Short birth intervals have been linked to higher rates of fetal loss, prenatal mortality, and poorer child survival. Therefore, for countries like Ethiopia that have a population policy intended at reducing fertility, understanding the level and factors influencing birth spacing is crucial in order to apply appropriate intervention. This study aimed to assess the prevalence and determinants of the short birth interval among child-bearing age women in the Gedeb Hasasa district of the West Arsi zone, Ethiopia.p-value of <0.05.A community-based cross-sectional study was conducted from 20 July to 20 August 2018. A multistage sampling method was used. Face-to-face interviews were conducted to gather data. The collected data were entered into Epi Data version 3.1 and later exported to SPSS version 21 for analysis. Logistic regression was used to identify factors associated with the short birth interval. The level of significance was declared at a A total of 714 women participated, with a 98% response rate. The median birth interval length was 32 months. The prevalence of the short birth interval was 50.4%. After adjusting for confounding variables, being a rural resident , having an illiterate husband , breastfeeding duration for 7–12 months  and 13–23 months , sex of the prior child , and previous child alive  were the determinants of short birth interval.One in every two women practiced short birth intervals. The median birth interval duration was 32 months, which is below the minimum standard recommended by the WHO duration for the birth interval, which is 33 months. Short birth intervals were determined independently by residence, husband education, breastfeeding time, previous child’s sex, and previous child’s survival. Therefore, increasing women’s awareness of the ideal birth interval should be done through community health professionals and health developmental armies. The time between two consecutive births is known as the birth interval , 2. The Short birth interval is a global public health problem that remains challenging in Ethiopia . Short bA large multi-country study was conducted to view the association between inter-pregnancy interval and prenatal outcomes across Latin America from 1990 to 2009. It indicated that birth intervals of <12 and >2 months are associated with pre-eclampsia, neonatal mortality, and preterm birth, but not with other maternal or offspring outcomes . A systeWomen in low- and middle-income nations are more likely to have a short pregnancy and birth interval . An impoA community-based cross-sectional study was conducted in the Gedeb Hasasa district, West Arsi Zone of Southeast Ethiopia from 20 July to 20 August 2018. Hasasa is located at a distance of 284 km from Addis Ababa, the capital city of Ethiopia, and 87 km on the way from Shashamane, the capital of the west Arsi zone. The district has 20 kebeles. According to the 2007 EDHS report, the total population of the district and the number of women of child-bearing age were 254,367 and 56,291, respectively . The disThe source population was all women who had at least two consecutive live births in the previous 5 years. The study population was randomly selected, women who had at least two consecutive live births in the previous 5 years in the study area. Women with serious mental illness and hearing impairment were excluded.p-value = 0.57) were used as a percentage of child-bearing age women practicing short birth spacing from a cross-sectional study conducted in southern Ethiopia  = 1.96, marginal error (d) = 0.05, and a single population proportion  of the districts were chosen by lottery to serve as the study’s representative sample. In each of the chosen kebeles, houses that met the requirements for inclusion were labeled. Households, where eligible women were discovered, were identified by a code. Systematic sampling procedures were then used to determine the skip interval, which was calculated as 12,542/726 = 17 by proportionally allocating sample size to each chosen kebeles. If there were two or more suitable women living in the same household, one of them was chosen by lottery. If no other eligible women could be identified in the household chosen, we moved on to the next family. For participants who were not present at the time of data collection, at least three visits were made to trace them.The dependent variable was a short birth interval. The sociodemographic characteristics , obstetric history , and place of delivery were the independent variables.Birth interval is the time duration/period between two recent consecutive live births measured in months , 2. A shBased on the examined literature and information gained from relevant studies, a structured questionnaire was prepared for data collection. The primary language in the study area, Afan Oromo, was used to collect the data. The questionnaire asks about the sociodemographics of the woman and her husband, their history of pregnancies, their family planning preferences, their nursing practices, and their awareness of the time between pregnancies. Cards for vaccinations were utilized to ascertain the dates of birth