To systematically examine infant size and growth, according to the 2006 WHO infant growth standards, as risk factors for overweight status in young adulthood in a historical cohort. Specifically, to assess: Whether accounting for length (weight-for-length) provides a different picture of risk than weight-for-age, intervals of rapid growth in both weight-for-age and weight-for-length metrics, and what particular target ages for infant size and intervals of rapid growth associate most strongly with overweight as a young adult.th v. <85th percentile, as well as rapid growth (Δ≥0.67 Z-score) through target age intervals. Models accounted for both maternal and paternal BMI.Data analysis of 422 appropriate for gestational age white singleton infants enrolled in the Fels Longitudinal Study. Odds ratios (OR) for overweight and obesity in young adulthood (age 20–29) were calculated using logistic regression models for the metrics at each target age  comparing ≥85th percentile of weight-for-age at each target age (except 3 months) had a greater odds of being overweight as a young adult. After accounting for length (weight-for-length) this association was limited to 12, and 18 months. Rapid weight-for-age growth was infrequently associated with overweight as a young adult. Rapid weight-for-length growth from 0 to 24 months, 1 to 6, 9, 12, 18, and 24 months and from 3 to 9, 12, 18, and 24 months was strongly associated with overweight status as a young adult.Infants ≥85The WHO weight-for-length metric associates differently with risk of being overweight as a young adult compared to weight-for-age. Intervals of rapid weight-for-length growth ranging from months (0–24),  and  displayed the largest OR for being overweight as a young adult. Extensive research has demonstrated overweight and obese adults experience a greater risk for a spectrum of health outcomes.A number of studies have examined size and growth during different periods of infancy with later obesity, and systematic reviews have concluded larger infant size and rapid growth are associated with later obesity in childhood and adulthood.To begin to address these knowledge gaps, we aimed to systematically examine infant size and growth as risk factors for overweight status in young adulthood in a historical cohort according to the 2006 WHO infant growth standards. Specifically, we assessed: 1) Whether accounting for length (weight-for-length) at target ages provides a different picture of risk than weight-for-age, 2) intervals of rapid growth in both weight-for-age and weight-for-length metrics, 3) if particular target ages for infant size or intervals of rapid growth associate more strongly with overweight as a young adult, and 4) if parental BMI modifies the relationship between infant growth and overweight status as an adult.All protocols and informed consent documents were approved by the Wright State University and University of Minnesota Institutional Review Board. Parents provided written consent for their offspring's participation until seven years of age, at which point the children provided their additional assent. The study sample consisted of 422 appropriate for gestational age white singleton infants  enrolled in the Fels Longitudinal Study. The Study began in 1929 as a study of individual variation in the growth and development of children,in lieu of recumbent length. Other inclusion criteria included a height and weight measurement between the ages of 20 and 29 years, as well as maternal and paternal age and BMI.For inclusion in this analysis, participants were required to have at least 3 serial weight and length measurements between the ages of 1 and 42 months, and a measured birth weight. Weight and recumbent length were collected at target ages of 0, 1, 3, 6, 12, 18, 24, 30, 36, and 42 months. For measurements over 24 months of age, standing height was used 2, age-by-sex and age-by-birth year interactions as fixed effects. Age3 and age4 random effects were not significant for length and therefore dropped out of the models for length. Residual and influence diagnostics indicated that model assumptions were not violated and estimates of fixed effects were not overly influenced by any single individual. The correlations between observed and predicted values for all ages were high (r>0.98). A mixed-effects regression model results in a reduction in error compared to the use of individual regression models.Missing growth data (<5% of subjects at any given time point) occurred randomly at the different target ages. To account for this we modeled the serial weight and length data for all children in a mixed effects regression model using a fourth-degree polynomial function of age, implemented in SAS PROC MIXED.From the mixed effects models, predicted weights and lengths at each specific target age from birth to 42 months were obtained ensuring a consistent sample size for weight and height at each target age and a reduction in error compared to the use of individual regression models.th percentile (Z-score ≥1.036) for each metric at each target age to infants below the 85th percentile. There was a threshold of no association with overweight or obesity in those below the 75th or 85th percentile upon detailed examination of the distribution . Covariates included sex, birth year, age at adult BMI assessment, gestational age at birth , and maternal age. Maternal and paternal BMI and paternal age were collected using the non-pregnancy weight closest to the birth date. We adjusted models examining weight-for-age or weight-for-length at subsequent ages for the WHO Z-score at birth in order to estimate associations at these ages that are distinct from associations due to size at birth. Further adjustment for parental BMI and ages occurred as well to demonstrate the influence these covariates had on the point estimates.Odds ratios (OR) for overweight and obesity in young adulthood were estimated using logistic regression models. We compared infants at or above the 85th–50th, 50th–75th, etc) on a growth chart. In logistic regression models, with a similar pattern of adjustment as the status measures, we compared infants who experienced rapid growth to those who experienced slow or gradual growth since there was no evidence of any association of slow growth with excess weight. Sensitivity analyses stratifying by sex for both size and growth status were performed, as well as examination of secular trends by birth year. All analyses were carried out using SAS version 9.2.In addition, we categorized infants as having rapid, slow or gradual/normal growth according to Ong et al2) and 101 were overweight (BMI ≥25 kg/m2) as young adults (age 20–29). th percentile) and then decline until 3 months, after which they begin to increase and level off slightly above the 50th percentile at 12 months. At birth, the mean Z-scores for length are greater than the 50th percentile and decline until 3 months and then experience a similar trend of increase to weight-for-age Z-scores thereafter. Due to greater birth lengths, the mean weight-for-length Z-scores were below the 50th percentile at birth and then increased until 18 months.Of the 422 infants in the analysis 22 were obese (BMI ≥30 kg/mth percentile) with overweight in young adulthood. Across the spectrum of infancy, except for 3 months, a high weight-for-age measure is associated with a 2–3 fold increased odds of being overweight as a young adult. Upon accounting for length (weight-for-length), an association is only observed in later target ages, specifically at 12 and 18 months and suggestively at 9 and 24 months. The strongest association for weight-for-length was at 18 months, OR = 2.65, 95% CI (1.51–4.65).The associations were all independent of birth Z-scores and parental data. Analyses examining only those who were overweight in young adulthood (BMI 25–29.9) as the outcome, and thus excluding obese subjects showed subtly attenuated, and consistent results (data not presented). There was no evidence upon stratification by sex that the associations between infant weight-for-age, or weight-for-length and young adulthood overweight differed in girls and boys (data not presented). Length-for-age percentile was not associated with overweight or obesity at any infant target age (data not presented).th%) born pre-1960 observed a strong association with overweight , as did those born 1960 and after . The 1960 birth year was chosen to align with the approximate onset of the current obesity epidemic. We were unable to carry out stratified analyses for obesity as the outcome due to the small number of obese young adults producing unstable estimates.We also accounted for the historical nature of the cohort in stratified analyses of infants born before 1960, and 1960 and thereafter. We observed associations highly similar to the main results. However, associations tended to be stronger for those born 1960 and thereafter. For example, 18 month old infants with a high weight-for-age percentile (≥85Table S1 in File S1 presents similar data to 2) as the outcome. Infants with elevated weight-for-age at birth and 1 month display strong associations with obesity, and there is a suggestive association for the 24 month point. Elevated weight-for-length at 12, 18, and 24 months are the only target ages strongly associated with greater odds of obesity in young adulthood. Due to small numbers there were no data for earlier target ages. Similarly, the strongest association for weight-for-length was at the 18 month point.Table S2 in File S1). However there was no association from any periods 6 months or on, and birth to 12 and 18 months also displayed significant associations. However, because of smaller number of obese young adults, and less precision the estimates require cautious interpretation. There was no association with obesity when categorizing rapid growth using WHO weight-for-age percentiles (Table S3 in File S1) or length-for-age percentiles (data not presented).When considering rapid weight-for-length growth with obesity as the outcome, similar trends were observed for the periods beginning at 1 and 3 months , and obese . Similar positive, albeit not as strong associations were observed for infants with overweight and obese fathers relative to normal weight  for overweight and  for obesity. Results represent fully adjusted models including mutually accounting for paternal/maternal BMI and age.th percentile of the 2006 WHO infant growth standards of weight-for-age had a greater odds of being overweight as a young adult. After accounting for length (weight-for-length), significant associations were observed only at 12 and 18 months, and suggestively at 9 and 24 months. Rapid weight-for-length growth from birth to 24 months, and 1 month to 6 months and thereafter in infancy was strongly associated with carrying excess weight as a young adult. Similar strong associations were observed from 3 to 9 months and beyond. Rapid weight-for-age growth displayed more modest and inconsistent associations; and was not uniform between overweight and obesity outcomes in young adulthood. Thus, the data suggest the more complete metric in respect to infant size and growth, the WHO weight-for-length standard, may provide a different view of risk relative to weight-for age.In this systematic examination of infant size and growth, infants at target ages from birth to 2 years (except 3 months) at and above the 85Overall, rapid growth intervals displayed stronger associations than static target-age measures and were independent of birth size. The strongest  target-age association with young adulthood overweight status for weight-for-length was at the 18 month point, and for rapid growth was from the period 1–12 months. We also observed strong associations between parental BMI, including paternal, and odds of overweight status as an adult. These estimates were as strong as or stronger than the association of the infant growth metrics, yet the infant growth metrics were independent of parental BMI and the estimates were only subtly attenuated by adjustment.In addition, the study results suggest the WHO 2006 infant growth standards have clinical utility since they strongly associate with a long term health outcome of public health significance. On the whole, this study provides a unique view of infant size, growth, and rapid growth relative to the literature base on the topic. Not only do our data suggest a wide swath of target ages and growth periods during infancy provide insight on risk of excess weight as a young adult, we also present results demonstrating the importance of accounting for length in studies of infant growth. Indeed, elevated weight-for-length percentile at birth did not predict overweight or obesity suggesting that greater birth weights need to be put in context of the length of the newborn when applying the 2006 WHO infant growth standards. Furthermore, when applying the 2006 WHO infant growth standards, our data suggest it may be prudent to consider rapid growth patterns beginning in the months (1 or 3) after birth when the infant has seemingly assorted on a certain growth trajectory.Secondary to the logistic regression models, the mean WHO Z-scores for the separate metrics suggest growth faltering occurs when examining weight and length Z-scores from birth to 3 months of age before recovering and stabilizing. This was most pronounced in length Z-scores, which aligns with international surveys of infant growth utilizing the WHO standards showing faltering in length Z-scores up to 24 months before stabilizing.The systematic reviews examining size and growth during infancy are in consensus that there is an association between larger size and rapid growth during infancy with later obesity.A Finnish study examining peak height and weight growth velocity from birth to two years, found that both were associated with adiposity at age 31.A few of these studies have been published since the original systematic reviews on the topic, but their underlying message does not differ. Our study also adds to the literature base on this since we are the first to use the WHO growth standards rather than a growth reference on this topic with adult overweight/obesity. Our ability to