Despite the prevalent use of antenatal corticosteroids (ACS) to prevent preterm infants’ adverse neonatal complications, there is currently no consensus on administration-to-birth intervals of ACS. International guidelines broadly agree that the administration of antenatal corticosteroids should be within 7 days prior to preterm birth. However, there is little evidence to support narrower optimal ACS administration-to-birth interval time. This study was undertaken to investigate the association between the administration-to-birth interval of ACS which is bounded by 48 hours and neonatal outcomes in very preterm infants.This is a single-center prospective observational study. Data were collected prospectively from eligible infants from January 2008 to April 2014 at the Santa Clara Valley Medical Center, neonatal outcomes were compared between two groups based on the interval of antenatal corticosteroid administration-to-birth: the interval of <48h, and the interval of >48h. It was noted that the entire study was completed by Dongli Song et al., and uploaded the data to the DATADRYAD website. The author only used this data for secondary analysis.After adjusting potential confounders , the interval of >48h group compared to the interval of <48h group had significant reductions in mortality , any retinopathy of prematurity , severe retinopathy of prematurity , any intubation  and higher 1 min Apgar .This study shows that in very preterm infants, compared with the interval of ACS<48h, the interval of ACS>48 hours has a significant health promotion effect. Preterm birth is a worldwide epidemic with a global incidence of 15 million every year . PrematuAntenatal corticosteroids (ACS) has been widely accepted as the standard for managing pregnancies at risk for preterm delivery, and the impact of ACS on reducing the morbidity and mortality of preterm infants has revolutionized perinatal medicine . In pretDespite the widespread use of ACS to prevent adverse neonatal complications in preterm infants, and several national and international clinical practice guidelines also make recommendations for initial prenatal corticosteroid administration, there is currently no consensus as to the type of corticosteroid to use, the dose and frequency of use, the timing of use and the route of administration –14. InteBased on data that has already been published, we conducted a secondary data analysis for this study . The admwww.Datadryad.org). This website permitted users to freely download the raw data. According to Dryad’s Terms of Service, we cited the Dryad data package in the present study. , Data from Duration of cord clamping and neonatal outcomes in very preterm infants, Dryad, Dataset, https://doi.org/10.5061/dryad.4q3d3). Variables included in the database file were as follows: birth weight, gestational age (GA), duration of cord clamping, multiple pregnancies, the administration-to-birth interval of ACS , delivery mode , Apgars at 1 and 5 minutes, delivery room (DR) intubation and positive pressure ventilation, DR chest compression and medications, admission temperature (temperature on NICU admission in Celsius), hypothermia (<36 degree Celsius on admission), hematocrit in the first 2 hours of life, hematocrit between 12–36 hours of life, surfactant administration, pneumothorax, intubation <24hr (intubation within 24 hours of life), any intubation (defined as at least once during NICU stay), any red blood cell transfusion (any red blood cell transfusion during the NICU stay), peak bilirubin (mg/dl), death (death before discharge home), any IVH , severe IVH , late onset sepsis , any ROP , severe ROP , NEC, CLD, survival without major morbidity .We obtained data from the ‘DATADRYAD’ database  and EmpowerStats . P values less than 0.05 (two-sided) were considered statistically significant.Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed in frequency or as a percentage. The One-Way ANOVA , Kruskal Wallis H (skewed distribution) test and chi-square tests  were used to determine any statistical differences between the means and proportions of the groups. Fisher Exact for categorical variables with Expects<10. Multivariate logistic regression analysis was used to analyze the significant results between groups, both non-adjusted and multivariate-adjusted models were listed in the paper. According to the recommendation of the STROBE statement, we simultaneously showed the results of unadjusted, minimally adjusted analyses and those fully adjusted analyses. Adjusted covariates include gestational age, sex, birth weight, Duration of Cord Clamping (DCC) group (the 30-45s DCC group and the 60-75s DCC group), and delivery mode. Due to the small proportion of missing values, cases with missing data were deleted during the analysis. All of the analyses were performed with the statistical software packages R  subgroup, the 5 min Apgar score was significantly higher in the interval of ACS>48h group (6.9±1.7 vs. 6.1±2.0). And any red blood cell infusion during hospitalization at the NICU was significantly lower (92.3% vs. 70.8%). Other DR and NICU measurements did not differ between the two ACS groups.We compared the differences in the interval of ACS and neonatal outcomes between preterm infants at <32 weeks and <28 weeks of gestational age. The results of the univariate analysis are shown in In terms of neonatal mortality, compared with the interval of the ACS<48h group, the interval of the ACS>48h group had significantly lower mortality (9.5% vs. 2.1%). A similar reduction was observed in the <28-week GA subgroup (26.9% vs. 7.7%). Regarding neonatal morbidity, any IVH, severe IVH, and severe ROP were significantly lower in the interval of ACS>48h group. A similar reduction was observed in the < 28-week GA subgroup except for any IVH, in addition, in the < 28-week GA subgroup, the mortality of severe ROP also decreased significantly in the interval of ACS>48h group. There were no differences in survival without major morbidity, CLD, LOS, and NEC between the two ACS groups.As shown in The administration of ACS to reduce morbidity and mortality in newborns at risk of preterm birth before 34–35 weeks of gestational age has been widely accepted and it is now firmly established by guidelines across the world as an evidence-based suggestion , 13, 19.extremely preterm birth. We also found that infants receiving the interval of ACS>48h required less respiratory intervention, had higher 1min Apgar and had a significantly lower risk of ROP.In the present study, we found a clear association between the interval of ACS and survival in very preterm infants, the mortality of very preterm infants with an interval of ACS>48h was significantly decreased compared with those with the interval of ACS<48h, as well as in According to most international guideline recommendations, prenatal corticosteroids should be administered within seven days before a premature birth , 19, 20.In terms of neonatal mortality, our results are consistent with these findings, in addition, due to the beneficial effects of ACS on the respiratory and cardiovascular systems , 28, higAn important finding in our study was that the interval of ACS>48 hours was associated with a significant reduction in ROP, at present, there is a lack of studies focusing on the interval of ACS and ROP in preterm infants. The retina of a full-term infant is nearly complete at delivery, but the retina of a premature infant is immature at birth , the incOur study is a secondary study of the effect of ACS interval on neonatal outcomes in preterm infants, the interval of ACS was prospectively collected, and the sample size was adequate for analyses that adjusted for mortality and neonatal outcomes according to the interval of ACS and a number of potential confounding variables, and the results were stable and relevant to the management of pregnancies at risk for preterm delivery. However, it has limitations as a single center observational study. First, the original study did not include severely compromised infants who did not have spontaneous respiration and needed resuscitation immediately, some of these preterm infants were already treated for ACS, so the exclusion may have introduced some bias. Second, this observational study itself includes unavoidable possible confounding elements, so in order to reduce these biases, we strictly apply statistical correction to reduce residual confounding. Third, due to raw data limitations, we can not obtain the specific time interval of prenatal exposure to ACS, so the group with ACS > 48 hours was mixed with people with ACS>1 week, some cohort studies have found that increased mortality and adverse outcomes with an ACS administration-to-birth interval exceeding 7 days , 34–36, In conclusion, this study shows that in very preterm infants, compared with the interval of ACS<48h, the interval of ACS>48 hours has a significant health promotion effect, this finding is important for clinicians when managing very preterm infants, which may help reduce infant mortality and retinopathy of prematurity.S1 Data(XLSX)Click here for additional data file.


