preterm birth occurs in response to a wide variety of triggers, and could be part of stereotyped response to adverse life conditions. Adverse early life conditions have also been associated in some females with an acceleration in the timing of puberty and an earlier age at menarche . Setting this in a life-history context, it has been argued that across species there is commonly an association between earlier age at sexual maturation and reduced adult body size, and that this earlier age at maturation is associated with conditions during which there is a high risk of predation or death ,51. Studectancy’ , p. 120.et al.'s review [We conducted a systematic review to ask the question: does length of gestation affect the timing of puberty? . We idens review  as a who9.Preterm birth can be associated with a range of cardiovascular, metabolic and psychological/behavioural modifications that extend into adulthood, even for individuals born at gestations close to term. One systematic review found that preterm birth was associated with a significantly higher systolic and diastolic blood pressure , potentiIn terms of mechanisms, studies suggest that induced changes in ‘epigenetic’ modifications including DNA methylation and histone modifications might be one mechanism by which adverse early life circumstances translate into phenotypic changes in adulthood. For example, altered DNA methylation has been reported in preterm infants at loci related to post-natal growth such as insulin-like growth factor 2 –63. AnotA final way in which preterm birth might influence the adult phenotype is through psychological/behavioural changes—the hypothesis of the predictive adaptive response being that early exposure to an adverse environment leads to longer-term behavioural changes as an adaptation to predicted ongoing adverse conditions. In animal models, prenatal factors such as stress or toxicological exposures have been associated with the development of specific behavioural phenotypes . Preterm10.What do the inconsistent findings outlined above imply for the theory of preterm birth forming part of an adaptive response to adverse life circumstances? An important consideration is that the evidence with which we are examining the hypotheses is inadequate. The assessment of gestational age is fraught with difficulty : the stu11.Drawing together the evidence, it appears that spontaneous preterm birth occurs commonly in humans, and can be triggered by a range of environmental factors. There are a number of associated longer-term phenotypic changes: not a marked temporal shift in the reproductive life-history trajectory, but potentially a re-programming of the cardiovascular and endocrine system, and effects on neurodevelopment. These, in the context of rapid weight gain, an obesogenic diet or other adverse life circumstances may lead to detrimental consequences for individuals.So should preterm birth be seen mainly as a disease process, rather than one with any evolutionary consequences? The high global prevalence of preterm birth and the relatively high survival rates at gestations of greater than 32 weeks, even in low-income settings, would argue against this. However, the rapidly increasing mortality rates with decreasing gestation would suggest that the idea of preterm birth as an adaptation to an adverse environment is probably best examined in those born at moderately preterm gestations.in utero environment. This view is consistent with Hales and Barker's proposal of an adaptive trade-off with relation to birthweight [It is therefore possible that preterm delivery serves distinct purposes at different stages of gestation. What are now considered (thanks to the advent of modern technology) to be gestations at borderline viability and extremely preterm birth may be an outcome that prioritizes maternal survival, and primarily adaptive for the mother. An adaptive response for the fetus might be more relevant at later gestations, at which infant survival is more likely, and early delivery with adaptation to an adverse environment is the best possible outcome. Here prematurity could be seen as adaptive, but mainly in the immediate sense. Faced with adverse circumstances, preterm birth might form part of a strategy to enhance the chance of survival, but the consequent lack of investment in skeletal muscle, nephron number, body size and neuronal tissue is the inevitable, and detrimental, cost of responding to these conditions while ensuring survival. The long-term consequences of these immediate compromises may well be deleterious, but as outlined earlier, preterm birth offers a greater chance of survival than continuing a pregnancy in a compromised thweight : LBW or thweight  or capilthweight  may lateDaphnia or voles. Pointers towards this may come from clinical studies looking at the outcomes of early nutrition for preterm infants. It is known that excessive catch-up growth in this group  can have detrimental consequences for the cardiometabolic health of these infants in later life [Ultimately, validation of the predictive adaptive response as a plausible explanation for the phenotypic changes seen in response to adverse early life conditions will depend on the demonstration of positive effects on reproductive fitness accruing from an alteration in developmental trajectories, as seen in examples of the PAR in ter life , suggest12.unexpected environmental conditions, or may instead be simply maladaptive in any context. As our understanding of the aetiology of spontaneous preterm birth is incomplete, and our ability to respond to the often devastating post-natal consequences of prematurity remains limited, focusing on the known preventable causes of preterm birth appears the most tractable approach at present to this substantial public health problem.Preterm birth is a common, and potentially highly deleterious, complication of many pregnancies. Risk factors associated with preterm delivery correlate with adverse life conditions for mothers, which can take the form of nutritional, social or psychological disadvantage. In common with LBW, preterm birth appears to be sometimes, but not always, associated with a suite of phenotypic changes that may represent maladaptation to


