One needs to recognize that the perinatal period is a vulnerable time where negative attitudes, words and actions can have an emotionally damaging effect on birthing women, who are especially sensitive to how they are treated, because of their high oxytocin levels. This case report depicts a traumatic birth in which the mother was needlessly separated from her baby and also harshly treated by the personnel, which had an emotionally devastating impact on the mother/baby relationship. This case report will demonstrate how psychotherapy was used to heal this distress. In my work as a psychotherapist, with a specialty in perinatal problems, I am often helping people work through a traumatic or disappointing birth experience. Women are especially vulnerable during the perinatal period because the body, mind and spirit are “wide open” to be able to birth a human being physically as well as to “take in” the baby psychologically. The high levels of oxytocin contribute to this openness, which may explain why women are so susceptible to both positive support and negative experiences during this period . The folA client, pregnant with her second child, appeared for therapy because she was having disciplinary trouble with her first child, and had unresolved distress, as she had been traumatized by the unexpected events of his birth. This case demonstrates how negative experiences in connection with birth may cause a long-term negative impact on the mother’s view of the baby and her future confidence in mothering. In working with this particular client, I created a safe setting for the patient by using Active Listening and then used a combination of methods such as Age Regression, Ego State Therapy, Affect Bridge, and Reframing of Meaning  in orderAs a young girl, Mrs. M loved babies and became a favorite of neighborhood families with new babies when she offered to play with them. When she was old enough, she became a trusted babysitter. After college she became a postpartum doula and was becoming a breastfeeding consultant. Her goal was to help other women with breastfeeding in the immediate postpartum period. She always planned to breastfeed her own children one day.She married a kind man who also believed in the importance of breastfeeding. When pregnant with their first baby, she arranged a home birth with a home birth midwife in hopes of avoiding unnecessary interventions from a hospital. She planned to have the baby skin-to-skin right after birth and looked forward to the “breast crawl”  which shAs soon as she recovered from the surgery, she called to the nurse and asked for her baby. She believed that even with a cesarean section she could have the baby as soon as she felt ready, and that the baby would be placed in such a way to avoid the operative area. However, unbeknownst to Mrs. M, the protocol of that hospital did not permit women to have the baby until several hours after recovery from major surgery.She pleaded with the nurse, “Please! Please! Bring me my baby.” The nurse refused. Eventually, after Mrs. M became very agitated and upset, continuing somewhat loudly calling for her baby, the nurse said to her, “You seem to be having a psychological episode, you have to wait.” Mrs. M immediately quieted and stopped any voice pleas, fearing that if she protested maybe the nurse would call (Child Protective Services) and take the baby away. When Mrs. M eventually got the baby, she had much difficulty managing him and became angry at the baby .She nursed him, but it was not a rewarding experience.Let us look at the physiology as well as the psychology of what is happening here. Oxytocin levels rise during pregnancy  and Mrs.Oxytocin levels are affected not only by labor, birth, and breastfeeding but also by kind looks, voice, and feeling being attuned to or cared about and being encouraged vs. being ignored, shamed, or frightened. These subtle events have enormous effects in particular during birth when mothers are having high oxytocin levels and become extra sensitive and open to both positive and negative environmental cues. Together the negative experiences decreased the positive effects of oxytocin normally occurring in connection with birth and consequently reducing the development of calmness, rewarding experiences and love for the newborn. In these situations, the effect pattern of oxytocin may even turn into defense and aggression against those who are experienced as intruders.I met Mrs. M when she was pregnant with her second child and came to prepare for her second birth. She arrived with her three-year-old little boy, who was very rambunctious. She wanted to talk about her son’s birth and described what a difficult child he was. He would not mind her, he would not respond to any actions of affection, like sitting on her lap. He did not play with her, as opposed to being different at his nursery school or with his father where he acted with more ease of interaction.In my therapy work I created a situation in which Mrs. M felt secure and safe. One of the keys to healing is to create an atmosphere of open, thoughtful listening . Some ofAs I took her history and listened to her story, she revealed how distressing the birth of her son had been . I wanteWhen she got to the memory of being angry at her little baby boy, I asked her to imagine putting another face on the baby . She immShe returned ten days later to plan for the second birth. Then she said something surprising: “You can’t imagine how different my little boy is. He is so loving, he wants to play with me, to sit on my lap, to hug me, to have me read him a story. It is an amazing change.”It is interesting to notice how powerful the oxytocin effect is in response to social interaction  emanatinThere are many therapeutic methods to help heal these events. But it is especially useful with imagery to tap into the emotions, the beliefs and the body experiences of the negative event and create the potential for healing by shifting to a positive reframing of the event. If one can recreate the preferred reactions or treatment, one can start to loosen or eliminate the original negative emotional effects of the experience. Human beings are open to healing after danger has passed.As a therapist, in the session or in an ensuing session, I always explore with the client any earlier thought, emotion, or experience where these emotions may have originated or been experienced. For example, if a previous event or experience may have laid the groundwork for being disregarded, the client becomes more susceptible to reacting in a similar way.In Mrs. M’s case, she shared that the nurse’s behavior reminded her of how she was treated as a little girl, when she was trying to tell her mother that she was being abused by a cousin and her mother would not listen to her . She recMrs. M’s story depicts how the cesarean section, the separation from the baby, as well as the insensitivity and a lack of awareness from the staff, affected her emotional and physical experience of birth. The nurse’s lack of training in communication skills was hurtful to Mrs. M as an adult but also triggered a childhood abuse memory .In every significant event in life, humans have many layers of history and experiences that can be triggered or activated in either a positive or negative manner. Of course, the nurse did not recognize the meaning of her behavior to this mother, but regardless of her lack of knowledge, sadly the nurse’s way of handling the situation created long term pain and disturbances in the relationship between the mother and her newborn. The therapy was helpful for Mrs. M and allowed a deeper opportunity for healing.Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.PK confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


It is important to assess the temporal reproducibility of circulating cytokines for their utility in epidemiological studies. However, existing evidence is limited and inconsistent, especially for the elderly population.Sixty-five elderly (mean age = 77.89 ± 6.14 years) subjects were randomly selected from an existing prospective cohort study. Levels of 41 cytokines in 195 serum samples, collected at three separate visits that were up to 15.26 years apart, were measured by the Luminex technology. The temporal reproducibility of cytokines was estimated by the intraclass correlation coefficient (ICC) calculated using a mixed-effects model. In addition, data analyses were stratified by the median (4.49 years) of time intervals across sample collection. Sensitivity analyses were performed when excluding subjects with undetectable samples.A total of 23 cytokines were detectable in more than 60% of samples. Fair to good (ICC = 0.40 to 0.75) and excellent (ICC > 0.75) reproducibility was found in 10  and 5  cytokines, respectively. The results were not changed dramatically in the stratification and sensitivity analyses.Serum levels of the selected 15 cytokines measured with Luminex technology displayed fair to excellent within-person temporal reproducibility among elderly population. Cytokines are secreted polypeptides or glycoproteins that regulate proliferation, apoptosis, and angiogenesis, and involved in the development and progression of various diseases . CytokinCirculating inflammatory molecules are widely used in epidemiological studies to investigate their association with chronic diseases –10. In sSeveral studies have explored the intra-individual temporal reproducibility of cytokines in humans  subjects, with 3 serum samples each. Results from this study will be useful to select appropriate cytokines as inflammatory biomarkers for elderly population in the future epidemiological studies.The Washington Heights-Inwood Community Aging Project (WHICAP) is an ongoing, prospective, population-based cohort study which is conducted to identify risk factors and biomarkers for aging and dementia. The sampling strategies, recruitment and examination methodology of WHICAP have been described previously , 25. ParFor the current study, we selected a total of 65 participants from the second and third waves of WHICAP who met the following criteria: (a) ≥ 3 blood samples donated at different visits, (b) large number of aliquots left, (c) without history of diagnosed dementia, and (d) complete information on ages at blood draw, sex, race/ethnicity and years of education. To ensure individuals with certain demographic characteristics to be included in this sample, we randomly selected subjects from each of the 24 strata, defined by sex , race/ethnicity , waves (1999 vs. 2009), and age groups (< 80 vs. ≥80 years). For each selected individual, we selected one serum sample from the baseline, the most recent, and a middle visit. With three repeated samples each for a total of 65 subjects, we had 80% power to detect acceptable ICC of ≥0.55 with