Negative effects of impaired postpartum mother-infant-bonding on mental health of mothers, their newborn children and subsequent child development are well documented. Previous research demonstrated an association between a negative birth experience and postpartum mental health affecting postpartum mother-infant bonding. This study investigates the extent to which prepartum depression and birth experience influence the postpartum mental health of mothers and their bonding toward their newborns, and whether these influences differ according to parity and self-reported prior mental health problems.M = 30.13, SD = 5.10) filled in the Edinburgh Postnatal Depression Scale (EPDS), the Maternal-Fetal Attachment Scale (MFAS), Salmon's Item List (SIL) assessing the birth experience, and the Postpartum Bonding Questionnaire (PBQ) at pre- and postpartum; they were also asked about birth complications and parity status.Three hundred and fifty-four women , with path analysis confirming this result (p < 0.001). Birth complications were associated with a more negative rating of the overall birth experience (p < 0.001). Mothers with self-reported prior mental health problems had higher prepartum depression scores (p < 0.001) but did not differ in other variables from mothers without prior self-reported mental health problems. Differences in depression scores between mothers with self-reported prior mental health problems and those without vanished at postpartum assessment (p > 0.05). Path-analysis highlighted the key role of postpartum depression, which was the only significant predictor of postpartum impairment in maternal-child bonding (p < 0.001). Birth experience and prepartum depression scores exerted an indirect effect on postpartum maternal-child bonding, mediated by postpartum depression.Primipara reported significantly more birth complications (The present study demonstrates the relevance of prepartum mental health of expectant mothers, especially of those who self-report prior mental health problems. The results support that reducing mental health problems of pregnant mothers might contribute to a more positive birth experience and potentially reduce postpartum depressive symptoms. As postpartum depression is associated with impaired parent-child bonding, such targeted interventions could promote child development. Group differences between primiparous and multiparous mothers suggest that the birth experience may be an influential factor for postpartum mental health. Pregnancy and childbirth are life-changing events for parents. This time is associated with many positive feelings like anticipation and excitement, but also with negative ones like fear and uncertainty –3. In adAll events occurring between the first week of gestation until onset of childbirth are considered prepartum. Apart from the physical challenges that a pregnant woman may have to confront, e.g., water retention, (permanent) heartburn, impaired mobility, or gestational diabetes , 6, otheApart from depressive symptoms, other mental stressors can influence the psychological well-being of mother and child. For example, prepartum anxiety is associated with obstetric interventions , 21 and Birth refers to the delivery of the child and all factors that can occur during child birth. Risk factors negatively affecting the well-being and health of the mother and her newborn can also occur during childbirth. Birth complications are frequent and often unexpected , 27. UmbStudies have shown that prepartum expectations are a significant moderator of birth and postpartum experiences , 38. AyeThe term postpartum designates all events after childbirth. However, recovery from birth injuries or hormonal changes can take much longer , 16. In There is a relatively high risk for the development of mental health problems in the postpartum period . PostparAttachment, which is more relational and describing two-ways (from child's perspective toward the mother and vice versa) and bonding, which describes only one direction, e.g., in our study the sensations and feelings of a mother toward her child—and not the other way around. Throughout the remainder of the article we will use the term bonding for those feelings from mother to child. Bonding between parent and child begins prepartum  will be the main predictor for impaired postpartum maternal-child bonding.Recruitment took place via gynecological practices, the University Hospital Giessen-Marburg (UKGM), various midwives and the birth center Marburg. Study information and questionnaires were handed out by the first author in a one-on-one interview or in a group setting . In addition, flyers with information about the online survey were distributed in various facilities such as daycare centers and pediatricians' offices. With the onset of the COVID-19 pandemic, the survey was mainly conducted online and disseminated on various social media internet sites.Our study was a longitudinal analysis with two assessments. Data collection was conducted from November 2019 until February 2021. Participants were asked to complete a self-assessment questionnaire before and within 6 months after childbirth. At the beginning of the study, expectant mothers were approached in person to complete a paper-pencil version of the questionnaire battery. With the onset of the COVID-19 pandemic, an online survey was launched to enlarge our sample via dissemination on social media networks. Apart from a current pregnancy there were no specific inclusion criteria for participation. In addition to the questionnaire, other ethically relevant documents were presented to the participants. Furthermore, participants had the option to provide an e-mail address if they wanted to receive a reminder about filling out the postpartum questionnaire.The study was approved by the Local Ethics Committee of the Department of Psychology at Philipps University Marburg (UMR) under the file number 2019-18k. All participants were informed about the general conditions regarding data protection, anonymity, and prerequisites. All participants received written study information and provided written informed consent to study participation. In order to be allowed to participate, a declaration of consent was signed by all participants or accepted via the online portal by “clicking” on a mandatory field. The participants were informed about their right to withdraw and about the procedure for deleting the data. A transparent explanation of data handling and participation revoke was ensured, and the voluntary nature of participation was highlighted. Anonymization was achieved with a personal code that participants assigned themselves. All data collected were kept confidential. Attention was drawn to the confidentiality of all project participants, and e-mail addresses. Expected birth dates were collected and kept separate from questionnaire data. It was guaranteed that no retroactive assignment of the data to the corresponding participants could take place.The data was collected via two self-assessment questionnaires (pre- and post-childbirth). In the first part of both questionnaires, participants completed a brief survey on general demographics such as age, educational attainment, number of children, and further self-reported whether they had experienced a prior mental disorder . The second part of the prepartum questionnaire contained questions regarding pregnancy and birth, such as experiences with abortions or stillbirths, gestation week, participation in a childbirth preparation course and complications during previous labors. The questionnaire administered postpartum contained questions about complications during the last childbirth (“Did you experience complications during your last birth?”) and difficulties in the postpartum period (“Are you having any problems in the postpartum period?”). The remaining parts of the survey were supplemented by standardized measurement questionnaires: The Edinburgh Postpartum Depression Scale (EPDS) was used both at pre- and post-partum to assess depressive symptomatology; the Maternal-Fetal-Attachment Scale (MFAS) was used for prepartum and the Postpartum-Bonding-Questionnaire (PBQ) for postpartum mother-child bonding; birth experience was assessed within the postpartum questionnaire using the Salmon's Item List (SIL). All standardized measures are explained in more detail below.r = 0.81 and internal consistency of α = 0.82, the German EPDS version demonstrates psychometric properties as good as the original version  is a widely used self-report instrument assessing postpartum depression, consisting of 10 items on a four-point Likert scale . Due to  version . Murray  version  validate version  conducte version  for desc version , the posICC = 0.77, Cronbach's alpha = 0.81) for the total scale  is a self-assessment questionnaire assessing prepartum mother-fetus bonding . It was al scale . The MFAThe Salmon's Item List (SIL) is a bipolar adjective scale assessing subjective birth experience on three subscales: “physical discomfort” “emotional distress” and “fulfillment” . For thiThe Postpartum Bonding Questionnaire (PBQ) is a self-report screening instrument for the early assessment of maternal postpartum bonding problems and has demonstrated satisfactory interrater reliability . Reck etN = 223). The mean age prepartum was M = 30.13 years (SD = 5.10), postpartum M = 31.32 (SD = 4.86). The majority of participants had at least a high school diploma (55.6%). A total of 38.7% (n = 138) of the women claimed to be multiparous, whereas 53.4% (n = 189) reported being primiparous. Median gestation was 27 weeks  at our prepartum survey. The pregnant mothers divided into n = 32 (9.0%) in the first (1st-12th week gestation), n = 163 (46.0%) in the second (13th-28th week gestation) and n = 154 (43.5%) in the third (29th-40th week gestation) trimester. In our postpartum sample of the survey (N = 131), the mean age of newborns was 8 weeks . We formed three age groups for the newborns: 0-2 weeks n = 6 (4.6%), > 2 weeks <2 months [2nd-8th week of life: n = 88 (67.2%)], > 2 months and older [9th-24th week of life: n = 33 (25.2%)]. At the prepartum assessment, 15.3% of participating women reported suffering from prior mental health problems. At postpartum this proportional share rose by 3.8-19.1%. For detailed information on our sample's characteristics, see A total of 354 pregnant women participated in our prepartum survey. The postpartum survey was completed by 131 mothers, resulting in a dropout rate of 62.0% (t-Tests (for continuous variables), and χ2-tests or Fisher's exact test . In case of varied inhomogeneity, a Welch correction was executed. Reported p-values were corrected via Bonferroni-Holm adjustment. The groups were compared by applying these dependent variables: “prepartum depressive symptoms” (EPDS1), “postpartum depressive symptoms” (EPDS2), “birth experience” (SIL), “prepartum fetal bonding” (MFAS), “impairment in postpartum maternal-infant bonding” (PBQ), “birth complications” (birthcompl), and “difficulties postpartum” (DiffPuerp).To examine differences between dropouts and completers, between primiparas and multiparas, and between mothers with and without self-reported prior mental health problems, we conducted a combination of ANOVAs and via self-reported prior mental health problems (mentdis1); (2) the prediction of the birth experience (SIL) via reported birth complications (birthcompl), which in turn should be predicted by parity (primipara); and (3) the direct and indirect effects between the prepartum (EPDS1) and postpartum depression score (EPDS2), partially mediated by birth experience (SIL). Pathways from the birth experience (SIL) and prepartum depressive symptomatology (EPDS1) to postpartum bonding impairment (PBQ) are also mapped, which should not be significant according to our assumptions. Therefore, based on our theory, only the postpartum depression score (EPDS2) remains as a significant predictor of postpartum bonding impairment (PBQ).t-values were then tested for significance. We considered a p-value of ≤ 0.05 to be significant. To evaluate the structural model, the coefficient of determination R2 can be used. Values of at least 0.75, 0.50, and 0.25 for endogenous latent variables are considered substantial, moderate, or weak, respectively  and subjects with missing data (n = 354) after imputation with the method of k nearest neighbor (kNN) using R package VIM  predicting maternal bonding operationalized by the PBQ. PLS-SEM can be regarded as a variant of structural equation modeling which uses an ordinary least squares regression-based method (OLS) in contrast to the maximum likelihood estimation procedure in covariance-based structural equation modeling. PLS-SEM is a variance-based approach and can handle small sample sizes, complex models, and makes almost no assumptions about the level of measurement of data . To evalectively . The effectively . A limitkage VIM . PLS-SEMkage VIM .p-values and effect sizes of the unifactorial analysis of variance (ANOVA), done to examine group differences between mothers with and without self-reported prior mental health problems and