In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years  with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years  and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years  and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years  and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets.Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients ( It clase versa” , 4. AlthThere is published data demonstrating that the condition is reversible across differing populations worldwide. Recent neurology practice guidelines concluded that there was evidence for “96% chance subjective improvement and 83% chance improvement on timed walk test at 6 months” and that shunting was possibly effective in idiopathic NPH .NPH presents as a challenging collection of patient cohorts along a spectrum of disease. Neuropsychological profiling, gait/ balance measurements and CSF infusion studies may help predict which patients have the potential to improve with surgical intervention. However, such techniques require significant patient cooperation for meaningful testing to occur. This may not be possible for patients presenting at the late or complex part of the NPH spectrum who are less able to participate in active testing methods. In these types of NPH cohorts, supplementary imaging methods to confirm and characterize NPH features are of critical importance. These methods provide supporting information in evaluating the NPH component remediable to CSF diversion in order to balance the risks vs. benefits of surgical intervention in patients where multiple clinical confounders co-exist.Yet, one of the major obstacles in the development of novel tools for the interpretation of NPH imaging findings is that the pathogenesis for classic NPH is still unknown. Published data have been contradictory across different imaging modalities . When patients were compared to healthy controls within the individual sites, nearly all DTI measures were significantly different between groups. Pre-drainage, both complex NPH responders and non-responders demonstrated significant differences in MD  and L1 (stretch/compression) compared to healthy controls. However, there were only significant differences in L2and3 compared to healthy controls in the complex NPH non-responder group  were statistically different between cohorts [complex NPH vs. classic NPH patients  underwent surgical intervention, with six ventriculo-peritoneal shunts placed. All responders maintained their predicted responses following shunting. One responder developed a delayed abdominal pseudocyst with subacute infection. He had no evidence of infection on CSF sampling but had drainage of the pseudocyst with temporary shunt externalization, due to concerns of ascending infection. He subsequently had a shunt reinsertion on the contralateral side without neurological deterioration. Two responders reported post-operative improvement exceeding that of testing levels. At 1 year post-shunting, all complex and classic NPH responders maintained their good outcomes. Good outcomes were primarily reflected in improvement of gait symptoms. In terms of urinary symptoms, one responder had subjective improvement in incontinence and two responders reported no change; one responder had known pre-existing bladder dysfunction. One non-responder subsequently died from a cerebrovascular accident, a known comorbidity, outside the study. Another had delayed improvement at home but declined surgery.In this study, we demonstrate the utility of using the morphology of DTI parameters to compare DTI profiles across collaborator sites, despite significantly different datasets. Due to the differing MR scanners and specifications unique to each collaborator site, it would not ordinarily be possible to directly compare DTI findings. The methodology of DTI profiles provides a framework for the rapid characterization of diffusivity measures to describe patient cohorts at the clinical-research interface that supports the new praxis of patient-centered international collaborative research.The challenges of comparing imaging datasets between differing collaborating units are well-accepted. Apart from MR field strengths, an analysis study by Cetin Karayumak et al.  illustraper se. Instead, we propose the use of DTI profiles to enable collaborators to confirm and characterize the comparability of their cohorts by providing a further layer of transparency, prior to the application of higher statistical methods. The checks afforded by DTI profiles also enable rapid detection of outliers for diffusivity parameters expected for local cohorts and allows individual units to ascertain if their presenting disease cohorts are comparable to international or open-access datasets of disease. The ability to perform these checks at the clinical-research interface contributes to the development of patient-centered collaborative research networks.Whilst such work is still necessary, good scan-rescan repeatability and cross-scanner comparability have already been confirmed across differing sites and scanners, supporting the feasibility of using DTI measures derived from multiple collaborating sites . OngoingNPH as a disease continuum is critical to the development and study of DTI profiles because it serves as a both a model of reversible and irreversible brain injury. In our previous work in classic NPH patients, we have shown that it is possible to use DTI methodology to confirm and characterize differing pathophysiological processes occurring concurrently . CompareSimilarly, we have found, using DTI profiles, that despite confounding factors such as comorbidities involving cardiovascular risk burden and overlay from neurodegenerative disease, complex NPH responders can be shown to demonstrate patterns that mimic classic NPH responders across all diffusivity measures. The changes exhibited by non-responders are different and exhibit DTI morphology that are distinct from responders. DTI is useful because of its ability to characterize microarchitectural changes within white matter. The application of DTI profiles allows for the interpretation of contrasting pathological mechanisms without assumed prior knowledge of the predominant patterns of changes leading to its clinical syndrome. Our methodology of DTI profiles provides a mechanism for describing morphological changes common to different cohorts within the same spectrum of disease. This shorthand does not require that such groups are homogenous; we have demonstrated its utility within separate and significantly different patient cohorts within NPH, suggesting the DTI profiles for the disease process is proportionately more important than variations of the disease phenotype within its spectrum.Our study has several methodological shortcomings. Firstly, our sample size is small, albeit relevant for the disease in question. The current study reflects improvements in DTI acquisition and analysis that is in some ways superior to that of the exemplar dataset. An optimal comparator study would involve simultaneous recruitment of different patient cohorts across both collaborator sites, and would require harmonization of DTI acquisition protocols in real time. Further validation work regarding the use of DTI profiles in comparison with international open-access datasets would be most helpful in this regard.In conclusion, comparability of DTI measures across disease cohorts and collaborative sites is an obstacle to its usability and application at the clinical-research interface. Our findings suggest that it is possible to overcome such challenges by the use of DTI profiles to understand the morphology of microstructural changes and to apply such characterization in consistent terms to international collaborator datasets. The use of such methodology should be considered within the context of interdisciplinary collaboration as part of the new praxis of translational medicine.This study was carried out in accordance with the recommendations of the SingHealth Centralized Institutional Review Board (CIRB) with written informed consent from all subjects or their legal representatives, in the event that the subjects were not able to consent for themselves. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the SingHealth Centralized Institutional Review Board.NCK and CL contributed to the conceptualization and design of the study and wrote the manuscript. JK coordinated study procedures and scanning for the study. JK and CL contributed to the collection, analysis and interpretation of study data. NCK supervised study procedures and data collection for the study, and contributed to the analysis and interpretation of study data. SK contributed to design of imaging acquisition parameters and optimization of the study protocol as well as interpretation. NK, E-KT, and AN contributed to the clinical and research characterizations of the complex NPH patients. JP, MC, and ZC contributed to the exemplar dataset of the classic NPH patients. VN, AA-A, AN, and YJT contributed to the validation of the methodology of DTI characterization of the complex NPH patients using fluid markers (not presented in this manuscript). All co-authors contributed to revisions of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To compare the prevalence of preterm birth, post term birth, intra-uterine growth restriction and distribution of Apgar scores in offspring of foreign-born women in Western Australia with that of their Australian-born non-Indigenous and Indigenous counterparts.A population-based linked data study, involving 767,623 singleton births in Western Australia between 1980 and 2010 was undertaken. Neonatal outcomes included preterm birth, post term births, intra-uterine growth restriction  and low Apgar scores. These were compared amongst foreign-born women from low, lower-middle, upper middle and high income countries and Australian-born non-Indigenous and Indigenous women over two different time periods using multinomial logistic regression adjusted for covariates.Compared with Australian born non-Indigenous women, foreign-born women from low income countries were at some increased risk of extreme preterm  and very early preterm  births during the period from 1980 to 1996. During the period from 1997 to 2010 they were also at some risk of extreme preterm  very early preterm  and post term birth . During this second time period, other adverse outcomes for children of foreign-born women from low income and middle income countries included increases in severe , moderate  and mild  IUGR compared to children of Australian-born non-Indigenous mothers. Uniformly higher risks of adverse outcomes were also demonstrated for infants of Indigenous mothers.Our findings illustrate the vulnerabilities of children born to foreign women from low and middle-income countries. The need for exploratory research examining mechanisms contributing to poorer birth outcomes following resettlement in a developed nation is highlighted. There is also a need to develop targeted interventions to improve outcomes for these women and their families.The online version of this article (10.1186/s12884-019-2437-x) contains supplementary material, which is available to authorized users. Relationships between adverse pregnancy and birth outcomes such as preterm birth, intra-uterine growth restriction (IUGR) and low Apgar scores and increased infant morbidity and mortality are well-recognised –8. ThereSeveral studies have found that foreign-born women living in developed countries are at increased risk of adverse obstetric and perinatal outcomes including preterm delivery, low birth weight, IUGR, Caesarean section, postpartum haemorrhage and neonatal mortality and infection –17. ObstAustralia is a multiethnic society with just over a quarter of citizens (28%) born overseas , includiA retrospective cohort study of children born in WA (1980 to 2010) was conducted using de-identified linked population-based data from the WA Midwives Notification System (MNS) and the WA Birth Register. The MNS is a statutory database of pregnancy, birth and neonatal information collected by attending midwives, on all births of at least 20 weeks’ gestation or at least 400 g in weight  and includes maternal and infant characteristics and infant outcomes. For this study, multiple births were excluded because they are associated both with poorer birth outcomes and country of birth . The WA Maternal variables collected were maternal age , marital status , parity (the number of live born and stillbirths a woman has had leading up to this particular pregnancy), and smoking (a binary variable only collected in the MNS from September 1997).Six categories were created using the maternal country of birth (MCB) variable, available from the Birth Register: 1) Australian-born mothers of non-Indigenous backgrounds (ANI), 2) Australian-born mothers of Indigenous background (AI), 3) foreign-born mothers from low-income countries (FB-LIC), 4) foreign-born mothers from lower-middle-income countries (FB-LMIC), 5) foreign-born mothers from upper-middle-income countries (FB-UMIC), and 6) foreign-born mothers from high-income countries (FB-HIC). Countries’ income groups were determined using the United Nations, World Health Organization and World Bank country listings –31 and iThe Australian Bureau of Statistics produces the Socio-Economic Indexes for Areas (SEIFA) score, which ranks areas in Australia according to relative socio-economic advantage and disadvantage from information collected during the Australian Census . We spec> 42 weeks). Any pre-term was defined as < 37 weeks and the category of full term birth (39–41 weeks) was used as the reference group for the multinomial regression data analysis. IUGR was determined using the POBW, which is the ratio of observed birth weight to optimal birth weight, and is a variable that is calculated and provided to researchers by the data custodians in WA.Infant variables were gender, gestational age, proportion of optimal birth weight (POBW) and Apgar score at 5 min. The adverse fetal outcomes were: (i) preterm birth, (ii) IUGR and (iii) low Apgar score. Preterm birth was determined using a final gestational age variable that was categorized into seven groups of gestation: extreme preterm (< 28 weeks), very early preterm (28–31 weeks), early preterm (32–33 weeks), late preterm (34–36 weeks), early term (37–38 weeks), full term (39–41 weeks), and post term  in a total population of singleton births without any recorded risk factors for intrauterine growth restriction such as maternal smoking , 35. Theanalysis  and POBWDescriptive statistics were used to summarise the characteristics of the study participants. Multinomial logistic regression models were used to estimate the risk of pre/post term birth relative to full term birth among MCB groups compared to Australian-born women of non-Indigenous background, after adjusting for potential confounders including maternal age, SEIFA score, parity, birth year and child’s sex. The model was also used for assessing the risk of suboptimal (POBW less than 95% or more than 104%) relative to optimal (POBW between 95 and 104%) birth weight and risk of low relative to normal Apgar score. Both crude and adjusted relative risk ratios, and their 95% confidence interval values were reported. Missing data were considered missing at random and complete case analysis was used. Since smoking data were only available