narrow 95% confidence interval (CI) (< ±0.13), or to detect acceptable ICC of ≥0.40 with narrow 95% CI (< ±0.15).Peripheral venous blood samples were collected from the participants at the time of their health examination, and were stored at − 80 °C. Never-thawed serum samples were packed in dry-ice and sent to the laboratory for analysis. A panel of 41 inflammatory biomarkers were selected according to the results of previous literatures  were assigned a value of LLOD divided by the square root of two . ObservaDue to the skewed distribution, cytokine levels were natural logarithm (log)-transformed for approximately normal distribution. The characteristics of subjects were presented as mean [standard deviance (SD)] and number [proportion (%)] for continuous and categorical variables, respectively. The repeated measures correlation (95% CI) between different cytokines were estimated with the R package “rmcorr” which accounts for non-independence among measurements from the same subject .The intraclass correlation coefficient (ICC) was employed to quantify the temporal reproducibility of cytokines. The mixed-effects model, fitted by the R package “lme4” (version 1.1.21) , was est2) categories  at each visit, or by additionally adjusting for the time of day (ante meridiem or post meridiem) of blood sample collection. Sensitivity analyses were also conducted by the stratification of sex.To examine the impact of time intervals on the cytokine reproducibility, data analyses were performed by the stratification of median of time intervals between the 1st and 3rd measures. Besides, we also repeated analyses by excluding samples with undetected values (< LLOD or > ULOD), or by additionally adjusting for the baseline comorbidities including hypertension, diabetes and cardiovascular diseases, or by additionally adjusting for the body mass index .Participant characteristics are presented in Table p < 0.05)  of cytokines measured in all samples collected at three separate visits was ranked and presented in Fig. Stratification analyses were additionally conducted, dividing by the median (4.49 years) of time intervals between the 1st and 3rd blood samples Fig. . CompareAfter excluding the subjects with undetectable levels of cytokines, for the cytokines with detectable rates less than 100% Table , the resIn the present study of 65 elderly subjects from WHICAP study, we assessed the temporal reproducibility of serum cytokines in samples collected at three separate visits over a relatively long period of time. The results revealed that 15 out of 41 cytokines measured by the Luminex technology were detectable in over 60% of serum samples and had good reproducibility (ICC > 0.40), indicating that a single measurement of these biomarkers well captures the within-individual average level over a long period of time.By definition, ICC measures the inter-person variability relative to the total variability . The higThe temporal reproducibility of circulating cytokines measured by multiplex immunoassays or ELISA has been reported previously. Our findings are consistent with previous studies, supporting good to excellent ICC for IL-17 , G-CSF , 14, 17,The circulating levels of cytokines are reported to be influenced by various factors including demographics , life styles , medical treatment and circadian physiological variability , 34–36. n = 28) [An assessment of the long-term reproducibility of biomarkers is essential to explore the associations between biomarkers and diseases with long etiological windows, such as the neurodegenerative disease, cardiometabolic disease, or cancer. Majority of the previous studies evaluating the reproducibility of cytokines had used samples spanning a shorter period of time, such as 14 days , severaln = 28)  or restrn = 28) .With increasing time intervals, the temporal reproducibility of G-CSF kept good to excellent over 14 days (ICC = 0.50) , 7 monthIn the sensitivity analyses without undetectable values, we found similar, although slightly reduced, temporal reproducibility for most cytokines except for MCP-3 of which the ICC increased  and similar reproducibility of cytokines between older males and females in this study, which might be due to the depletion of sex steroid hormones in elderly subjects. Although it has been reported that BMI is significantly correlated with levels of cytokines in cerebrospinal fluid [Results from previous studies demonstrated sex differences in levels of some cytokines among young adults (median age = 22 years) , and in al fluid , and thaal fluid , we founThere were several advantages in this study. Few studies have examined the elderly population previously. Our study was performed among subjects with a mean age of 77.89 years, which provided useful information for the studies focusing on the health effects of cytokines among elderly individuals. In addition, a large panel of cytokines  were analyzed in the present study, while fewer (no more than 20) cytokines were investigated in some previous studies , 21, 37.Some limitations should be noted. Although this study represent one of the largest study in terms of number of cytokines measured, a total of 41 cytokines may still not give a comprehensive insight into the overall inflammatory profile, which may involve more cytokines , 45. BesIn conclusion, the present study demonstrated a good temporal reproducibility of 15 serum cytokines  which were measured by the multiplex technology. This suggests that a single measurement of the selected cytokines is likely to be suitable for characterizing the immune and inflammation status over a long period in the prospective epidemiological studies, especially for the elderly population.Additional file 1:Table S1. Assessments on the temporal reproducibility of circulating cytokines in previous studies. Fig. S1. Paired repeated measures correlation among different cytokines. Fig. S2. ICC (95% CI) of cytokines by excluding the subjects with undetectable values. Fig. S3. ICC (95% CI) of cytokines when additionally adjusting for baseline comorbidities. Fig. S4. ICC (95% CI) of cytokines when additionally adjusting for BMI categories. Fig. S5. ICC (95% CI) of cytokines when additionally adjusting for time of day of blood sample collection. Fig. S6. ICC (95% CI) of cytokines stratified by sex.


SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model.Babies born clinically Small- or Large-for-Gestational-Age  <10fetal = 0.75  and 1.32 ; ORmaternal = 0.81  and 1.17 , respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight . Higher maternal SBP GS was associated with higher odds of SGA P = 0.005.Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA  for a given gestational age are referred to as Small- or Large-for-Gestational-Age (SGA or LGA) respectively. These babies have higher risks of complications compared with babies with BW closer to the average. SGA and LGA babies may have experienced growth restriction or overgrowth, respectively, but may alternatively just be at the tail ends of the normal growth distribution. The relative proportions of normal vs. sub-optimal growth within these groups is unclear. To examine the role of common genetic variation in SGA and LGA, we tested their associations with a fetal genetic score (GS) for BW in 11,951 European-ancestry individuals. We also tested associations with maternal GS  for offspring BW, fasting glucose and systolic blood pressure, each of which influences fetal growth via the  A fetu or IUGR  or due t or IUGR . It is l or IUGR ,3 Howeve or IUGR , and the or IUGR , in addi or IUGR .th percentile) is associated with a higher risk of obstructed labour, which can lead to complications for both mother and baby, including injury, neonatal hypoglycaemia and even fetal death [At the upper end of the birth weight distribution, large for gestational age  of birth weight . The genOur analysis included a total of 6,769 term-born, singleton individuals with birth weight and fetal genotype data, from 2 studies, plus 5,182 mother-offspring pairs with maternal and fetal genotype data and birth weight from 2 further studies. Studies are described below, and summary data is shown in The ALSPAC  is a longitudinal cohort study covering the area of the former county of Avon, UK ,19. WomeThe Exeter Family Study of Childhood Health (EFSOCH) is a prospective study of children born between 2000 and 2004 in the Exeter region, UK, and their parents . After gThe Northern Finland Birth Cohort 1966 (NFBC1966) consists of mothers expected to give birth in the provinces of Oulu and Lapland in 1966 . Birth wst July 1985 and 30th June 1986. Birth weight data was collected from hospital records after delivery. Following genotype QC, 3742 children with genotype data were available, with 3248 of these having phenotype data [The Northern Finland Birth Cohort 1986 (NFBC1986) consists of individuals born in the provinces of Oulu and Lapland between 1ype data .Since different mechanisms may lead to SGA and LGA in term and preterm infants, and in multiple births, we focused on term, singleton infants. Birth weight Z scores were calculated using growth standards separately for each cohort. The UK 1990 growth standards , were usSince the use of growth standards results in different proportions of SGA and LGA by cohort, we conducted sensitivity analyses for comparison by defining SGA and LGA as the lower and upper 10% within each cohort. To do this, we regressed birth weight against sex and gestational age in term births , and then calculated residuals from the regression model. Individuals with the smallest and largest 10% within each cohort of this residualised birth weight variable were defined as SGA and LGA respectively. Controls for comparison with SGA were taken as birth weight > = 10%, and for comparison with LGA as birth weight < = 90%. To test the effect of including babies classified as LGA in the control group for SGA and vice-versa, we conducted sensitivity analysis restricting the control group for both analyses to 10%< = birth weight< = 90%.SNP is the total number of SNPs, wi is the weight for SNP i and gi is the genotype at SNP i. The same SNPs were included in the maternal and fetal GS. To calculate the SNP weightings, wi, since the cohorts used in our study were included in the largest available GWAS meta-analysis of birth-weight of Warrington et al [Genetic scores (GS) for birth weight, fasting glucose (FG) and systolic blood pressure (SBP) were calculated for all included individuals in each cohort, with higher GS corresponding to higher birth weight, FG or SBP, respectively. GS were calculated using Eq  where NSon et al , we re-ron et al . We thenon et al . These aFetal genotypes  were available in ALSPAC , EFSOCH (N = 612), NFBC1966  and NFBC1986 . Associations were tested between the fetal GS for birth weight