between primi- and multiparous mothers.FEPDS1  = 17.02, p < 0.001, adj. p < 0.001, η2 = 0.21, CI of η2). This effect disappeared postpartum  = 0.59, p = 0.444, adj. p > 0.05, η2 <0.01, CI of η2). Descriptive examination of clinically relevant cases concerning depressive symptomatology, shown in Consistent with our expectations, mothers who self-reported prior mental health problems demonstrated significantly higher depression scores prepartum  = 0.67, p = 0.414, adj. p > 0.05, η2 <0.01, CI of η2 nor postpartum in their subjective birth experience  = 6.52, p = 0.012, adj. p = 0.06, η2 =.05, CI of η2), in postpartum bonding impairment  = 0.40, p = 0.529, adj. p > 0.05, η2 <0.01, CI of η2) or in the number of reported birth complications .We detected no other significant effect in either the prepartum maternal-fetal bonding  = 4.45, p = 0.036, adj. p = 0.150, η2 = 0.01, CI of η2), MFAS  = 0.41, p = 0.522, adj. p = 0.522, η2 <0.01, CI of η2) and SIL  = 4.85, p = 0.030, adj. p = 0.150, η2 = 0.04, CI of η2).ANOVAs revealed no significant group differences between primipara and multipara in the continuous variable EPDS at T1  = 4.03, p = 0.047, adj. p = 0.150, η2 = 0.03, CI of η2) and PBQ  = 2.23, p = 0.138, adj. p = 0.276, η2 = 0.02, CI of η2), but primiparous were more likely to report birth complications than multiparous mothers .Neither were there any group differences in EPDS at T2 , age, number of children at the prepartum time, highest educational attainment, and prepartum maternal-fetal bonding (MFAS). Participants who failed to complete the second questionnaire were significantly younger at the prepartum time , and had more children . After alpha adjustments, they did not differ in prepartum depression , maternal-fetal bonding , educational attainment  or distribution of mothers with vs. without self-reported prior mental health problems .Our high dropout rate necessitated a dropout analysis. For this purpose, Cronbach's alpha and composite reliability are used as the lower and upper bounds to assess the internal consistency reliability of multi-item scales. Cronbach's alpha for EPDS1 was 0.797, its composite reliability was 0.844, for EPDS2 the values were 0.840 and 0.875, for SIL 0.858 and 0.888, and for the PBQ 0.869 and 0.888, respectively. All values can be classified as satisfactory.To evaluate convergent validity, we examined average variance extracted (AVE). The value for EPDS1 was 0.364, meaning that on average, the construct explains 36.4% of the variance of its indicators, which amounts to a construct's communality. For EPDS2 the value was 0.419, for SIL it was 0.418, and for the PBQ it was 0.340. The threshold of 0.50 was not reached, which is not surprising as the AVE is calculated as the sum of the squared loadings divided by the number of indicators. As most of the loadings were below 0.708 , an AVE All of the indicators' loadings on the associated variables have higher loadings than their correlations with the other constructs. Thus, our data meet the first criterion of discriminant validity. All HTMT ratios were well beyond 0.85 and therefore discriminant validity was met.We examined multicollinearity by relying on the variance inflation factor (VIF). As just two SIL items slightly exceeded the threshold of 5, relevant multicollinearity cannot be assumed .2 adjusted value after bootstrapping for maternal bonding (PBQ) was 0.408 and thus tended to move in a moderate direction.The R2 effect size of 0.258 after bootstrapping showed a substantive impact of EPDS2 on maternal bonding (PBQ). The impacts of EPDS1 (0.054) and SIL (0.033) on maternal bonding (PBQ) were small, while another substantive impact of SIL on EPDS2 (0.226) was evident.A medium fThe same model displayed in We used Cronbach's alpha and composite reliability as the lower and upper bounds to assess the internal consistency reliability of multi-item scales. Cronbach's alpha for EPDS1 was 0.804, composite reliability was 0.851, for EPDS2 the values were 0.819 and 0.861, for SIL post 0.796 and 0.805, and for the PBQ 0.848 and 0.871, respectively. All values can be classified as satisfactory.We again examined AVE to assess convergent validity. The EPDS1 value was 0.373, meaning that on average, the construct explains 37.3% of its indicators' variance. The value was 0.402 for EPDS2, 0.295 for SIL post, and 0.312 for the PBQ. The threshold of 0.50 was not reached, but most factor loadings are nevertheless acceptable .All of the indicators' loadings on the associated variables have higher loadings than their correlations with the other constructs; our data thus meet the first criterion of discriminant validity. All HTMT ratios were well beyond 0.85, thereby fulfilling discriminant validity2 adjusted value after bootstrapping for maternal bonding (PBQ) was 0.489 and thus moved in a moderate direction.The R2 effect size of 0.579 after bootstrapping showed a strong EPDS2 impact on maternal bonding (PBQ). The impacts of EPDS1 (0.01) and SIL (0.007) on maternal bonding (PBQ) were negligible, while another substantive impact of SIL post on EPDS2 (0.234) was evident.A medium fOur analyses support our first hypothesis, that mothers with a self-reported prior mental health problem differ significantly from mothers without such prior problems. Mothers with prior mental health problems reported more depressive symptoms according to EPDS scores, in line with other findings of the field . HoweverRegarding our second hypothesis, we were able to demonstrate significant differences between primiparous and multiparous mothers. Primipara reported more birth complications , 44 whicWith respect to our fourth hypothesis, our results demonstrate that birth experience is influenced by prepartum depression scores as well as by birth complications . Prepartum depression scores and birth experience had an independent effect on the postpartum depression scores and those proved to be the main predictor for impaired postpartum maternal-child bonding, moderated by prepartum depressive symptoms and birth experience, thus proving our final hypothesis. The results of our pathway analysis confirm the influence of postpartum depression symptomatology on postpartum bonding shown in prior research , 75, 76.Overall, our findings demonstrate how different pregnancy- and birth-related variables can influence each other and affect the mental health of mothers and subsequently their child bonding. It is therefore essential that we continue to improve our understanding of how exactly pre- and post-partum mental health as well as the birth experience affects the mental health of mothers and their newborn. In particular, the potential association between a negative birth experience and postpartum posttraumatic stress disorder , 113 shoThere are several limitations to be considered. First, we were not able to continue recruiting in person due to the onset of the COVID-19 pandemic and had to resort to a digital questionnaire, which made it almost impossible to foster feelings of commitment and interest of the participants regarding our post-survey. The pandemic has caused additional psychosocial stress in almost all areas of life and for some time partners were not allowed to be present at birth. Those multidimensional stressors  could haSecond, drop-out rates were large. Analysis indicated that mothers who dropped out were younger and had more children, though they did not differ from completers with respect to prepartum depression scores, self-reported mental health problem, maternal-fetal bonding and educational attainment. Thus, the analyses with data imputation are not biased in that respect. However, having more children does require more capacities from parents and it might be that families with younger mothers are still in a phase of consolidating family and work which is highly demanding. As reminder letters were a voluntary option, mothers may not have remembered the survey after the birth of their child. Or else, those mothers who did remember may have been particularly healthy and not as stressed in the postpartum period, which could represent a further bias in the sample. Therefore, to compensate for missing post-measurements, we conducted thorough statistical analyses on the complete pre- and post-data set and replicated results with imputations with the method of k-nearest neighbor, that resulted in similar findings.Third, previous research found differences in depression symptoms and fear of childbirth over the course of pregnancy. While we had mothers in all stages of pregnancy (1st to 3rd trimester) this unstandardized assessment might have influenced results.Fourth, mental health problems were only assessed based on self-report with one question in the pre- and post-partum survey. Additionally, the number of participants reporting (prior) treatment of a mental disorder was small. Those questions were dummy coded (yes/no) for analyses. There is the possibility of mothers not answering truthfully, although we assume that mothers who do report on prior mental health problems and birth complications did in fact experience those. Still, those aspects limit the validity and clinical implications of the result. In follow-up studies, participants should undergo a comprehensive clinical examination in addition to self-report questionnaires to obtain more valid information about the mental health and potential diagnosis.Fifth, we did neither assess whether pregnancies were planned nor cultural background. An unplanned pregnancy might be a pleasant surprise or a significant stressor, and factors such as cultural background affect this. Such stress factors should thus be addressed in the future.Sixth, we did not assess physical complaints/symptoms during or after pregnancy. As outlined in the introduction, such physical complaints , 6 have Last, though we aimed at including partners, the sample of participating partners was so small that it was not possible to include them in analyses. Partners play a crucial role during pregnancy and in the postpartum period as depression scores of mothers and their partners correlate significantly and are predicted by perceived parenting stress . While tThis study demonstrates that mother-child bonding is significantly influenced by maternal postpartum depressive symptoms, and those are predicted by prepartum depressive symptoms as well as the birth experience. Accordingly, pregnant females should undergo regular screening during pregnancy to facilitate early identification and treatment of mental health problems. Postpartum aftercare should be offered more frequently and continue until at least the infant's first birthday, focusing not only on the child's development, but also on the mother's psychological well-being, especially concerning postpartum depression symptomatology.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Department of Psychology at Philipps-University Marburg (UMR) under file number 2019-18k. The patients/participants provided their written informed consent to participate in this study.HC and PE contributed to conception and design of the study. SK supported site recruitment. PE organized study implementation and data collection and wrote the first draft of the manuscript. PE and OH performed statistical analysis. All authors contributed to manuscript revision, read, and approved the submitted version.Open Access funding provided by the Open Access Publication Fund of Philipps University Marburg with support of the Deutsche Forschungsgemeinschaft .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. Leah Millard, The University of Manchester, UK in collaboration with reviewer MWW.