examine target ages and growth ranges throughout infancy provides a different and thorough approach to the topic. Expanded investigation of the range of birth through infancy allows this study to be compared to the earlier published studies which focused on certain points or ranges, while also providing distinctive data. As well, our data are unique in since they account for maternal and paternal BMI. The previous aforementioned reviews and studies largely included only maternal BMI as available. Our results demonstrate the importance of considering both of these aspects related to infant size and growth. Further research applying the WHO infant growth standards will provide insight into different status measures or ranges for rapid growth that best predict excess weight and other outcomes in adults.The limitations of our study also need to be considered. In line with the general base of research on the topic there are numerous unmeasured environmental, lifestyle, behavioral, and genetic factors that may confound the association between infant size and growth and excess weight in young adulthood. A study with these aforementioned confounders would greatly enhance the understanding on this topic. Another limitation was the low prevalence of obesity which did not allow for any stratified analyses and provided somewhat unstable estimates. This low prevalence may be at least partially attributable to the historical nature of the cohort and many participants being born in and exposed to a different era environmentally. However, our stratified analyses by year of birth were consistent for overweight as an outcome. Furthermore, as in most birth cohorts and life course studies, there is loss to follow up and potential for sampling bias. We did not find any significant differences between baseline characteristics in participants who had and who did not have full parental data and were thus excluded; or between birth characteristics of those in this sample and the whole cohort. The results may also only be applicable to infants born appropriate for gestational age. Lastly, consideration that our study population is homogenous in both geographic and racial composition needs to be considered.In conclusion, the data from this study demonstrate the importance of accounting for length in infant size and growth in relation to risk of later excess weight, and highlight how the whole range of infant growth may inform on risk of excess weight in adulthood. Overall, the results suggest that both static measures of size at target ages, and rapid growth intervals in infancy are associated with excess weight in young adulthood independent of birth-size and parental BMI. The strongest associations are in measures of rapid growth from birth to 24 months, 1 to 12, 18 and 24 months, and 3 to 9 and 12 months during the infancy period. Additionally, this study supports the clinical applicability of the WHO infant growth standards. Research incorporating the WHO infant growth standards with later obesity and other clinical risk markers will further inform understanding of these standards with health factors.File S1(DOC)Click here for additional data file.


Increasing numbers of survivors of preterm birth are growing into adulthood today. Long-term health-effects of prematurity are still poorly understood, but include increased risk for diabetes, obesity and cardiovascular diseases in adult life. To test if reduced physical fitness may be a link in the causal chain of preterm birth and diseases in later life, the association of preterm birth and adult exercise capacity was investigated. The hypothesis was that preterm birth contributes independently of other risk factors to lower physical fitness in adulthood.max in Watt) performed at conscription. Association to perinatal and socioeconomic risk factors, other co-variates and confounders were analysed. General linear modelling showed that preterm birth predicted low Wmax in a dose-response related pattern, with 25 Watt reduction in Wmax for the lowest gestational ages, those born ≤27 weeks. Low birth weight for gestational age also independently predicted low Wmax compared to normal and high birth weight (32 Watt reduction for those with a birth weight Standard Deviation Score <2). Low parental education was significantly associated with reduced Wmax (range 17 Watt), as well as both low and high current BMI, with severe obesity resulting in a 16 Watt deficit compared to Wmax top performance.Population-based national cohort study of all males conscripting for military service in 1993–2001 and born in Sweden 1973–1983, n = 218,820. Data were retrieved from the Swedish Conscript Register, the Medical Birth Register and the Population and Housing Census 1990. Primary outcome was the results from maximal exercise test (WBeing born preterm as well as being born small for gestational age predicts low exercise capacity in otherwise healthy young men. The effect size of being born preterm equal or exceed that of other known risk factors for unfitness in adults, such as low parental education and overweight. Advances in perinatal medicine have dramatically increased survival after preterm birth Physical Activity (PA) is important for well-being and has a well-documented favourable effect on many of the established risk factors for cardiovascular disease Observational studies indicate that subjects born very or extremely preterm end up less physically active or less resilient to PA in later life We hypothesized that preterm birth is an independent risk factor for reduced exercise capacity in young adults. To test this hypothesis and control for potential confounding from fetal growth restriction, socioeconomic and familial factors, we studied the results of a graded cycling exercise test performed within the assessment for military service in a large, population-based cohort of 18-year-old Swedish men born 1973 through 1983.This cohort study was based on data from four population-based Swedish registers: the Medical Birth Register (MBR), the Conscript Register, the Population and Housing Census 1990 and the Multigeneration Register. The national registration number, assigned to each Swedish resident at birth, was used for individual record linkage. Linking of data from the different registers was performed by the Central Bureau of Statistics Sweden. The final dataset that was released to the authors and used for analysis was anonymous. Individual consent was not obtained from subjects included in the study and the approving ethical review board waived consent.The MBR contains data on >99% of all births in Sweden. Starting at the first prenatal visit, information is prospectively collected on standardized forms and forwarded to the register. The MBR has been validated, and the quality was considered high The Conscript Register contains information about young men assessed for military service. Conscription includes physical examination, health assessment and tests of exercise capacity. The results from maximal exercise test on cycle ergometer were used as outcome in this study. All men conscripted for military service in 1993–2001 and born in Sweden 1973–1983 were eligible for the study, but subjects without records of exercise capacity or perinatal risk factors were excluded . During The Population and Housing Census 1990 is a register to which adults in Sweden reported facts about education, profession, household, income and family structure in 1990. It was mandatory for all citizens 16 years and older. The response rate was 97.5% In The Multigeneration Register blood relationship of all Swedish citizens is registered. It was used to identify mothers and fathers of the conscripts.max, expressed in Watt, W) that the conscript could manage on cycle ergometer. Only conscripts with a normal electrocardiography and without diseases or injuries that could influence the results were allowed to perform the test. The test was performed according to the conscription protocol with initial workload determined by weight and estimated physical fitness  in complete weeks was estimated from the date of the last menstrual period In addition, the following variables from the MBR were obtained: maternal age , maternal origin , parity (primi- or multipara) and singleton or multiple birth.2) and blood pressure (mmHg) - measured in the right arm after 5 to 10 minutes rest in the supine position - were collected from the conscript register.Body Mass Index  categorizes people according to occupation. There are 15 index categories ranging from leading position, farmers and workers to non-occupied. Each index category has a dominance in relation to the others that is defined based on the expected impact on the child’s SEI All data were presented using descriptive statistics, i.e. number of subjects, mean and standard deviation for continuous variables, and frequency and relative frequency (percentage) for categorical variables. Data were analysed using General Linear Model, Analysis of Variance, ANOVA, with gestational age, BWSDS, number of births, maternal country of birth, maternal age, parity, parental education, socioeconomic index, parental income, BMI, blood pressure, health status and age at conscription as fixed factors in univariate models and multivariate models. Least square means was used to calculate the point estimates in the multivariate model and thereby control for co-variates and evaluate the independent contribution by each factor to the outcome.All tests were two-sided and p<0.05 was regarded as statistical significant. Analyses were performed using the STATISTICA software, version 9.0, Statsoft Inc., Tulsa, US.During the 1993 to 2001 period 428,092 men conscripted for military service, of who 395,164  were born in Sweden 1973–1983, comprising 71% of all male births these years. Most of the men born these years and not included in the study were conscripted during another period of time. After exclusion of subjects with missing or misclassified data, the analysed cohort consisted of 218,820 men . A compaThe overall mean exercise capacity in young Swedish men was 306 W +/−50 SD. In the univariate analysis (ANOVA) there was a linear increase in exercise capacity with increasing GA . The largest impact on Wrent BMI . Least srent BMI . Exercisrent BMI . The intrent BMI . There wrent BMI . The higrent BMI . The BMIThis is the first study to report that preterm birth predicts reduced exercise capacity in young healthy men, also after accounting for fetal growth. The association to preterm birth was found to be independent of other determinants of adult exercise capacity such as parental education, socioeconomic status and income, as well as of current BMI. The association was not limited to those men born very or extremely preterm, instead exercise capacity increased linearly with GA in a dose-response related manner. The effect size of being born preterm equalled or exceeded that of other known risk factors for unfitness in young adults, such as low parental education The strengths of this study were the population-based design and the long-term follow-up, where prospectively collected data at birth could be linked to outcome 18–25 years later. The study was also large enough to assess inter-relationships between perinatal and other major determinants  of exercise capacity in adulthood, while adjusting for maternal origin and multiple births. Importantly, we had sufficient power to separate the effects of preterm birth and fetal growth restriction on later exercise capacity. Low BWSDS - a proxy for poor fetal growth - was also found to predict low exercise capacity in young men. Accordingly, preterm birth is a perinatal risk factor for low exercise capacity in males later in life, even when taking fetal growth into account.We have previously found that the conscription rate varied across the GA range, with the lowest conscription rate among men born extremely preterm Yet another aspect that may affect the outcome on exercise capacity in subjects born preterm is psychological function. Subjects born preterm have been shown to have psychological difficulties to a greater extent than term subjects Our data demonstrate a linear relationship between preterm birth and exercise capacity, suggesting but not proving causality. Underlying mechanisms could be that preterm birth stops normal development and triggers adaptations in tissues and organs, ultimately resulting in lasting physiological alterations such as fewer alveoli In this study the difference in maximal work load between male subjects born at term (306 W) and those born extremely preterm (278 W) is comparable to the difference in maximal aerobic capacity for an average man and an average woman Preterm birth is a public health problem affecting between 6–12% Being born small was also associated with lower exercise capacity in later life. This finding was independent of gestational age and suggests that the effect of intrauterine growth restriction on future exercise capacity is similar after term as well as preterm birth. It also underlines the fact that to avoid significant health problems in coming generations In conclusion, at an age where physical fitness and capacity peaks, healthy men born preterm have a lower exercise capacity compared to men born at term, irrespective of socioeconomic factors and current BMI. Reduced exercise capacity may add to future health problems faced by children growing up today following preterm birth and may play a role in the causal chain towards overweight, diabetes and hypertension. Early intervention programs to improve physical fitness in children and adults born preterm may be of value to reduce the risks for later disease and improve life-long health. Further studies on this issue, as well as on the underlying mechanisms, are warranted.The study was approved by the Regional Ethical Review Board in Stockholm.File S1Instructions for cycle ergometer exercise capacity test.(DOCX)Click here for additional data file.File S2Explanation of codes classifying health status at recruitment.(DOCX)Click here for additional data file.File S3BMI, body weight and height at conscription according to gestational age.(DOCX)Click here for additional data file.