and outcomes (SGA/LGA) using logistic regression. Maternal genotypes were also available in ALSPAC  and EFSOCH (N = 612). In these cohorts, associations between SGA/LGA and maternal GSs for birth weight were also tested in analogous regression models. Additional analyses including both maternal and fetal GS in the same regression model were performed to control for any residual correlation between maternal and fetal genotype. Results were meta-analysed using inverse variance weighted meta-analysis and heterogeneity between studies was assessed using Cochran’s Q test.s is the simulated phenotype for individual s, GSs is the simulated genetic score for sample s and xs is sampled from a normal distributionWe performed simulations to assess whether there was any evidence of deviation from an expected additive polygenic model, under which we would not expect additional genetic variation or non-additive genetic effects in the tails of the birth weight distribution. Briefly, within ALSPAC and EFSOCH we calculated the associations of each fetal and maternal SNP with birth weight within each cohort, adjusted for maternal or fetal genotype, respectively. We simulated genotypes under the allele frequencies observed within each cohort. GSs were calculated for each simulated individual using simulated genotypes weighted by the within-cohort effect sizes. Phenotypes were then simulated asi. The mean GS within each bin of simulated phenotype was calculated. Simulations were performed 10,000 times to generate a simulated expected distribution of GS under an additive polygenic model. The observed mean GS was then compared to the expected distribution and an empirical p value was calculated. These p values were then meta-analysed.Where rd centile [Bins used in this analysis are 10% and 3% bins. Bin sizes of 3% were chosen because the rates of adverse outcomes were previously found to be highest in babies below the 3 centile .In ALSPAC and EFSOCH, where maternal genotypes were available, we tested the associations between the maternal GSs for FG and SBP, with outcomes (SGA/LGA) using linear regression, including sex and gestational age as covariates to control for residual confounding. We included both maternal and fetal GS in the same regression model to control for the correlation between maternal and fetal genotype. Results were meta-analysed using inverse variance weighted meta-analysis.-32) and a lower odds of SGA . Similarly, the maternal birth weight-raising GS showed strong associations with LGA  and SGA . Using Cochran’s Q to test heterogeneity between studies we found no strong evidence of heterogeneity among studies across all meta-analyses run other than fetal GS for birth weight  and SGA (P = 0.008). These results were very similar to those of a sensitivity analysis of fetal GS conditional on maternal GS (and vice versa) in mother-child pairs  is shown in ld pairs , indicatld pairs . Resultsld pairs .fetal = 0.001, Pmaternal = 0.001). Repeating the analysis using 3% bins showed evidence of deviation in the lowest 3% bin for fetal birth weight GS (P = 0.0142). The maternal birth weight GS showed strong evidence of deviation in the 3–6% bin (P = 0.002), and weak evidence of deviation in the lowest 3% bin  we identified evidence of deviation from the expected additive polygenic model in the lowest 10% bin of the phenotype distribution . We saw some evidence of a lower maternal GS than expected in the top 10% group  but in the top 3% of the phenotype distribution there was no evidence of deviation , but some evidence of a lower maternal GS than expected in the 88–91% group   . This ef-3) . Sensiti-3)  suggestiWe have shown that common birth weight-associated genetic variation in both the mother and the fetus contribute to the probability that term infants will be born small or large for gestational age. While these results indicate that a large proportion of those infants classified as SGA/LGA represent the tail ends of the normal distribution of birth weight, we also found some evidence of an excess of individuals with a higher GS for increased birth weight than expected under an additive polygenic model in the bottom 3% of the birth weight distribution.rd centile [The terms IUGR and SGA are often used interchangeably , which c centile .We observed a higher GS than expected in the bottom 3% of birth weights, indicating that this group contains a proportion of babies whose birth weights are smaller than would be expected given their genetics. The demographics of the bottom 3% of individuals are presented in We found no evidence that the fetal GS for birth weight deviated from the polygenic model in the top 10% of the birth weight distribution, but there was some evidence of deviation for the maternal GS in this group. When we looked in smaller 3% bins, however, there was no evidence of association in the top 3% of the distribution. Overall our results do not suggest strong deviation from the polygenic model in babies with high birth weights, but we cannot rule out that smaller deviations would be detectable in a larger sample.Although we have used a population based definition of SGA, customised birth weight standards including maternal height, weight and ethnic group, for defining SGA have been shown to increase association between SGA classification and neonatal morbidity and perinatal death compared to using population based definitions , althougin utero environment contributes to variation in SGA and LGA risk independently of the fetal genotype. Previous studies have shown that maternal FG and SBP have causal effects on birth weight in the normal range [Fetal genetic effects on birth weight represent the constitutional growth potential of the fetus, while maternal genetics influence birth weight indirectly by modifying the intrauterine environment . The stral range ,16. In wal range ). A highThe current study has a number of strengths and limitations. Strengths include the fact that we have been able to construct independent maternal and fetal GS for birth weight. Separating maternal and fetal genetic contributions to birth weight is important because maternal and fetal genotype are correlated. This means that to avoid confounding, it is necessary to account for this correlation and obtain independent estimates of maternal and fetal genetic effects. To construct the GSs we chose to use only SNPs associated with the exposure  at a genome-wide threshold in their discovery samples. This decision ensures that the SNPs are robustly associated with the exposure and unlikely to also capture pleiotropic associations with other correlated phenotypes. In addition, the relationship between maternal and fetal genotype causes difficulty in estimating independent maternal and fetal genetic associations at each SNP. Limiting the SNPs to those with good power to estimate these independent associations improves the separation of maternal and fetal effects of the GSs. Both a limitation and strength of our study is that all of the cohorts used were of European ancestry. The GSs used in this study were discovered in studies of European ancestry and generalisability to studies of non-European ancestry has not been widely tested. In addition, well powered cohorts of mother-child pairs with genotype data as well as birth weight data are not currently available, meaning that the conclusions of the present study are not necessarily generalisable to individuals of non-European ancestry. As such there is a need for genetic studies in populations of ancestries other than Europeans. The use of only singleton, term babies in our analysis means that our results do not necessarily translate to pre-term babies or multiple births. While we had sufficient sample size to estimate the association of birth weight GS with SGA/LGA, the limited number of mother-child pairs which were available to examine the associations of FG and SBP GS with SGA/LGA meant that these estimates had large confidence intervals. Larger numbers of mother-child pairs would allow for more precise estimates, for example of the association of low SBP on LGA which has potentially clinically relevant implications. Although SGA and FGR are often used synonymously, there are differences between the terms. In our study do not have information required to distinguish FGR babies from SGA ones, meaning that we were not able to examine the association between BW GS and FGR specifically.Our analysis has shown that common birth weight-associated genetic variation contributes to the risk of babies being born small or large for gestational age. We found evidence of deviation from the polygenic model in the smallest 3% of babies, consistent with enrichment for fetal growth restriction in this group.S1 FigFraction of babies born SGA (left) or LGA (right) by percentile bins of fetal birth weight GS in ALSPAC .(PNG)Click here for additional data file.S2 FigFraction of babies born SGA (left) or LGA (right) by percentile bins of maternal birth weight GS in ALSPAC .(PNG)Click here for additional data file.S3 FigMean birth weight in ALSPAC by percentile bins of fetal (left) and maternal (right) birth weight GS .(PNG)Click here for additional data file.S1 TableSource PMID:31043758.(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 TableA) Associations between fetal and maternal birth weight GS and LGA/SGA. Fetal GS associations include ALSPAC, EFSOCH, NFBC86 and NFBC66. Maternal GS associations include ALSPAC and EFSOCH. Odds ratios represent the increase in risk per decile of birth weight GS. B) Associations between fetal and maternal BW GS and LGA/SGA, adjusted for maternal and fetal BW GS respectively in ALSPAC and EFSOCH mother-child pairs.(XLSX)Click here for additional data file.S5 TableA) Associations between Fetal and Maternal BW GS and LGA/SGA. The control group consists of babies with birth weight >10th centile and <90th centile. Odds ratios represent the increase in risk per decile of BW GS. B) Associations between Maternal FG and SBP GS, adjusted for fetal genotype, and LGA/SGA. The control group consists of babies with birth weight >10th centile and <90th centile. Odds ratios represent the increase in risk per decile of FG/SBP GS.(XLSX)Click here for additional data file.S6 TableA) Associations between Fetal and Maternal BW GS and LGA/SGA defined within each cohort. Odds ratios represent the increase in risk per decile of BW GS. B) Associations between Maternal FG and SBP GS, adjusted for fetal genotype, and LGA/SGA defined within each cohort. Odds ratios represent the increase in risk per decile of FG/SBP GS.(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 TableAssociations include mother-child pairs from ALSPAC and EFSOCH. Odds ratios represent the increase in risk per decile of FG/SBP GS.(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file.