from September 1997, we conducted regression analysis separately for the two-time periods: 1980–1997 (without adjusting for smoking) and 1997–2010 (with adjusting for smoking). All analyses were performed using STATA version 14 .For the years 1980 to 2010 our study included 769,695 singleton births with a valid MCB  of which 66.2% were children of ANI mothers, 19.0% were children of FB-HIC mothers, 5.8% were children of AI mothers, 4.3% were children of FB-LMIC mothers, 4.1% were children of FB-UMIC, and 0.6% were children of FB-LIC. Only 0.1% of our sample population had missing data for MCB. Socio-demographic factors including smoking status are presented in Table Perinatal outcomes  in relation to maternal country of birth are presented in Tables For the period from 1980 to 1996, children of FB-LIC mothers had a non-significantly increased risk of preterm birth compared to those of ANI mothers . During this period children of FB-LMIC mothers had a small but significantly increased risk of preterm and post-term births . Children of AI mothers had significantly increased risk in all categories of preterm and post term births during this period. For the period from 1997 to 2010, a non-significant increased risk of preterm and post-term births was observed for FB-LIC mothers . FB-LMIC mothers also had increased risks of extreme preterm  and very early preterm  births. Whilst a slight increased risk of late- preterm  and early term births  was seen in children of FB-UMIC during the first period and an only slightly increased risk of early term in the second period, children of FB-HIC had only a very slight increased risk of late preterm birth during the first period .Children of AI mothers had increased risk of severe IUGR and increased risk of excessive fetal growth during the period from 1980 to 1996 Table . There wCompared to children of ANI mothers, children of FB-LIC mothers had an increased adjusted relative risk of critically low 5-min Apgar score  and an elevated risk of fairly low 5-min Apgar scores in the second period  Additional file 2:Table S2. High income countries. (PDF 243 kb)


The aim of study was to identify risk factors of birth asphyxia among newborns in public hospitals of Central Zone Tigray, Ethiopia 2018.A total of 88 cases and 176 controls were included in the study. Thirty (34.1%) cases and 28 (15.9%) of controls were not able to read and write. Twenty-one (23.9%) cases and 9 (5.1%) controls were had meconium stained on pelvic examination. Multivariable logistic regression analysis showed that maternal illiteracy , low birth weight , preterm , prim parous , antepartum hemorrhage  and meconium stained amniotic fluid  were independent risk factors of birth asphyxia. Birth asphyxia is defined as a failure to initiate, establish and sustain breathing at birth. It can also be defined as placental or pulmonary gas exchange impairment leading to hypoxemia and hypercarbia , 2. BirtA diagnosis of birth asphyxia may be made when a baby has a < 7 Apgar score. Another way of identifying birth asphyxia is checking the acidity of the blood in the umbilical cord. If it is too acidic, it can be a sign that the baby has had a period of oxygen deprivation . A baby Over 130 million infants born every year globally and about four million neonatal deaths occurred each year . NeonataThere are tested risk factors of birth asphyxia in different studies however there are factors which are not tested particularly in our setting . Hence, The study was carried out in public hospitals of Central Zone Tigray, Ethiopia. Data collection for this study was undertaken from January up to February 2018.A facility based unmatched retrospective case–control study design was employed.The source population was all mothers were born their child in central zone, Tigray, Ethiopia.Mothers with their newborns who diagnosis as birth asphyxia.Mothers with their newborns who diagnosis without birth asphyxia.Sample size of the study was calculated using EPI Info software version 7.1.1 with the following parameters for unmatched case control study: confidence level = 95%; power = 80%; odds ratio = 2.53; case to control ratio = 1:2; proportion of controls with exposure 17.7% ; proportSystematic random sampling technique was used to select the study subjects from four public hospitals with every two study subjects for both cases and controls.Birth asphyxiaDependent variableAntepartum factorsIntrapartum factorsFetal factorsIndependent variablesWhen the newborn has at least one of the following signs, not breathing, gasping, < 30 breaths per minute or < 7 APGAR score .When the newborn weight was < 2500 g .When the newborn was born < 37 gestational age .Data was collected using interviewer administered structured questionnaire adapted , observaQuality of the data was assured with properly designed data collection instruments. The enumerators and the supervisors were given training for 5 days on procedures, techniques and ways of collecting the data. Five percent pretest was done at Shul hospital to check consistency of the questioner. The collected data was reviewed and checked for completeness by principal investigator and co-investigators weekly.Data was entered and cleaned using Epi info version 7.1.1. Data was analyzed using SPSS version 22.0 statistical software. Cross tabulation was done among dependent variable and independent variables. Binary logistic regression model was used to determine significant association between birth asphyxia and possible risk factors. Variables which were show statistical significance during bivariate analysis at p-value ≤ 0.25 were entered to multivariable logistic regression. Multivariable logistic regression was done with considering a selected variables of bivariate logistic regression analysis. Data was finally presented and interpreted at p-value < 0.05 being considered as statistically significant.In this study, a total of 88 neonates who had birth asphyxia (cases) with their index mothers and 176 newborns who had no birth asphyxia (controls) with their index mothers were included making a response rate of 100%. Forty-nine (55.7%) of cases and 64 (36.4%) controls were living in rural areas. Regarding to marital status, 75 (85.2%) cases and 166 (94.3%) of controls were married. Forty-seven (53.4%) of cases and 89 (50.6%) of controls were house wives and 30 (34.1%) cases and 28 (15.9%) of controls were not able to read and write (Table Seventy-six (86.4%) cases and 159 (90.3%) controls their mothers were had antenatal care follow up and 11 (12.5%) cases and 6 (3.4%) controls their mothers were had preeclampsia. Two (2.3%) cases and 5 (2.8%) controls their mothers were with the complication of polyhydramnios and 6 (6.8%) cases and 3 (1.7) controls their mothers were had oligohydramnios as a complication. Three (3.4%) cases and 5 (2.8%) controls their mothers were anemic patients and 8 (9.1%) cases and 11 (6.3%) controls their mothers were had maternal infection. Three (3.4%) cases their mothers had experience of having history of smoking and 10 (11.4%) cases and 34 (19.3%) controls had history abortion. Forty-three (48.9%) cases and 64 (36.4%) controls were prim parous parity.Twenty-three 26.1%) cases and 36 (20.5%) controls their mothers were had experience of prolonged labor and 7 (8.0%) cases and 8 (4.5%) controls their mothers were had prolapsed cord as a complication of labor. Sixty-three (71.6%) cases and 135 (76.7%) controls their mothers were delivered spontaneously and 78 (88.6%) cases and 158 (89.8%) controls their mothers were had vertex presentation. Twenty-one (23.9%) cases and 9 (5.1%) controls their mothers were had meconium stained on pelvic examination. Forty-three (48.9%) cases and 19 (10.5%) controls were low birth weight and 49 (55.7%) cases and 40 (22.7%) and controls were preterm ].Parity was significantly associated with birth asphyxia. This study showed that those who were primiparous 3 times higher risk than those who were multiparous to effect birth asphyxia .Antepartum hemorrhage was significantly associated with birth asphyxia. Mothers who had antepartum hemorrhage had 12 times higher risk than those who were not had antepartum hemorrhage to the outcome of birth asphyxia .Status of meconium stained had significant association with the outcome variable of birth asphyxia. Those who had meconium stained were 7.9 times higher risk than were not had meconium stained to birth asphyxia .Preterm babies were 2.2 times higher risk than term developing birth asphyxia . Similarly, the weight of the neonate had also a significant association with birth asphyxia. Low birth weight neonates were 6.9 times higher at risk than normal weight as determinant of birth asphyxia  . This finding is similar with studies conducted in Pakistan and Thailand , 21 presPreterm babies were 2.2 times more likely to be asphyxiated than term babies. This study is in line with a study conducted in Jordan discovered that preterm babies had risk of development birth asphyxia , 22. ThiMeconium stained mothers had a significant association with birth asphyxia. Those who had meconium stained were 7.9 times higher risk than were not had meconium stained to birth asphyxia. This study is in line with other previous study . In healParity had significant association with birth asphyxia. Those who were prim parous 3 times higher risk than those who were multiparous to effect birth asphyxia. This study is consistent with other studies , 24. ThiAntepartum hemorrhage had significant association with birth asphyxia. Mothers who had antepartum hemorrhage had 12 times higher risk than those who were not had antepartum hemorrhage to the outcome of birth asphyxia. This study is in line with studies reported previously . This coBirth asphyxia is one of the worldwide problem of neonates. It arises different complications, if the cases left untreated and leads to death. There are different variables which culprits of birth asphyxia. In this study, maternal illiteracy, prim parous, low birth weight, preterm delivery and meconium stained amniotic fluid were the risk factors of birth asphyxia. Most of these variables are preventable by holistic care of pregnancy, labor and delivery and post-natal care.This study is quantitative; it was better if qualitative approach was also employed to investigate in detail on extra determinant factors of birth asphyxia.The study was done in single one region of Ethiopia. It is difficult to generalize for the whole country with small sample.This study also subjected to recalling bias of mothers when they remembered their previous history.


Controls were randomly chosen from among singleton births that were not preterm (n = 242) or SGA (n = 241) infants during the same time period. Women provided blood samples at 10–14 weeks’ gestation for serum iodide, Tg and TSH measurement. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for preterm birth and SGA. Each log-unit increase in serum iodide was associated with higher odds of preterm birth , but was not associated with SGA . Tg was not associated with preterm birth , but was inversely associated with SGA . Neither high nor low TSH  were associated with either outcome. These findings suggest that among Finnish women, iodine status is not related to SGA, but higher serum iodide may be positively associated with preterm birth.Normal maternal thyroid function during pregnancy is essential for fetal development and depends upon an adequate supply of iodine. Little is known about how iodine status is associated with preterm birth and small for gestational age (SGA) in mildly iodine insufficient populations. Our objective was to evaluate associations of early pregnancy serum iodine, thyroglobulin (Tg), and thyroid-stimulating hormone (TSH) with odds of preterm birth and SGA in a prospective, population-based, nested case-control study from all births in Finland (2012–2013). Cases of preterm birth ( Normal maternal thyroid function during pregnancy is essential for fetal development . HypothyDespite increased risk of iodine deficiency during pregnancy, even in developed countries ,6, and aThe aim of the present study was to evaluate associations of serum iodide concentrations and thyroid hormones indicative of iodine status  with risk of preterm birth and SGA among pregnant Finnish women, a population considered to be mildly iodine deficient, but with relatively low prevalence of other nutritional deficiencies .We conducted a population-based, nested case-control study within the Finnish Maternity Cohort (FMC), using the Finnish Medical Birth Register (MBR) to ascertain pregnancy and perinatal outcome data. Beginning in 1983, the FMC has collected more than 2 million serum samples from more than 950,000 pregnant women living in Finland, which reflects ~98% coverage of the pregnant population. Blood samples were collected to screen for hepatitis B, human immunodeficiency virus (HIV), syphilis, and rubella antibodies. The samples were drawn in general between 10 and 14 weeks gestation at local maternity care units and sent to the prenatal serology laboratory of the Finnish Institute for Health and Welfare in Oulu. There, sera were separated by centrifugation, screening analyses were performed and the remaining serum (1–3 mL) was stored at −25 °C.Biochemical data were linked to clinical data from the MBR via unique personal identification numbers given to all Finnish citizens and residents at birth or at time of permanent residence. The MBR includes data on all live births and stillbirths in Finland with a birth weight ≥500 g or a gestational age at birth ≥22 gestational weeks. Maternal data collected by the MBR includes age, height and weight, socioeconomic status based on self-reported occupation, marital status, pregnancy history, smoking status, and other factors. Data collected on infants included sex, gestational age at birth, and birth height and weight.Women gave written informed consent for their samples to be used for research purposes. This study was approved by the steering committee of the FMC, the ethical review boards of the Northern Ostrobothnia Hospital District and the Finnish Institute for Health and Welfare, Oulu, Finland, and the Office of Human Subjects Research, National Institutes of Health, Bethesda, MD, USA (#13459).th percentile for gestational age), using the same control group. Nine control pregnancies were SGA and reclassified as such, resulting in 209 SGA cases and 