Markers of illness and macronutrient intakes  were recorded. Bayley Scales of Infant Development-III (BSID) were administered at 12 and 24 months of age in a subset of these infants (n = 66 and n = 50 respectively). Body composition z-scores were calculated using recently developed reference curves. Linear regression was used to test the associations between clinical factors and body composition z-scores, as well as z-scores and BSID scores. Increased calories and protein received in the first week after birth and protein intake throughout hospitalization were associated with increased FFM z-scores at discharge, but not with %BF z-scores. After adjustment for both early acute and chronic illness, associations of nutrient intake with FFM z-score remained unchanged. FFM z-scores at discharge were positively associated with scores on the BSID at 12 and 24 months CA. In conclusion, increased energy and protein intakes both early in hospitalization and across its entire duration are associated with higher FFM at discharge, a key marker for organ growth and neurodevelopment in the VLBW neonate. Optimizing caloric intake, irrespective of illness is critical for enhancing body composition, and by extension, neurodevelopmental outcomes for preterm infants.Preterm infants have altered body composition compared to term infants, which impacts both neurodevelopment and metabolic health, but whether increased dietary intake during hospitalization, independent of illness, may improve body composition is unknown. This prospective, longitudinal study ( Fat-free mass (FFM) gains are closely linked to brain development and are thus important growth parameters for the study of nutritional and physiological stressors on the preterm infant. Faster gains in FFM throughout hospitalization, as well as after hospital discharge, have been associated with improved neurocognitive outcomes, including higher cognitive and motor scores on standardized testing at 12 months corrected age for prematurity (CA), faster speed of processing in infancy and at preschool age and larger brain volumes at term CA ,4,5. ResMultiple factors have been shown to influence body composition in preterm infants, however many remain largely out of the neonatologist’s control. A few studies have shown that infants who received higher amounts of nutrients during hospitalization had improved FFM gains and neurodevelopment, however, it remains unclear if these associations are due to healthier infants receiving more nutrition and therefore having improved outcomes ,6,7,8 NuMarkers of critical illness have also been shown to influence short- and long-term growth and body composition amongst VLBW preterm infants ,10. We hIt remains unclear whether the negative influence of illness on growth is independent of the decreased nutrient intake typically provided to ill infants due to concerns of tolerance or other factors inherent to illness such as growth hormone suppression, altered nutrient accretion due to inflammation, etc. Improved understanding of these relationships is critical to improving the nutritional care of this vulnerable population and in turn long-term outcomes.In this study, we evaluated the influence of both illness and nutrient provision on later body composition to allow a better understanding of whether an increased nutrient provision is beneficial in terms of FFM gains for both healthy and sick preterm infants. In addition, we sought to determine whether early findings of improved neurodevelopment with increased FFM were sustained out to 24 months CA.One hundred and three infants were recruited from the Neonatal Intensive Care Unit (NICU) of the University of Minnesota Masonic Children’s Hospital from February 2012 to June 2016 into one of two observational studies with identical inclusion criteria. Inclusion criteria included birth weight <1500 g and appropriate for gestational age status (between the 10th and 90th percentile at birth on the Fenton Growth Curve) . During It was not possible to collect body composition measurements between 34–42 weeks PMA on 21 infants due to chronic lung disease requiring continuous respiratory support or transfer to a community hospital at an early gestational age. Eighty-one infants returned for follow-up at 4 months of age and 66 returned for neurodevelopmental testing at 12 months CA and 50 for neurodevelopmental testing at 24 months CA.Infants were followed daily while they were inpatient by the neonatal nutrition support service. Intake was recorded by the NICU dietician (J.S.). First-week intake was calculated by adding all calories and protein provided either enterally or parenterally from days 2–8 (DOL2–8). These dates were chosen as infants were born at different times on the first day of life and therefore the amount of nutrition provided on day of life one was variable based on the time of birth. The average daily energy and protein deficit was calculated as the average difference between 120 kcal/kg for energy and 4 g/kg for protein and the actual intake/kg of each up to 35 weeks PMA. Illness severity on postnatal days 12–14 were calculated using the score for neonatal acute physiology (SNAP-II), validated illness severity and mortality risk score for neonates, in which a higher score indicates increased severity of illness and a higher risk of mortality .Body composition was measured prior to hospital discharge (between 34–42 weeks PMA) using air displacement plethysmography by the PEA POD. A detailed description of the PEA POD’s physical design, operating principles, validation in preterm infants, and measurement procedures have previously been detailed ,14,15,16Neurodevelopmental testing was performed utilizing the Bayley Scales of Infant Development-III that was performed by a pediatric neuropsychologist (C.B.) in our Neonatal Follow-up Clinic.p values < 0.05. Analyses were performed using SAS 9.4.Infant characteristics were described using means and standard deviations or frequencies. Multiple linear regressions were used to test the associations between individual nutrient intake measures  and body composition z-scores (FFMZ and %BFZ) at two time points  in separate models. Multiple linear regression models were also used to test the association between body composition z scores (FFMZ and %BFZ) at both of the above time points and BSID scores at 12 and 24 months CA in separate models. For the first set of models (with body composition z-scores as the dependent variable), model 1 included covariates for study and gestational age at birth. Given that our primary hypothesis was that the relationship of nutrient intake on body composition was independent of early and chronic critical illness, we then included SNAP-II score at day of life 12–14 scores as a measure of early critical illness in model 2, and then added days requiring positive pressure as a statistical control for chronic critical illness in model 3. In the models with BSID scores as the dependent variable, model 1 included covariate adjustment for study and gestational age at birth. Given that IVH is a profound determinant of later neurodevelopment, model 2 added an indicator for IVH grade 2 or higher. Sensitivity analyses, including only participants who had complete data at all time points, were performed as a way of assessing whether any observed differences in the magnitude of the associations at different time points  were likely to be due to differential attrition. Associations were considered significant with p = 0.03) and higher mean gestational age at birth (28.1 weeks vs. 26.6 weeks p = 0.02) compared to those who were unable to be measured. There were no significant differences in birth weight or gestational age at birth between those included and not included at any other visit time .Infant characteristics are detailed in First-week caloric and protein intakes were positively associated with FFMZ at discharge in the minimally adjusted models, and these associations remained statistically significant after the addition of illness variables (SNAP score and days requiring positive pressure) . AverageFirst-week caloric intake and the average daily caloric deficit remained negatively associated with FFMZ at four months of age . These ap ≤ 0.04 for both), and with motor scores on the BSID at 24 months CA (p = 0.04). For each of these associations, there was an approximately 3-point improvement on the Bayley for each increase in FFM z-score. Neither FFMZ nor %BFZ at 4 months CA were associated with any score on the BSID at either 12 or 24 months CA .We prospectively gathered detailed data on nutrient intake and markers of critical illness and utilized air displacement plethysmography to measure body composition at hospital discharge and four months CA to