Exposure to household air pollution (HAP) from cooking with unclean fuels and indoor smoking has become a significant contributor to global mortality and morbidity, especially in low- and middle-income countries such as Nigeria. Growing evidence suggests that exposure to HAP disproportionately affects mothers and children and can increase risks of adverse birth outcomes. We aimed to quantify the association between HAP and adverse birth outcomes of stillbirth, preterm births, and low birth weight while controlling for geographic variability. This study is based on a cross-sectional survey of 127,545 birth records from 41,821 individual women collected as part of the 2018 Nigeria Demographic and Health Survey (NDHS) covering 2013–2018. We developed Bayesian structured additive regression models based on Bayesian splines for adverse birth outcomes. Our model includes the mother’s level and household characteristics while correcting for spatial effects and multiple births per mother. Model parameters and inferences were based on a fully Bayesian approach via Markov Chain Monte Carlo (MCMC) simulations. We observe that unclean fuel is the primary source of cooking for 89.3% of the 41,821 surveyed women in the 2018 NDHS. Of all pregnancies, 14.9% resulted in at least one adverse birth outcome; 14.3% resulted in stillbirth, 7.3% resulted in an underweight birth, and 1% resulted in premature birth. We found that the risk of stillbirth is significantly higher for mothers using unclean cooking fuel. However, exposure to unclean fuel was not significantly associated with low birth weight and preterm birth. Mothers who attained at least primary education had reduced risk of stillbirth, while the risk of stillbirth increased with the increasing age of the mother. Mothers living in the Northern states had a significantly higher risk of adverse births outcomes in 2018. Our results show that decreasing national levels of adverse birth outcomes depends on working toward addressing the disparities between states. Adverse birth outcomes (ABO) including low birth weight (LBW), preterm birth, and stillbirths represent an unmet public health need in Nigeria. The World Health Organization (WHO) classes infant birth weight of less than 2.5 kg as LBW . LBW is Household air pollution (HAP) is a prominent global public health concern and is a leading environmental health risk globally . In 2016A primary source of HAP is the use of unclean fuel in cooking . Common Global evidence suggests an association of HAP with increased pregnancy complications , pretermHere, we explore the impact of HAP on adverse birth outcomes, such as stillbirths, pregnancy duration, and LBW in Nigeria. We will evaluate the geographic distribution of the association to identify regions with more significant HAP effects on births. This study will add to the existing literature by analyzing the impact of HAP on ABO in Nigeria while accounting for geographic heterogeneity.This study was based on the Nigerian Demographic and Health Survey (NDHS) phase 6 2013–2018 . NDHS is a cross-sectional nationally representative survey that has been conducted every five years in Nigeria since 2003 . The NDH2 , birth weight , and wealth quintiles. As some mothers were identified with multiple birth records, we also controlled for the mother’s effect on birth outcomes. This allowed us to account for the correlation between children with the same mother. We used the states to identify the effect of residence on adverse birth outcomes and the geopolitical regions as a fixed effect. See t-test to assess the difference in mother’s age across adverse birth outcomes. We used frequencies and percentages to describe categorical variables and means and standard deviations for continuous variables. We tested the association between cooking fuel type and categorical variables  using Pearson’s chi-square test or Fisher’s exact test and presented the estimated prevalence ratios (PR) with their 95% confidence interval (CI) ,40. We ui, A Bayesian approach to generalized structured additive regression (STAR) ,42,43,44h(.), such as the probit link for ease of interpretation,Using an appropriate link, A unique model was fitted for each adverse birth outcome: birth status, birth weight, and pregnancy duration. All outcome variables were analyzed using STAR multivariable logistic regression. Four models from simple to complex formulations were considered to select important predictors for each adverse birth outcome. Positive coefficients correspond to an increased risk for the modelled outcome. Model 1 includes the exposure variable, types of cooking fuel, and spatial components (unstructured and structured). The mother’s random effect was added to Model 1 to form Model 2. An additional nonlinear effect of the mother’s age effect was added to formulate Model 3. For the fourth model (Model 4), we included additional covariates, mother’s education, and geopolitical regions. We excluded household wealth quintiles from the multivariable Model 4, due to issues with collinearity with cooking fuel. The Bayesian models were fitted via Markov Chain Monte Carlo (MCMC), carrying out 25,000 iterations with a burn-in of 5000. Model selection was based on the smallest deviance information criterion (DIC); we also report the posterior mean of deviance . Lower wealth quintiles, older age, and low education levels were associated with a larger proportion of reported stillbirths (p < 0.001). On the other hand, smoking was not associated with birth outcomes , 97.2% were from households with mothers who used unclean cooking fuel and 2.8% of the pregnancies were from households with mothers who used clean cooking fuel . There woutcomes . About 7.6% (442/5815) of mothers who used unclean fuel in this study had children born with LBW compared to 6.5% (113/1746) of births from mothers who use clean fuel. However, there was no significant association between the type of cooking fuel and birth weight. The bivariate analysis shows that only the mother’s age and education level are independently significantly related to LBW . MothersPreterm births accounted for 1.0%  of births in this study. Surprisingly, the proportion of preterm births in households where mothers used unclean fuel  was significantly less than households where mothers used clean fuel . Wealth status, education levels, and mother’s age were significantly associated with preterm outcomes . Due to the small sample of mothers with smoking status, we focused only on cooking fuel as the main exposure variable. As shown in Results from Model 4 show that mothers using unclean cooking fuel are significantly at higher risk of stillbirth  after adjusting for age, education, and region . It alsoWe have shown that 89.3% of the mothers included in this study primarily used unclean fuel for cooking. This suggests that a substantial proportion of the population is still dependent on unclean cooking fuel for cooking in Nigeria. This is a significant public health concern due to the associated risks associated with unclean cooking fuel ,16. In tOur result indicates that HAP was associated with an increased risk of stillbirth but not for LBW and preterm birth. Overall, northern states had a higher rate of unclean cooking fuel use and a higher rate of adverse birth outcomes. Northern states were associated with a higher proportion of stillbirths and LBW than the southern states. Previous studies conducted in Nigeria showed a link between HAP and childhood acute respiratory tract infections, which was a leading cause of deaths in children under 5 years ,49. Our Our study suggests that HAP is significantly associated with an increased risk for stillbirth and is supported by a recent meta-analysis that concluded that HAP increased the risk of stillbirth in developing countries . HoweverPoverty has also been suggested to be a key factor in preventing access to clean fuel but also compounds the burden associated with HAP by worsening access to adequate health care . This maWe acknowledge the following limitation in this study. The response rates for some adverse birth outcomes were relatively low. There was a 100% response rate for stillbirth outcomes, but there were low response rates for birth weight (6.1%) and pregnancy duration (31.2%). The smoking status of the mother was only recorded in a small proportion (0.2%) of mothers who identified as smokers. Reporting pregnancy in duration in months could introduce measurement bias in our analysis. Measuring pregnancy duration in weeks would result in a more accurate and sensitive model to variability in pregnancy duration. We also could not distinguish when the pregnancy ended. There may be different associations for perinatal mortality and miscarriages if analyzed separately. Amount of time spent around HAP could contribute to the magnitude of its effect on adverse birth outcomes, but we were unable to include this variable in this study. We could not control for all possible confounding variables such as access to medical services, medical history, and BMI. Despite these limitations, this study has several strengths. As the study was based on a large representative dataset, the 2018 Nigeria DHS, we are confident that our sample is an excellent representation of the Nigerian population. The use of STAR models for analysis allows for flexible modelling of possible nonlinear effects of independent variables and the geographical effects of the data ,42,43,57This paper studied the association between HAP and adverse birth outcomes using the 2018 NDHS. It highlighted the risk of adverse birth outcomes due to mothers using unclean cooking fuel. In order to decrease the prevalence of adverse birth outcomes in Nigeria, efforts should address the dependence on unclean cooking fuel. Disparities in Nigerian states account for disproportionate risks of stillbirth and LBW, even when the effects of wealth and education are controlled for. This shows that decreasing national levels of adverse birth outcomes depends on working toward addressing the disparities between states.Further research should be performed to analyze the effects that our study could not control for, such as access to prenatal medical services, and the mother’s medical history. This includes accounting for a combination of different fuels instead of studying only the primary cooking fuel. Analyzing dose-response using the combination of cooking fuels would clarify the strength of the relationship between HAP and adverse birth outcomes. As our study is a cross-sectional study, we cannot analyze causal pathways between HAP, adverse birth outcomes, and other explanatory variables. Further research should be done to study these causal pathways and include a larger selection of adverse birth outcomes, as we limited our study to three outcomes.