241 controls. We randomly selected 200 cases of preterm birth (defined as a live birth <37 weeks gestation) and 250 potential controls from among all singleton births in Finland between 2012 and 2013 with available serum samples in the FMC. Because the 250 potential controls were randomly selected without regard to case/control status, 8 control pregnancies were delivered preterm and were thus reclassified as cases. After reclassification, the final analytic sample included 208 cases and 242 controls. Similarly, we randomly selected 200 cases of SGA  and multiple reaction monitoring. Serum Tg and TSH concentrations were measured using a commercial immunoassay , as they have been shown to be reliable markers of thyroid function in pregnant women [Details regarding the iodide measurement in this study population have been published previously and are provided in nt women . The int2 tests for categorical variables. Equivalent non-parametric tests were used where appropriate. For analyses evaluating continuous exposures, serum iodide, Tg, and TSH values were normalized by log-transformation. Participants were divided into quartiles of iodide and Tg based on the distribution of these biomarkers in the control group. For TSH, we categorized participants as having high TSH , normal TSH , or low TSH , according to previously defined reference ranges for this population [Characteristics of the cases and controls were compared using t-tests for continuous variables and χpulation .Using logistic regression, we estimated unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) for preterm birth and SGA according to each biomarker. We then estimated adjusted ORs and 95% CIs adjusting for maternal age, maternal body mass index (BMI), socioeconomic status, smoking status, parity, and marital status. Covariates were selected for inclusion in multivariable models based on directed acyclic graphs . IndividWe also examined possible non-linear associations of iodide with preterm birth and SGA non-parametrically utilizing restricted cubic spline models. In these models, we specified 3 knots and evaluated the individual spline term contributions to the model fit and overall test for nonlinearity.In sensitivity analyses, we excluded women with conditions associated with medically-indicated preterm birth  to determine whether these conditions may have influenced the results. All analyses were run using SAS, version 9.4 . 2), gravidity (1.3 vs. 1.4) and parity (0.8 vs. 1.1) than controls, and were also more likely to be smokers (52% vs. 37%). SGA cases were also more likely than controls to have preeclampsia during the pregnancy (16% vs. 4%). The Spearman rank correlation coefficients for each biomarker were as follows: iodide and Tg, rs = 0.02 (P = 0.54); iodide and TSH, rs = 0.001 (P = 0.97); and Tg and TSH, rs = −0.13 (P < 0.001).Characteristics of preterm birth and SGA cases and controls at blood draw are presented in In unadjusted models, each 1 log-unit increase in serum iodide was positively associated with preterm birth  . After aSerum iodide was not associated with odds of having an SGA infant in unadjusted or adjusted models.  For examIn this population-based, nested case-control study, we found that neither low- nor high-serum iodide was associated with SGA, and some suggestion that higher serum iodide may be associated with increased risk of preterm birth. Levels of TSH, which were largely within the normal range, indicated a mostly euthyroid population. Tg, which is generally higher during periods of both iodine insufficiency and extreme excess ,25,26, wTo date, only a handful of studies have evaluated associations of iodine status with preterm birth and SGA, and data are mixed ,11,12,13Only a few previous studies have evaluated associations of Tg and TSH with preterm birth and SGA. In two prospective studies of pregnant Spanish women, high TSH, which is indicative of hypothyroidism, was associated with increased risk of SGA ,8. SimilWhile our findings for iodine are somewhat difficult to compare directly with prior studies due to our use of serum versus urine concentrations, the observed elevated risk of preterm birth associated with higher levels of serum iodide in our data are compatible with the possibility of a true U-shaped relationship observed in several previous studies, with both high and low levels of iodine being associated with increased risk of preterm birth. However, because the women who comprised our study population were only mildly iodine insufficient , and the3 and T4, which are essential for fetal central nervous system and skeletal development. When iodine deficiency is severe (UIC <50 µg/L), the production of T3 and T4 is impaired, and circulating levels of the thyroid hormones decrease. Paradoxically, when iodine intake is excessive (defined as UIC >500 µg/L), a transient decrease in T3 and T4 also occurs, known as the Wolff–Chaikoff effect [Potential biological mechanisms to explain our observed positive associations of serum iodide with preterm birth and inverse associations of Tg with SGA are somewhat unclear. During periods of iodine deficiency, TSH, which is secreted from the pituitary gland, increases and stimulates uptake of circulating iodine by thyrocytes in the thyroid . The iodf effect . In normf effect . Althougf effect .Strengths of our study include the population-based, nested case-control design, which ensures minimal impact of selection and recall biases, and improves generalizability to the source population. In addition, our study population included women who were mildly iodine-insufficient, but with relatively low prevalence of other nutritional deficiencies that might otherwise confound the associations between iodine status and preterm birth and SGA . FurtherOur study also has limitations. First, we were limited to a single serum iodide measurement, rather than longitudinal iodine measurements over the course of the pregnancy. Serum iodide decreases during pregnancy, and as such, some women may have developed iodine deficiency later in pregnancy. Additionally, serum iodide reference ranges have not been established in this population, making it difficult to compare with prior research and World Health Organization iodine recommendations established for pregnant women. We also cannot rule out potential confounding by unmeasured factors such as dietary patterns, chronic thyroid conditions or iodine supplementation initiated after blood collection. Residual confounding by measured factors such as smoking and socioeconomic status is also possible, but the similarity between unadjusted and adjusted estimates suggest that this is an unlikely source of substantial bias.In conclusion, we found that in a mildly iodine insufficient population of Finnish women, higher-serum iodide was positively associated with risk of preterm birth, but was not associated with risk of having an SGA infant. High levels of Tg were inversely associated with risk of SGA. In light of our findings, it appears that mild iodine insufficiency is unlikely to be a substantial contributor to preterm birth and SGA in Finland. Findings of increased risk of preterm birth associated with high-serum iodide warrant further investigation.