investigate clinical factors associated with improved FFM in early infancy (discharge and four months CA). In addition, we performed standardized neurodevelopmental testing at multiple time points to establish whether associations between FFM and neurodevelopment extend beyond 12 months CA. The importance of quality of growth as a marker of long-term outcomes is becoming increasingly recognized. Yet, it is still unknown how to effectively modify FFM gains in preterm infants. In this group of very low birth weight preterm infants, we found that increased energy intake in the first week after birth as well as throughout hospitalization is associated with increased FFM throughout early infancy independent of early and chronic critical illness. In turn, FFM z-scores, but not %BF z-scores calculated using newly released reference curves , were asThere are several small and/or retrospective studies that have documented associations between markers of critical illness and long-term growth outcomes. Increased days receiving antibiotics or steroids and days requiring positive pressure ventilation have been associated with decreased linear growth out to two years of age . In addiOne of the largest studies specifically looking at both nutritional and non-nutritional factors influencing body composition involved 141 preterm infants born in France. The infants involved in this study were born prior to 35 weeks with a mean gestational age at birth of 31.5 weeks , represeWhile it is accepted that more critically ill preterm infants have poorer growth when compared to healthier infants born at similar ages, it remains unclear how much of this is due to restricted intake provided to this subset of infants versus a direct effect of inflammation on nutrient accretion. In a mediation analysis of more than 1000 preterm born infants, Eherenkranz et al. found that infants who were less critically ill had a higher nutrient intake, increased weight gain, and better long-term outcomes and that these relationships were largely mediated by first-week nutrient intake . In thisOur study also confirmed the findings of several other studies related to the positive relationship between FFM gains during hospitalization and long-term neurodevelopment. These previous studies also found that gains in FFM, but not FM, prior to hospital discharge, during a time of rapid brain growth and development, were associated with faster speed of brain processing in infancy and at preschool age ,4, higheOur current study utilized newly published reference curves for infant body composition , showingUnfortunately, there was significant participant drop-out over time leading to smaller sample sizes at 12 and 24 months CA. A sample size calculation was not made in advance in this observational study; therefore, there is a possibility of type I error. Further, interpretation of the results should consider that an adjustment for multiple comparisons was not made. Due to the observational design, the causality of the associations cannot be inferred. Randomized nutrition intervention trials are needed to determine whether an enhanced nutrient provision is both feasible and beneficial when given to critically ill inflamed preterm infants.In conclusion, early nutrition has a lasting impact on growth that persists beyond the period of provision and is beneficial with regards to FFM gains, without increasing FM gains, regardless of critical illness. Results from this study could inform future randomized trials and neonatologists as they make decisions regarding the nutrient provision and in turn improve long-term neurodevelopment and overall health outcomes for critically ill preterm neonates.


Background: Reproduction rates are declining in Hamadan, western Iran. This study identified theinfluence factors associated with reproduction rate and birth spacing in Hamadan as an area of lowpopulation growth in Iran.Study design: A cross sectional study.Methods: The study considered reproductive status of 812 women referred to health care centers ofHamadan, western Iran in 2015. Data were obtained through frequency and percentage. PWP-GTmodel was used to determine the influence factors on women's reproductive by R software (version3.3.2). The parity progression ratios were determined based on Yadava and Kumar.Results: The median time for the second, the third and the fourth birth was 4.53, 4.65 and 5.27 yr,respectively. PWP-GT model showed that women age at marriage (P=0.001), women's (P=0.005) andtheir husband's (P=0.039) employment had significant effect on time birth of first child. The women'seducation (P=0.001) was the only variable that had a significant effect on the birth time from the firstto the second child as well as from the third to the fourth child. Education of women (P=0.001) andtheir husbands (P=0.034) had significant effect on the time interval from the second to the third child.The birth probability from marriage to the first birth (0 to 1st child) was high (0.91), while the probabilityhad been fallen from the third birth and more (0.31).Conclusions: Birth spacing in Hamadan is more than WHO recommended. In addition, reducing ofthe population growth and childbearing has started in the past few decades in Hamadan the same asIran. The chance of fertility has dramatically declined from the third child and then. Knowing the average of family size and parity progression ratios (PPRs) are the most important information on population policies2, so that rise and fall of the PPRs indicate transmission of the population. Therefore, study and continuous tracking of changes in fertility and its components is important in each geographic area.The structure of populations will change over time by fertility, mortality, and migration. Then, determination of birth rate, birth spacing, and its influence factors are important. WHO recommends that all countries to apply demographic information such as registration of current events and in economic planning3; but now, has been faced with reduction population growth. The fertility rate of Iranians' women in 2016  was approximately three times smaller than 1975 4. Hence, research for the fertility status of women in the past two decades and even before, could be interesting. In addition, such studies can show the impact of demographic policy of the government in reducing population growth.Iran's strategy has focused on the prevention of pregnancy in past two decades5. Hamadan Province is ninth for total fertility rate in Iran6. Furthermore, according to the Statistical Center of Iran report, Hamadan Province was among the areas with the lowest population growth in the West of Iran7. Population growth in Hamadan Province has fluctuated over the years 2005 to 2010, and has not a clear increase or decrease trend8. However, detailed results among previous censuses show that growth of birth registered in Hamadan Province has a decreasing trend8. Continuing the downward trend in the long term may reduce population growth in this province. Total fertility rate in the province was 1.6 in 2009, smaller than a whole country8. The most influence factors in reducing fertility rate are may be birth spacing, high literacy10, higher marriage age11, the employment situation couples12 and other demographic characteristics.In Iran, parity progression ratio from first birth to the second birth and more was relatively high, and several demographic factors have influenced on itTherefore, the study on the dynamics of demography in Hamadan is necessary. The purpose of this study was to model the factors related to the birth spacing in Hamadan. In this study, the dynamic demographic indicators, especially parity progression ratios (PPRs) which reflect the status of increasing/decreasing household size, were determined.This cross-sectional study was approved by the Ethics Committee of Hamadan University of Medical Sciences, Hamadan, Iran.The study considered reproductive status of 812 women in Hamadan, western Iran in 2015. Women participating in the study must have had at least one legal marriage, 45 yr or older, and had been living in Hamadan. Participants were selected by the two-stage sampling method. In the first stage, 15 centers (50%) from 32 Hamadan’s health care centers were randomly selected. In the second stage, six heads of the cluster were randomly selected from the list of households in these centers.Recurrent childbirth modeling: As for the repetitive nature of childbirth, women may experience its several times in their lifetime. The time interval between deliveries can be analyzed using models for recurrent events. In these models, the given event  occurs more than once for each individual does. To investigate recurrent events, selection of the appropriate model depends on the research objective, researcher, and the nature of the data.In the present study, the Prentice-Williams-Peterson gap time (PWP-GT) conditional model was used to evaluate different influence factors on the time interval between deliveries. The follow-up time in each event reset to zero and the time interval between the two events was considered as birth spacing.The hazard function model for the ith individual is:s is the number of strata for each person at time t, Xi(t) denotes the predictor variable for individual i at time t, and ts-1 denotes the former occurrence time of the event.where, l in the s stratum is shown by tsl.The time interval equals:The occurrence time of the event for the individual t(s-1)l is the occurrence time for the individual l at s-1 stratum.And s(l))<us(2)<...