of the kids. We used maternal recall for those who had not received vaccinations, and community-based health extension workers were interviewed. After providing the appropriate information to the study participants and obtaining consent, face-to-face interviews with eligible women using a standardized questionnaire with closed-ended questions were undertaken. The first six health extension workers were chosen from their respective kebeles and instructed by the principal to label families and collect data. Health extension workers were taken into consideration since they are working closely with the community, particularly women, and because they have a deeper knowledge of household arrangements in the study area. Following the completion of the home labeling, six female nurses with a diploma who were proficient in both Afan Amara and Afan Oromo were sought out. For 2 days, the primary investigators trained them on the study’s goals, how to choose families, how to conduct interviews, how to obtain consent, and how to handle data.To confirm the quality of the data, a pretest was conducted on 5% of the sample size from the nearby district (Dodola district), which has a setting similar to the research area. Based on the results of the pretest, the necessary modifications were made. Training on the objectives of the study, the questionnaire’s questions, how to help study participants, and how to get respondents’ consent was provided to facilitators and data collectors for 2 days. The purpose of the study, its benefits, and the confidentiality of the information collected were all explicitly explained to study participants, allowing them to freely answer the questionnaire. The primary investigator, three BSc nurses, and a health extension worker in each kebeles monitored the fieldwork, and the principal investigators and the extension worker in each kebeles verified the collected data constantly on a daily basis for completeness.p-value of less than 0.25. The Hosmer–Lemeshow test of goodness-of-fit, which considers a good fit at a p-value of >0.05, was utilized to assess the goodness-of-fit of the final model. Finally, independent variables associated with the short birth interval were identified using a p-value of less than 0.05, and the strength of the association was evaluated using AORs with 95% confidence intervals.Data were initially entered into Epi Data version 3.1 and exported to SPSS version 21 for additional analysis. Frequency distribution, mean, and median were computed as descriptive statistics. First, bivariate analyses were performed to evaluate the relationship between dependent and independent variables. For multivariate logistic regression analysis, variables were suitable if their associations with the dependent variables had a A total of 714 eligible women participated with a response rate of 98%. Of the 714 respondents participated, 600(84%) were rural residents. Nearly three-fourths of the respondents (74%) were women with no formal education, and 80% of them were homemakers in occupation. More than one-fourth (27.8%) of the respondents were married at the age of <18 .A total of 672 (94.1%) of the respondents had heard about the optimum birth interval between two successive live births. Of 672 respondents who had awareness about optimum birth interval time, 250 (35%) of them responded “to be below 3 years,” 350 (49%) of the respondents responded to be within 3–5 years, and the rest (16%) were believed to be greater than 60 months. The majorities, 679 (95.1%), believed that the short birth interval had a negative impact on both maternal and child health.At the time of the data collection period, 337 (47.2%) of the women had five children and more. A total of 664 (93%) women were required to have additional children. Of those who required additional children, 38.1% of them wanted to become pregnant then and the rest 61.9% desired to delay the pregnancy to sometime later. A total of 360 (50.4%) of the study participants practiced short birth intervals and the rest practiced above the minimum recommended standard by the WHO duration for the birth interval, which is 33 months. The median duration of the actual birth interval was 32 months. Whereas, the median duration of preferred birth interval for mothers was 36 months for the last two succeeding births.Regarding the practice of breastfeeding, 98% of women breastfed their children and the rest of them fed formula milk. A total of 379 (53.1%) of the respondents breastfed their child for 13–23 months, and 506 (70.9%) stopped breastfeeding while the child was 24 months. The median duration of breastfeeding was 18 months. In total, 680 (95.2%) of the respondents were aware of the presence of modern contraceptive methods that help to delay or avoid pregnancy. Of 680 respondents, 676 (99.4%) of the respondents used contraceptives for birth spacing. The most preferred methods of contraception were injections accounting for 54.7%, followed by pills (24.9%).After adjusting for confounding variables, being a rural resident , having an illiterate husband , breastfeeding duration for 7–12 months  and 13–23 months , sex of the prior child , and previous child alive  were the determinants of short birth interval .To lower the frequency of unfavorable pregnancy outcomes, the World Health Organization suggested a minimum of 33 months between consecutive live births. Poor mother and child health outcomes, such as low birth weight, stillbirth, uterine rupture, neonatal death, maternal mortality, child malnutrition, and maternal hemorrhage, are linked to poorly spaced pregnancies . This stAs a result, the median birth interval duration was 32 months, which is shorter than the minimal birth-to-birth interval which is advised to be 33 months . It was Birth interval length was linked to the husband’s educational status. In this study, women with illiterate husbands were four times more likely than those with educated husbands to practice short birth intervals. This finding was consistent with studies –28. ThisPlace of residence is found to be linked with birth interval duration. Women who reside in rural areas are 2.5 times more likely to have short birth intervals than those who reside in urban areas. This finding was supported by studies in Ethiopia , 21, 26.The duration of breastfeeding was significantly associated with birth interval. Women who breastfed for 7–12 months and 13–23 months had 3.2 and 2.5 times more likely to have a short birth interval compared with those who breastfed for more than 24 months. This finding was supported by the following studies , 29–31, The sex of the previous child was statistically associated with the duration of the birth interval. Women who had a previous male child were 37% less likely to have a short birth interval than those who had a female child. This finding was supported by the following studies , 31, 33,The life of the previous child was significantly associated with the duration of the birth interval. A woman whose previous child was alive was 80% less likely to have a short birth interval than a woman whose previous child died. This finding was supported by the following studies , 33–35, Recall bias may underestimate or overestimate the study findings . The cross-sectional nature of the study makes it difficult to demonstrate cause-and-effect linkages between the dependent and independent variables.One in every two women practiced short birth intervals. The median birth interval duration was 32 months, which is below the minimum standard recommended by the WHO duration for the birth interval, which is 33 months. Short birth intervals were determined independently by residence, husband education, breastfeeding time, previous child’s sex, and previous child’s survival. Therefore, increasing women’s awareness of the ideal birth interval should be done through community health professionals and the health developmental army.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 the Institutional Review Board (IRB) of Arsi University. The patients/participants provided their written informed consent to participate in this study.TY, DD, and NS contributed to the idea and design of the study, collection, analysis, and interpretation of data, writing and revision of the manuscript, the decision to submit it to the current journal, the final approval of the manuscript that will be published, and they also agreed to be responsible for all aspects of the work. All authors contributed to the article and approved the submitted version.


Despite significant government investments to improve birth outcomes in low and middle-income countries over the past several decades, stillbirth and neonatal mortality continue to be persistent public health problems. While they are different outcomes, there is little evidence regarding their shared and unique population-level risk factors over a mother’s reproductive lifespan. Data gaps and measurement challenges have left several areas in this field unexplored, especially assessing the risk of stillbirth or neonatal mortality over successive pregnancies to the same woman. This study aimed to assess the risk of stillbirth and neonatal mortality in Indonesia during 2000–2014, using maternal birth histories from the Indonesia Family Life Survey panel data.Data from three panels were combined to create right-censored birth histories. There were 5,002 unique multiparous mothers with at least two singleton births in the sample. They reported 12,761 total births and 12,507 live births. Random effects (RE) models, which address the dependency of variance in births to the same mother, were fitted assuming births to the same mother shared unobserved risk factors unique to the mother.The main finding was that there having had a stillbirth increased the odds of another stillbirth nearly seven-fold and that of subsequent neonatal mortality by over two-fold. Having had a neonatal death was not associated with a future neonatal death. Mothers who were not educated and nullipara were much more likely to experience a neonatal death while mothers who had a prior neonatal death had no risk of another neonatal death due to unmeasured factors unique to the mother.The results suggest that for stillbirths, maternal heterogeneity, as