Aims. Our objective was to examine Apo J protein expression in a total of 27 early liveborn neonatal deaths (less than 7 days of age) selected from the Scottish Perinatal Study (gestation of 25–42 weeks) comparing a group with histological pontosubicular necrosis (PSN) (n = 12) to a control group lacking PSN (n = 15). Methods. Using immunohistochemistry we evaluated postmortem pons and hippocampus from patients with PSN versus controls. Results. In the group with PSN, 11/12 (92%) cases showed positive Apo J neurones in the hippocampus/pons compared with 6/15 (40%) cases without PSN —independent of gestation, presence or absence of clinical asphyxia, duration of labour, or postnatal age. Clinical asphyxia was present in 10/15 (67%) without PSN compared with 11/12 (92%) with PSN. Neuronal Apo J positivity was present in 15/21 (71%) of clinically asphyxiated cases compared with 2/6 (33%) of the cases with no evidence of clinical asphyxia . Conclusions. Apo J neuronal protein expression is significantly increased in cases with PSN compared to cases without PSN—independent of gestation, presence of clinical asphyxia, duration of labour, or postnatal age.  Apolipoprotein J (Apo J),  was first identified from chromaffin granules of the bovine adrenal medulla and in the ram rete testis , 2. LikeAt a molecular level, Han et al. have shown in an experimental animal model of HI that Apo J accumulates in dying neurones and that Apo J-null mice suffered 50% less brain injury compared with wild-type mice subjected to HI (hypoxic/ischaemic) insults .Pontosubicular necrosis (PSN) describes the association on histology between hypoxic death of neurones in the ventral pons and the subiculum in human neonates. Experimental studies have shown that the mode of death in these neurons is apoptosis . We examn = 12) or absence (n = 15) of pontine and/or hippocampal neuronal eosinophilia or karyorrhexis following review of routinely stained sections (haematoxylin and eosin). An anti-Apo J (clusterin) antibody  was used at a dilution of 1 : 1000 after pretreatment with 0.01 M citrate buffer in the microwave for 3 × 5 minutes and visualised with diaminobenzidine. A wider survey of Apo J in other areas in the brain was undertaken in 2 of the positive cases and negative cases. Positive controls included biopsies from a Burkitt's lymphoma and Alzheimer's disease conditions in which clusterin expression has been previously described [U, and prism statistical software.27 cases were selected from the Scottish Perinatal Neuropathology Study, which included Scottish early liveborn neonatal deaths (less than 7 days of age) with the exclusion of infants with known chromosomal, cardiac or central nervous system (CNS) abnormalities, and CNS infections . Detailsescribed , 17. ApoP = 0.584) (see Tables P = 0.599); median postnatal age in the PSN group was 12.72 hours (0–51.13) compared with 7.98 hours (0.25–131.67) in controls, (P = 0.495); with no significant differences between groups. Clinical signs of asphyxia were present in 11/12 (91.7%) cases with PSN compared with 10/15 (66.7%) controls without PSN, with no significant difference between groups (P = 0.182).The median gestational age in the cases with PSN was 39 weeks (range 25–42 weeks) compared to 34 weeks (24–42) in controls without PSN, with no significant difference between groups —independent of gestation, presence or absence of clinical asphyxia, duration of labour or postnatal age (see P = 0.054). 4/12 (33%) cases in the PSN group showed glial expression compared to 7/15 (46%) in the comparison group (P = 0.696). This positivity was localised to the astrocytic cell cytoplasm .In the PSN cases 11/12 (92%) showed Apo J immunopositivity in neurons the base of the pons or hippocampus or both regions compared with 6/15 (40%) with Apo J neuronal positivity in the comparison group —independent of gestation, presence or absence of clinical asphyxia, duration of labour, or postnatal age.Our main finding is significant neuronal Apo J expression in 92% (11/12) of perinatal deaths with pontosubicular necrosis compared with 40% (6/15) of the cases without PSN  . Previous studies have shown that neurones within the trigeminal motor, facial, trigeminal somatosensory, and mesencephalic nuclei in particular contain high levels of Apo J mRNA [We also found Apo J positivity in the brainstem nuclei within the tegmentum of the pons 9/12 (75%) in the pontosubicular necrosis group and 5/15 (33%) in the control group (o J mRNA .P = 0.696). Apo J mRNA has previously been demonstrated in astrocytes and neurones but not microglia [Our study has shown Apo J glial positivity in the group with pontosubicular necrosis 4/12 (33%) and in the group without pontosubicular necrosis 7/15 (46%) with no significant difference between the groups (icroglia . Moreoveicroglia , 20, raiWe found ependymal staining of Apo J in all cases and choroid plexus positivity when present  acting aHan et al. have suggested that in animal models Apo J contributes to caspase-3 independent brain injury or necrosis and have suggested that it may be a therapeutic target for modulating necrotic cell death following acute brain injury . InteresOur results raise the possibility that Apo J is similarly upregulated by hypoxia/ischaemia in the developing human brain, in keeping with animal models and previous studies , 14, 15.