<us)s is the predictor variable for the i individual in the s stratum in the time tsi , and s before the time interval u13.where ith children) of children who go onto have another child th children). The parity progression ratios is were determined based on Yadava and Kumar (4) as follows,Parity Progression Ratios (PPRs): The PPR is the proportion of women with a certain number  and 12 months. In addition i(t) denotes the distribution function of closed birth interval of females at ith parity. In this study we considered C1=12 and C1=60, 72, 84, 96, 108, and 120 month. Therefore, the expression [3] is rewrite as follows,where, pDescription of the collected information was performed through frequency and percentage, while data analysis was conducted using the PWP-GT model with the R software (version 3.3.2). The statistical significance level was less than 0.05.The parity progression ratios and influence factors on recurrent birth child were assessed for 812 women, aged 45 yr or older. The minimum and maximum number of children for the women was zero to seven, respectively. However, the study did not go beyond fifth labor due to the small sample size. Of 812 women, 770 (94.83%) had only one child, 671 (82.63%) had two children, 254 (31.28%) had three children, and 73 (8.99%) had four children. In addition, the first infertility rate was 5.17%. The mean±sd age of the women and their husbands at the first delivery was 22.36±4.58 and 27.66±5.31 yr, respectively. The sex ratio at first birth was 104. Median of birth interval at the second, the third, and the fourth children was 4.53, 4.65 and 5.27 yr, respectively. P<0.001, P=0.005, P=0.039, The results of the PWP-GT model fitting revealed that maternal age, mother and father employment status were significantly effective on the birth interval from marriage to the first child, so that increased maternal age at marriage was associated with reduced child birth ratio th children) of childbirth among the women. The parity progression ratios were high since marriage to the first birth (0 to 1st child), while these ratios has been fallen from the third birth and more.The study obtained estimates of the parity progression ratios  for parities one to four as 0.955, 0.838, 0.557, and 0.349, respectively.The chance of the first to the fourth birth was decreasing, such that these chances for the third and the fourth children after 10 yr were 0.592 and 0.354, respectively .6. The number of parity depends on the fertility rate and the number of women in reproductive age15. In addition, the fertility rate is dependent on cultural, social and economic of societies15. Therefore, knowing of fertility status and birth spacing are important for policy makers at all fields . In our study, women 45 yr or older were selected because they passed their reproductive age.Fertility status has direct association on the structure and pyramid of population8. One of the most important results in this study was high spacing  between deliveries among Hamadan women. The evidence has indicated that a birth interval of more than 2 yr gives a better chance of infant survival16. In this study, not only the first birth spacing was more than 2 yr, but also the median time of the second, the third and the fourth deliveries was 4.53, 4.65 and 5.27 yr, respectively. Birth interval in Hamadan was larger than WHO recommendation17. Furthermore, developing countries have shorter birth intervals, while women in Hamadan (west of Iran) had large birth intervals18. Therefore, a decline in the population growth in Hamadan may be due to the large birth intervals.The sex ratio is a useful index to family programming, and was about 104 at the first birth in Hamadan. The sex ratio in 2015  is similar to 2010 in Hamadan, but it is higher than in Iran 19, but unlike them we have shown that it had a negative relationship with the first birth spacing. Because the maternal age at marriage and their education level are concordance, hence, the negative relationship between maternal age at marriage and the first birth spacing may be due to women continue education after marriage.In the study, we showed that maternal age at marriage had relation with the first birth spacing the same as previous studies20. Neither employment status of maternal nor employment status of their husbands had significant effect on the second and more birth spacing. In this study, we obtained parity progression ratios. It seems that chance of parity progression of the third to the fourth child and more are relatively low, and may be due to the implementation of family planning or increasing use of contraceptives in the past few decades21.In addition, we showed that employment status of women and their husbands had a negative relationship with the first birth spacing, in consistent with Begna et al22, while we could not found it. Ethiopian women whose previous sibling had died had twelve months shorter birth interval22.The relationship between stillbirth and birth interval was observedThis research shows that parity progression ratio at 5-yr period from marriage to the first birth is 0.91, which is high. Such results show a delay in childbearing after marriage, despite the family wishes to have a first child. Delay in childbearing may be due to the socioeconomic situation couples, social support, continuing education of parents, or family support of couples. Of course, we are not sure. Therefore, we suggest that a study is done on the causes and factors associated with delayed childbearing.st to 2nd and 2nd to 3rd children at 5-yr period was 0.82 and 0.557, respectively and the subsequent birth had fallen. Hence, the average family size has reduced in the area. According to McDonald et al23, parity progression ratio from the third birth and more is highly reduced in Iran same the present study. Therefore, a national commitment is needed to prevent the continuation of this negative trend.As shown, parity progression ratios 18. The results of this study and previous census shows that some population changes  in Hamadan and Iran are the same during the last few decades23, so that the average of family size in both Hamadan and Iran was reduced. However, it seems that Hamadan the same as Iran23 is experiencing transition and in both population growths is declining in the past few decades.Detailed results of census 2010 showed that Hamadan had the lowest average annual population growth after Ardabil, Ilam, Lorestan and Gilan over the 2005-2010The study shows that chance of delivery at the third child and more have been declining in the past years in Hamadan. Accordingly, employment and education of parent may be affecting to the declining. This process will cause many problems such as aging population and increasing actual depending rate. In addition, the results showed that the chance of the second and the third birth, after at 10-yr period of marriage is reduced severity. With just a glance, it clearly observed that the decline in population growth occurred in Hamadan, west of Iran, and most families have been turn to one or two children.Since the number of women having five or more children was small in this study, hence we limited the analysis up to fifth birth order.Reduced population growth and childbearing has been occurred since few decades ago in Hamadan. The main obstacle to reaching the third birth and more was the parents' education level in Hamadan.Hamadan University of Medical Sciences financially supported this research. The authors would like to thank the women and interviewers.No conflict of interest is declared.The study was funded by Vice-chancellor for Research and Technology, Hamadan University of Medical Sciences (No. 9104131928).Birth spacing in Hamadan is more than WHO recommendation Chance of childbearing in Hamadan have dramatically decline from the third child and then. One of the main causes of the redaction is maternal education level and employment of couple.