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Biological aging and particularly the deviations between biological and chronological age are better predictors of health than chronological age alone. However, the predictors of accelerated biological aging are not very well understood. The aim was to determine the role of birth outcomes, time of puberty onset, body mass index (BMI), and body fat in accelerated biological aging in the third decade of life.n = 262) to determine the role of birth outcomes, pubertal timing, BMI, and body fat on biological aging. Birth outcomes included birth weight, length, and gestational age at birth. Pubertal timing was determined by the presence of secondary sexual characteristics at the age of 11 and the age of first menarche in women. Biological age was estimated using the Klemera-Doubal Method (KDM), which applies 9-biomarker algorithm including forced expiratory volume in one second (FEV1), systolic blood pressure, glycated hemoglobin, total cholesterol, C-reactive protein, creatinine, urea nitrogen, albumin, and alkaline phosphatase. Accelerated/decelerated aging was determined as the difference between biological and chronological age (BioAGE).We have conducted a second follow-up of the Czech part of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC-CZ) prenatal birth cohort in young adulthood  and late 20s (R2adj = 0.22)], subcutaneous (R2adj = 0.21) and visceral fat (R2adj = 0.25), puberty onset (ηp2 = 0.07), birth length (R2adj = 0.03), and the increase of BMI over the 5-year period between the two follow-ups in young adulthood (R2adj = 0.09). Single hierarchical model revealed that shorter birth length, early puberty onset, and greater levels of visceral fat were the main predictors, together explaining 21% of variance in accelerated biological aging.The deviations between biological and chronological age in young adulthood ranged from −2.84 to 4.39 years. Accelerated biological aging was predicted by higher BMI [in both early (ROur findings provide comprehensive support of the Life History Theory, suggesting that early life adversity might trigger accelerated aging, which leads to earlier onset of puberty but decreasing fitness in adulthood, reflected by more visceral fat and higher BMI. Our findings also suggest that reduction of BMI in young adulthood slows down biological aging. We live in an era of unprecedented aging . The perTo measure the aging process, US National Health and Nutrition Survey (NHANES) studied participants aged 30–75 years and developed a 10-biomarker-based measure of “Biological Age”, which was more successful in predicting mortality in the 20-year follow-up than chronological age . Using tGrowing evidence in the last decade suggests that higher Body mass index (BMI) can have detrimental effect on life expectancy –12. ObesHigher BMI in adulthood was associated with earlier onset of puberty , 18, anoAccording to Belsky and Shalev , 24, earThis emerging evidence suggests that higher mortality in adulthood is associated with accelerated biological aging, which might have its roots in early life. The current study aims to use data from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC-CZ) prenatal birth cohort  and its n = 110, 51% men) also took part in the first follow-up of this prenatal birth cohort at the age of 23–24 years, entitled Biomarkers and Underlying Mechanisms of Vulnerability to Depression   participated in the Health Brain Age project at the Central European Institute of Technology, Masaryk University (CEITEC MU), a follow-up of the Czech part of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC-CZ) (n = 131) , and thu2). Total body fat and amount of visceral fat in young adulthood were estimated by bio-impedance using the scale Tanita BC-545 N. The bio-impedance scale was used in a standardized manner for all participants; the procedure followed the collection of fasting blood sample, and all participants were provided water during the consent procedure. All participants were also instructed not to drink alcohol the day before. Subcutaneous fat in young adulthood was measured with skinfold calipers at four locations  using a standard procedure and the mean of these four measures (in millimeters) was used in the subsequent analyses.Weight and height were measured once at birth and twice in young adulthood . BMI in young adulthood was calculated as the ratio of the participant’s weight (kg) and height  on a scale from 1 (least developed) to 4 (most developed). Participants with less developed secondary sexual characteristics at the age of 11 were classified as the early puberty onset group. In women, the age of menarche served as an additional predictor of puberty onset.In the late 20s, forced expiratory volume in one second (FEV1) was calculated using MIR Smart One Spirometer. Systolic and diastolic blood pressure were assessed according to standard protocols. Blood samples were taken in the morning before the first meal. Cholesterol, C-reactive protein (CRP), glucose, albumin, creatinine, urea nitrogen serum levels (mg/dL) as well as alkaline phosphatase activity in serum (U/L) were measured on ROCHE analyzer . The percentage of glycated hemoglobin was calculated based on glucose levels according to published equations and recommendations of the international consensus statement –37.Biological age was calculated using Klemera-Doubal Method (KDM), available through the R package “Bio-Age”  that appAll statistical analyses were performed in SPSS version 28.0.0 (IBM SPSS Statistics). First, we assessed the distribution of data, and variables that did not follow a normal distribution were transformed using logarithmic transformation. Outliers that were greater than three standard deviations were removed from the analysis.t-test. Group by puberty onset interaction was assessed using two-way ANOVA. Multiple comparisons were corrected using the False Discovery Rate (FDR) method and thus FDR-corrected p-values larger than 0.05 were considered significant.Measures of secondary sexual characteristics were fed into Two-Step Cluster Analysis (separate for both sexes) using Schwarz’s Bayesian Criterion to automatically detect clusters. Linear regression was used to assess the predictors of BioAGE. In each model where men and women were treated as one group, sex and the interaction between sex and the predictor were treated as covariates. The significant predictors were then used in a hierarchical multiple linear regression to assess the multiple predictors of BioAGE within a single model. Predictors entered the model following the order of the lifetime: 1. Birth length, 2. Puberty onset, 3. Fat measures in adulthood . Two analogous models were estimated: one for the whole group with sex as a covariate, and another one for women only, where the year of the first menarche was used as a more precise measure of puberty onset. Simple group differences were analyzed using an independent samples While all participants were 28–30 years old, their current biological age ranged from 26.07 to 34.20 years, and thus their BioAGE ranged from −2.84 to 4.39 years .2adj = 0.22, F = 25.03, β = 0.10, p < 0.001], overall body fat , subcutaneous fat  and visceral fat . In addition, we found an interaction effect between sex and BMI  and between sex and visceral fat .BioAGE in the late 20s  was predPost-hoc regressions in each sex revealed that BioAGE in late 20s was predicted by BMI in both women  and men , and by visceral fat in both women  and men .2adj = 0.05, F = 3.09, β = 0.04, p = 0.037], overall body fat  and subcutaneous fat . There were no interactions with sex (p = 0.022).BioAGE in the early 20s  was sign2adj = 0.09, F = 4.39, β = 0.08, p = 0.009] and subcutaneous fat , but not of overall body fat (p = 0.431) over the 5-year period in young adulthood were associated with lower BioAGE in late 20s (p = 0.189).Decrease of BMI , higher BMI , overall body fat , subcutaneous fat  as well as visceral fat  in late 20s than the late puberty onset group (p = 0.053).Two-way ANOVA revealed a significant effect of puberty timing on BioAGE, BMI as well as body fat. Early puberty onset group had more accelerated BioAGE , higher BMI , higher overall body fat , subcutaneous fat  and visceral fat  than late puberty onset group (p = 0.261). Complete statistics is reported in Sex-specific by women . In womeet group . No simip < 0.001]  = 6.13, β = 0.26, p = 0.015]  = 3.93, < 0.001]  and earl= 0.015] .2adj=0.03, F=3.61, β=−0.08, p = 0.042], but no significant relationship emerged between birth weight (p = 0.127) or the duration of gestation (p = 0.843) and BioAGE (see p = 0.382).Shorter birth length was associated with higher BioAGE . While birth length explained 3.7% of the variance , early puberty onset explained additional 5.2% , and visceral fat another 12.1% . For every cm of birth length, BioAGE decreased by 0.119 years . Participants with early puberty onset had on average 0.56 years more advanced BioAGE than those with late puberty onset . For every% of visceral fat, BioAGE increased by 0.167 years . The effect of subcutaneous fat did not reach significance in the multiple regression (p = 0.737). Complete statistics with all regressors are in Multiple regression evaluating the effects of birth length, puberty onset, and visceral and subcutaneous fat in the late 20s on BioAGE in the whole sample showed that all the predictors together explained 21% of the variance in biological aging . While birth length explained 6.9% of the variance , adding year of first menarche explained additional 0.9% although not significant , and body fat another 22.2% . For every cm of birth length, BioAGE decreased by 0.137 years . For every% of visceral fat, BioAGE increased by 0.247 years . The effect of first menarche (p = 0.149) and subcutaneous fat (p = 0.634) did not reach significance in the multiple regression. Complete statistics with all regressors are in Similar multiple regression in women, where we could use the age of menarche as a more accurate measure of puberty timing, showed that the whole model explained even 30% of the variance [RWe studied biological aging in young adults from the ELSPAC-CZ prenatal birth cohort and demonstrated that accelerated biological aging in young adulthood was associated with higher BMI as well as higher overall, subcutaneous, and visceral body fat, with visceral fat showing the strongest association. Moreover, we showed that the effects of BMI and body fat on biological aging are stable–present in both early and late 20s–and reach a greater effect size in women as compared to men. Most importantly, we demonstrated that reduction of BMI over the 5-year period between the measurements was associated with decelerated biological aging, suggesting that reducing weight over a relatively short period of time during adulthood can possibly slow down the pace of biological aging.These findings extend previous prospective cohort studies, which linked higher BMI –12 and bThe relationships between accelerated biological aging and higher BMI in both the late and early 20s demonstrate the stability of the effect. But interestingly, a reduction of BMI over the 5-year period predicted lower BioAGE, suggesting that we might be able to slow down the speed of our biological aging by relatively accessible management options. This is in agreement with previous research suggesting dieting  and caloEarly puberty onset was another key predictor of accelerated biological aging, particularly in women. This is in agreement with previous studies that found a relationship between earlier menarche and accelerated epigenetic aging in women , 23. WhiWe found only limited evidence for the hypothesized early life origins of biological aging. In particular, newborns who were shorter (but not lighter or younger) at birth were aging faster in their late 20s. This might be related to the fact that all our participants fell within the healthy range and the low variance in gestational age and birth weight might not have allowed us to detect any significant relationships with biological aging in young adulthood.Finally, combining predictors of BioAGE from birth to adulthood allowed us to explain up to 21% of the variance in the whole sample and up to 30% of the variance in the women’ group. Interestingly, visceral but not subcutaneous fat was a significant predictor of BioAGE. While both types of fat have been associated with increased morbidity , 50, theOverall, our findings support the Life History Theory, according to which early pubertal maturation can be accounted for accelerated biological aging . The ratOur study has several limitations that need to be acknowledged. First, the sample size is considerably small, which can be, at least in part, attributed to the longitudinal design of our study. Second, members of our prenatal birth cohort were not born preterm and had a healthy birth weight, limiting the possibility to study the impact of birth outcomes. Third, while our study uses longitudinal data for the predictors, the blood sample to estimate biological age was collected only at a single point at the late 20s. Further research is needed to assess the stability of the biological age gap (BioAGE) across the lifespan. Fourth, potential confounders such as lifestyle and dietary behavior might have affected the results and should be considered by future studies. Finally, this is a correlational study and therefore does not allow us to prove causal relationships between BioAGE and its predictors.In conclusion, using longitudinal data on the ELSPAC-CZ prenatal birth cohort, we demonstrated that birth length, puberty timing, and visceral fat predict biological aging in young adulthood. In particular, the results of our study provide comprehensive support for the Life History Theory, suggesting that early life adversity might trigger accelerated aging, which in turn leads to earlier pubertal timing but decreasing fitness in adulthood, reflected by higher visceral fat and BMI. Moreover, we discovered that a reduction of BMI in young adulthood might slow down biological aging.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by European Longitudinal Study of Pregnancy and Childhood (ELSPAC-CZ) Ethics Committee. The patients/participants provided their written informed consent to participate in this study.MJ: investigation, formal analysis, and writing the original draft. LZ: investigation. PP: resources. LA: resources. MB: review and editing. KM: conceptualization, methodology, supervision, funding acquisition, review, and editing. All authors contributed to the article and approved the submitted version.