Cardiovascular diseases are one of the leading causes of mortality. Hypertension (HT) is one of the principal risk factors associated with death. Chronic kidney disease (CKD), which is probably underestimated, increases the risk and the severity of adverse cardiovascular events. It is now recognized that low birth weight is a risk factor for these diseases, and this relationship is amplified by a rapid catch-up growth or overfeeding during infancy or childhood. The pathophysiological and molecular mechanisms involved in the “early programming” of CKD are multiple and partially understood. It has been proposed that the developmental programming of arterial hypertension and chronic kidney disease is related to a reduced nephron endowment. However, this mechanism is still discussed. This review discusses the complex relationship between birth weight and nephron endowment and how early growth and nutrition influence long term HT and CKD. We hypothesize that fetal environment reduces moderately the nephron number which appears insufficient by itself to induce long term diseases. Reduced nephron number constitutes a “factor of vulnerability” when additional factors, in particular a rapid postnatal growth or overfeeding, promote the early onset of diseases through a complex combination of various pathophysiological pathways. Cardiovascular diseases ((CVD) hypertension, coronary disease and stroke, and heart failure) are one of the leading causes of mortality in industrialized countries, and the prevalence is increasing in emerging societies. All cardiovascular diseases account for 4.3 million deaths per year in the European Union, and the prevalence of chronic heart failure in the United States of America is approximately 6 million , 2. In iDuring the last two decades, it has been raised the concept of developmental programming of adult chronic diseases ) , 9. The This review discusses factors which influence nephron endowment and the complex relationship between nephron endowment and chronic kidney disease. We hypothesize that the developmental “programming” of chronic kidney disease is a complex phenomenon. It may integrate different factors and pathophysiological pathways. Reduced nephron number constitutes a “factor of vulnerability” which is insufficient by itself when it is moderate. In such a situation, early onset of CKD occurs with additional factors including early growth and nutrition. This concept states that chronic and noncommunicable diseases that are currently observed at adulthood have origins in the fetal and perinatal periods of life. Events or stimulus during particular stages of development can alter permanently the structure and function of various systems. After a silent period, diseases occur at adulthood. David Barker and colleagues discovered in the 1980s', in a cohort of people born in Hertfordshire, UK, at the beginning of the nineteenth century, that the mortality ratio due to coronary heart disease was inversely correlated with birth weight , 23. LowMore recently the risk of chronic kidney disease (CKD) has been related to low birth weight –35. In aAdults born preterm constitute an emerging population at risk for cardiovascular and renal diseases. Prenatal and postnatal events may influence renal function and structure later on. The Dutch POP study revealed an inverse relationship between birth weight and long term urinary microalbumin/creatinine ratio and plasma creatinin level in young adults born preterm . IncreasWhile a rapid postnatal growth during childhood and infancy favours the development of cardiovascular diseases, obesity, and type 2 diabetes; the consequences on renal function and structure are relatively unknown in humans –57. The Similar effects have been reproduced in animals. We, and others, have shown that early postnatal overfeeding, obtained by reduction of litter size and limited to the suckling period, induces obesity, cardiovascular, metabolic, and renal diseases in ageing adult rat offspring –70. Suchin utero and accelerates the development of adult diseases (“mismatch hypothesis”), a slow postnatal growth and breastfeeding in particular (possibly through reduced protein and sodium intakes) tend to prevent such diseases. Altogether, these findings show that early postnatal nutrition  and early postnatal growth exert a considerable influence on adult health. Early growth and nutrition can modulate the “fetal programmed” adult chronic diseases. While a rapid postnatal growth and/or overfeeding enhances the “vulnerability state” acquired It has been proposed, for a long time, that the pathogenesis of hypertension and chronic kidney disease involves a reduction of nephron number , 81–84. However, reduced nephron number is not systematically associated with hypertension and impaired GFR, especially when it is moderate. In humans, Hughson et al. did not find this relationship in a group of African-American adults . SeveralThe development of the kidney is a complex process in mammalian. The time at which nephrogenesis ends differ according to species: in rodents, nephrogenesis continues after birth up to postnatal days 7 to 10, whereas in sheep, the nephrogenesis is achieved before birth at gestational days 125–130 . In human, the nephrogenesis is completed by 34–36th weeks of gestation, that is, before birth. About 60% of the nephrons develop during the third trimester of gestation. The definitive kidney, the metanephros, develops from the specific interaction between the epithelial ureteric bud (UB) and the undifferentiated metanephric mesenchyme (MM). An insignificant event occurring during the early stage of nephrogenesis (the branching morphogenesis) can have dramatic effects on the final nephron number (nephron endowment). Nephron number varies widely in the general population and ranges from 2 to more than 10-fold –92. In tThe principal factor which determines nephron number is birth weight , but it Various factors can alter nephrogenesis , 99, 107in utero to maternal low protein diet [The underlying pathophysiological mechanism is incompletely known. Reduction of nephron number may result from an imbalance between pro- and antiapoptotic factors towards apoptosis. Downregulation of the renal renin angiotensin system, fetal overexposure to glucocorticoids, or altered midkine expression has been reported in various IUGR models , 112–118ein diet , 119. Thein diet , 119. Thein diet . Hypometein diet . In addiein diet . AdditioBirth weight is not the only predictive factor of the nephron endowment. In animal, the nephron endowment is also characterized by a certain rate of variability. In rodent, despite strictly controlled conditions, the nephron endowment can vary by an average of 10% to 15% for a birth weight situated within normal range , 123. EvPostnatal environment can influence nephron endowment in certain situations when the nephrogenesis continues after birth. Recent studies in rodents showed that neonatal undernutrition  reduced nephron endowment (−20%), but early neonatal overfeeding (through reduction of litter size) enhanced postnatal nephrogenesis (+25%) , 129. HoSuch findings emphasize that birth weight is a predictive factor of nephron endowment but is certainly not the only one. Nephron endowment may result from a complex process which integrates the interaction of the fetal environment  and the genetic background. Normal birth weight does not always signify a sufficient nephron endowment and low birth weight a severe nephron deficit. The relationship between birth weight and nephron endowment is not so linear and it could be difficult to predict nephron endowment for an individual based only on birth weight. Relationship of birth weight with chronic kidney disease is complex and integrates various factors and pathophysiological mechanisms of which nephron number plays a pivotal role Figures  and 3.Predominant factor which determines nephron endowment is birth weight. However, it is not the only one. Nephron endowment, acquired at birth (or after birth for preterm infants), may result from an interaction between genetic background and environmental factors. Environment may alter nephrogenesis through epigenetic pathway, and genetic background may make the kidney less or more sensitive to environmental factors. For example, some mice strains are less sensitive to nephron deficit and glomerular sclerosis induced by maternal gestational administration of aminoglycosides . When neVarious postnatal factors can induce a single nephron glomerular hyperfiltration or glomerular hypertension and together with a reduced filtration surface area may accelerate the occurrence of CKD. Nutrition or growth early in life is one of them. We and others have shown that a rapid postnatal growth and overfeeding  early in life induced in young adult IUGR rat offspring a renal hypertrophy and proteinuria (a surrogate of a glomerular hyperfiltration or glomerular endothelium barrier injury) , 132. PrSome of these experimental findings have been reported in human. Early high protein diet and rapid growth rate tend to induce a renal hypertrophy. Two recent studies have prospectively evaluated the effects of different diets on renal structure (using ultrasound) in infants born at term with birth weight adapted for gestational age , 142. In+ : K+ : 2Cl− cotransporter (NKCC2) and altered the Na+ : K+ ATPase activity responsible for a tendency to sodium retention and a higher sensitivity to high salt intake [Early nutrition and growth can alter renal function and structure through other pathways. In animal, early postnatal overfeeding is associated with hypertension, obesity, and type 2 diabetes, known as risk factor for CKD. A rapid postnatal catch-up growth and/or overfeeding is associated with hyperleptinemia, hyperinsulinism and insulin-resistance, upregulation of the RAS and HPA-axis, and overactivity of the nervous sympathetic activity (see above). Such effects are responsible for impaired endothelium-dependent vasodilatation, systemic vasoconstriction, oxidative stress, and systemic inflammation which alter in turn vascular structure and arterial stiffness and lead to hypertension. Obesity and hyperglycaemia induce a single nephron glomerular hyperfiltration , 144, but intake , 154–160Altogether these additional factors in combination with “vulnerable” kidneys accelerate the onset of CKD through the increase in the SNGFR, the reinforcing of the exacerbation of the pre-existing “renal stress”, and through the transmission of elevated systemic blood pressure to enlarged glomerular capillaries. Hence, the kidney appears both as the underlying pathophysiological mechanism and as the target organ of developmental programming of CKD.Early life conditions are of particular importance in the comprehension of chronic kidney disease (CKD). Their importance equals or may exceed that of other later environmental risk factors. Various systems, including the kidney, are permanently altered. Reduced nephron number, with renal tubular changes, constitutes a “factor of vulnerability” when additional factors as the early postnatal growth/nutrition promote early onset of hypertension and CKD through various pathways. Despite this clear pathophysiologic rationale, a number of points still need to be addressed to allow the design of effective preventive strategies. The criteria for a subject being considered at particular risk need to be defined. This is the less easy since a number of epidemiologic and clinical studies show that the long term programming of hypertension and of renal disease does not occur only in well-defined, pathological conditions such as low birth weight, preterm birth, and exposure to maternal diabetes in pregnancy. Even in apparently healthy children, estimated glomerular function has been shown to be correlated with size at birth . Questio