In the United States, racial disparities in birth outcomes persist and have been widening. Interpersonal and structural racism are leading explanations for the continuing racial disparities in birth outcomes, but research to confirm the role of racism and evaluate trends in the impact of racism on health outcomes has been hampered by the challenge of measuring racism. Most research on discrimination relies on self-reported experiences of discrimination, and few studies have examined racial attitudes and bias at the US national level.This study aimed to investigate the associations between state-level Twitter-derived sentiments related to racial or ethnic minorities and birth outcomes.We utilized Twitter’s Streaming application programming interface to collect 26,027,740 tweets from June 2015 to December 2017, containing at least one race-related term. Sentiment analysis was performed using support vector machine, a supervised machine learning model. We constructed overall indicators of sentiment toward minorities and sentiment toward race-specific groups. For each year, state-level Twitter-derived sentiment data were merged with birth data for that year. The study participants were women who had singleton births with no congenital abnormalities from 2015 to 2017 and for whom data were available on gestational age  or birth weight . The main outcomes were low birth weight (birth weight ≤2499 g) and preterm birth . We estimated the incidence ratios controlling for individual-level maternal characteristics  and state-level demographics, using log binomial regression models.The accuracy for identifying negative sentiments on comparing the machine learning model to manually labeled tweets was 91%. Mothers living in states in the highest tertile for negative sentiment tweets referencing racial or ethnic minorities had greater incidences of low birth weight  and preterm birth  compared with mothers living in states in the lowest tertile. More negative tweets referencing minorities were associated with adverse birth outcomes in the total population, including non-Hispanic white people and racial or ethnic minorities. In stratified subgroup analyses, more negative tweets referencing specific racial or ethnic minority groups  were associated with poor birth outcomes for black people and minorities.A negative social context related to race was associated with poor birth outcomes for racial or ethnic minorities, as well as non-Hispanic white people. Preterm birth and low birth weight (LBW) are the leading causes of infant mortality and childhood disability ,2. In thTraditionally, experiences with discrimination are assessed at the individual level by self-reports ,10. SelfThere are several mechanisms by which discrimination may impact poor birth outcomes. For example, the experience of discrimination may activate a stress response that may contribute to poor birth outcomes if experienced chronically. Maternal stress may impact birth outcomes through the following three major pathways: (1) altered neuroendocrine function, which leads to activation of the maternal-placental-fetal endocrine system that promotes childbirth ,16; (2) An innovative study highlighted the potential impact of a race- or ethnicity-related event that creates a change in the contextual-level social climate. The authors investigated birth outcomes after a federal immigration raid in Postville, Iowa in 2008, which at the time, was the largest single-site raid in US history . CompariSocial media represents an under-used source of data for public health research. Millions of tweets are sent daily, and 90% of Twitter users have made their profile public . In the Previous studies have used Twitter data to examine topics, such as vaccination  and natiTo provide a race- or ethnicity-related measure of the social climate and address prior limitations of self-reported individual-level measures, we developed a novel area-level measure of racial sentiment and examined its association with LBW and preterm birth. We took a broad approach and collected tweets referencing racial or ethnic groups, not just hate speech tweets or tweets using racial slurs. However, terms conventionally perceived as racial slurs can be used in nonderogatory ways, and such reappropriation is common on Twitter. For instance, in popular culture, the term “nigga” is often used as an in-group term without valuation . FurtherA random 1% sample of publicly available tweets was collected from June 2015 to December 2017, using Twitter’s Streaming application programming interface. The analysis included English language tweets from the United States with latitude and longitude coordinates or other “place” attributes that permitted the identification of the state where the tweet was associated. All tweets included in the sample also used one or more of the 518 identified race-related keywords . The terThe Twitter data were cleaned and processed for the analysis. We removed duplicate tweets according to the “tweet_id.” We identified exclusion terms that tended to retrieve irrelevant tweets such as “black smoke” and “Indian Rd.” To prevent undue influence from a small number of very frequent users, we excluded tweets from users who tweeted more than 1000 times a year in the data set, which represented 3% to 4% of all tweets. In total, we collected 26,027,740 tweets from 2,498,717 Twitter users. This study was determined to be exempt by the Institutional Review Board of the University of California, San Francisco.We utilized support vector machine (SVM), a supervised machine learning model, to label the tweets. We obtained training data from manually labeled Sentiment140 (n=498) , Kaggle We used data from the 2015-2017 restricted US natality files with geographic identifiers as individual-level birth outcome data. The files were obtained after submitting a research proposal to and obtaining approval for data access from the National Center for Health Statistics . The ana2), smoking during pregnancy , first birth (yes/no), and prenatal care initiation during the first trimester (yes/no). We also adjusted for state-level characteristics including proportions of non-Hispanic black and Hispanic individuals, population density (per square mile), southern state indicator (yes/no), and economic disadvantage , race , Hispanic ethnicity, marital status (married/unmarried), education , body mass index  was used for statistical analyses, and R software  was used for mapping [For each year, state-level sentiment toward racial or ethnic minorities was merged with data on births during that year. We estimated incidence ratios (IRs) using log binomial regression models, controlling for individual-level maternal characteristics and state-level demographic characteristics. In our main analyses, we modeled negative sentiment of tweets using race-related terms, but in the sensitivity analysis, we modeled the ratio of negative to positive sentiments to examine whether the results were robust for modeling different polarities of sentiment. We evaluated statistical significance at  mapping .From 2015 to 2017, we collected 26,027,740 tweets containing at least one of the relevant keywords pertaining to a racial or ethnic group. Among the 518 terms assessed, 20 terms were present in 75% of all tweets with reference to a racial or ethnic minority group. The top Twitter terms were “nigga/niggas” , “racist” , “Mexican” , “white people” , and “Chinese”  . AdditioThe geographic distributions of negative and positive sentiment tweets are displayed in State-level racial sentiment was associated with LBW and preterm birth. In the entire population, mothers living in states with the highest level (third tertile) of negative tweets referencing racial or ethnic minorities had a 8% greater incidence of LBW (95% CI 1.04-1.13) and 8% greater incidence of preterm birth (95% CI 1.00-1.14) compared with mothers living in states with the lowest level (first tertile) of negative sentiment . On inveExamining sentiment toward specific groups, we found that states in the highest level (third tertile) of negative tweets referencing Middle Eastern people were associated with a greater incidence of LBW among racial or ethnic minorities . More negative tweets referencing black people  were associated with a greater incidence of LBW among black mothers . A similOn examining the association between negative sentiment and birth outcomes over time, there was evidence of an interaction between sentiment referencing black people and year. As a result, we present the absolute differences in the proportions and numbers of LBW and preterm births by year in Sensitivity analyses were conducted by modeling the ratio of negative to positive sentiments to investigate whether the findings were robust for modeling different polarities of sentiment. The findings showed a similar pattern  as compaThis study found that negative sentiment toward racial and ethnic minorities, expressed in tweets geolocated to states, was associated with LBW and preterm birth. These adverse associations were similar for the population of all births, births in non-Hispanic white mothers, and births in racial or ethnic minorities overall. Negative tweets referencing black people were associated with adverse birth outcomes for black mothers. Similarly, negative tweets referencing Middle Eastern people were associated with poor birth outcomes among minorities. Associations were not consistently