explained by a prior stillbirth, could capture underlying pathology while the relationship between observed risk factors and neonatal mortality could be much more dependent on context. Establishing previous adverse outcomes such as neonatal deaths and stillbirth could help identify high-risk pregnancies during prenatal care, inform interventions, and improve health policy. Nearly half of the estimated 5.2 million under-five deaths occurring worldwide in 2019 were among neonates –5. PregnMore recent survey data from India also supports the clustering of neonatal mortality, with a twofold increase in the odds of subsequent neonatal mortality among mothers who have had a prior neonatal death . In Tanzmother-specific risk factors, i.e., risk factors attributable to the mother that yield different risk profiles across different mothers, may impact consecutive births but are unobserved or unaccounted for in the available data. Vaupel referred to this dependence as unobserved heterogeneity or ‘frailty’ (referred to as vulnerability in this paper) and showed that it could bias the interpretation of cohort and period mortality rates for individuals who have different (but constant) underlying overlooked risks affecting mortality [This evidence suggests that some births may not be genuinely independent observations, as certain women may have been more likely to experience an adverse birth outcome due to inherent risk factors. These ortality . The conortality , randomiortality , hospitaortality , and neiortality . AnalyziThis study used the IFLS, a longitudinal household survey, to estimate the contribution of mothers’ observed and unobserved characteristics to their risk of stillbirths and neonatal mortality. This study is innovative because it accounts for statistical dependence between births to the same mother using complete pregnancy histories from household survey data, allowing for evaluations of stillbirth and neonatal mortality in the same population.IFLS is a population-representative, longitudinal survey of 13 (of 27) provinces consisting of five panels: 1993, 1998, 2000, 2007–08, and 2014–2015. In 1993, IFLS covered an initial sample of 7,224 households spread across six islands. This sample was selected to maximize the representation of Indonesia's cultural and socioeconomic diversity, representing approximately 83% of the Indonesian population at the time, while being cost-effective [IFLS included a household survey, with adult and children’s questionnaires, as well as a community and facility survey. The adult questionnaires included modules on education, marriage, migration, employment, health status, utilization of health services, individual and household assets, fertility and contraception, infant feeding practices, as well as proxy data on household members who were away. All ever-married women were asked questions about marriage, contraceptive use, pregnancies and outcomes, use of antenatal care, children ever born, infant feeding, and the status of child survival.Due to missing date and gestation data, especially for stillbirths, birth histories reported in 1993 and 1998 were excluded. The newer datasets were much less likely to be missing gestational age for each birth, which was important for defining stillbirths, as well as the year of birth which was important for removing duplicates across panels. Births reported in the 2000, 2007, and 2014 panels were extracted to produce birth histories for mothers for births ending in stillbirth or live birth. All self-reported miscarriages were deleted, but miscarriages with gestation over 7 months were recoded as stillbirths. Similarly, self-reported stillbirths with gestation under 7 months were recoded as miscarriages and excluded. Duplicates reported in subsequent panels were removed based on year of birth and outcome. Births that were missing gestation and other covariates were excluded (l.0%). For the analysis, only multiparous women were included in the final sample. Data were right-censored since some mothers had not completed their reproductive span at the time of the final survey. The data were also panel unbalanced, meaning that mothers had different numbers of births in the sample.Birth histories of mothers were used to calculate two primary risk variables for each birth: any history of stillbirth and any history of neonatal death. For stillbirth history, a binary variable was constructed with a value of 1 if the mother had a prior stillbirth and 0 if not. For neonatal mortality history, a binary variable was constructed with a value of 1 if the mother had a prior live birth that resulted in neonatal death and 0 if not.There were two outcomes evaluated in separate models: stillbirth, defined as a pregnancy with seven months (or 28 weeks) or longer gestation that ended in a fetal death, and neonatal mortality, defined as death in the first 28 days of life per World Health Organization (WHO) recommendations . For neoCovariates were measured at the level of birth, mother, and household. For example, pregnancy duration and parity were specific to birth, education was specific to the mother, and