The main goal of this manuscript was to investigate the neurodevelopment of children exposed by Zika virus in the intrauterine period who are asymptomatic at birth. Newborns with documented Zika virus exposure during the intrauterine period who were asymptomatic at birth were followed in the first two years of life for neurodevelopment using Bayley III test. Children were classified as having normal or delayed neurodevelopment for age based on most recent Bayley III evaluation results. Eighty-four infants were included in the study. The first Bayley III evaluation was performed at a mean chronological age of 9.7±3.1 month; 13 children (15%) had a delay in one of the three domains, distributed as follow: 10 (12%) in the language domain and 3 (3.5%) in the motor domain. The most recent Bayley III evaluation was performed at a mean age 15.3±3.1 months; 42 children (50%) had a delay in one of the three domains: 4 (5%) in cognition, 31 (37%) in language, and 20 (24%) in motor performance. There were no statistical differences in Gender, Gestational Age, Birth Weight and Head Circurference at birth between children with normal and delayed neurodevelopment for age. A very high proportion of children exposed ZIKV during pregnancy who were asymptomatic at birth demonstrated a delay in neurodevelopment, mainly in the language domain, the first two years of life. The first 1,000 days of life are critical for children to reach their full development potential ,3. AdequFollowing the Zika Virus (ZIKV) epidemic in the Northeast of Brazil between 2014 and 2015, an increase in the number of newborn with severe microcephaly and other malformations were observed, characterizing the Congenital Zika Virus Syndrome (CZS) . The potin utero, some were born asymptomatic, despite having proven intrauterine infection. It is well established that this ZIKV can causes microcephaly in newborns and is associated with Guillain-Barré Syndrome in adults [unknown whether this virus can cause an asymptomatic infection at birth, leading subsequently to impaired brain development. The consequences would be apparent later in childhood, depending on the functions compromised. The main objective of the present study was to investigate the neurodevelopment of newborns exposed with ZIKV in the intrauterine period, who were asymptomatic at birth, during the first two years of life.Although, many newborns were affected by ZIKV exposure n adults –13. HoweThis is an exploratory case series in which newborns exposed by ZIKV in intrauterine period who were asymptomatic at birth were followed from birth to 2 years of life, between May 2016 and January 2018, in the outpatient clinic at Instituto Fernandes Figueira (IFF)-Fundação Oswaldo Cruz (Fiocruz), a reference center for congenital infection in Rio de Janeiro, Brazil.We included infants whose mothers had Zika positive reverse-transcriptase polymerase chain reaction (RT-PCR) during pregnancy. Exposure by ZIKV was defined by the presence of at least one positive RT-PCR result from either the mother’s urine or blood, placenta, amniotic fluid or the infant’s blood, urine, or cerebrospinal fluid (CSF). They were considered exposed to ZIKV ,13. NewbNewborns with CZS, TORCH , Varicella-zoster virus, Epstein-Barr virus, Human Immunodeficiency Virus and congenital anomalies, unrelated to ZIKV infection were excluded from the study. The definition criteria of CZS was the presence of at least one of the following findings: severe microcephaly with partially collapsed skull; thin cerebral cortices with subcortical calcifications; macular scarring and focal pigmentary retinal mottling; congenital contractures; and marked early hypertonia and symptoms of extrapyramidal involvement .Social demographics: maternal age (years), paternal age (years), Tertiary mother’s level of education (more than 12 years in school)  and housst, 2nd or 3rd trimester), presence of gestational hypertension, pre-eclampsia, alcohol or tobacco use during gestation, type of delivery  and multiple gestations;Maternal pregnancy parameters: trimester of Zika infection , neurological abnormalities  and scores of Bayley III motor, cognitive and language domain scores .st and the WHO charts were used for the calculation of the Z-scores measurements at each point of evaluation [Household income was classified into three ranges: up to 2 minimum wages, from 3 to 5 and above 5 minimum wages, considering values at the moment of evaluation. Gestational age was defined as the number of full weeks by the Ballard examination . Weightsaluation ,20.st chart at birth. Newborns with a birthweight Z-score less than -2 standard deviation (SD) from the mean were considered small for gestation age (SGA), between -2 SD and 2 SD as appropriate for gestational age (AGA), and higher than 2 SD as large for gestational age (LGA). The Delta HC was obtained by the difference between the HC at the nearest visit for the Bayley assessment and the HC at birth.The weight adequacy for gestational age was classified using the Intergrowth 21The Development Scales for Toddlers and Infants Third Edition (Bayley III) was used . This scThe first and the last Bayley results available in each domain were compared to investigate the evolution of neurodevelopment. Results of the last Bayley evaluation were used to determine the child’s development in each domain. Children with scores in the normal range in all three domains were considered developmentally normal; children any score bellow 85 (-1 SD) in any of three domains were considered delayed.All data were collected with standardized forms and stored using the software Microsoft Access. Categorical variables were analyzed as frequency and the numerical variables as mean and SD. Potential association were evaluated between neurodevelopment delay and all collected variables. Chi-square or Fisher exact text (for frequencies below 5) were used to evaluate the statistical association of the categorical variables. Student t-test  or the Mann-Whitney test  were used for the numerical variables.Study population was drawn from the cohort “Vertical exposure to Zika virus, and its consequences on children’s neurodevelopment” registered in ClinicalTrials.gov (NCT 03255369), and approved by the Ethics Committee of IFF.Two hundred ninety six infants with ZIKV exposure were followed at our institution as of May 2016 considering maternal symptoms and RT-PCR positive. Ninety-three infants presented CZS characterized by microcephaly, hydrocephaly, cerebral calcifications, cerebral atrophy or arthrogryposis. However, only 174 mothers of the infants included presented proven ZIKV with RT-PCR positive. Eighty-four asymptomatic infants from proven mothers exposed to ZIKV were enrolled for neurodevelopment evaluation using Bayley III Scales because they had at least two evaluations and their mothers had Zika RT-PCR positive. At birth their Dubowitz test, cerebral ultrasound and head circumference were normal .At the time of the first Bayley III assessment, the mean chronological age of the children was 9.7±3.1 months (range 6–18 months). It was observed 13 children (15%) had a delay (considering score less then -1 SD) in one of the three domains, with following distribution: 10 (12%) in the language and 3 (3.5%) in the motor domain . None chThe maternal mean age at birth was 30.6±6.5 years (range: 16–42 years) and paternal mean age was 33.6±6.9 (range: 18–52 years). Almost half of mothers had a complete university education (n = 37–44%); most reported a household income higher than three minimum wages (n = 63–76%). No statistically significant difference were noted between demographic and income parameters in children with normal versus delayed development as the depicted in nd trimester of gestation, with a low proportion reporting alcohol and tobacco use. All 84 children were tested by RT-PCR after birth. Between them, 17 were positive and 67 negative. There was a high proportion of cesarean section. None of the gestational variables or neonatal variables were significantly associated with developmental delay, as shown in Tables For most mothers, infection occurred at the 2Exclusive breastfeeding was maintained in 49 (58.3%) children up to 6 months of age; hospital admission occurred for 9 (10.7%) children, and 56 children (66.7%) showed neurologic abnormalities during clinical follow-up . Although the HC Z-score mean was within the normal range both at birth and at the time of the last examination, the difference between these measurements (Delta HC) was significantly lower in the developmentally delayed group, as seen in Much is still unknown about the neurodevelopment of infants with congenitally acquired ZIKV infection who are asymptomatic at the time of birth–24. We fLanguage competence depends on the integration of many neural systems for adequate development, including cognitive development, hearing, central auditory processing, motor function, vision and visual information processing . All theet al. demonstrated that Brazilian ZIKV strains cross the placenta and cause microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment [Our preliminary findings are of concern, for now there are yet no other comparative data. In vitro studies have demonstrated that ZIKV infects and damages human neural stem cells . Cugola elopment . Additioelopment .The role of infection during pregnancy in child development was already described in the classical group of teratogenic pathogenesis is referred to as TORCH . A fetalWaldorf et al. inoculated ZIKV in pregnant primates and observed a loss of fetal neural progenitor cells, describing a characteristic pattern of cerebral injury in their fetus, even in the absence of microcephaly . They idet al. in a review of the most frequent clinical findings in children born to women with documented ZIKV infection, during gestation. They described a broad spectrum of abnormalities, which could be the result of an inflammatory reaction to the virus or a direct effect of the virus itself, causing CNS injury and neurological abnormalities [The same recommendation was made by Saad malities .One single marker for development delay which showed a statistically significant difference in our pediatric cohort was the delta HC. Different authors have reported the relationship between head circumference growth and neurodevelopmental abnormalities –39. RaghAlthough asymptomatic at birth, our group of children developed a host of neurological abnormalities which demonstrated a statistical trend towards association with suboptimal.A limitation of this study was that many of our families had difficulty maintaining appointments at regular windows, so for this reason we were not able to assess infants at exactly the same age. On the other hand, we were able to enroll a significant number of asymptomatic infants at birth, with documented ZIKV vertical exposure, who had at least two successive Bayley III evaluations in the first 24 months of age.Other limitation is the absence of not exposed group in order to compare the influence of cofactors in neurodevelopment as maternal age (years), paternal age (years), maternal level of education and household income, that usually describe as related with development . HoweverAnother issue that can be discussed is the cutoff point used to defined developmental delay (-1 SD) that can increase the frequency of abnormalities or describe only suboptimal neurodevelopment. However, this is the recommendation of the Bayley test manual and the study is been conducted in a pediatric hospital where wider cutoff points for developmental delays may be important for early referral for neuro-stimulation .Congenitally ZIKV-exposed infants who were asymptomatic at birth showed suboptimal neurodevelopment when evaluated by Bayley III assessments Abnormalities were mainly in the language domain during the first two years of life. The significant lower delta HC in the group with suboptimal development, as well as the concurrent presence of neurologic abnormalities are likely result of ZIKV infection in the developing brain.Children with vertically ZIKV exposure require a longer follow-up period of evaluation in order for neurodevelopment to be adequately assessed. Studies in larger populations, evaluation of other confounding variables related to neurodevelopment and results of brain imaging studies should be taken into account for a better understanding of the broader effects of ZIKV on neurodevelopment.