observed for negative tweets referencing non-Hispanic white or Hispanic mothers. While associations tended to be stable over the period from 2015 to 2017, for black mothers, the association between racial sentiment referencing black people and adverse birth outcomes became stronger over time.This is among the few papers utilizing social media data to assess the racial climate in relation to health outcomes. Moreover, we did so on a national basis and accounted for individual characteristics. The results are consistent with prior work showing that the community-level racial climate is related to birth outcomes ,20 and mPrevious research has provided evidence for the influence of the social context on the health of communities. Past studies have compared birth outcomes before and after a single-site immigration raid , the attOur results indicate that negative sentiment tweets referencing racial or ethnic minorities impacted the total population including non-Hispanic white people. Prior studies on racial bias and discrimination have tended to only examine the impact on racial and ethnic minorities. This study is unusual as it examined the health outcomes of the total population. A social climate that is hostile to racial and ethnic minorities might create an environment that is detrimental to all, including white people. This is consistent with prior work indicating that social cohesion promotes population health ,46. AnimAlthough the rates of adverse birth outcomes have declined for all groups over the past century, a marked racial disparity has persisted. Similar disparities prevail for many other outcomes, including maternal mortality  and manyNonetheless, the study has some limitations. The analyses did not take into account residential histories and the length of time individuals lived in their current communities. The data collected represent what people were willing to express on Twitter. Twitter users are not representative of the US population, with younger populations being over-represented on Twitter as compared with the US population . HoweverWhile the sentiment analysis represents a substantial contribution to the creation of an area-level measure of racial sentiment, there are important limitations to sentiment analysis. The sentiment analysis used the entire tweet to assess the sentiment or emotional tone of the tweet rather than focusing on just the racial terms mentioned in the tweet. Similarly, coders, who manually labeled tweets to provide training data for the machine learning algorithm, labeled the emotional tone of the tweet as a whole. Thus, it is possible that while the tone of the tweet may be negative, the race or ethnicity referenced in the tweet may not be the subject of that negativity, which was the case in many of the tweets. Additionally, the emotional tone of the tweet may display a negative sentiment, but it does not necessarily express a prejudiced statement, which was also common in our data. Our prior research indicated that prejudiced tweets can be distinct from the sentiment of the tweet . For somThis study contributes to the nascent body of literature on place-level indicators of racial attitudes and bias. While not comprehensive, our measure of racial sentiment may represent a signal of the broader social and cultural context in which mothers reside. Data collected from Twitter may be unique as compared with what can be obtained from traditional surveys on racial attitudes or bias. Social media can represent a rich source of timely data regarding perspectives on a range of topics, including racial attitudes. This study revealed that the racial climate toward minorities may have implications for racial or ethnic minorities, as well as the entire population. The promotion of a social climate of respect, positivity, and inclusion may have beneficial health impacts for birth outcomes in the population at large.


During this period, we observed modifications in volume, shape, and sulci configuration. Our findings indicate that the major white matter tracts follow four waves of development. The first wave (13 GW) involves the corpus callosum, the fornix, the anterior commissure, and the uncinate fasciculus. In the second one (14 GW), the superior and inferior longitudinal fasciculi and the cingulum could be identified. The third wave (17 GW) concerns the internal capsule and in the fourth wave (20 GW) all the major tracts, including the inferior-occipital fasciculus, were depicted. Our results suggest an earlier development of the white matter tracts than estimated by DTI tractography studies. Correlating anatomical dissection with tractography data is of great interest for further research in the field of fetal brain mapping.Neuroplasticity is a complex process of structural and functional reorganization of brain tissue. In the fetal period, neuroplasticity plays an important role in the emergence and development of white matter tracts. Here, we aimed to study the architecture of normal fetal brains by way of Klingler’s dissection. Ten normal brains were collected from  From ontogeny to adulthood, the brain remains the most plastic structure of the body. The formation of its cortical areas and white matter fibers is characterized by neuroplasticity. This process can be defined as the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections. Since all the brain complexity stems from the neural tube, the fetal period corresponds to the most elaborate process of neuroplasticity, which is well regulated by genetic and molecular mechanisms.The white matter tracts have recently come to the attention of researchers looking for a better understanding of brain functionality. The connectivity of the brain still remains a mostly uncharted area. The bundles of fibers which form the white matter can be classified in commissural , projection , and association fibers . Their development begins in the embryonic period and is consolidated postnatally, when myelination is still ongoing. Structural refinements in the architecture of the white matter were observed even in adolescence .Recent studies have shown some of the signaling pathways involved in the development of white matter. The tracts form along the path traced by the “pioneer axons” which are guided by various molecular cues . This isin utero. However, the major drawback of these techniques is the high number of false positive fiber tracts returned (The development of fiber tracts has been studied using diffusion tensor imaging (DTI) tractography and increasingly complex imaging techniques. Used in the context of fetal MRI, tractography has the potential to diagnose anomalies in the development of the white matter tracts returned , which mTo improve the further research on the white matter, we used the classic dissection approach described by The present study is the first one to use Klingler’s dissection technique on fetal brains with the purpose of evaluating the dynamic evolution of the white matter tracts. Our approach can be further developed by association with other imagistic and molecular techniques.The study was conducted on 17 normal brain hemispheres aged between 13 and 35 gestational weeks (GW). The ages of the brains were: 13, 14, 17, 20, 23, 32, 34, and 35 GW. All the brains were collected from spontaneous intrauterine death cases, caused by non-cerebral pathologies. Fetal necropsies were performed by specialized pathologists following standard protocols for intrauterine death diagnostics. The gestational age was determined based on the day of the last menstruation of the mother and on fetal ultrasonographic evaluations performed by obstetricians during the pregnancy. The brains were collected in the first 1 to 6 h after the extraction of the fetuses and they were preserved in 4% formaldehyde solution by way of intravascular perfusion and post fixation.Some specimens included both hemispheres of the brain but some of them consisted of only one hemisphere, the other half was being utilized to histopathological examination. The study protocol was approved by the Ethics Committee of our University.For the tridimensional white matter dissection, the brains were prepared according to the Klingler method . They wein utero imaging investigations, the latero-medial and medio-lateral stepwise fiber dissection protocols used previously by our group in the adult human brain . The cortex on the medial surface of the hemisphere was removed first and the fibers of the cingulum where exposed along their trajectory (Step 2). Then, the cingulum was removed and the underlying corpus callosum was dissected (Step 3). At this stage, the hemisphere was switched to its lateral surface (Step 4) and the cortex on this surface was removed (Step 5). The long association fascicles that were present at the particular gestational age were exposed and removed one by one in a latero-medial order. Depending on the degree of development, the insular cortex or the sylvian fissure were used as principal landmarks for the dissection of the most superficial tracts, namely the uncinate fasciculus on the ventral part and the superior longitudinal fasciculus on the dorsal side of this region (Step 6). The inferior longitudinal fasciculus was identified as being located between the previous tracts (Step 7). The protocol continued with the removal of the layer formed by these fascicles and with the dissection of the successive white matter/gray matter