To investigate the risk of preterm birth in women with a placenta previa or a low-lying placenta for different cut-offs of gestational age and to evaluate preventive interventions.MEDLINE, EMBASE, CENTRAL, Web of Science, WHO-ICTRP and clinicaltrials.gov were searched until December 2021. Randomized controlled trials, cohort studies and case-control studies assessing preterm birth in women with placenta previa or low-lying placenta with a placental edge within 2 cm of the internal os in the second or third trimester were eligible for inclusion. Pooled proportions and odds ratios for the risk of preterm birth before 37, 34, 32 and 28 weeks of gestation were calculated. Additionally, the results of the evaluation of preventive interventions for preterm birth in these women are described.In total, 34 studies were included, 24 reporting on preterm birth and 9 on preventive interventions. The pooled proportions were 46% (95% CI [39 – 53%]), 17% (95% CI [11 – 25%]), 10% (95% CI [7 – 13%]) and 2% (95% CI [1 – 3%]), regarding preterm birth <37, <34, <32 and <28 weeks in women with placenta previa. For low-lying placentas the risk of preterm birth was 30% (95% CI [19 – 43%]) and 1% (95% CI [0 – 6%]) before 37 and 34 weeks, respectively. Women with a placenta previa were more likely to have a preterm birth compared to women with a low-lying placenta or women without a placenta previa for all gestational ages. The studies about preventive interventions all showed potential prolongation of pregnancy with the use of intramuscular progesterone, intramuscular progesterone + cerclage or pessary.Both women with a placenta previa and a low-lying placenta have an increased risk of preterm birth. This increased risk is consistent across all severities of preterm birth between 28-37 weeks of gestation. Women with placenta previa have a higher risk of preterm birth than women with a low-lying placenta have. Cervical cerclage, pessary and intramuscular progesterone all might have benefit for both women with placenta previa and low-lying placenta, but data in this population are lacking and inconsistent, so that solid conclusions about their effectiveness cannot be drawn.https://www.crd.york.ac.uk/prospero/, identifier CRD42019123675.PROSPERO  Women with a placenta previa, overlying the internal os of the cervix, or a low-lying placenta, within 20 millimeter (mm) of the internal os of the cervix, have an increased risk of maternal and fetal complications during pregenancy , 2. The The risk of neonatal morbidity and mortality depends mainly on the severity of the prematurity , 24. It To a greater and lesser extent, cerclage, pessary and progesterone are known interventions that prolong gestation in women at high-risk of preterm delivery –27. Yet,This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement . The revWomen with a placenta previa or a low-lying placenta are the subject of this systematic review. When possible, we compared women with placenta previa to women without placenta previa or with women with a low-lying placenta. All possible preventive interventions for preterm birth described for these women were evaluated.An information specialist (JL) performed a systematic search in OVID MEDLINE, OVID EMBASE, Web of Science, the Cochrane Controlled Register of Trials (CENTRAL) and the prospective trial registers clinicaltrials.gov and WHO-ICTRP from inception to December 6th, 2021. The search strategy consisted of controlled terms, including MESH-terms, and text words for placenta previa or low-lying placenta and preterm birth. Randomized controlled trials, cohort studies and case-control studies assessing preterm birth in women with placenta previa or low-lying placenta of the internal os in the second or third trimester were eligible for inclusion. Animal studies, conference abstracts, reviews and case reports were (safely) excluded if appropriate. We applied no date or language restrictions. We cross-checked the reference lists and the citing articles of the identified relevant papers in Web of Science and adapted the search in case of additional relevant studies. The bibliographic records retrieved were imported and de-duplicated in ENDNOTE. To evaluate the interventions a similar search strategy was performed on interventions, e.g. cerclage, pessary and progesterone to prevent preterm birth in women with placenta previa or low-lying placenta.Articles were selected in a staged process using the electronic screening tool RAYYAN. Two reviewers  independently screened titles and abstracts of all retrieved articles and selected potentially eligible studies. Both reviewers then independently examined the full-text papers. Disagreements about inclusions were resolved by consensus or by consulting a third reviewer (CK). Over the years, various definitions have been used for placentas that are implanted in the lower part of the uterus such as; minor and major placenta previa, placenta previa totalis, placenta previa partialis, placenta previa marginalis and low-lying placenta. In this review, we have used the currently recommended definitions for placenta previa, overlying the internal os of the cervix, and low-lying placenta, not overlying but within 20 mm of the internal os , 31. AimA predesigned data extraction form was used by two independent reviewers to retrieve study characteristics from each included study. For studies on risk of preterm birth, extracted preterm birth outcomes were proportions  or odds ratios with 95% confidence intervals for preterm birth below 37, 34, 32 and 28 weeks of gestation, or gestational age at delivery. Data was extracted separately for women with a placenta previa or a low-lying placenta. For intervention studies, we extracted data on gestational age at delivery, prolongation of gestation (i.e. the time from randomization to delivery), or odds ratios with 95% confidence intervals for preterm birth.metafor and meta packages in Rstudio version 3.6.1.For studies reporting the results for more than one group, we compared women with placenta previa to women without placenta previa or with women with a low-lying placenta. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated for the risk of preterm birth before 37, 34, 32, and 28 weeks of gestation.Results of all studies reporting a proportion  of preterm birth before 37, 34, 32 and/or 28 weeks of gestation were pooled for women with placenta previa and for women with a low-lying placenta, as appropriate based on available data. Analyses of pooled proportions were performed using inverse of the Freeman-Tukey double arcsine transformation using To illustrate the effect of the interventions to prevent preterm birth in women with a placenta previa described in our overview, we calculated ORs with 95% CI for the risk of preterm birth or mean differences with 95% CI for gestational age at delivery and prolongation of gestation for women with and without preventive interventions . The meta-analyses were conducted using Review Manager version 5.3 from the Cochrane Collaboration. In all meta-analyses, a random-effects model was used.The quality of the studies was assessed with the Newcastle Ottawa scale. Articles with seven or more stars were found to be of high quality, four to five stars have moderate quality and articles with three or less stars were found to be of low quality. The Cochrane Handbook was used to judge the quality of each randomized controlled trial. To assess publication and small study bias, funnel plots were conducted, when at least 10 studies are available, because with fewer studies the power of the test is too low to distinguish chance from true asymmetry (Cochrane Handbook).The search identified 1653 unique records. Of these, 24 were included based on full-text –54. FigThe results of the quality assessment are shown in the The pooled proportions of preterm birth for women with a placenta previa and low-lying placenta are shown in The risk of a preterm emergency cesarean in women with a placenta previa is shown in Women with placenta previa were more likely to have a preterm birth before 37 weeks of gestation (risk difference 0.37 (95% CI [0.31-0.42]) and before 34, 32, and 28 weeks of gestation (OR 6.12 (95% CI [4.29-8.72]), OR 8.58 (95% CI [6.35 – 11.58]) and OR 5.61 (95% CI [4.02-7.83]) respectively) than women without placenta previa Figure 4The interventions to prevent preterm birth were reported in nine studies –63. TabProgesterone –Three studies investigated the use of intramuscular progesterone in women with a placenta previa. No intervention studies were found in which vaginal progesterone was used as a treatment. All studies reported on the mean gestational age at delivery, which was significantly higher in the group of intramuscular progesterone. The pooled effect on the use of intramuscular progesterone showed a significant prolongation of gestation in favor of the women treated with progesterone in two studies  vs. 36.0 (SD 2.00) weeks, p=0.032). However, the study was underpowered as the trial was stopped early before completion, secondary to slow enrolment and withdrawal of financial support by the sponsor. They did show however, that the number of antepartum admissions for bleeding was twofold higher in women randomized in the expectant management group , suggesting that a cervical pessary placement in women with a placenta previa is associated with reduction of antepartum bleeding leading to preterm delivery .The second study showed that in women with a placenta previa, already treated with progesterone because of a high risk of preterm birth due to other reasons, additional therapy of a pessary significantly reduced preterm delivery < 34 weeks (8.6 vs 23.5% P=0.031). Moreover, the use of a pessary in pregnancies with a placenta previa resulted in a three-fold reduction of the risk of bleeding during pregnancy and/or delivery  .Cerclage – Four studies compared a cerclage with expectant management in women with a low-positioned placenta. The pooled effect of all four studies comparing cerclage with expectant management was in favor of cerclage considering the prolongation of gestation  (– 5.54]) –60. Howe– 5.54]) , 59. AlsThis review found a high risk of preterm birth across all gestational ages for women with a placenta previa and in women with a low-lying placenta. More specifically, a higher risk of preterm birth was found in women with placenta previa compared to women with a low-lying placenta and compared to women without placenta previa. Three interventions for the prevention of preterm birth were investigated of which cerclage, pessary and intramuscular progesterone might have benefit, but data in this population are lacking and inconsistent, so that solid conclusions about actual effectiveness cannot be drawn.First, a major strength of this study is the