Many very-low-birth-weight (VLBW) infants experience growth faltering in early life despite adequate nutrition. Early growth patterns can affect later neurodevelopmental and anthropometric potentials. The role of the dysbiotic gut microbiome in VLBW infant growth is unknown. Eighty-four VLBW infants were followed for six weeks after birth with weekly stool collection. DNA was extracted from samples and the V4 region of the 16S rRNA gene was sequenced with Illumina MiSeq. A similar microbiota database from full-term infants was used for comparing gut microbiome and predicted metabolic pathways. The class Gammaproteobacteria increased or remained consistent over time in VLBW infants. Out of 228 metabolic pathways that were significantly different between term and VLBW infants, 133 pathways were significantly lower in VLBW infants. Major metabolic differences in their gut microbiome included pathways involved in decreased glycan biosynthesis and metabolism, reduced biosynthetic capacity, interrupted amino acid metabolism, changes that could result in increased infection susceptibility, and many other system deficiencies. Our study reveals poor postnatal growth in a VLBW cohort who had dysbiotic gut microbiota and differences in predicted metabolic pathways compared to term infants. The gut microbiota in VLBW infants likely plays an important role in postnatal growth. A common outcome in very-low-birth-weight infants (VLBW infants weight < 1500 g)) is postnatal growth failure. Significant efforts during Neonatal Intensive Care Unit (NICU) hospitalization are directed towards nutrition, with provision of nutrients and calories calculated to promote the growth that matches intrauterine growth for both length and weight. Equivalence to intrauterine growth is seldom achieved postnatally due to multiple reasons that are known and postulated [500 g) isThe ultimate goal of optimizing nutrition for growth is to reduce the long-term complications and achieve better outcomes for VLBW infants. The common quantitative measurements of growth in the Neonatal Intensive Care Units (NICUs) are serial weights, lengths, and head circumferences. The most commonly used calculations of weight gain are g/kg/day, g/day, and z-score relative to a growth chart . Z-scoreEnterobacteriaceae are the most common family of Gammaproteobacteria in VLBW infants, and these bacteria are unable to digest human milk oligosaccharides HMOs, which represent 20% of the carbohydrate content of milk [Enterobacteriaceae are facultative anaerobes and are capable of saccharolytic fermentation but they will switch to proteolytic fermentation when carbohydrates are depleted. They use mixed acid fermentation anaerobically if there are available electron acceptors, such as nitrate or fumarate. If those electron acceptors are not available, they will ferment glucose to acetate, succinate, lactate, or formate. They produce less adenosine triphosphate (ATP) through metabolic pathways compared to Bifidobacteria [Enterobacteriaceae, along with their production of proinflammatory LPS, may alter the enteric barrier and account for poorer colonic absorption of nutrients by the preterm infant [A potential mechanism for this faltered growth may be microbial dysbiosis.  of milk . The Entbacteria . The lacm infant .We hypothesized that the Enterobacteriaceae dominant dysbiosis we have observed in VLBW infants plays a metabolic role in the faltered infant growth we have previously reported . This dyParticipant recruitment of VLBW infants was done in a single NICU. Out of a pool of 220 admissions over the year and a half of recruitment, parents of 84 infants agreed to participate in the study (38%). Parents provided written informed consent and the study was approved by the hospital and university Institutional Review Boards Pro00019955). The study was conducted in accordance with the Declaration of Helsinki. The exclusion criteria included HIV exposure, congenital anomalies, and moribund status. A comparable set of microbiome data of full-term infants from a previous study was used for comparison . Feeding955. The www.earthmicrobiome.org). Library preparation and sequencing methods for all the VLBW infants were as previously described [https://cran.r-project.org) and further analyzed with DADA2 package v1.10.1 [DNA was extracted using the QIAamp PowerFecal DNA Kit  with modifications based on the Earth Microbiome Project protocols  were uploaded to the Piphillin server  and the A total of 84 VLBW infants  were enrolled in a single NICU located in Tampa, Florida. C-sections were performed for 78.0% of the samples and 48.8% were male. Ethnicity was 20.5% Hispanic, 41.0% African American, and 32.0% Caucasian. All infants were prematurely born except for one small for gestational age infant born at 34 weeks. Feeding types were recorded and feeding compositions by volume were calculated daily. Fecal samples were obtained from infant diapers at least once a week, and stored at −80°C until processed for DNA extraction for 16S rRNA gene amplicon sequencing. Clinical data for the study  were extracted from the electronic medical record (EMR). Additional information about pregnancy, labor, and maternal characteristics were collected by questionnaire. Length, weight, and head circumference were measured weekly. These measures were transformed to z-scores using the Fenton growth charts . OverallOn average, the VLBW population of infants were born with a z-score of 0, indicating that their birth weights were near the 50th percentile, on a Fenton growth chart. However, most infants lost weight within the first week but did not regain the birth weight as expected. Weight-for-age z-scores remained consistently almost one standard deviation lower after the initial weight loss. The infants’ length-for-age z-scores slowly and continuously decreased over time and became more stable by week 5 postpartum. Finally, infants lost almost a full standard deviation in head circumference during the first week postpartum, reached the lowest point at week 3, and made some recovery in weeks 5 and 6. p = 0.08), but the increase was significant for week 3 (p = 0.009), week 4 (p = 0.005), week 5 (p = 0.0003) and week 6 (p=0.0001). No trend was observed for the Shannon index for the first six weeks of life in term infants (p = 7.2E × 10−8) ), while the abundances of Bacteroidetes and Actinobacteria were lower  (p = 0.76). Similarly, Gammaproteobacteria class was significantly higher in the VLBW infants (p = 1.22 × 10−11) while the abundances of Bacteroidia (1.14 × 10-42), Alphaproteobacteria (p = 5.88 × 10−10), and Betaproteobacteria (p = 1.14 × 10−15) were lower. Overall, 14 classes of bacteria were significantly associated with the VLBW infants differently than with the term infants as shown in The Shannon index, a representation of alpha diversity, increased from week 1 to week 6 in the VLBW infants. Alpha-diversity at week 2 was not significantly higher than week 1 ( infants . The difctively) . FirmicuThe pie chart is based on the relative abundances for all preterm and term infants across all the first six weeks.The microbial metagenomes and corresponding KEGG pathways were predicted from all the samples. In this part of the work, the focus was once again on the differences in pathways between the VLBW and the term infants. A total of 279 different metabolic pathways were identified for all the infants. Out of 279, 228 pathways were significantly different between the term and the VLBW infants. Among them, 133 pathways were significantly lower in the VLBW infants, while the rest were higher. All the results are presented in As one of the main objectives of this study was to understand the association of the gut microbiome in VLBW infants with their growth, the top 20 significantly different metabolic pathways were analyzed for differences between VLBW infants and term infants. Among the predicted pathways, we found that there were three which were specific to the Gammaproteobacteria. They are ko04961 , ko05130 (Pathogenic Escherichia coli infection) and ko05131 (Shigellosis).PCA plots  were conThe data indicate very significant differences in taxa, diversity, and predicted metagenomic pathways in VLBW infants compared to term infants. Gut microbiome alpha diversity was much lower in VLBW infants and the taxonomic composition was also very different, with a dominance of Enterobacteriaceae in the VLBW infants. The sources of Gammaproteobacteria, which ultimately dominate the VLBW infant gut, are unknown. Milk has a very substantial percentage of these organisms, so they may play an early role in the immune priming of the gut, but are normally transient in the term infant gut . They maBifidobacteria and Firmicutes, both low in abundance in the VLBW infants. Butyrate is a product of bacterial fermentation. Upon the fermentation of HMOs and sugars, Bifidobacteria produce, in addition to lactic acid, acetate, which can cross-feed other Firmicutes, resulting in the production of butyrate [These facultative anaerobes remain dominant in the VLBW infant gut due to many factors including the immaturity of the GI tract and the inability to produce an anaerobic environment in the colon. Facultative anaerobic microbial abundance is potentially perpetuated by the depletion of butyrate, which is normally formed through interactions of butyrate . Butyratbutyrate . If butybutyrate ,26. The VLBW infants in our study revealed a drop in both weight and height z- scores during the first 6–8 weeks postnatal age, and many were discharged home with faltered growth, even though they were provided the appropriate standard or higher daily caloric intake for VLBW infants. The dysbiotic, low propionate producing gut microbiome likely plays an intermediary role on poor postnatal growth in VLBW infants. The metabolic pathways predicted to be significantly decreased in these infants included pathways that likely contribute to energy harvest, fuel utilization and growth. They were also at increased risk for antibiotic resistance and enteric infections. A smaller study of preterm compared to term infants found similar metabolic pathways to be reduced in VLBW infants . A recenGastrointestinal (GI) immaturity impacts both the absorption of nutrients and the tolerance for enteral feeds required for normal growth. Peristalsis in the GI tract and the suck-swallow reflex are impaired by prematurity, which in turn impact feeding behaviors . This imA well-established “gold standard” for VLBW infant nutrition is human milk, preferably from the mother , but oftBifidobacteria, a largely commensal genus, but even exclusively breast milk fed VLBW infants do not develop Bifidobacterial dominance. Rather, these infants develop a delayed succession of bacterial blooms, and are dominated by Gammaproteobacteria for many weeks while in the NICU [Bifidobacterial dominance benefits infants because these microbes have a role in the development of immunity, protect against virulent microorganisms colonizing the gut, and support colonic health through production of SCFAs like butyrate [The composition of human milk is well studied, with regards to its immunonutritional composition, the oligosaccharides (HMOs) content, and to some extent, its microbiome ,47. Sincthe NICU ,51. The butyrate . Butyratbutyrate . Infant The current study has several limitations that impact interpretations and the significance of results. The full term infant group was collected separately from the VLBW group, so DNA extraction and sequencing may play a role in results. We do not have corresponding phenotypic data on the term infants. Our data for the VLBW infants only extends to the 6–8th postpartum weeks, so further longitudinal analysis over the entire admission to the NICU is warranted. The metabolic data is entirely based on microbial abundances so it is predictive only and we have not measured metabolites and transcription pathways directly in the stool sample.In our VLBW infants, the predicted metabolic pathways from microbiota data showed major reductions in glycan biosynthesis and metabolism and biosynthetic capacity, interruptions in amino acid metabolism, increases in susceptibility to infections, and many other system deficiencies that play a role in normal gut microbiota succession and maturation as well as infant growth and development. Further functional studies are needed to clarify if microbes or particular metabolic pathways play a more direct effect on infant growth, and what interventions can be made, either nutritionally, or that could directly affect the dysbiosis, to improve health and nutrition as these infants grow. A follow-up validation study based on quantitative PCR (qPCR) would help to validate these findings. These preliminary data are the first step in generating hypotheses. In the future, we plan to validate the findings by metagenomics and metatranscriptomics.