There is an overwhelming body of evidence strongly suggesting that periodontal infection may have a significant negative impact on pregnancy outcome in some women. The aim of this study was to determine the association, if any, between periodontal disease and preterm low birth weight.A total of 211 mothers between the ages of 17 and 35 were grouped into two categories based on the gestational age and weight of the baby as cases  and controls . Relevant obstetric history and information on other primary risk factors for preterm low birth weight were obtained. Investigation reports on blood group, Rh factor and hemoglobin (Hb) were also gathered. Oral assessments included: simplified oral hygiene index (OHI-S), gingival bleeding index, probing pocket depth and clinical attachment level (CAL).Cases had significantly more attachment loss and probing pocket depth, poor oral hygiene, more percentage of sites with attachment loss (Extent) and more mean attachment loss per site (Severity) and less Hb than controls. The number of visits for prenatal care and the percentage of sites with CAL≥2mm (Extent 2) remained significant when compared to other variables.The study indicated that periodontal disease is a contributing factor for preterm low birth weight. Preterm birth is a major medical, social and economic problem, accounting for a large proportion of maternal and especially neonatal mortality, acute morbidity and long-term sequelae. The normAmong the risk factors for preterm low birth weight (PTLBW) deliveries are high or low maternal age, inadequate prenatal care, smoking, tobacco use, alcohol or drug use during pregnancy, genetic background, low socioeconomic status, maternal stress and genitourinary tract infections. However, these risk factors are not present in approximately one fourth of preterm low birth weight deliveries, leading to a continued search for other causes.4Bacteroides, or premature rupture of membranes [premature rupture of membranes (PROM) — rupture of membranes  occurring before the onset of labor and not resulting in labor within 6 hours of rupture] and gestational age less than 37 weeks with birth weight of the baby being less than 2.5 kg were included in the case category {109 mothers}.Patients with normal labor and gestational age more than 37 weeks with birth weight of the baby being more than 2.5 kg were included in the control category {102 mothers}.Mothers who had a history of cardiovascular problems, eclampsia, respiratory disorders and those who had undergone cesarean section.Obstetric factors such as maternal age at delivery, number of pregnancies, previous induced abortions and spontaneous abortions, previous preterm deliveries, previous full-term deliveries and live births, respectively, were recorded. Onset of prenatal care — whether prior to 20 weeks, between 20 and 25 weeks, after 25 weeks or no prenatal care and the total number of prenatal visits, use of tobacco and alcohol were also noted. Other outcome variables, like hypertension, genitourinary tract infection, were recorded, and investigation reports on blood group, Rh factor and hemoglobin were also gathered. Oral examination was carried out using artificial light, a mouth mirror, explorer and William’s periodontal probe. The clinical parameters recorded were ‘simplified oral hygiene index,’ gingival bleeding index (Ainamo and Bay), probing pocket depth and clinical attachment level.After recording all the clinical parameters, the Extent and Severity of attachment loss were derived from the clinical attachment level.Extent of attachment loss - PercenIt is calculated using the formulaSeverity of attachment loss - Mean CIt is calculated using the formulawhere n=number of sites actually examined,i= measurement of attachment level,xi=,x= runs from 1 to n, i.e., x∑= summation, andi=attachment loss exceeding 1 mm, i.e., di=1 if xi>1 and di=0 otherwise.dThe statistical package SPSS PC+  was used for statistical analysis. Mean±standard deviation and proportion were estimated from the sample for each study group.t test. Proportions were compared by chi-square test/ Fisher exact test appropriately. Multiple logistic regression analysis was done to identify the predictive factors to the ‘cases.’The mean values were compared by Student independent P<.05 was considered as the level of significance.In the present study, Analysis of the data obtained from the 211 mothers who were examined gave the following results.P<0.0001)  hal. (2000) and Halll. (2000) In contr. (1996), where alet al. (1995),[et al. (1984),[et al. (1984),[et al. (1991),[et al. (1993)[et al. (1995)[Studies by Meis . (1995), Minkoff . (1984), Mfller e. (1984), Krohn et. (1991), Holst etl. (1993) and Hilll. (1995) have shoThe present study showed an association between previous full-term deliveries and preterm low birth weight; cases had significantly less number of previous full-term deliveries than controls. Similarly there was an association between low hemoglobin levels (anemia) and preterm low birth weight; but there was no association between onset of prenatal care, blood group, Rh factor, hypertension and preterm low birth weight.et al. (1996)[Inadequate prenatal care was found to be an independent prognostic factor in cases in the present study; but in contrast, the study by Offenbacher l. (1996) did not et al. (1996),Results of multivariate logistic regression analysis in a study by Offenbacher et al. (1995),[et al. ,[et al. (2000),[et al. (2001)[Numerous studies — by Damare . (1995), Offenbacl. 1996, 1998),[6, 1998,[6l. , Lieff et. (2000), Jeffcoatl. (2001) — have sIn the present study, the number of visits for prenatal care and Extent 2 remained significant when compared to other variables; thus the lesser the number of visits for prenatal care and the more the extent of attachment loss (percentage of sites with CAL ≥2 mm), the higher is the risk for delivering a preterm low birth weight infant.Therefore, the present study indicates that periodontal infection is a contributing factor for preterm low birth weight. However, more prospective studies are needed to confirm whether periodontal infection could act as an independent risk factor for preterm low birth weight.


FTO gene, located on chromosome 16q12.2, and the MAF gene, located on chromosome 16q22-23, were identified as genes harboring common variants with an impact on obesity predisposition. We studied the association of common variants with birth weight, gain of body weight, body mass index (BMI), Ponderal index and relevant neonatal outcomes in a large German cohort of infants with a birth weight below 1500 grams.The FTO gene) and rs1424233 (MAF gene) were genotyped using allelic discrimination assays in a prospective multicenter cohort study conducted in 15 neonatal intensive care units in Germany from September 2003 until January 2008. DNA samples were extracted from buccal swabs according to standard protocols.The single nucleotide polymorphisms rs9939609 (FTO and 2149 infants at MAF. Allele frequencies were not significantly different from other European cohorts. The polymorphisms were in Hardy-Weinberg equilibrium. The polymorphisms did not show associations with birth weight, BMI and Ponderal Index at discharge, and weight gain, neither testing for a dominant, additive nor for a recessive model.1946 infants were successfully genotyped at Since an association of the polymorphisms with weight gain has been demonstrated in multiple populations, the lack of association in a population of preterm infants with regular tube feeding after birth and highly controlled feeding volumes provides evidence for the hypothesis that these polymorphisms affect food intake behavior and hunger rather than metabolism and energy consumption. FTO and MAF gene to be associated with obesity Obesity is a major cause of morbidity and mortality, associated with an increased risk of type 2 diabetes mellitus, heart disease, metabolic syndrome, hypertension, stroke and certain forms of cancer FTO gene is located on chromosome 16q12.2. It is harboring common variants with an impact on obesity predisposition and fat mass at a population level FTO (T = >A) has been associated with BMI in numerous studies, altering the body weight of homozygous adults about 3 kilograms et al.The et al. have recently published a GWAs in which they identified a novel locus, with rs1424233 being the lead SNP, which is associated with obesity in Europeans MAF gene is mapped about 48 kb away from rs1424233. The ubiquitously expressed c-MAF transcription factor is involved in developmental and cellular differentiation processes, notably of the immune system Meyre Despite these associations, the mechanisms by which these polymorphisms affect the predisposition on obesity are not yet understood. Whether they might influence weight gain by alteration of food uptake, energy consumption, or metabolism is still subject to research Very low birth weight (VLBW)-infants are defined by birth before 37 weeks of gestation  and a birth weight below 1500 grams. About 1% of all newborns are VLBW-infants. They are furthermore characterized by the following conditions: 1. They are closely monitored since all individuals stay in hospital from birth on. 2. They are fed similarly tolerating only small deviations of the recommended amount of calories per kilogram (if infants are not drinking the recommended amount of milk they are fed by gastric tubes). 3. They are kept in warm and moist surrounding (e.g. incubators) to minimize energy consumption during their stay in hospital.These special conditions may provide evidence for or against an impact of the polymorphisms on energy consumption or metabolism.FTO and MAF polymorphisms with birth weight, gain of weight, BMI, Ponderal index and relevant neonatal outcomes in a large German birth cohort of VLBW-infants.The objective of our study was to search for an association of The study was approved by the ethics committee of the University of Lübeck  and local ethics committees of all participating centers . Parents gave written informed consent to all parts of the study.The study population has been previously described in detail DNA samples were obtained by buccal swabs. Antenatal and postnatal treatment and outcome data were recorded by participating centers on standardized data sheets. A physician trained in neonatology evaluated the data quality by on-site monitoring every 6 months.2) were calculated. Mean weight gain per day until discharge and mean gain of body length were also calculated for analysis.Birth weight, body-length and head circumference at birth were available of all infants. Length of hospital stay until discharge or until death were recorded in days as well as body measurements at discharge or death. Hypertrophy  and hypotrophy  were calculated stratifying the population by gestational age and allocating each stratum minimum or maximum weight according to the Fenton scale MAF gene and rs9939609 from the FTO gene were genotyped using an allelic discrimination assay . The sequences of the polymorphisms and the assay components have been described previously DNA samples were extracted from buccal swabs according to standard protocols. The single nucleotide polymorphism (SNP) rs1424233 from the For dichotomous variables, such as birth weight >97th percentile, association was tested using the Wald test from the logistic regression for additive, dominant, and recessive genetic models. For continuous outcome variables, such as mean weight gain per day, linear regression was performed using additive, dominant, and recessive genetic models.Both SNPs were investigated for compatibility with Hardy-Weinberg equilibrium using relative excess heterozygosity using the nominal 5% test level Statistical analyses were performed with SAS  and SPSS for Windows .FTO-A-allele frequency was 0.43 and the MAF-C-allele frequency 0.49. The distribution of the variants was in Hardy-Weinberg equilibrium  ); rs1424233; ω = 1.02 )). Only 3.3% of the study population had a mother of non European descent.2488 VLBW- infants participated in the study. There were 1261 male study participants and 1227 female participants. Sixty children died before discharge from hospital. Clinical data are given in th percentile and >90th percentile) and hypotrophy (<10th percentile) with adjustment for confounding by gender, multiples, year of birth, maternal ethnicity, and treating NICU did not reveal significant findings.Associations according to mean birth weight by genotype are displayed in Association analyses using linear regression for mean weight gain per day until discharge from hospital, mean gain of length, Ponderal index, and BMI did not reveal significant associations. Even adjustments for gender, multiples , year of birth, APGAR in minute 10, umbilical-cord-artery-pH, birth in a level 1 neonatal intensive care unit, sepsis, surgical procedures, and treating NICU did not reveal associations with p<0.05. For these analysis VLBW-infants with fatal outcome were excluded (n = 60) to reduce variance until discharge.Furthermore, none of the polymorphisms showed any influence on birth weight or weight gain if compared to established clinical factors such as gender or surgical treatment of necrotizing enterocolitis .We could neither find an association of the rs9939609 or rs1424233 with birth weight nor weight gain in VLBW-infants. These findings support the hypothesis that the polymorphisms have no impact on energy consumption and metabolism but rather on food uptake behavior.FTO and MAF genes have been recently described to be major