broad search that was performed thereby including studies originated from various countries without a restriction for publication year. Second, our findings are in line with a review dating from 2015 reporting risks for preterm birth of 44% and 27% for placenta previa and low-lying placentas, respectively . However2 ranging between 62 -98%) between the included studies, which reduces the strength of evidence. Furthermore, there is only 1 outcome for which more than 10 studies could be included, so only 1 funnel plot could also be made to examine publication bias.Several limitations require to be commented as well. In general, the available studies on the interventions to prevent preterm birth are often more outdated, being 14 to 38 years old. Variation in equipment, technique and terminology could have impact on the interpretation of data and reliability of their conclusions. In addition, there was a large difference between the size of the included studies (ranging from 16 patients to 22 million patients) and the included patients differed greatly in gestational age. This results in high to very high heterogeneity  number of patients that can produce misleading results and some only involve a single study or two small studies - which is limiting the validity of a “meta-” analysis and ensures that a sensitivity analysis to the between-study heterogeneity has no added value. The same applies to the cohort studies, where there is also considerable heterogeneity between the studies. The small numbers of patients per cohort, the large variation in gestational age at inclusion, and the large variation in (obstetric) history seem to contribute mainly to this.The well-recognized high risk of preterm birth for women with a placenta previa or low-lying placenta is comparable with or even higher than other known high-risk pregnancies, for example women with a history of spontaneous preterm birth (sPTB) have a risk of 15-30% on sPTB before 37 weeks of gestation in their index pregnancy . HoweverStrong conclusions considering the interventions cannot be drawn, however we do suggest a benefit for progesterone, pessaries and cerclage. Progesterone acts primarily through maintaining uterine quiescence in the latter half of pregnancy, however the mechanism is unclear. Proximate to the onset of labor both term and preterm, progesterone activity withdrawals in the uterus. Therefore, progesterone supplementation in pregnancy may establish uterine relaxation, so it is reasonable to hypothesize that progesterone may be effective for women with a higher risk of preterm birth because of a placenta previa or low-lying placenta , 68, 69.However, given the previously described limitations, more profound and proper designed research of larger groups of patients, using the correct current definitions is necessary before incorporating preventive interventions in common practice.In conclusion, both women with a placenta previa and a low-lying placenta have an increased risk of preterm birth. This increased risk is consistent across all severities of preterm birth between 28-37 weeks of gestation. Women with placenta previa have a higher risk of preterm birth than women with a low-lying placenta. Progesterone, cervical pessary and cervical cerclage seem potentially effective preventive interventions for women with a placenta previa or low-lying placenta, but data in this population are lacking and inconsistent, so that solid conclusions about their effectiveness cannot be drawn.The original contributions presented in the study are included in the article/CJ, EL, and EP designed the paper outline. JH and AS conducted a preliminary search led by CJ. JL designed and performed a systematic search in consultation with CJ. CJ and CD conducted the search and consulted CK in case of disagreement. Data collection and analyses were conducted by CJ and CK. All authors  critically reviewed subsequent paper drafts and approved the submitted version. All authors agree to be accountable for all aspects of the work.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Over recent decades, there has been a global increase in preterm birth rate, which constitutes about 11% of total births worldwide. The present review aims to summarize the current knowledge on the long-term consequences of prematurity on renal and cardiovascular development and function. Recent literature supports that prematurity, intrauterine growth restriction or low birth weight (LBW) may have an adverse impact on the development of multiple organ systems, predisposing to chronic diseases in childhood and adulthood, such as arterial hypertension and chronic kidney disease. According to human autopsy and epidemiological studies, children born preterm have a lower nephron number, decreased kidney size and, in some cases, affected renal function. The origin of hypertension in children and adults born preterm seems to be multifactorial as a result of alterations in renal, cardiac and vascular development and function. The majority of the studies report increased systolic and diastolic blood pressure (BP) in individuals born preterm compared to full term. The early prevention and detection of chronic non-communicable diseases, which start from childhood and track until adulthood in children with a history of prematurity or LBW, are important. Over recent decades, there has been a global increase in preterm birth rate, which constitutes about 11% of the total number of births worldwide . PretermFirst, Barker observed an inverse association between birth weight and the incidence of CVD, such as ischemic heart disease, stroke and hypertension during adulthood. He advanced the question of “developmental programming”, that is, whether the intrauterine environment and the stress that is experienced during fetal and early postnatal life increase the risk of later-life chronic diseases, such as hypertension and chronic kidney disease . Since tNephrons are the functional units of kidneys whose formation begins at the ninth gestational week. The majority of nephrons are developed during the third trimester of pregnancy and complete at 34–36 weeks of gestation . The totAccording to human post-mortem autopsy studies, glomerulogenesis is markedly decreased in preterm infants, and the extra-uterine nephrogenesis continues to a maximum of 40 days after birth by the development of abnormal glomeruli without achieving a full complement of nephrons ,18,19. ASince there is no non-invasive method for correlating nephron number with kidney mass, many authors have used kidney volume as a surrogate marker  21,22,2,34,35,36However, findings from the studies that have examined long-term renal function after preterm birth are less conclusive. The parameters that have been examined in published literature are microalbuminuria as an early sign of hyperfiltration, albuminuria, levels of blood urea nitrogen, serum creatinine, serum cystatin C, estimated GFR (eGFR), impairments in electrolyte excretions and newer biomarkers of renal dysfunction, such as serum or urine neutrophil gelatinase-associated lipocalin (NGAL), symmetric dimethylarginine (SDMA) and serum b2 microglobulin  21,23,2,43,44,45The origin of HTN in children and adults born preterm may possibly be multifactorial as a result of alterations in renal, cardiac and vascular development and function of the neuroendocrine system. As mentioned above, according to Brenner’s theory, preterm birth leads to low nephron endowment and diminished filtration surface area, which results in restraint sodium excretion and elevated BP . MoreoveOver recent decades, the impact of prematurity or intrauterine fetal growth in the development of hypertension during childhood and adulthood has been a significant topic of interest in several studies. A recent meta-analysis showed that being born preterm was associated with 3.26 mmHg higher mean systolic BP and 1.32 mmHg higher mean diastolic BP compared to being born at term. Subgroup analyses demonstrated that higher systolic BP was identified from early adolescence until adulthood among those born preterm and that the difference in systolic BP was greater in the extreme and very preterm born individuals compared to term . In otheSeveral studies that examined kidney size, renal function and BP in children and adults have shown that preterm had smaller kidney size, impaired renal function and elevated BP compared to term ,32,47. NEven if the mean differences in BP seem insignificant between preterm and full-term children, the clinical implications are neglectable. Even a 2 mmHg reduction in BP is associated with 10% lower mortality from stroke and 7% lower mortality from ischemic heart disease in middle-aged adults . MoreoveIn conclusion, preterm birth is truly a global problem, with a high burden on both the poorest and the richest countries. According to reliable trend data on 65 countries, there has been an increase in preterm birth rates over the past 20 years in the majority of these countries. This increase may be due to the improved gestational assessment and the improved registration of most preterm neonates among countries. It may, however, represent a true increase because of health issues, such as an increase in maternal age, underlying maternal health problems, especially with increasing age of pregnancy, wider use of infertility treatments and increased rates of multiple pregnancies. The understanding of the real causes of the increase in preterm birth rate will advance the development of prevention solutions . Preterm