urban residence was specific to the entire household.Calculated as the number of births (live and still) that a woman reported across the full birth history. Each birth was assigned a value based on this history, grouped into three categories: none, 1–2 birth, and 3 or more births.The age of a mother at birth was calculated as the difference in years between her birth year and the year of each one of her births. The age of the mother at the time of the survey was not used in the analysis. Any ages below 15 years were excluded.Madrasah Islamic schools.Education level was measured at the time of the survey. It was introduced as a categorical variable in the following four groups: none, elementary, junior high, senior high, college, or religious/vocational. ‘Religious’ education included Whether a woman lived in an urban or rural cluster was based on her IFLS cluster, which was listed as urban or rural in the sampling frame .Additional covariates that would have been useful but excluded because they were missing data for a significant proportion of women included access to antenatal care, place of birth, and skilled care at birth. Data on maternal body mass index (BMI) and household per capita expenditures were also available in the survey but only measured at the time of the interview. For many births, these would be far removed from the year of birth and were not used to avoid spurious correlations.rho in the model statistics [This study uses Random Effects (RE) models to estimate the underlying unmeasured subject/mother-specific risk of having either a stillbirth or a neonatal death, given observed group-level risk factors and covariates among women with at least two births in the sample. RE models describe variation in mother-specific responses according to unmeasured characteristics. Using the RE approach allows the mother-birth relationship to have mother-specific effects assuming this relationship varies by mother but is similar for births to the same mother. In RE models, all unmeasured factors are assumed to contribute to heterogeneity regardless of whether they can ever be observed. This variance is allowed to be random and uncorrelated between mothers and observed variables and allows for the estimation of the effect of maternal independent variables that remain constant across births  regardless of the number of observations in each cluster. The combined variance of unobserved heterogeneity is output as atistics . It can The model-building strategy was based on the evaluation of biological and socioeconomic factors from relevant public health literature. Biological factors included age of the mother at birth, parity, female birth , and any prior history of a stillbirth or neonatal death. Socioeconomic factors included urban or rural residence and education level. Some independent variables' exposure timing can produce causal estimates, while others can only be interpreted as correlates. In particular, the age of the mother at birth, parity, and history of stillbirth or neonatal death could be established as occurring before birth. Therefore, estimates for these variables can be interpreted as predictive of the outcome. Mothers’ education level and urban residence could only be correlated with the outcome as they were measured at the time of interview. However, they could not be evaluated as predictive or causal as it was not possible to determine whether these characteristics were true at the time of birth. Male birth would be associative but not necessarily causal in the absence of other information but established research has shown higher mortality among male newborns .p-values were 2-tailed. Calculations were weighted to account for survey design and attrition over time and to adjust estimates for the Indonesian population in the panel year.Standard errors were adjusted for robust estimates for maternal clustering. Clustering within communities was not adjusted to avoid adding greater complexity to an already complex dataset and survey design. Shared community-level factors that impact stillbirth and neonatal mortality that may exist would be included in maternal clustering estimates, introducing bias in interpreting maternal effects. Hierarchical clustering affects standard errors but does not influence effect estimates. All analyses were performed in Stata statistical software version 17 . Statistn = 902) of mothers interviewed in 2000 were also interviewed in 2007 and 23.2% (n = 302) were also interviewed in 2014. An additional 11.6% (n = 151) were interviewed in the 2000 and 2014 panels but not in 2007. Table There were 5,002 unique multiparous mothers reporting at least two singleton births, of whom 1,303 were new in the 2000 panel, 2,461 were new in the 2007 panel, and 1,238 were new in the 2014 panel. Approximately 69.2% .2(13) = 43.01, p = 0.0000). RE models can also be assessed based on the rho or intraclass correlation coefficient, representing the correlation between the (latent) risk of having a stillbirth across two births for the same mother. For the intermediate model, the rho was 0.41 meaning that 41% of the variance of the risk of