layers underlying the insular cortex  resulting in the exposure of the fronto-occipital fasciculus (Step 8). By removing this fasciculus, the lateral surface of the internal capsule was reached (Step 9). At this point, the hemisphere was switched again on its medial side and the dissection of the pillars of fornix situated under the lateral wall of the third ventricle was performed (Step 10). In the situations where it was not too small, the trunk of the anterior commissure was identified immediately anterior to the pillars of fornix and its anterior projections were followed in the orbitofrontal region (Step 10’). Its posterior projections were followed as they ran on the lateral surface and they were removed in order to completely uncover the optic radiations (Step 10”). Next, the body of corpus callosum was lifted and the frontal horn of the lateral ventricle was opened. The head of the caudate nucleus and the body of fornix were visible at this stage of the dissection (Step 11). The columns of fornix where followed in the temporal horn of the ventricle, which was also opened, and the fornix was extracted together with the hippocampus uncovering the dorsal surface of the thalamus and the body and tail of the caudate nucleus, which were removed in the final step of the dissection in order to expose the medial surface of the internal capsule (Step 12).During the interval of development that was investigated here, 13–35 weeks of gestation, the volume of the brain increases almost three times . The shape of the brain evolves from a globular one  to an ovoid . The aspect of the cortex is flat between 13 and 17 weeks of gestation. The primary sulci appear at 20 weeks and the secondary and tertiary sulci are observed by the gestational age of 34 weeks , 2.On the medial surface of the hemisphere , the calFor a white matter tract to be identified at a certain age by fiber dissection, the following conditions had to be fulfilled: (I) the tract should have been in the appropriate position relative to the surface of the brain; (II) a consistent bundle of fibers with parallel directions could be followed for at least one centimeter on the predicted trajectory of the tract and (III) the consistency of the fibers, subjectively assessed by the dissector based on the resistance they opposed to the dissection instrument, should have been greater than that of the tissues surrounding it. Based on these criteria nine fiber tracts have been identified, which cover the major fasciculi in the human brain.According to the gestational ages at which they could be identified, there are four waves of emerging white matter tracts . The firThe corpus callosum is a commissural tract located in the superior half of the hemispheres. It connects the following areas on the two hemispheres: frontal pole, prefrontal area, premotor area, motor area, somatosensory area, superior parietal lobe, inferior parietal lobe, occipital lobe and posterior temporal lobe.It is already recognizable on the medial surface of the hemispheres . Its dorThe fornix is a mostly commissural tract that also contains association fibers. It encircles the thalamus, has close relations with the cerebral ventricles and the caudate nucleus, and connects the hippocampus, amygdalae, mammillary bodies, and the accumbens nuclei.in situ only partially with our protocol because of the tract’s deep position in the lateral ventricle. The pillars of fornix and the anterior part of its body can be visualized by removing the ependymal layer of the third ventricle , connecting the inferior frontal gyrus (Broca area) to the posterior and middle thirds of the superior temporal gyrus (Wernicke area – Word Form Area), middle temporal gyrus, and the middle third of the inferior temporal gyrus and a more superficial indirect component, the anterior and the posterior tracts, connecting the inferior frontal gyrus with the inferior parietal lobule (Geschwind area) and the inferior parietal lobule with the posterior portion of the superior temporal gyrus, respectively.It can be dissected by removing the periinsular cortex in the early stages, or the frontal and temporal opercula in the later stages of development . By 14 wThe inferior longitudinal fasciculus is an association tract which occupies a baso-lateral position in the brain, running from the temporal pole to the visual association areas in the occipital pole. It is the most superficial tract of the temporo-occipital region.For the dissection of the inferior longitudinal tract, the cortex and the short association fibers of the inferior portions of the temporal and occipital lobes have to be removed. The tract can be identified starting with 14 weeks of gestation . With thThe cingulum is the only major association tract located on the medial region of the hemisphere. It encircles the corpus callosum and the hippocampus and connects the cingulate gyrus, the parahippocampal gyrus, the uncus, the amygdala, and the medial surfaces of the frontal and parietal lobes.The dissection of the cingulum involves the removal of the cortex of the medial and basal surfaces of the cerebral hemispheres. It can be identified as early as at 14 weeks of gestation . Its terThe internal capsule is a region in the center of each cerebral hemisphere where all the projection fibers converge in their path from/to the cortex, thalamus, basal ganglia, brainstem nuclei and spinal cord. Its fibers are in close vicinity to the basal ganglia, the thalamus and the association tracts, and are intersected perpendicularly by the callosal fibers.To expose this tract, either from the medial surface or from the lateral surface of the hemispheres, one needs to remove all the other gray matter and white matter structures of the brain. The tract meets all the identifying criteria at 17 weeks of gestation although vertical fibers can already be seen at 13 weeks of gestation. These are considered to belong to the radial glia . The lenThe inferior fronto-occipital fasciculus is the deepest located association tract. It connects the inferior frontal gyrus, the middle frontal gyrus, the frontal pole, the orbitofrontal gyri, the superior parietal lobule, the occipital pole, and the visual association areas.It can be exposed after the extraction of the cortex of the lateral surface of the brain, followed by the short association tracts, the superior longitudinal fasciculus, the insular cortex and the claustrum. The fiber dissection technique allows the identification of this tract starting with 20 weeks of gestation . In the In the present study, we have investigated the trajectory and architecture of the cerebral white matter by means of gross dissection.Our findings indicate that the major white matter bundles emerge in four waves of development. The first wave consists of tracts already present in our youngest specimens, namely at 13 GW, and includes: the corpus callosum, the fornix, the anterior commissure and the uncinate fasciculus. What is gained by employing this technique is an even earlier observation of the fascicles compared to what can be accomplished through traditional tractography. While the fornix and the anterior commissure can be observed by DTI in 13 weeks specimens , the uncThe second wave involves fibers observed at 14 GW, such as the superior and inferior longitudinal fasciculi, as well as the cingulum. Again, our results suggest that these tracts appear earlier than estimated by DTI. Data from the literature indicates that the inferior longitudinal fasciculus can be identified by DTI at 19 weeks, the cingulum can be traced at 17–19 weeks and the superior longitudinal fasciculus cannot be appreciated even at birth . AlthougThe internal capsule fulfilled our tract identification criteria at 17 weeks of gestation, accounting for the third wave. Although some vertical fibers were identified using Klingler’s dissection at 13 weeks, they did not meet two of our three criteria , so we considered them to belong to the radial glia, which is known to have the same position . DTI stuFinally, all major tracts, including the inferior fronto-occipital fasciculus, can be well identified at 20 GW, thus completing the fourth wave of development. DTI studies can trace the inferior fronto-occipital fasciculus in 19 weeks brains, along with the inferior longitudinal fasciculus and the cingulum . HoweverThe age differences in our study compared to previous ones using different methods show that the order of development of the white mater tracts is still controversial. The fact that gestational age is always estimative and that the criteria for its approximation may differ from one study to another can play a role in these discrepancies. Moreover, Klingler’s dissection consists of subjective observations made by the dissector and cannot always follow a strict protocol . AnotherFrom a clinical point of view, the developmental waves described in this study can be linked with possible neurocognitive implications of lesions occurring at particular gestational ages based on the current knowledge on the cognitive roles played by different tracts in the adult. Starting with the first wave of development (13 weeks), we can notice that it lays the foundation of social interaction and memory. Thereby the corpus callosums functions are: interhemispheric transfer of information, integration of inputs from one or both hemispheres, facilitation of some cortical activities, and inhibition of cortical functions . The forThe second and fourth waves are mostly involved in language formation. The tracts involved can be divided into two streams: the dorsal stream, involving the arcuate fasciculus, which processes the phonological aspects of language , and theRegarding the cingulum, it has been demonstrated that a higher microstructural organization of this fascicle is linked with a higher cognitive performance . It is iThe third wave is responsible for the development of the internal capsule, which provides sensorimotor connections .The objective of the study was to establish the brain architecture at different gestational ages, opening a path for further research on the fetal brain architecture in more complex brain abnormalities. Neuroplasticity can determine fibers rearrangement in different neuro-developmental pathologies , leading to normal functioning brains . Having All datasets presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca. The Ethics Committee waived the requirement of written informed consent for participation.RP, SS, and BS: study design. SS and FS: brain collection. BH, MM, ABo, and RP: dissections. RP: image processing. BH, RP, MM, ABo, ABu, and SS: manuscript preparation. SS, RP, BH, MM, ABo, ABu, BS, IS, and C-MM: manuscript review. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Is the incidence of birth defects and childhood cancer among children conceived via in vitro fertilization different from that among children conceived naturally?In this population-based cohort study of 1 053 415 children in 4 states, the presence of a birth defect and the number of birth defects were associated with an increased risk of childhood cancer. The increased risk was 2-fold higher for children conceived via in vitro fertilization than for children conceived naturally.In this study, cancer risk increased in the presence of birth defects at a higher rate in children conceived via in vitro fertilization than in children conceived naturally; further study is warranted. Children with birth defects have a greater risk of developing cancer, but this association has not yet been evaluated in children conceived with in vitro fertilization (IVF).To assess whether the association between birth defects and cancer is greater in children conceived via IVF compared with children conceived naturally.This cohort study of live births, birth defects, and cancer from Massachusetts, New York, North Carolina, and Texas included 1 000 639 children born to fertile women and 52 776 children conceived via IVF (using autologous oocytes and fresh embryos) during 2004-2016 in Massachusetts and North Carolina, 2004-2015 in New York, and 2004-2013 in Texas. Children were followed up for an average of 5.7 years . Data analysis was conducted from April 1 to August 31, 2020.Conception by IVF for state residents who gave birth to liveborn singletons during the study period. Birth defect diagnoses recorded by statewide registries.Cancer diagnosis as recorded by state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for birth defect–cancer associations separately in fertile and IVF groups.A total of 1 000 639 children  were in the fertile group and 52 776 were in the IVF group . Compared with children without birth defects, cancer risks were higher among children with a major birth defect in the fertile group  and IVF group . The HR of cancer among children with a major nonchromosomal defect was 2.07  among children in the fertile group and 4.04  among children in the IVF group. The HR of cancer among children with a chromosomal defect was 15.45  in the fertile group and 38.91  in the IVF group.This study found that among children with birth defects, those conceived via IVF were at greater risk of developing cancer compared with children conceived naturally. This population-based cohort study assesses the association between birth defects and cancer risk among children conceived via in vitro fertilization vs children conceived naturally in 4 US states. A growing body of literature reports an association between birth defects and the development of cancer, but this association has yet to be evaluated among children conceived via IVF.6 In this study we present the results of a population-based linkage of IVF births, birth defects, and childhood cancer in 4 US states to estimate the risk of cancer among children with birth defects conceived through IVF vs those conceived naturally.Births conceived with in vitro fertilization (IVF), the ex vivo manipulation of both sexes’ gametes to achieve conception, accounted for 2% of all US births in 2017.5 The remaining data  were obtained in the current study of the risk of birth defects in assisted reproductive technology. New York, Texas, Massachusetts, and North Carolina were chosen for the current study because they are large and ethnically diverse, with birth defect registries using the same case definitions and data collected. These 4 states ranked second, third, sixth, and twelfth in highest number of annual IVF births in the United States, respectively, in 2016, with IVF births accounting for 3.0%, 1.5%, 4.7%, and 1.4% of all births in each state.7 This study was approved by the institutional review boards at Michigan State University with a waiver of informed consent as research not involving human participants, as well as the institutional review boards at the University of Michigan and the 4 study state departments of health. This study followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.9This study linked 2004-2016 birth certificates data to birth defects registries, cancer registries, and the national IVF database, the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System (SART CORS), in 4 US states . Data from birth certificates (2004-2013) linked to the SART CORS and the cancer registries were collected in a study of the risk of childhood cancer and IVF.2 The Society makes data available for research purposes to entities that have agreed to comply with SART research guidelines. Patients undergoing IVF at SART member clinics sign clinical consent forms that include permission to use their data for research with appropriate provisions for safeguarding confidentiality. Data are submitted by individual clinics and verified by the medical director of each clinic. Approximately 10% of the clinics are audited each year to validate the accuracy of reported data.2 During each audit visit, data reported by the clinic are compared with information recorded in the medical record; most data fields have discrepancy rates less than 2%. IVF cycle data reported to the SART CORS is available within 24 months after the close of the cycle year. Ninety percent of SART CORS cycles resulting in a live birth to residents of the 4 study states during the study period linked to their respective birth certificates; all other live births were classified as fertile (non-IVF).The SART CORS database contains comprehensive information on IVF procedures from more than 83% of all clinics providing IVF and more than 92% of all IVF cycles in the US. Data were collected and verified by SART and reported to the Centers for Disease Control and Prevention (CDC) in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493).8 Children born in 2004-2013 were initially linked to the state cancer registries through December 2013  and then relinked to the registries through December 2016 (Massachusetts) or 2017 (New York) to identify additional cancers. Children born in 2014-2016 were linked to the state registries through December 2016 (Massachusetts and North Carolina) or 2017 (New York). All of the cancer registries participating in this study follow the same standards in terms of 90% or greater ascertainment by 12 months and 95% or greater by 24 months of the close of the diagnosis year, which is when most registries construct analytic files and publish incidence rates. All study children were also linked to state death records.Each of the 4 study states maintains a high-quality cancer registry with data going back at least as far as 2004, our earliest year of cancer linkage. All of the study states’ cancer registries are part of the CDC-funded National Program of Cancer Registries. In addition, all 4 study state’s cancer registries were certified at the highest levels for data during the study years. The North American Association of Central Cancer Registries (NAACCR) is the collaborative organization for cancer registries that coordinates standards for cancer registries and annually certifies member registries as Gold or Silver according to evaluations of completeness, accuracy, and timeliness. Massachusetts and New York were certified as Gold for their incidence data from 2004 to 2017, Texas was certified Gold for their 2005-2017 data, and North Carolina was certified Silver for their 2005 data and Gold for their 2004 and 2006-2017 data. Cancers were categorized according to the International Classification of Childhood Cancers, third edition.International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding  and code birth defects using the CDC coding system adapted from British Pediatric Association codes, which is more specific for birth defects than Maternal race and ethnicity were obtained from the birth certificate; maternal race and ethnicity were also the assigned race of the infant, a rule that was initiated in 1989 by the National Center for Health Statistics. Classification of race and