The prolonged effects of disasters on reproductive outcomes among the survivors are less studied, and the findings are inconsistent. We examined the associations of maternal exposure to the 2008 Wenchuan earthquake years before conception with adverse birth outcomes.We included 73,493 women who delivered in 96 hospitals in 24 provinces and autonomous regions from the 2015/16 China Labor and Delivery Survey. We weighted the multivariable logistic models based on the combination of coarsened exact matching (CEM) weight and survey weight, and performed sex-stratified analysis to test whether associations of maternal earthquake exposure with adverse birth outcomes  varied by sex.P = 0.010). The sex-stratified analysis showed the association was significant among male births (aRR (95%CI): 1.40(1.12–1.75),P = 0.002),but unsignificant among female births. The sensitivity analysis reported similar findings.The bivariate models showed that the weighted incidence of each adverse birth outcome was higher in exposed group than unexposed group: stillbirth (2.00% vs. 1.33%), PTB (14.14% vs. 7.32%), LBW (10.82% vs. 5.76%), and SGA (11.32% vs. 9.52%). The multivariable models showed maternal earthquake exposure was only associated significantly with a higher risk of PTB in offspring among all births (adjusted risk ratio [aRR](95%CI):1.25(1.06–1.48), The 2008 Wenchuan earthquake exposure has a long-term effect on PTB. Maternal acute exposure to disasters could be a major monitor for long-term reproductive outcomes. More attention should be paid to the underlining reasons for disaster-related adverse birth outcomes. Adverse birth outcomes, such as low birthweight (LBW), preterm birth (PTB) and small for gestational age (SGA), are associated with numerous risk factors, including not only maternal characteristics , 2 and eMoreover, the few existing studies of prolonged effects of disasters on reproductive outcomes among the survivors reported mixed results, with one showing negative effects among women exposed to the 2001 World Trade Center disaster in Unites States  and anotThe 8.0-magnitude Wenchuan earthquake hit Wenchuan, Sichuan province on May 12, 2008, leading to 69,197 deaths, 374,176 injuries and 18,222 missing persons  among thTo bridge the gap, we evaluated the data from a national hospital-based cross-sectional study to investigate the long-term effects of the Wenchuan earthquake on birth outcomes. We hypothesized that the women exposed to the devastating earthquake and became pregnant years later would be associated with elevated risks of adverse birth outcomes in offspring. Given that male births are more vulnerable to maternal stress , we, theData in the present study were from the China Labor and Delivery Survey (CLDS), a multi-center, hospital-based cross-sectional survey throughout China to estimate the national labour and delivery information of new births between March 1, 2015, and December 31, 2016. Using a stratified multistage cluster sampling design, the CLDS selected 112 hospitals with at least 1000 childbirths per year from 25 provinces and autonomous regions across China mainland. Details on the sampling strategy of CLDS have been described elsewhere [Although the CLDS was a cross-sectional observational study, the Wenchuan earthquake generated a natural experimental setting to investigate the long-term effects of the earthquake for birth outcomes among the female survivors who became pregnancy years following the devastating earthquake , 16. In The Research Project Review Panel at the Department of Reproductive Health and Research of World Health Organization (WHO) reviewed and approved the protocol of the CLDS for technical content. The CLDS was approved by the WHO Research Ethics Review Committee and the ethics committees in all participating hospitals. Informed consent was not required, as the collected data from hospital records were anonymized and de-identified to preserve privacy for the participants.In this natural experiment, individual-level maternal exposure to the 2008 Sichuan earthquake was unmeasured in the original design and is difficult to define, as noted in the previous review , indicatThe main outcomes of interest were the outcome of delivery, gestational age, birthweight, and birthweight for gestational age. The corresponding adverse birth outcomes included stillbirth, PTB, LBW, and SGA.We defined stillbirth as the death of a baby before or during delivery after 23 weeks gestation or weighing at least 500 g at birth. We divided gestational age at birth as preterm (< 37 weeks), term (37–41 weeks) and post-term (≥42 weeks) birth. We classified birthweight into low (< 2500 g), normal (2500–3999 g) and high (≥4000 g) groups. We categorized sex-specific birth weight-for-gestational age as small (<10th percentile), appropriate (10th–90th percentile) and large (>90th percentile) categories.2), healthy weight (18.5–24.9 kg/m2), and overweight or obesity (≥25 kg/m2) [We divided maternal age into young (< 20 years), reference (20–34 years) and advanced (≥35 years) class. We categorized maternal education attainment as low (junior school or below), middle , and high (bachelor degree or above) group. We labeled the women as residents if they held the hukou in the province where they delivered, or migrants if not. According to the WHO classification of body mass index , we categorized maternal pre-pregnancy BMI as underweight (< 18.5 kg/m5 kg/m2) .Maternal medical conditions in the present study included maternal diseases , history of PTB, method of conception, parity (primipara or multipara), multiple pregnancy or singleton pregnancy, mode of delivery and sex of newborns.svy and subpop option were used to account for complex survey design.Statistical analysis was performed from January 5, 2020, to March 12, 2020. Statistical analyses were performed using Stata/SE 15.1. To obtain a national estimation of labour and delivery information, survey weight for each newborn included in CLDS was calculated using the delivery data from 2016 China Statistical Yearbook in the previous study [2 tests, and found the distribution of a few covariates was not balanced between the two groups (Table svyset command with the new weight. We reported CEM–weighted adjusted risk ratio (aRR) and 95% confidence interval (CI) using adjrr command [We first examined distributions of the exposure indicator, outcome variables, and covariates, and investigated the associations of exposure indicator with outcome variables and covariates using χps Table . To accops Table . We obta command  after weIn sensitive analyses, we restricted our analysis to singleton births, given that multiple pregnancies carry significantly higher risks of birth outcomes, including preterm birth  and stilWe drew a total of 73,493 hospital records in our primary analysis, including 34,170 female births (47.30%), 1569 multiple births (1.78%) and 10,150 pregnant migrant women (12.85%), more details of the delivery information can be found in Table P = 0.018), PTB , LBW , and SGA .The weighted incidences of adverse birth outcomes were 1.35% for stillbirth, 7.55% for PTB, 5.93% for LBW, and 9.58% for SGA in our sample Table . As showP = 0.010) among all births, and similar results were found in other subpopulation, including singleton births, all livebirths, and singleton livebirths  may be useful, but the datasets before the earthquake are not available. Third, we were unable to distinguish between the earthquake-related stress and other social stressors due to limitations in data availability. Fourth, the dose-response relationship between distance from the epicenter of the earthquake and incidence of PTB could support our findings. However, the sample size in Sichuan province is not large enough to allow us to conduct the dose-response analysis. Last, we only included secondary and tertiary hospitals in this study, which may introduce select bias and underestimate the associations. However, few pregnant women delivery in home or primary hospitals in China, and mostly due to exceptional circumstances , 37. ConMaternal exposure to the 2008 Wenchuan earthquake elevates the risk of PTB in offspring several years later after the earthquake, and only the male birth is vulnerable to the long-term effect. Maternal acute exposure to disasters could serve as a major monitor for long-term reproductive outcomes, and more research is needed to understand the underlining reasons for long-term disaster-related adverse birth outcomes.Additional file 1: Table S1. Associations of maternal exposure to Wenchuan earthquake with adverse birth outcomes among all births of local pregnant women. Table S2. Associations of maternal exposure to Wenchuan earthquake with adverse birth outcomes among all livebirths of local pregnant women.


Significantly higher SCr levels and lower eCCI were observed in mid-late preterm neonates with BA than in preterm neonates without BA . Very preterm neonates showed a higher UOP  after the development of BA than before. In preterm neonates with BA, the incidence of SCr > 133 μmol/L, CCI < 16 mL/min/1.73 m2 and UOP < 1.0 ml/kg/h, was 10.94%, 62.50%, and 20.31%, respectively. Within 24 h after birth, BA was associated with eCCI < 16 mL/min/1.73 m2  in preterm neonates. Different renal function profiles were observed in preterm neonates of different GAs within the first 24 h of life after the development of BA. Candidate therapies based on different renal function statuses will bring these vulnerable patient populations of different GAs closer to receiving precision medicine.The characteristics of early renal function in preterm neonates of different gestational ages (GAs) with birth asphyxia (BA) remain unclear. Kidneys are sensitive to oxygen deprivation, and renal insufficiency may occur within 24 h of BA. We aimed to elucidate the renal function profiles within the first 24 h after the development of BA among vulnerable preterm neonates of different GAs. The medical records of 128 preterm neonates born to mothers with normal renal function were retrospectively analyzed. Data regarding the serum creatinine (SCr) and urea nitrogen (BUN) levels in venous blood, estimated creatinine clearance (eCCI) within the first hours after birth, and urinary output (UOP) in the first 24 h after birth were compared between the preterm with BA population and GA-matched population without BA ( Renal function in neonate changes markedly daily, and different degrees of renal immaturity exist in preterm neonates of different gestational ages (GAs) ; Thus, eBA leads to dysfunction of the central nervous system and multiple organs, including the heart, lungs, kidneys, and bowel . KidneysAfter obtaining institutional ethical clearance (2019-KY-023-01), this retrospective, matched case-control study was conducted in a neonatal intensive care unit (NICU) of our institution between March 2014 and March 2018.The preterm neonates diagnosed with asphyxia by an experienced neonatologist team were included as preterm neonates with observed BA. Premature neonates  were continuously included as controls until the patients in each group were evenly distributed. The exclusion criteria were as follows: (a) congenital malformation in the newborn; (b) inherited metabolic diseases in the neonate; (c) congenital renal dysplasia detected on prenatal screening; (d) family history of kidney disease; (e) maternal use of opioids , captopril, indomethacin, or other drugs that affect renal function during pregnancy; (f) maternal renal dysfunction during the perinatal period; (g) severe maternal anemia during pregnancy; (h) inadequate liquid intake within 24 h after birth; and (i) use of mannitol, ibuprofen, or diuretics within 24 h after birth.Asphyxia was diagnosed based on a delivery history of fetal distress and/or 5 min Apgar score of <7, which was defined by the World Health Organization as failure to initiate and sustain normal breathing at birth –14. FetaAll observed premature neonates with BA and controls were admitted to the NICU within 30 min after birth, managed by the same experienced neonatology team, given timely treatment, and guaranteed standard input, but they did not received diuretics during the observation.2) = [0.34 × length (cm)]/SCr (mg/dL) (1 μmol/L = 0.0113 mg/dL) . The eCCI rate was calculated using the Schwartz formula: eCCI (mL/min/1.73 m3 mg/dL) . UOP was3 mg/dL) , 17, eCCg/dL) .t-test, whereas those with non-normally distributed values  were compared using the Mann-Whitney U-test. The chi-square or Fischer's exact test (as