stillbirth, beyond that explained by age, residence, education, and panel, could be attributed to other characteristics of the mothers. For the full model in Table rho was 0.0015, meaning that after adjusting for prior stillbirth, less than 1% of the latent risk of having a stillbirth was attributed to unobserved characteristics of the mother. Thus, prior stillbirth history was a key component of a mother’s underlying vulnerability. Another way of thinking about this is that around 41% of her vulnerability in successive births was explained by risk factors that led to her prior stillbirth and the experience of the stillbirth itself, after adjusting for her parity, residence, education, and age at birth.The final model showed an improvement in the log-likelihood over the null model (χTable 2(12) = 67.66, p = 0.0000) and for stillbirth history (χ2(12) = 73.32, p = 0.0000). For the full models in Table rho was 0.31 with adjustment for prior neonatal death, meaning that 31% of the latent risk of having a neonatal death was attributed to other unobserved characteristics of the mother. After adjusting for stillbirth history, the rho was 0.36 as in the intermediate and null models, suggesting that given prior stillbirth, another 36% of the latent of having a neonatal death was attributed to other unobserved maternal characteristics. Thus, for a mother, prior stillbirth history did not explain additional underlying vulnerability for neonatal death than the intermediate models, as it had for an additional stillbirth. Neonatal death was still vulnerable to unobserved maternal as was not the case for stillbirths, after adjusting for neonatal death or stillbirth history, sex of the newborn, parity, residence, education, and maternal age at birth.The final models showed an improvement in the log-likelihood over the null model for neonatal death history (χThis study estimated the effects of selected independent variables on the odds of a pregnancy resulting in stillbirth or neonatal death conditional on the maternal risk profile for women interviewed in Indonesia between 2000 and 2014. The main finding was that having one stillbirth increased the risk of having another. Similar trends have been observed in other countries. Compared to the seven-fold increase in the odds of stillbirth in our study, in Finland having a stillbirth increased the risk of future stillbirths and spontaneous abortions by 20% even after controlling for all major obstetric complications . In a poThe main finding regarding neonatal deaths was that after adjusting for unobserved heterogeneity, having had a prior neonatal death was not predictive of neonatal death in future live births, but having had a prior stillbirth increased the odds of having a future neonatal death. However, contrary to the findings in our study, previous history of neonatal mortality was also associated with future risk for the same in India  and otheGiven that the role of prior stillbirth and neonatal mortality was starkly different across pregnancies, a prior stillbirth may capture ongoing maternal risk factors whereas a prior neonatal death could have risk factors not shared across births to the same mother. These could be attributable to unobserved baby-level factors or maternal and neonatal health service factors. Several variables were missing data in the sample for neonatal mortality, which could have helped resolve the magnitude of unobserved heterogeneity. These included measures of use of prenatal services, pregnancy complications and maternal morbidity, the place of birth, the quality of labor and delivery care, birth weight, neonatal care, and breastfeeding. In high-income countries, there is a very low risk of recurrent neonatal death given the quality of services, A stillbirth followed by a neonatal death, as found in this study, could be indicative of the underlying maternal risk for adverse birth outcomes shared across pregnancies.As expected, living in an urban area was correlated with lower neonatal mortality risk but not associated with stillbirth. This finding supports the notion that stillbirths may have risk factors that are not addressed sufficiently in poorly resourced health systems, although some risk seems to be carried out due to maternal genetics or pathophysiology that are not addressed even in high-quality care. Attending a religious or vocational school was associated with a higher risk of having a stillbirth than having even an elementary school education. Most of the women in this category had attended a religious school and it is possible that being enrolled in a religious school approximates other cultural beliefs and practices that may carry a higher risk of stillbirth. One potential explanation for this might be consanguinity which is more common in Muslim nations but data on the prevalence of such marriages is scant in Indonesia and assumptions should not be made without further evidence , 32. ForAdvanced maternal age was not a substantial risk factor for stillbirths in this study but being younger was associated with a lower risk of stillbirths. Others have found that stillbirth and neonatal