This study aimed to investigate the effects of maternal exposure to external radiation on perinatal outcomes among women who experienced the Fukushima Daiichi Nuclear Disaster (FDND) using the Fukushima Health Management Survey (FHMS).Data from the Pregnancy and Birth Survey and Basic Survey in the FHMS were combined to analyze external maternal radiation exposure following the FDND, and the relationship between radiation dose and perinatal outcomes was analyzed using binomial logistic regression analysis. Missing dose data were supplemented using multiple imputation.A total of 6,875 individuals responded to the survey. Congenital anomalies occurred in 2.9% of patients, low birth weight (LBW) in 7.6%, small for gestation age  in 8.9%, and preterm birth in 4.1%. The median maternal external radiation dose was 0.5 mSv . Doses were classified as follows: <1 mSv (reference), 1 to <2 mSv, and ≥2 mSv. For congenital anomalies, the crude odds ratio for 1 to <2 mSv was 0.81  . At 1 to <2 mSv and ≥2 mSv, the respective adjusted odds ratios were 0.91  and 1.21  for LBW, 1.14  and 0.84  for SGA, and 0.91  and 1.05  for preterm birth.External radiation dose due to the FDND was not associated with congenital anomalies, LBW, SGA, or preterm birth. The BS covered all residents of Fukushima Prefecture between March 11 and July 1, 2011 and estimated the external radiation doses in the 4 months following FDND, obtaining baseline data for health monitoring and protection. The Pregnancy and Birth Survey (PBS), a questionnaire-based survey, was commissioned by Fukushima Prefecture and conducted by Fukushima Medical University to assess the health status of pregnant and nursing mothers in Fukushima Prefecture who may have been forced to evacuate or change medical facilities.5–9 postpartum depression,10,11 hypertensive disorders of pregnancy (HDP),12 and the impact of the earthquake on newborns.13 Rates of stillbirth, preterm birth, LBW, and congenital anomalies did not deviate from the Japanese standard frequency,1,5 and SGA incidence was not elevated by the earthquake or its aftermath.8 Depressive symptoms were observed in some new mothers in Fukushima Prefecture,10 particularly those living near the power plant or who experienced miscarriage or stillbirth.11 Pregnant women living near the earthquake epicenter during their third trimester were at a higher risk for HDP, suggesting an association with psychological stress.12 However, no regional differences in the mothers’ and infants’ conditions were observed at 1-month postnatal check-ups.13The PBS provides data on perinatal outcomes, including preterm birth, low birth weight (LBW), small for gestational age (SGA), congenital anomalies,14–18 Radiation exposure following the Chernobyl accident did not change the frequency of fetal malformations,14 and no fetal effects or association with maternal exposure were observed among those who survived the Hiroshima and Nagasaki bombings.16 Similarly, low-dose exposure following FDND is considered free from effects, but no studies have examined associations with actual exposure dose.The negative effects of fetal radiation exposure, transgenerational effects of radiation exposure, and effects on germline de novo mutation have been elucidated.Here, we investigated the relationship between maternal external radiation dose and major PBS outcomes—congenital anomalies, LBW, SGA, and preterm birth—based on individuals’ external radiation doses. Few reports have examined these relationships, and our results will impact disaster medicine greatly.In Japan, pregnant women receive a Maternal and Child Health Handbook from their municipality when they register their pregnancy and receive free antenatal and infant health check-ups. The PBS, a cohort study and a division of FHMS, was conducted as follows: fiscal year (FY) 2011 PBS questionnaires were sent to women who received a handbook from municipalities in Fukushima Prefecture between August 1, 2010, and July 31, 2011, and were completed voluntarily and returned by mail. This practice continued subsequently, with online responses introduced in 2016. Subjects in the FY2011 survey were defined as Group A if March 11, 2011, fell between 2w0d of pregnancy, which coincides with the time of fertilization, and the delivery date. Respondents from FY2011 whose 2w0d of pregnancy fell after March 11, 2011, and respondents between FY2012 and FY2018 were designated as Group B. Participants living outside the prefecture when the disaster occurred were excluded, as were those with multiple pregnancies and pregnancy termination at <22 weeks’ gestation. Infants with congenital anomalies, stillbirth, or missing birth weight and maternal parity data were excluded.19 Preterm birth was defined as delivery between 22 and 37 weeks’ gestation.The primary outcomes of this study were perinatal outcomes, namely congenital anomalies, LBW, SGA, and preterm birth. A congenital anomaly was defined as any indication of congenital anomaly in the questionnaire. We excluded cases with missing data on the following congenital anomalies: cataract, heart, kidney, or urinary tract anomaly, neural tube defects, microcephaly, hydrocephaly, cleft lip or palate, digestive tract atresia, imperforate anus, polydactyly, syndactyly, or other (with free response). Stillbirths and cases with missing data regarding gestational age at delivery were also excluded. LBW was defined as birth weight <2,500 g, excluding infants with congenital anomalies, stillbirth, or missing birth weight data. SGA was defined as birth weight <10th percentile for the gestational age based on the child’ sex and mother’s parity.20,21 Returning the survey was optional. Respondents’ behavior and location (“trail”) were used to estimate their external radiation dose in a manner similar to studies on the Chernobyl accident.22 The BS response rate was 27.7%, and the maternal external radiation dose distribution was confirmed using BS results; these values were then categorized. External radiation dose data were supplemented for PBS respondents who did not respond to the BS. We used multiple imputation by chained equation with predictive mean-matching methods under fully conditional specification to generate 10 datasets with imputation for the missing estimated external radiation dose.23–27The primary variable was maternal external radiation dose. In the BS, we implemented a precise system to estimate external radiation dose using technical support from the National Institute of Radiological Sciences. Self-administered questionnaires were mailed to 2,055,257 residents living in Fukushima Prefecture at the time of FDND to obtain information regarding their residence, places visited, time spent indoors and outdoors, and travel time in the 4-month period between March 11 and July 11, 2011, when atmospheric radiation levels peaked.Other explanatory variables included maternal parity and child’s sex, height, and weight. Maternal age was defined as that on April 1 of the year following the survey. Stillbirth was defined as delivery of a dead fetus after 22 weeks’ gestation. Options for mode of pregnancy were “natural pregnancy,” “induced ovulation,” “artificial insemination with husband’s semen,” and “assisted reproductive technology.” All options, except “natural pregnancy,” were considered infertility treatments. Trimester of pregnancy at the time of the earthquake  was regarded as a variable. As pregnancy complications, HDP and placenta previa were entered as outcome-related variables. HDP was defined as indicating pre-pregnancy hypertension and the development of hypertensive disease after pregnancy in the questionnaire. Placenta previa was considered present in participants who stated that they had the disease. Mental disorders were considered pregnancy complications and defined as a pre-pregnancy history of mental illness or insomnia, anxiety, and other mental disorders during pregnancy.2 “Forced to change health check-up facility or intervals between visits due to disaster” was defined as responding “No” to the questions “Did you continue to have your antenatal check-ups and delivery at the facility where you had originally planned?” and “Were you able to receive a prenatal check-up as scheduled?” or the answer “I had to change to a facility outside of the prefecture by myself (not on the doctor’s instruction)”.After FDND, the government ordered residents of 12 municipalities to evacuate.t-test for continuous variables and the chi-square or Fisher’s exact probability test for categorical variables (proportion and frequency). Significance was set at 5% was set using two-sided probability. Statistically significant variables were used in univariate logistic regression analysis. Fetal height was excluded as it associated with fetal weight and duration of pregnancy. To examine the association between primary outcomes and external radiation, variables found to differ significantly in the univariate analysis were employed in the multivariate binomial logistic regression analysis except as follows: Only univariate analysis was performed during congenital anomaly analysis as no covariates were suitable for multivariate analysis. Congenital anomalies include various diseases often accompanied by smaller body size, shorter gestation period, and stillbirth; therefore, gestational days at delivery, LBW, SGA, and preterm birth were not included in the multivariable analysis. Items not biologically associated with the occurrence of congenital anomalies, such as changes in health check-up facility and mental disorders during pregnancy, were also excluded. Regarding other multivariate analysis models, birth weight was strongly associated with pregnancy duration, and these items define the outcomes; therefore, we did not employ them as independent variables. The crude odds ratio and 95% confidence interval (CI) are shown for univariate analysis, and the adjusted odds ratio (aOR) and 95% CI are shown for the multivariate analysis.For each major outcome, two-group comparisons were performed using the Statistical analyses were performed using SAS .The ethics committee of Fukushima Medical University approved this study , which was conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The survey aims were detailed in a cover letter attached to the questionnaires sent to the participants. Participants were considered to provide informed consent by responding to the survey, as it was optional.Figure The distribution of the external exposure dose estimates for 3,300 participants before imputation (∼48%) is shown in Figure Table P = 0.007), weighed less , had a shorter gestation period , and higher frequencies of preterm birth , LBW , and stillbirth . These values increased among individuals “forced to change health check-up facility or intervals between visits due to disaster”  and those with maternal mental disorders .Congenital anomalies were observed in 189 of 6,600 participants (2.9%). Infants with a congenital anomaly were smaller  and infants with LBW were shorter  and were born earlier  and was therefore more common in preterm births . LBW also occurred more commonly in those treated for infertility  and those with HDP .LBW was observed in 445 of 6,561 participants (6.8%). LBW was less common in males , less commonly born to first-time mothers , and more common among those with HDP . Infant sex, gestational age at delivery, and preterm birth and infertility treatment rates did not differ significantly, whereas these values differed among those with LBW.SGA was observed in 518 of 6,034 participants (8.6%). Infants with SGA were shorter , and was associated with smaller infant height , lower birth weight , and increased LBW incidence . Preterm birth was also more common in cases of placenta previa .Preterm birth was observed in 212 of 6,111 participants (3.5%), and tended to occur in those with higher maternal ages compared to those of term births . Congenital anomalies, usually identified prenatally, may have necessitated a change of facilities after the disaster or caused mental disorders. Accordingly, post-disaster