appropriate) was used to compare dichotomous variables between the groups. Univariate logistic regression analysis was performed to evaluate the potential associations of demographic and clinical variables with deteriorating renal function risk. A p < 0.05 was considered to indicate statistical significance. Statistical analysis was conducted using SPSS version 23.0 .Quantitative variables are expressed as median (interquartile range), whereas categorical variables are expressed as absolute frequency (percentage). The neonate characteristics were compared between the preterm BA and preterm control groups. Continuous variables with normally distributed values  were compared using the independent Student' Between March 2014 and March 2018, 2,977 hospitalized preterm neonates were treated in the NICU. Seventy-one preterm neonates had a history of fetal distress and an Apgar score <7 at 5 min. After screening by the exclusion criteria, 64 preterm neonates with BA (BA group), including 32 very preterm neonates (GA: 28–31 weeks) and 32 mid-late preterm neonates (GA: 32–36 weeks), were enrolled in the observation group. Sixty-four GA-matched preterm neonates without BA were included as controls until patients in each group were evenly distributed. All 128 patients had NICU admission charts available for review, and their mothers had normal SCr levels.p = 0.260). The vaginal delivery rate was higher in the BA group than in the control group (p = 0.040).Demographic and clinical characteristics of the neonates and their mothers are summarized in p < 0.001), but a significantly lower eCCI rate , especially in the mid-late preterm neonates  than GA-matched controls. However, no significant difference was found in the SCr levels and eCCI rate between the very preterm neonates with and without BA. Although the very preterm neonates with BA had a significantly higher UOP than the GA-matched controls , there was no significant difference in the UOP between the mid-late preterm neonates with and without BA and between all preterm neonates with BA and without BA. Additionally, BA did not associated with the BUN level in all preterm neonates, including the mid-late and the very preterm neonates , 62.50% (40/64), and 20.31% (13/64), respectively. There was no significant difference in the incidences of SCr > 133 μmol/L  between the 64 preterm controls and 64 preterm neonates with BA. However, the incidence of eCCI < 16 mL/min/1.73 m2 was significantly higher in the 64 preterm neonates with BA than in the preterm controls , especially in the 32 mid-late preterm neonates . The incidence of eCCI < 16 mL/min/1.73 m2 was similar in the very preterm neonates with and without BA , perinatal complications of neonates , Preterm birth with very small GA (GA < 32 weeks) , and natural birth  were significantly associated with an increased risk of eCCI < 16 mL/min/1.73 m2 in all preterm neonates within the first hours after birth. Preterm birth with very small GA (<32 weeks)  and gestational complications  were inversely associated with UOP < 1.0 ml/kg/h in preterm neonates within 24 h after birth. Primiparity and gender were not significantly associated with the change of renal function in preterm neonates within 24 h after birth  was inversely associated with UOP < 1.0 ml/kg/h. BA was associated with an increased incidence of eCCI < 16 mL/min/1.73 m2, at an OR of 2.83. Therapies based on the different renal function statuses may bring these vulnerable patient populations of different GAs closer to receiving precision medicine after BA.Our research showed that the renal function of preterm neonates was altered after BA in the first hours after birth, and different renal function profiles were observed in neonates of different GAs after BA in the first day of life. In mid-late preterm neonates after BA, a higher initial SCr value and lower initial eCCI were observed. In the very preterm neonates after BA, higher UOP was seen within the first day after birth. The incidences of SCr > 133 μmol/L, eCCI < 16 mL/min/1.73 mIn preterm neonates hospitalized in the NICU, the incidence of acute kidney injury (AKI), functional renal failure, and intrinsic renal failure were reported to be 12, 48.14, and 51.85% respectively . despiteEvaluating kidney injury in preterm neonates is challenging, but it is relevant for postnatal care and crucial for the future of a patient. Although the definitions of kidney impairment and AKI staging in adults and children have become widely adopted, no single-accepted definition exists for AKI in neonates, and no single accepted definition exists for AKI in neonates and no definition has been proposed for preterm neonates . Additio2 at birth, and a rapid increase is then seen within the first 14 days of life and GFR is typically between 35 and 45 mL/min/1.73 m2. VIEUX et al.  at 24 h after birth, and similar SCr, BUN, and UOP values but a reduced eCCI value was observed . The difX et al.  reporteda et al. , AKI wasty level . Furtherty level .The Acute Kidney Injury Network (AKIN) criteria; the modified pediatric risk, injury, failure, loss, and end-stage (RIFLE) kidney disease criteria, and the Kidney Diseases: Improving Global Outcomes (KDIGO) criteria were used in numerous researches for the diagnosis of neonatal AKI based on the increase in SCr levels and/or decrease in UOP, and UOP < 1.0 ml/kg/h was the most often used cut-off value for oliguria , 29. Alm2 in the preterm neonates. The potential risk factors of a higher incidence of eCCI < 16 mL/min/1.73 m2, including very small GA (<32 weeks), perinatal complications of neonates, and natural birth, were also observed in this study. The precise cut-off value of eCCI for neonates of different GAs needs to be further studied with a large sample in the future. Additionally, we found that preterm birth with very small GA (<32 weeks) and mothers' gestational complications were negatively associated with UOP <1.0 ml/kg/h in preterm neonates within 24 h after birth. Oliguria was not likely to occur in very preterm neonates, which may be related to the high proportion of water content in their body and the immature function of renal tubular concentration and dilution  of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. The clinical and research activities being reported are consistent with the principles of the Declaration of Helsinki. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.YZ and H-HZ contributed to the study conception and design. Data collection was performed and the first draft of the manuscript was written by YZ. Data analysis was performed by H-HZ. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The pericardial cysts (PC) are rare congenital anomaly. They are usually asymptomatic or incidentally found during surgery or by an imaging modality. We report a 35-yr-old man referred to Imam Ali Hospital, Kermanshah, western Iran in 2017, with palpitation, chest pain and dyspnea and physical exam revealed sign and symptoms of right atrial compression and tamponade. Clinical sign and symptoms of these cystic masses are similar to another neoplasm of the pericardium such as hydatid cyst, loculated pericardial effusion. Thymoma, thymolipoma, lipoma and rare malignant tumors  as a rare congenital disorder, comprising approximately 7% of all mediastinal mass. The incidence of this lesion between the pericardial masses is estimated to be from 10% to 17%. These cystic masses as the most common benign neoplasm of the pericardium and may have an embryologic base for their occurrences . They art tumors ,4.A 35-year-old man admitted to our emergency center  with complaint of palpitation, dyspnea and nonproductive cough for recent three weeks. His past medical history except for temporary paroxysmal palpitation was unremarkable. Chest x-ray revealed a dumping in the lower right cardiac border . RoutineThe patient was not feverish, the pulse was 112 beats/min, and the respiration rate was 22/min. The blood pressure was 110/65 mm Hg. He was tachypneic and tachycardic and had low blood pressure (80/50 mm gH). The physical exam also showed the signs of right atrial tamponade with rapid, weak pulse with paradoxical nature, jugular veins were distended and accentuated with inspiration. The physical exam showed, moderate hepatomegaly , pitting lower extremities edema, and vague heart sounds. The lungs sound was clear, and the neurologic examination was unremarkable. Electrocardiography showed normal sinus rhythm at a rate of 118 beats/min with normal intervals with no ST segments change in the cardiac leads. The electrocardiogram showed low volt QRS height, with T-wave flattening in all of the ECG leads. Due to lung air interposition, a transthoracic echocardiogram was unremarkable without obtaining a diagnostic benefit, and a transesophageal two-dimensional echocardiogram was denied by the patient.The cystic lesion closely attached to the surrounding cardiac structures, most probably representing a hydatid cyst . CT scanWith the impression of ruptured hydatid cyst, the patient scheduled for open surgery performed by midline sternotomy and with beating off-pump approach. During intraoperative inspection, he had an intrapericardial cystic mass compressing the right atrium and inferior border of the right hemi-diaphragm. There was mild sero-sanguineous pericardial effusion . The cysErosion of cyst wall to thin atrial wall caused silent bleeding to cyst cavity and subsequent thrombus formation. No connecting vascular pedicle from cyst to aorta or great vessels was found. On histopathological exam, some evidence of necrotic, fibrinous and thrombotic material with an inflamed pericardial layer were found and no malignant tissue or cells were detected .thday of operation and in the 6thmonths of follow-up, no recurrence of effusion was detected by TEE as his clinical condition was good.The postoperative course was uneventful and discharged in 6Pericardial cysts occur because of an aberrant embryologic process in which from mesenchymal diverticula that form the future pericardial sac a bud-like outgrowth protrudes to the lateral side, separated from main diverticula, and formed a pericardial cyst. Others believed that failure of fusion of two bud leads to the formation of an accessory PC .Near 80% of PC are asymptomatic and usually detected incidentally during a routine evaluation for another’s pathology. Seventy percent of pc is detected at the right border of heart toward the costophrenic angle, and 20% located on the left cardiac border and the remaining ten percent of cyst are found in the posterior or anterior mediastinum . It needOther complications include inflammation of cyst’s wall; infection of cyst is content and rupture of cyst into surrounding structures resulting from partial erosion of necrotic cyst wall. Rupture commonly occurs in plural cavity however rare cases of pericardial erosion or rupture into pulmonary tissue or main bronchus has been reported and in two separate studies two cases of supra valvar pulmonary stenosis, and compression of right ventricular outflow tract by cyst, have been observed .The spontaneous resolution of a cyst is rare event and, most likely result from erosion of cyst wall and subsequent drainage of cyst contents into the pleural space. The spontaneous resolution of cyst occurs only in non-inflamed and non-infected cases. CT scan with contrast is the imaging modality of choice for proper diagnosis of PC. However, no studies have been confirmed the superiority of one imaging modality on others such as MRI or echocardiography. On contrast CT scan, in the infected PC cases, or with inflammation of the wall the PC, appears as thick-walled with sharp border and homogeneous content. Failure to enhancement is due to intactness of wall in relation to cardiac chambers ,8.The three modalities of treatment of PC include following up with symptomatic management, non-surgical intervention by percutaneous cyst content drainage, and unblocked resection of mass. The indications of surgery include huge size, protracted symptoms, unknown nature and behaviour of cyst and prevention of serious complications such as rupture into pericardial cavity tamponade, suffocation by obstruction of respiratory tract and respiratory failure , 10.The PC are rarely the cause of dyspnea and this symptom may be a cause of patient’s referral to heart centers for further evaluation. Simple lain chest x-ray highlights the presence of a pc verified by further imaging especially with CT scan. Definitive treatment for symptomatic pc is surgical removal.