Allostatic load has been suggested as a pathway through which experiences become biologically embedded to influence health. Research on childhood predictors of allostatic load has focused on socioeconomic and psychosocial exposures, while few studies include prospective measures of biomedical exposures. Further, findings on sex differences in the association of childhood predictors with various health outcomes related to allostatic load are ambiguous.To examine the influence of early life biomedical and social factors in the first year of life on midlife allostatic load, assessing potential sex differences.This prospective cohort study includes early life information collected at birth and a one year examination for 1,648 members of the Copenhagen Perinatal Cohort who also participated in the Copenhagen Aging and Midlife Biobank study . Allostatic load based on 14 biomarkers was selected as a measure of midlife health status. Early life factors were categorized as predominantly biomedical or social, and their associations with midlife allostatic load were examined in domain-specific and combined sex-stratified multiple regression models.The biomedical factors model explained 6.6% of the variance in midlife allostatic load in men and 6.7% in women, while the social model explained 4.1% of the variance in men and 7.3% in women. For both sexes, parental socioeconomic position at one year and maternal BMI significantly predicted midlife allostatic load in a model containing all early life factors. For women, additional significant predictors were complications at birth, birth weight and not living with parents at one year.The results confirm an association of lower childhood socioeconomic position with higher adult allostatic load while demonstrating the importance of other prenatal and early life exposures and highlighting potential sex differences. Over tiout life . Allostaout life . The defout life . Secondlout life , and AL out life . Finallyout life .Studies have confirmed associations between low childhood SEP and potentially related psychosocial factors such as abuse and maltreatment, parental death or divorce, and social isolation with increased levels of later AL ,11,14–16Using prospective data from a Danish birth cohort, the aims of the present study were to evaluate the extent to which early life biomedical and social factors are associated with midlife AL and to examine potential sex differences in these associations.The Copenhagen Perinatal Cohort (CPC) consists of 9,125 individuals born to 8,949 mothers at the Copenhagen University Hospital during October 1959–December 1961, with 8,400 children surviving the first month. The mothers were predominantly residents of the Copenhagen area, although some were referred due to single mother status or obstetrical complications. Information on demographic, socioeconomic, pre-, peri-, and postnatal medical factors was collected in personal interviews during pregnancy, at delivery, and at a 1-year examination; this data collection is described in detail elsewhere .During 2009–2011, the Copenhagen Aging and Midlife Biobank (CAMB) was established as a follow-up of three cohorts: the Danish Longitudinal Study on Work, Unemployment, and Health consisting of a random sample of Danish men and women born in 1949 and 1959 , the MetAmong the 1,718 participants with blood samples, 53 twins were excluded to ensure statistical independence of the data and comparability of perinatal factors such as birth weight. Of the remaining 1,665 participants, AL was not calculated for 17 participants for whom less than seven biomarkers were available. The final study sample consisted of 1,648 participants.1c, percent body fat). Data collection and blood sample analyses are described in detail by Hansen et al. [th percentile, except in the case of HDL, for which high risk was defined as below the 25th percentile. Cut-points are provided in The AL index score used in the current study was based on 14 biomarkers collected at midlife (mean age 49.9 years) representing the cardiovascular , immune (interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), high sensitivity C-reactive protein (hsCRP)) and metabolic system (low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol, body mass index (BMI), waist/hip ratio (WHR), blood glucose, triglycerides, HbAn et al. . The AL n et al. . The higBased on relevant epidemiological findings and theoretical considerations, potential predictors were selected among information on early life factors collected at birth and the 1-year examination and divided into predominantly biomedical or social factors.2), duration of breastfeeding (months), and maternal age at birth (years).The following factors were selected as potential biomedical predictors: Maternal smoking in the final trimester of pregnancy , gestational age (weeks), presence of one or more birth complications, e.g. mechanical hindrance, weak labor, precipitous birth or ‘other’ , hospital stay within the first year , birth weight (grams), maternal BMI (weight in kg/(height in m)The following factors were selected as potential social predictors: Attitude toward the pregnancy (child wanted vs. child unwanted), marital status of the mother at conception (married vs. unmarried), change in maternal marital status from conception to one year , whether the child was living with parent(s) at one year , and parental SEP. Information on parental SEP was collected at the 1-year examination and was based on points from 0–5 for four factors in accordance with the social grouping of the Centre International de l’Enfance : 1) educt-tests and chi-square tests were conducted to examine gender differences in all variables. For early life predictors, the missing data rate ranged from 0% (sex and whether the child was living with parents at one year) to 16.9% . The largest amount of missing data was found for gestational age (16.9%), duration of breastfeeding (14.4%) and parental SEP (15.8%). This is likely due to the fact that information on duration of breastfeeding and parental SEP was collected at the 1-year