candidate genes for human obesity FTO and MAF allele-frequencies in our cohort were similar to those reported in other populations FTO and MAF SNPs was not associated with hypertrophy or hypotrophy in our study. Thus, we found no evidence for a relevance of these polymorphisms in intrauterine growth. These results are in line with the study by Frayling et al. who found no association of rs9939609 with birth weight in children from the UK The As published previously, twin analysis support a strong genetic influence on postnatal growth in preterm infants et al. found an association of the FTO-polymorphism with gain of weight during the first two weeks of life in term born children FTO and MAF polymorphisms in our cohort did not differ significantly from other large populations et al. found no association of FTO-variants with birth weight in the GINI and LISA birth-cohort and could show that significant association developed over time in their population at the age of 4 years In several cohorts association of the polymorphisms was found with obesity in children. In a small population Lopez-Bermejo FTO and MAF genes do have a stronger impact on food intake behavior and hunger, than on metabolism and energy consumption. This supported by Wardle et al. who found not only a significant association of the rs9939609 AA genotypes with reduced satiety responsiveness scores, but also a mediating effect through satiety responsiveness on the association with increased adiposity et al. concluded from their analysis in a large cohort that FTO variants had impact on food intake and a preference for energy-dense foods Both polymorphisms were neither associated with birth weight nor with growth of neonates. It may therefore be hypothesized that the SNPs rs9939609 and rs1424233 from the Our study has several limitations. Due to our study design, we were not able to measure hunger and food intake directly. Furthermore, longitudinal assessment was limited until discharge. Therefore, we were not able to measure the combined long-time effects of metabolic programming (e.g. due to intrauterine growth restriction) and genotypes associated with obesity. This will be an important aim of the ongoing longitudinal GNN-study.FTO gene nor rs1424233 from the MAF gene influence metabolism and energy consumption, but might be of importance for food uptake behavior. Further research on the pathophysiologic effects of polymorphisms in these genes is needed to reveal the origin of association with obesity.In summary, our negative results provide further evidence that neither rs9939609 from the


Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs.We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0–12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group . Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers .Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for their analgesic, antipyretic, and anti-inflammatory effects. They are among the most common drugs prescribed in the first trimester of pregnancy Since NSAID use during pregnancy is common, even small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of first trimester NSAID use are inconsistent. Recent epidemiologic investigations showed an increased risk of congenital heart defects, especially cardiac septal defects, and orofacial clefts The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. All participants gave their written informed consent.MoBa is a prospective cohort study conducted by the Norwegian Institute of Public Health, which enrolled women in early pregnancy between 1999 and 2007. The objective of this study is to estimate the effects of a wide range of exposures during pregnancy on pregnancy outcome and maternal and child health Information on the type and timing of both prescribed and over-the-counter NSAID use was available from the questionnaire. If a woman reported use of an NSAID in the six months before or during pregnancy, she could specify five exposure windows: before pregnancy, gestational weeks 0–4, 5–8, 9–12, and 13+ (until completion of the first MoBa questionnaire). We defined NSAID exposure as use of any NSAID  Only birth defects diagnosed by pediatricians and/or geneticists in the first week after birth or while the infants were in the hospital during their first year of life are included in the MBRN records. Birth defects are coded according to the n = 69,929). Mothers with pre-existing diabetes were excluded from the analyses because of the known association between this condition and birth defects Our study population consisted of all women who completed the first MoBa questionnaire between 1999 and 2006 for whom data on pregnancy outcome from the MBRN were available  with 95% confidence intervals (CIs). We performed multivariable logistic regression analyses using a complete case analysis approach to estimate the risk of selected birth defects associated with NSAID exposure during the first 12 weeks of gestation, adjusted for maternal age at delivery (in years), maternal education (12 years or less vs. more than 12 years), parity (no previous live births vs. one or more previous live births), presence or absence of a history of miscarriages, stillbirths, or induced abortions, prepregnancy body-mass index , any maternal folic acid use from 4 weeks before pregnancy through week 8 of gestation, and fever and any maternal smoking during gestational weeks 0–12. Adjusted ORs were only calculated if at least three exposed cases were available. We used the same potential confounder set in all models, except when small numbers or a relatively high proportion of missing values (≥10% in either the group of affected or unaffected infants) prevented us from including one or more co-variables. In secondary analyses, we performed crude and adjusted analyses to assess the associations between the different types of NSAIDs  and four specific NSAIDs  and the occurrence of the selected birth defects. We also evaluated the effects of exposure to multiple NSAIDs during gestational weeks 0–12 on the risk of the selected birth defects. Additional analyses were performed on time window-specific exposure to NSAIDs. In sensitivity analyses, we assessed whether restricting the analyses to women without pre-existing diseases  or to infants with isolated defects only changed the effect estimates. Furthermore, we determined whether clustering due to enrollment in MoBa of multiple pregnancies by one woman influenced the results by including primiparae only, as we did not have information on the number of times a particular woman participated in MoBa. Finally, we estimated the potential effect of bias resulting from the relatively low response rate on the results. All statistical analyses were performed using SPSS version 17.0 for Windows .n = 390), diagnosis of a chromosomal abnormality (n = 121), multiple gestation , and missing information on the timing of NSAID use (n = 256). Consequently, the final study population consisted of 67,891 women. A total of 6,972 (10.3%) women reported use of an NSAID in the 6 months before pregnancy and 3,023 (4.5%) women reported NSAID use during the first 12 weeks of gestation. Women who reported NSAID use in gestational weeks 13+ only (n = 569) and women who did not report the exact timing of NSAID use during pregnancy (n = 225) were omitted from further analyses. Ibuprofen was most commonly used (3.4%), followed by aspirin (0.5%), diclofenac (0.3%), and naproxen (0.2%). Most NSAID-using women used one NSAID (97.2%). Women who used NSAIDs during gestational weeks 0–12 were less likely to have more than 12 years of education, to be married or cohabiting, and to have had a previous live birth compared to non-using women . The selected birth defects were diagnosed in 638 infants (1.0%). A total of 18 infants had a neural tube defect , 435 a congenital heart defect , 134 an orofacial cleft , 20 an esophageal defect, 16 an anorectal malformation, 11 a diaphragmatic defect, and 21 an abdominal wall defect . No infants in our study cohort were diagnosed with amniotic bands. Of the infants with selected birth defects, 42 infants (6.6%) were classified as having multiple defects. Our study cohort included 65,287 infants without a major birth defect.The crude and adjusted odds ratios for overall NSAID exposure and the selected birth defects are shown in We conducted several secondary analyses to evaluate the effects of exposure to different types of NSAIDs on the occurrence of the selected birth defects . RestricThe detailed results of the sensitivity analyses are shown in In this large prospective cohort study, we did not find associations between exposure to any NSAID in the first 12 weeks of gestation and the occurrence of birth defects such as congenital heart defects and orofacial clefts, which were selected based upon results of previous animal and epidemiologic studies and the proposed teratogenic mechanism of NSAIDs. However, we did observe a non-statistically significantly increased risk of septal defects after exposure to multiple NSAIDs in the first 12 weeks of gestation. Furthermore, it should be kept in mind that NSAIDs have been associated with spontaneous abortions Although NSAID use during pregnancy is prevalent, epidemiologic studies on the teratogenic risks are relatively sparse. Recent case-control studies, which may be prone to recall bias, showed possible associations between NSAID exposure and ventricular septal defects In secondary analyses, we observed a possible association between exposure to multiple NSAIDs and septal defects with two (2.3%) of the exposed infants being diagnosed with either a ventricular or an atrial septal defect. This finding was based on very small numbers, but there are several reasons why this finding might indicate a truly increased risk. First, all outcomes of interest, including septal defects, were selected based on biologic plausibility. Secondly, mothers of exposed cases used a combination of either ibuprofen and ketoprofen or ibuprofen and diclofenac, which all inhibit COX-1 by more than 60% when COX-2 is inhibited by 80% The absence of associations between maternal use of NSAIDs during pregnancy and the occurrence of the selected birth defects may partly be due to the relatively low prevalence of exposure in this cohort (4.5%). Studies conducted in the U.S. found much higher prevalence estimates of NSAID use during the first trimester up to approximately 19% The main strength of this study is its longitudinal design which features prospective ascertainment of NSAID use and other covariate information obtained at a median of 17 weeks of gestation. However, as MoBa has a relatively low participation rate (43.5%), selection bias may have occurred. A recent non-response study showed that the prevalence estimates of several exposures and birth outcomes are biased in MoBa, but that estimates of exposure-outcome associations are not biased due to self-selection Non-differential misclassification of the exposure status may have occurred since data on NSAID use were collected using self-administered questionnaires. In addition, there might be a chance that the lack of an increased risk of the selected birth defects in NSAID-exposed infants is due to the inability to separate occasional users from the more frequent or continuous users. Confounding by indication cannot be excluded completely either, although restricting our analyses to women without pre-existing diseases did not change the results of the primary analyses, in which fever in the first 12 weeks of gestation was also included as a potential confounder.Several validation studies have been conducted regarding the accuracy of the MBRN, which showed that the ascertainment of congenital malformations varies according to the type of defect and its severity. For the years 2001–2005, 82% of clinically verified cases of Down syndrome were recorded in the registry The findings of this large prospective cohort study showed no associations between exposure to NSAIDs during the first part of pregnancy and the risk of selected birth defects, although an increased odds ratio was seen for septal defects after exposure the multiple NSAIDs. This observation, based on only two exposed cases, was not statistically significant and needs confirmation by other studies. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded.Table S1Characteristics of the 23 infants born with selected birth defects after prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs).(PDF)Click here for additional data file.Appendix S1Results of the sensitivity analyses on the effect of prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and selected birth defects.(PDF)Click here for additional data file.