ethnicity was either self-reported by the mother after delivery or by the birth registrar in the birthing facility and reported to the state vital records, as per the local and state policy. Race and ethnicity were included as a factor in this study because of known associations with birth defects and cancer.5 Briefly, IVF cycles to residents of the study states resulting in a live birth during the study period were linked to their birth certificates, and non-IVF births were selected in a 10:1 ratio and within the same 4- to 6-week period as the IVF births. For this study additionally the IVF-birth certificate data and the fertile-birth certificate data was linked to each state cancer registry and birth defects registry through 1 year of age; study children were relinked to their state’s cancer registry in later study years to identify cancers diagnosed after infancy. All data were deidentified before transfer to the investigators.The SART CORS database, linkage of data from the SART CORS database to the birth certificate, cancer registries, and death certificates, and transfer of the deidentified data to the investigators has been described previously.Birth records with gestational age less than 22 weeks or birth weight less than 300 g were excluded because such births are considered nonviable. Because IVF is rare for a mother younger than 18 years of age, we did not request to include parents aged less than 18 years in the study; therefore, those with ages less than 18 years were excluded; in addition, mothers whose ages were not specified were also excluded. Among the IVF births, only those conceived with autologous oocytes  and fresh embryos (not thawed) were included because these IVF conditions are most parallel to the conditions of the fertile births. The few infants where sex was not specified were also excluded. Births were categorized as fertile and IVF. The number of defects in a child was classified as none, 1, 2, or 3 or more. The analyses in this study are limited to singleton births because there were fewer twin births and higher multiple births and, as a result, too few infants with major malformations to provide stable estimates of cancer incidence.P = .04. The probability of 1 or more tests will be significant when 12 random tests are conducted is 0.46. In addition, we repeated the models without covariates and obtained similar results. All analyses were performed using SAS version 9.4 (SAS Institute). Associations were statistically significant at P < .05, and all P values were 2-sided.Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% CIs for childhood cancer risk separately in IVF and fertile groups. We also fit models to all participants that included an interaction between group and major defect and a variable defined by all 4 combinations of group and presence or absence of a major defect. Months from birth (expressed in years) were analyzed as the time scale and adjusted for parental ages, maternal race and ethnicity, infant sex, and state of birth. Covariates were selected based on known associations with cancer and/or birth defects risks. Each child was censored at the time of cancer diagnosis, death, or end of follow-up . To validate the assumptions of the Cox regression model, we tested the proportionality assumption for each covariate in the models with major defects. There are 2 models with 6 covariates each. All but 1 test was not significant; 1 for sex of the child had a The study population included 1 000 639 children born to fertile women (18 435 children with and 982 204 children without a major birth defect) and 52 776 children born to IVF-treated women (1263 children with and 51 513 children without a major birth defect). Among children in the fertile and IVF groups, 51.3% in both groups were male; 25.0% and 9.8% Hispanic, 69.7% and 81.3% White, 15.5% and 5.8% black, 7.8% and 10.3% Asian, 7.0% and 2.6% other or missing; 32.7% and 34.9% were born 2004-2008, 38.3% and 39.6% were born 2009-2012, and 29.0% and 25.5% were born in 2013-2016. Descriptive characteristics are presented in The associations between birth defects and cancer risk are presented in 21=5.52; P = .02). This significance indicates that the difference in HRs between cancer with a major defect and cancer without a major defect is associated with the group; ie, the 2 groups are not parallel. Therefore, we fitted a model with 4 levels defined by the combinations of groups (fertile or IVF) and the presence or absence of a major defect .10 The 2.07-fold increase in cancer risk among children with major nonchromosomal birth defects in the fertile group that we report is consistent with the other US population-based cohort studies that linked to state birth defect and cancer registries, with increases ranging from 1.58-fold11 to 2.0-fold12, 2.5-fold,14 to 2.86-fold.15 The finding of a 15.45-fold cancer risk among children with chromosomal birth defects in the fertile group is also consistent with the point estimates and 95% CIs of previous reports, ranging from 11.6  to 15.52 .15 The finding that children conceived via IVF with birth defects have substantially higher cancer risks adds to this growing literature. It has been hypothesized that embryonal tumors may be associated with developmental disruption, sharing pathophysiologic features with birth defects.14 In his 2-hit theory, Knudson suggested that cancer is caused by two variational  events: in the hereditary form, 1 variant inherited from germinal cells and the second from somatic cells; in the nonhereditary form, both variants occur in somatic cells.17 With IVF conception, the first hit may be related to parental factors underlying their fertile status or aspects of infertility treatment, and the second hit the occurrence of a birth defect.More than 80 studies have reported an association between birth defects and cancer, based on a variety of study designs, sample sizes, and data sources.18 In brief, epigenetic alterations cause changes in gene expression that are heritable during cell division but do not result in changes to the underlying DNA sequence. DNA methylation and genomic imprinting, two important epigenetic alterations, undergo extensive reprogramming during normal gametogenesis.19 IVF conception has been hypothesized to lead to variations in this reprogramming, which could ultimately result in both birth defects and cancer.18 A recent assessment using data from national health registries in Denmark and Finland demonstrated an association between IVF conception and imprinting disorders.20 Specifically, children conceived via IVF were 2.84 times  more likely to develop Beckwith-Wiedemann syndrome compared with naturally conceived children. Notably, Beckwith-Wiedemann syndrome is an imprinting disorder characterized by overgrowth and birth defects , as well as an increased risk of developing several types of embryonal tumors, including Wilms tumor.21 This finding provides evidence of the role of epigenetic alternations on the co-occurrence of birth defects and cancer among children conceived via IVF.22Several potential mechanisms could be factors in cancer risk in children conceived via IVF with birth defects. For example, a growing body of evidence suggests that IVF is associated with epigenetic alterations.23 Germline de novo variants have been reported to cause several genetic diseases, including birth defects  and some childhood cancers, including neuroblastoma.26 While more work is warranted to understand the role of de novo germline genetic variants in the interface between birth defects and childhood cancer, this remains a plausible mechanism as these events are also more likely in children conceived via IVF.27Another potential genetic phenomenon that could explain the role of IVF in the association between birth defects and childhood cancer is germline de novo variation. De novo genetic variation has been demonstrated in IVF-conceived embryos, and whole-genome sequencing has been proposed as a method for detecting these events in embryos for preimplantation genetic diagnosis.28 Additional years of follow-up, through ages 10 to 14 years and 15 to 19 years, when cancer rates increase to the high levels observed during infancy, may offer a broader picture of this association. The strengths of this study include its population-based design and contemporary time period, inclusive of the years when IVF has been widely used in the US. The 4 study states include racially and ethnically diverse populations, with high linkage rates, and birth defects and cancer registries that use similar case definitions. The data on infertility, birth defects, and cancer were independently collected, minimizing ascertainment bias. In addition, we limited our analyses to singletons because of the known higher risk of birth defects in twin births and higher order multiple births.This study has limitations. The primary limitation of this study is that we were not able to explore specific birth defect–cancer combinations due to small sample sizes of children conceived via IVF with major birth defects and cancer. Another limitation is that the follow-up period averaged 5.8 years, when the incidence of childhood cancer is at its lowest rate.This study found a stronger association between birth defects and cancer in children conceived via IVF vs children conceived naturally. With IVF births rising worldwide, further investigations into these associations are warranted.