change of facilities and mental disorders were excluded from the binomial logistic regression analysis, despite being significant in univariate analysis.Maternal external radiation dose (1 to <2 mSv) was not associated with congenital anomalies  for 1 to <2 mSv and 1.21  for ≥2 mSv. Male sex was independently associated with reduced LBW incidence , whereas infertility treatment  and HDP  were independently associated with increased LBW.Multivariate analysis of LBW was adjusted for dose , sex , infertility treatment, and HDP. The doses did not cause significant differences, with aORs of 0.91  and 0.84  for 1 to <2 mSv and ≥2 mSv, respectively, were observed. Primiparity was independently associated with reduced SGA , whereas HDP was independently associated with increased SGA .Multivariate analysis of SGA was adjusted for maternal radiation dose , primiparity, and HDP. Different doses did not cause significant differences, and aORs of 1.14  and 1.05  for 1 to <2 mSv and ≥2 mSv, respectively, were observed. Placenta previa  and HDP  were independently associated with increased preterm birth.Multivariate analysis for preterm birth was adjusted for dose , maternal age, placenta previa, and HDP. The results did not differ significantly based on dose, and aORs of 0.91 , a nationwide birth cohort study encompassing the same period as this survey.35 The JECS lacks information on radiation exposure but surveyed 12,804 pregnant women during the same period in Fukushima Prefecture.Exposure was low, especially as evacuees of the Chernobyl accident exhibited an average internal and external exposure of 31 mSv.36 Our study was based on surveys completed by the mothers themselves, while the latter two studies were conducted using medical records. Fetal radiation exposure causes congenital anomalies at an estimated threshold of 100 mGy.37–39 The threshold for the development of microcephaly is 120 mGy or more.40 No participants reporting congenital anomalies were exposed to radiation doses >2 mSv. Radiation is evenly distributed over the body during maternal exposure, and the effective dose (mSv) can be directly replaced by the equivalent dose (mGy) for the fetus.41 Causes of congenital anomaly other than external exposure should be considered.In our study, congenital anomalies were observed in 2.9% of cases, but only in 1.7% of participants in the JECS survey. The International Clearing House for Birth Defects Monitoring Systems Japan Center, which collects congenital anomaly statistics from all over Japan, reported an incidence rate of 2.4% nationwide in 2011.42,43 HDP was also an independent risk factor for SGA (<−1.5 SD) in the FHMS in FY2011.8 We adopted the standard international definition of weight <10th percentile for gestational age as SGA.44 Assisted reproductive technology increases the risk of LBW and SGA and is associated with preterm births.45–47 We defined fertility treatment as any mode of pregnancy besides spontaneous. We could not investigate the details of assisted reproductive technology in this study, which may have influenced the results.LBW was less common among males, while SGA was more common among first-time mothers, as previously reported.35 and is strongly associated to preterm birth.48HDP was observed in 3.3% of cases in this study but was observable in 2.5% of 12,804 cases evaluated during the JECS in Fukushima Prefecture ,49 during CS, is an acceptable cause of CS at <37 weeks gestation50 and was associated with preterm birth.Placenta previa, which may require cesarean section (CS) due to sudden genital bleeding or causes massive bleeding51 As we observed previously,8 no trimester was associated with perinatal outcomes for LBW or preterm birth, possibly due to the small sample size (versus 2.6 million in the literature).Indicators of physical and mental stress  were not associated with any outcomes. Prenatal maternal stress in the fifth and sixth months of pregnancy increases the risk of LBW, SGA, and preterm birth.This is one of the few epidemiological studies of pregnant women conducted over several years in a single region with support from a public institution. The strengths include the use of multiple imputation to clarify the results. Similar results were obtained through sensitivity analysis without multiple imputation conducted with information of those with maternal external radiation dose data. However, the results regarding the presence or absence of the main outcomes and survey variables may be inaccurate, as this survey was questionnaire-based. Another limitation is the lack of data on maternal body size or lifestyle , which cannot be addressed in a survey of perinatal outcomes. The response rate of 60% may raise concerns about the representativeness of the target population; however, the factors associated with perinatal outcomes in this study were similar to those observed previously, so the results can be considered reliable. This survey confirms that maternal external radiation dose was low and not associated with the frequency of perinatal outcomes, which was a major concern of the people in Fukushima Prefecture. The results must be explained to pregnant and nursing mothers in Fukushima Prefecture. The impact of FDND on the perinatal outcomes remains a concern. The PBS aims to elucidate these outcomes and will continue to be conducted.Maternal external radiation exposure following FDND was not associated with congenital anomalies, LBW, SGA, or preterm birth.


It is the main cause of neonatal and child deaths in the world and is the major public health problem in developing countries including Ethiopia. This study aims to assess the proportion and factors associated with fetal adverse birth outcomes among mothers who gave birth at Felege Hiwot Comprehensive Specialized Hospital, Bahir Dar city, North-west, Ethiopia 2019.institution-based cross-sectional study was conducted from March 1- to April 30 in 2019 among 371 delivered mothers. The data were collected by systematic random sampling technique, entered into a computer using Epi data 3.5, and analyzed using Statistical Package of Social Sciences version 23.0. Bivariate and multivariable logistic regression analyses were done to estimate the crude and adjusted odds ratio with a confidence interval of 95% and a P-value of less than 0.05 considered statistically significant.in this study, the proportion of fetal adverse birth outcome was 33.2%. Mothers who lived in rural area , < 4 antenatal care visit , bad obstetrical history , complication in the antepartum period , medical illness , and maternal hemoglobin level < 11 mg/dl  were significantly associated with fetal adverse birth outcomes.the proportion of fetal adverse birth outcomes in this research was high. Living in a rural area, the number of antenatal care visits, bad obstetrical history, current pregnancy complications, medical illness, and hemoglobin levels less than or equal to 11 mg/dl were significantly associated with fetal adverse birth outcomes. Getting full service of antenatal care visits and advance in the quality of maternal health services could minimize fetal adverse birth outcomes. Fetal adverse birth outcomes (FABO) are abnormal birth outcomes which include: preterm birth, low birth weight (LBW), stillbirth, and congenital anomaly. Globally, more than one in ten newborn babies develop FABO . FABO is2, inter-pregnancy interval <2 years absence of antenatal care (ANC) visits, history of stillbirth, maternal malaria, gravidity, parity, the onset of labor, previous bad obstetrical history (BOH), hemoglobin level less than 11 mg/dl, type of pregnancy and chronic medical illness like HIV-infected women were significantly associated with adverse birth outcomes , Zα/2= critical value for normal distribution at 95% confidence level, which is equal to 1.96  or 5% level of significance (α=0.05) and a 5% margin of error (ω =0.05).The sample size was calculated using a single population proportion formula by considering the following assumptions: proportion of FABO in Dessie referral hospital was 32.5% , < 4 ANC visit , has history of BOH , complications in the antepartum period , has history of medical illness  and maternal hemoglobin < 11 mg/dl  were significantly associated with FABO at P-value less than 0.05 .This study finding showed that the proportion of FABO was 33.2% [95% CI: 28-38.5]. This figure was in line with studies conducted in Dessie referral hospital 32.5% , and GamMothers with hemoglobin levels < 11 mg/dl have encountered 4.63 higher odds of experiencing FABO than those with hemoglobin levels greater than 11 mg/dl. The finding was in line with studies conducted in Dessie Ethiopia , NortherMothers who had < 4 ANC visits were almost two times more likely to experienced FABO than those mothers who had > 4 ANC visits. The reason might be due to a lack of getting full services of ANC visits which includes early identification and management of any complications and prevailing diseases, health promotion, and care provision as well as birth preparedness and complication readiness plan. Furthermore, mothers who had a history of medical illness were found to be two times higher odds of experiencing FABO than mothers who did not have a medical illness. This finding was in line with studies done in Dessie , HawassaLimitation of the study: clinician differences while determining the gestational age and hemoglobin level of some mothers who were determined after delivery were some of the limitations.In this study, the proportion of FABO was high compared to most of the studies done in Ethiopia. From the FABO: LBW and preterm birth cover the highest percentages. Place of residence, number of ANC visits, bad obstetric history, antepartum complications, medical illness, and maternal Hgb level are the predictors of FABO. Health education and counseling of pregnant mothers about nutrition, the importance of attending the recommended numbers of ANC visits, prevention and treatment of complications of pregnancy, early seeking of medical care, and management of antepartum complications are important elements to decrease FABO. Additionally, taking the supplemented iron and folic acid for three months before the first or next pregnancy and at least for three months during pregnancy are recommended to decrease FABO like a congenital anomaly.Fetal adverse birth outcomes are in increasing mortality and morbidity of neonates and under-five children;The most common fetal adverse birth outcome are low birth weight and preterm birth.We found that high prevalence of fetal adverse birth outcome at Felege Hiwot comprehensive specialized hospital;Factors associated with fetal adverse birth outcome at Felege Hiwot comprehensive specialized hospital;Integration of number of Antenatal care visit and fetal adverse birth outcome.