With the increasing use of probabilistically linked administrative data in health research, it is important to understand whether systematic differences occur between the populations with linked and unlinked records. While probabilistic linkage involves combining records for individuals, population perinatal health research requires a combination of information from both the mother and her infant(s). The aims of this study were to (i) describe probabilistic linkage for perinatal records in New South Wales (NSW) Australia, (ii) determine linkage proportions for these perinatal records, and (iii) assess records with linked mother and infant hospital-birth record, and unlinked records for systematic differences.This is a population-based study of probabilistically linked statutory birth and hospital records from New South Wales, Australia, 2001-2008. Linkage groups were created where the birth record had complete linkage with hospital admission records for both the mother and infant(s), partial linkage (the mother only or the infant(s) only) or neither. Unlinked hospital records for mothers and infants were also examined. Rates of linkage as a percentage of birth records and descriptive statistics for maternal and infant characteristics by linkage groups were determined.Complete linkage  was available for 95.9% of birth records, partial linkage for 3.6%, and 0.5% with no linked hospital records (unlinked). Among live born singletons (complete linkage = 96.5%) the mothers without linked infant records (1.6%) had slightly higher proportions of young, non-Australian born, socially disadvantaged women with adverse pregnancy outcomes. The unlinked birth records (0.4%) had slightly higher proportions of nulliparous, older, Australian born women giving birth in private hospitals by caesarean section. Stillbirths had the highest rate of unlinked records (3-4%).This study shows that probabilistic linkage of perinatal records can achieve high, representative levels of complete linkage. Records for mother’s that did not link to infant records and unlinked records had slightly different characteristics to fully linked records. However, these groups were small and unlikely to bias results and conclusions in a substantive way. Stillbirths present additional challenges to the linkage process due to lower rates of linkage for lower gestational ages, where most stillbirths occur. The ability to conduct linkage of perinatal records, obtained as part of routinely collected administrative health data, has increased the scope for population based studies of mother and infant health. When a Advantages of linkage of administrative health records include; describing the total disease burden in a population, assessment of risk factors and inveMismatches are possible with probabilistic linkage. Two different individuals could be linked resulting in incorrectly reported outcomes or risk factors , or two records from the same individual may not be linked , resulting in missing information. The success of linkage, often described in terms of minimizing mismatches, can depend upon a number of factors, including the quality of the information used in the linkage process and how uniquely identifying reported information is. Recent studies have shown that, unlike deterministic methods, the flexibility of probabilistic record linkage allows for minimization of mismatches under variations in data quality. With thThe aims of this study were to (i) describe probabilistic linkage for perinatal records in New South Wales (NSW) Australia, (ii) determine linkage proportions for these perinatal records, and (iii) assess records with complete linkage of mother and infant hospital-birth record and unlinked records for systematic differences.th revision of the International Classification of Disease, Australian Modification (ICD10-AM) and the Australian Classification of Health Interventions (ACHI).This study used linked records of the NSW Perinatal Data Collection (PDC), and the NSW Admitted Patient Data Collection (APDC). The PDC (referred to as ‘birth records’) is a population-based statutory surveillance system that includes all live births and stillbirths of at least 20 weeks gestation or if gestational age is not known of at least 400 grams birth weight, and includes information on maternal characteristics, pregnancy, labor and delivery factors and infant outcomes. ‘Hospital records’ (for mothers and infants) that relate to the birth (birth admission records) were obtained from the APDC, which includes demographic and hospitalization related data for every inpatient admitted to any public or private hospital in NSW. Diagnoses and procedures for each hospital admission are coded according to the 10The study population included all mothers who gave birth, and their infants, in NSW, Australia, from 1 January 2001-31 December 2008. NSW is the largest state in Australia with around 7,287,600 million people representing 32% of the Australian population. HomebirBirth, and maternal and infant hospital records for 2001 to 2008 were probabilistically linked by the CThe link between the mother and infant is provided by the common birth record. Probabilistic linkage is used to link records for the same individual, and in this context the outline that follows is in reference to linking the mothers’ birth and hospital records, and the infants’ birth and hospital records.The CHeReL used a variety of fields that are common to both datasets for matching records in the linkage process. These include first name, last name, address, sex, date of birth, and country of birth. Additional information used, where available, includes hospital code and medical record number (MRN), admission date, discharge date, hospital discharged from, hospital discharged to, alias names, plurality and birth order for multiple pregnancies .Standardization and parsing techniques are used to allow a comparison of common fields and to facilitate matching. As a first stage, blocking is used to quickly search the target database for records that are possible matches. ‘Blocking’ is an automated algorithm designed to find as many as possible records that potentially match each other without exceeding a given and manageable block size. This increases the efficiency of a second stage of more detailed matching by reducing the number of pairs that are compared in the more accurate second stage matching. Records within the same block are scored during the second stage of matching. ‘Scoring’ generates the probability that two records match based on a series of weighted ‘clues’. Clues  are attributes of records that are suggestive of match or non-match decisions. Examples of clues are that the date of birth does not match, or there is a match on the phonetic code for the first name. Phonetic code is generated from coding schemes such as Soundex and the New York State Identification and Intelligence System (NYSIIS). This reduces the effect of minor typographical errors or spelling variations by assigning the same codes to words or syllables with similar pronunciation i.e. Robert and Rupert. The weight for each clue has been derived using previously matched data and a machine learning process called Maximum Entropy Modeling. During the scoring process these weights are combined using a formula based on maximum entropy theory to create a probability between 0 and 1 that two records match. Upper and lower probability cut-offs (thresholds) determine whether records are classified as matches, non-matches, or possible matches requiring clerical review , representing the ‘complete’ set of perinatal records. The ‘mothers only’ group includes birth records with a linked hospital birth admission record for the mother but without one for the infant, while the ‘infants only’ group includes birth records with a linked hospital birth admission record for the infant but without one for the mother. These two groups represent the ‘partial linkage’ groups. Finally, there are three different groups of unlinked records. The first is ‘unlinked birth records’ which includes birth records without a linked birth admission record for either the mother or the infant. The second is the ‘unlinked maternal hospital records’ which includes hospital birth admission records identified for a pregnancy that did not link to the birth records. The third is the ‘unlinked infant hospital records’ which includes hospital birth admission records identified for infants that did not link to the birth record.Stillbirths are reported on the mother’s hospital birth admission record and do not usually generate an infant hospital admission record for the infant. Therefore most will not have complete linked mother and infants records. Further, there may be misclassification of stillbirths and miscarriages and it has been indicated previously that linkage for stillbirths is problematic.Linking is conducted separately for singleton and multiple pregnancies as multiple pregnancies generate infant records with identical information such as mothers name, date of birth, hospital of birth and even sex, so extra care is required,32.ICD10-AM diagnosiInfant birth admissions were initially selected where records indicated an age of 0-1 days and either a live birth (ICD10-AM = Z38), born in hospital, or a birth weight and an ICD10-AM code for a condition of the perinatal period. For those records that linked to the birth record, we required the admission date to be within ±1 day of the date of birth and the hospital of birth reported on the hospital record to match that reported on the birth record , birth in a private hospital, delivery by caesarean section, diabetes, hypertension, induction of labor, maternal age, parity (number of previous births), smoking during pregnancy, placenta praevia, placental abruption, duration of pregnancy less than 26 weeks gestation and socio-economic status . Infant Reported for all births are (i) rates of linkage for the birth-hospital record linkage groups by plurality and live born/stillborn as a percentage of all birth records and (ii) rates of identification for deliveries and births as ascertained from the hospital birth admissions as a percentage of the number of deliveries/births reported in the birth records. Note that delivery is used to refer to a mother giving birth, and birth to refer to a baby being born. Thereafter, we limited the analysis to live born singleton deliveries/births. Descriptive statistics of both maternal and infant characteristics by linkage groups were reported using either information from the birth or hospital birth record. For those variables reported on both, information from the birth record was used unless the hospital birth admission record was indicated as being more reliable according to validation studies of birth and hospital data-37. DescIn the period January 2001 to December 2008, there were 706,685 deliveries resulting in 713,522 live births and 4,460 stillbirths recorded in the birth records (PDC). The rate of complete linkage  dropped from around 96% at 37 weeks gestation to <90% at 30 and <70% at 25  Table. PartialFrom the hospital records, 713,190 infant birth records were identified, almost the same number of live born birth admissions as reported in the birth records , > 99.9%. From the hospital records, 704,009 delivery records (mothers) were identified, representing 99.6% of those reported in the birth records .For the largest group of birth records, live born singletons, 96.5% of records had complete linkage to both a mother and an infant birth admission record compared to 96.0% of live born multiple births. For stillbirths, the largest linkage group was the ‘mothers only’ at around 94% for both singletons and multiple births. Unlinked birth records were more common for stillbirths (3-4%) than live births (0.3-0.4%).Given the incomplete linkage of stillbirths  and the difficulty of presenting results for multiple births , comparisons of maternal and infant linkage groups are presented for singleton live births. Coding of