examination, for which there was some attrition, and for 20% of the full CPC sample gestational age could not be established with certainty [p < .05) or marginally significant (p < .10) for four factors , complications at birth (p = .072), maternal BMI (p = .011) and not living with parents at one year (p = .032), all analyses were stratified by sex.Independent samples ertainty . Becauseertainty –33, and R2  and model R2, respectively. To handle missing data and increase comparability between models, we used Stata’s structural equation modeling procedure with full information maximum likelihood (FIML) estimation, which uses all available information rather than listwise deletion [For the main statistical analyses, associations of the biomedical and social factors with AL were first examined separately in domain-specific linear regression models 1 and 2. Further, the information on biomedical and social predictors available from the birth cohort data enabled a test of whether the well-established associations of social factors with AL persist when accounting for early life biomedical exposures, which often co-occur with social exposures . Model 3deletion . SensitiTwo additional sensitivity analyses were conducted: first, though medical treatment for conditions related to AL (e.g. hypertension) may influence biomarkers levels, unfortunately information on medical treatment status was not available. However, to address the fact that certain biomarkers may be influenced by recent infections and current morbidity, a sensitivity analysis was performed adjusting for self-reported systemic infections  within the past 3 weeks (n = 438), hypertension (n = 222) or diabetes (n = 24). Second, all analyses were performed using an alternative AL index based on clinical rather than sample-based cut-points where available. Clinical cut-points were derived from established criteria ,45 and aCollinearity was evaluated by variance inflation factors (VIF) and did not indicate any problems . Normalp < .05). Higher birth weight, longer duration of breastfeeding, higher maternal age at birth and higher parental SEP at one year were associated with lower AL. Further, significant associations were observed among parental SEP and most of the additional factors, except gestational age, complications at birth and not living with parents at one year. Zero-order inter-correlations among study variables are presented in In men, higher maternal BMI was significantly associated with higher AL at midlife, and higher maternal age at birth was significantly associated with lower AL in the biomedical model (model 1). Parental SEP at one year was the only significant predictor in the social model (model 2), with lower levels of SEP related to higher AL scores. In women, several biomedical factors significantly predicted AL: maternal smoking in the final trimester, complications at birth and higher maternal BMI were associated with higher midlife AL, while birth weight and maternal age were inversely associated with AL. In the social model, not living with parents at the age of one year and parental SEP at one year were significant predictors of AL, indicating higher levels of AL among women who did not live with their parents at age one year. In both sexes, maternal BMI explained the largest amount of variance in the biomedical model while parental SEP at one year explained the largest amount of variance in the social model.R2) with AL (3.6%). Additionally, the effect of attitude toward the pregnancy was strengthened, indicating lower levels of AL among those for whom the mother characterized the pregnancy as unwanted . In women, all variables except maternal age at birth remained significantly or marginally significantly associated with midlife AL in the combined model; while the estimates for maternal smoking, not living with parents at one year and parental SEP were slightly attenuated, estimates for complications at birth and change in marital status were slightly strengthened. The largest increment R2 was found for parental SEP (1.7%). In men, explained variance (model R2) was 6.6% for the biomedical model and 4.1% for the social model. The combined model explained approximately 8.4% of the variance in midlife AL. In women, explained variance was 6.7% for the biomedical model and 7.3% for the social model. The combined model explained 9.5% of the variance in midlife AL for women.When combining the biomedical and social factors in model 3, maternal age at birth was reduced to non-significance in both sexes. In men, maternal BMI and parental SEP remained significantly associated with AL, with maternal BMI displaying the largest squared semipartial correlation (increment p = .28). In women, some parameter estimates were attenuated to nonsignificance (complications at birth and birth weight in model 1 and 3), while others were strengthened: the estimate for not living with parents at one year was strengthened though no longer significant in model 2  while strengthened and significant in model 3 , in which the effect of maternal smoking was also strengthened . In a second sensitivity analysis, adjusting for recent infections or current morbidity showed no substantial changes in results, though in model 3 the effect of attitude towards the pregnancy was attenuated to marginal significance in men , as was the effect of birth weight in women . Finally, using an AL index based on clinical rather than sample-based cut-points resulted in slightly higher mean AL scores (4.33 in men and 3.54 in women). Though the overall results were unchanged, in model 1 the effect of maternal smoking was attenuated in women , maternal age at birth was attenuated to nonsignificance for both sexes in model 2, and attitude towards the pregnancy was no longer significant in men in model 3 .In sensitivity analyses of models 1–3 based on complete cases, results were generally consistent with those based on FIML estimation in men, though in model 1 the effect of maternal age at birth was no longer significant Click here for additional data file.S2 Table(DOCX)Click here for additional data file.