stillbirth/live birth and plurality could not be identified for 1,505 of the 704,009 deliveries identified in the hospital records (0.2%) and pregnancies with duration <26 weeks were over-represented in this group (3.2%). Similarly, 415 infant birth admissions (<0.1%) could not be classified and preterm birth was over-represented in this group (6.4%).Among singleton live births the rate of complete linkage dropped from around 96% at 25 weeks gestation to only 72% at 20 weeks gestation Figure.Maternal characteristics differed across the groups of linked and unlinked records Table. The twoThe ‘mothers only’ group , had higher levels of social disadvantage (quintile 5), women aged less than 25, non-Australian born mothers, births by unmarried women, smoking during pregnancy, commencement of antenatal care after 14 weeks gestation, caesarean section, placental abruption, and duration of pregnancy less than 26 weeks.Infant characteristics also varied across linkage groups Table. The ‘moTo our knowledge, this is the first study that has assessed the linkage of mother and infant birth and hospital records rather than mothers and infants separately. As maternal and pregnancy factors are important predictors of infant outcomes, assessment of the complete linkage is important. In this study the level of complete linkage (95.9%) was high for all births and highest for live singleton births (96.5%). Partially linked mother records  had slightly higher rates of adverse events and common risk factors while the partially linked infant records  were very similar to those with complete linkage.This study has shown that stratifying linkage by plurality to overcome the recognized difficulty of linking multiple births,32 has gAmong singleton live births, the proportions of birth records with partial (1.4-1.6%) or no linkage (0.4%) to hospital records was small. However, there was some evidence of systematic differences for the partially linked records that had no infant hospitalization record (‘mothers only’). This group has slightly higher rates of adverse infant outcomes and associated risk factors, consistent with observations in other studies,39-41. ROur finding that the unlinked birth records represent a relatively low risk group of mothers and babies is likely to be a local phenomenon. The over-representation of births in private hospitals in the unlinked birth records is likely a result of missing name information. It is at the discretion of private hospitals as to whether name information is collected, and so generally have a large amount of missing name information for both mothers and infants, thus affecting linkage rates for both mothers and infants. Changes to the data provided from private hospitals for linkage could potentially reduce the size of the unlinked birth records.The results highlight the importance of comparing the characteristics of probabilistic record linkage for perinatal research for mothers and infants, given the potential bias introduced into analysis by incomplete record linkage. It is recommended that for the chosen study population, linked and unlinked records should be requested for analysis and a comparison of linked and unlinked records be undertaken as part of any research using probabilistically linked data. This is of even greater importance when newly-established datasets and linkages are used, which is in contrast to the well-established datasets and linkage protocols used by the CHeReL which generated the linked data for this study. Further, in order to properly discuss the potential impacts, it is necessary for researchers to have a reasonable understanding of how the probabilistic linkage process works and the matching processes involved.The hospital birth admission records for mothers and infants that did not link to a birth record were small in number and of comparable size to the number of unlinked birth records, and inevitably include some missed links. However, particularly for mothers, there is difficulty in establishing birth admission records as more than one hospitalization may be identified as a birth admission. Although used in the past,43, we fProbabilistic methods can achieve high, representative levels of complete linkage for mothers and infants. Although some systematic differences occur for the mothers records that do not link to a corresponding infant record, and to a lesser degree for unlinked birth records with respect to private hospitals, these groups are very small and unlikely to bias estimates of effect or conclusions in a substantive way, particularly if the study population is live born singletons.The author(s) declare that they have no competing interests.CLR and JBF conceived the project and developed the idea in collaboration with LKT and KAI. All authors  contributed to study design, LKT, KAI, CLR and JBF, were responsible for data acquisition and JPB conducted the data analysis. JPB, CLR and JBF initially drafted the manuscript and all authors  were involved in critical revision of the intellectual content. All authors  approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/12/149/prepub


Song and Xiang  develope It is well-known that a variety of pest species pose a serious health risk to humans and pets, as well as causing great damage to property and crops. For virtually all pest species, biological eradication is biologically impossible or economically infeasible  + x2(nT))x2(nT), where b is the growth parameter, as considered in the model in Tang and Chen  | x1 ≥ 0, x2 ≥ 0, y1 ≥ 0, y2 ≥ 0}. For details on the theory of impulsive differential equations, we refer to the reader to the monograph  of the system, we have |u(t) − ũ(t)| → 0 as t → ∞.Lemma 3.2  has the positive, periodic, globally asymptotic solutionwith initial valuesTheorem 3.1. The pest eradication periodic solution , ỹ2(t)) of system (1) is locally asymptotically stable ifor equivalently, ifand globally asymptotically stable ifwhereProof. We first prove that the solution is locally asymptotically stable using Floquet Theory for impulsive differential equations , u2(t), ỹ1(t) + v1(t), ỹ2(t) + v2(t)) of the pest eradication solution , ỹ2(t)). Linearizing, we obtain the systemt) is the fundamental solution matrix of the system with Φ(0) = I, the identity matrix. The linearization of the pulse behavior is given byHence, the monodromy matrix of the system isM are less than one. This is always the case for the two eigenvalues exp(−(my + μ)T) and exp(−μ T). The other two eigenvalues are the eigenvalues of the submatrixBy Floquet Theory, the solution is locally asymptotically stable if the absolute values of the eigenvalues of The two eigenvalues of the matrix Clearly, inequality (7) is always satisfied, and inequality (8) is satisfied by the hypothesis. Hence, the solution is locally asymptotically stable.1 > 0 and ϵ2 > 0 sufficiently small so thatWe next prove the global attractivity of our solution following the technique in Song and Xiang . Choose We observe thatBy Lemma 3.1, system (9) has a globally asymptotically stable, positive, periodic solutionBy the Comparison Lemma for impulsive differential equations T,t.By direct calculation, we observe that for w(t) = x1(t) + x2(t). From the first two equations of system (1), we obtainnT < t ≤ (n + 1)T, andt = nT. For w(t), we consider the comparison systemNow let t = nT+ to t = (n + 1)T, we obtainBy integrating from We now obtain the stroboscopic mapz3(nT+) = δnz3(0+), and z3(nT+) → 0 as n → ∞. Equation (18) has the unique equilibrium z*3 = 0, which is globally asymptotically stable. Thus, system (16) has the globally asymptotically stable solution t → ∞w(t) = 0, and hence limt → ∞x1(t) = 0 and limt → ∞x2(t) = 0, since x1(t) ≥ 0 and x2(t) ≥ 0.Hence, t → ∞y1(t) = 0 and limt → ∞y2(t) = 0. For sufficiently small ϵ3 > 0, there exists T1 > 0 such thatWe next show that limx1(t) < ϵ3 and 0 < x2(t) < ϵ3 for all t > T1. The functionw(t) ≥ 0. Let0 < We now haveConsider the comparison systemBy Lemma 3.1, this comparison system has the positive, periodic, globally asymptotically stable solution4 > 0 and large enough t, we haveHence, for sufficiently small ϵt. Letting ϵ1 → 0, ϵ3 → 0, and ϵ4 → 0, we obtain t → ∞. Hence, limt → ∞y1(t) = ỹ1(t).From the inequalities (10) and (20), we obtainUsing the fourth equation from system (1) and the inequality (20), we obtain the inequalityFor this inequality, we consider the comparison systemnT < t ≤ (n + 1)T. By the Comparison Lemma, we havet. The inequalities (12) and (22) imply thatt. Letting ϵ2 → 0, ϵ3 → 0, and ϵ5 → 0, we obtain t → ∞. Hence, limt → ∞y2(t) = ỹ2(t).        □This system has a periodic, globally asymptotically stable solutionIn this paper, we consider an integrated pest management (IPM) model with two stages for both predator and prey, where prey births occur according to a birth pulse. We found conditions for global stability of the pest eradication periodic solution. In particular, we express this relationship in terms of an upper bound on b, the parameter in the birth pulse expression.b of the prey species given in system (1) to be random. As special case, we consider b to follow a right-skewed distribution reflecting the ecosystem where small birth rates are prevalent, while due to climatic changes, infrequent but large spikes in the birth rate are probable. However, the approach employed here can be easily implemented if a priori information indicates a different birth rate behavior. In fact, even if no information regarding the nature of the birth rate of the prey species is available, one can still implement the model given herein by simply using a uniform distribution for the birth rate, where all possible values of the birth rate are equally likely.We now turn to the stochastic model. Specifically, we consider the birth rate parameter The model in Song and Xiang  considerE, the pesticide potency or application effectiveness, under randomly varying birth rates in an attempt to maximize the eradication probability. Our approach with stochastic birth rate parameter forms a class of models, which accommodate a wide spectrum of cases where the eradication probability depends not only on the pesticide use but also on the abundance of the prey species.Here we seek a value of b, while holding all other values fixed and then compute the probability of eradication. To be more specific, we simulate a population of exponentially distributed birth rate parameters with mean b. Next we check the proportion of runs for which the total pest population is below a predetermined tolerance after a given length of time, which we define as eradication. Figure E and mean of b values. In this particular case when the magnitude of the prey birth rate follows a right-skewed random behavior with varying averages, the pesticide amount or potency may be determined based on the eradication probability. As expected, large pesticide values while the birth rates vary around a small mean result in high eradication probability.In a model with deterministic birth rate, whether the eradication occurs depends on the model parameters. Using our model, with the introduction of a stochastic parameter, we capture the process of varying birth rates that result in a realization for mx = 0.8, my = 0.7, r = 0.1, μ = 0.2, h = 0.5, λ = 0.1, p1 = 0.4, p2 = 0.3, and T = 1. With these values and E = 0.5, local asymptotic stability of the pest eradication solution occurs when b < 2.5985428. This is consistent with the results shown in Figure The graph in Figure b of the prey species. We modified the model by considering b to be random. The stochastic version of our model extends the model in Song and Xiang (b and the efficacy of the pesticide E needed for pest eradication.We began this study by considering an integrated pest management IPM model in which prey births occur according to a deterministic birth pulse. We established conditions for global stability of the pest eradication solution in terms of the birth rate parameter nd Xiang  by allowThe 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.