mortality risk increases with increasing maternal age even when accounting for maternal morbidities , 35. In The most critical assumption in this study was that stillbirth and neonatal deaths were not misclassified and therefore, the estimates were valid for these specific outcomes. Misclassification of these outcomes is an important and well-documented issue that could not be resolved here . A seconThis study has several strengths. First, it uses a novel approach to accommodate clustering of births to the same mother when longitudinal data allows for the analysis of longer birth histories. This approach allows one to investigate the effect of having had a history of adverse outcomes, which is rarely possible from population survey data in low and middle-income countries. Second, using RE analysis, we can model two outcomes that share similar risk factors but show that critical differences in unobserved maternal or community factors, such as health service access and use, impact neonatal survival differently from stillbirths. These community factors are essential considerations in deciding where to invest resources. Because of these potential community factors and greater need for health services, establishing the risk of another stillbirth or neonatal death for a woman who has had a prior stillbirth is important. Targeting antenatal and obstetric services to accommodate both known risks and the potential vulnerability of the fetus or neonate to succumb to unobserved risks, also shines a light on the need for evaluating these two outcomes separately in greater depth.There are also several limitations. First, there was incomplete data on measures for use of antenatal care, place of birth, and access to newborn care – all factors which can impact birth outcomes. Therefore, the contribution of health system factors was limited and some of these factors could bias the estimation of maternal risk from observed variables. Second, it was not possible to build a birth history over the length of the panels due to missing year of birth data, especially for stillbirths and neonatal deaths in the first two panels. This missing data would have disproportionally biased the results and made it difficult to calculate the mother's age at the time of birth for adverse outcomes. Women with missing data likely had other characteristics that increased their risks such as lesser education, rural residence, older age, or higher parity. Third, it was not possible to adjust for the first stillbirth, which would have no available prior history. In this analysis, the first stillbirth was analyzed as having the same risk as birth with no prior history, which is a flawed assumption. Adjusting for parity was a potential solution and this explained some of the higher odds for nulliparous women. Nonetheless, it would be useful to understand whether there is greater unmeasured vulnerability for first stillbirths. For example, not using health services could be an unexplained vulnerability in first stillbirths.Birth history data from population-based surveys have become increasingly important for estimating the global burden of stillbirths and neonatal mortality. The retrospective collection of birth histories results in documentation of multiple births for each respondent. In the analysis of population-based birth history data, the clustering of births within a mother is a concern because birth outcomes are likely to be more similar than different for valuable indicators such as birth weight or gestation. This study improved upon birth-average estimates of risk factors that predict poor stillbirth and neonatal outcomes by adjusting for the effect of shared maternal vulnerabilities across births. The study has implications for collecting birth histories to predict stillbirth and neonatal mortality and suggests that survey-based data collection for these outcomes requires different sets of questions and assumptions. The focus of current household surveys on livebirth histories limits the study of stillbirths. Including both outcomes in the same survey improves the ability to study clustered effects for each. This study supports the policy recommendation that in addition to neonatal mortality, research should focus on establishing the history and potential cause of any stillbirth among pregnant women during prenatal care.


Respiratory distress syndrome (RDS) is caused by a deficiency of a molecule called surfactant. It occurs in newborns born before 37 weeks of gestation. It is a main cause of morbidity and mortality in the early neonatal period.Therefore, this study aims to assess median time to recovery and predictors of preterm neonates with respiratory distress syndrome admitted in University of Gondar comprehensive specialized hospital Northwest Ethiopia 2020.Institution based retrospective follow up study was conducted on 386 preterm neonates with hyaline membrane disease who were admitted in the neonatal intensive care unit from January, 2016 to December 2018. The data were entered in to EPI info version 7.0 and transferred to Stata version 14.0 for analysis. Both bi-variable and multi variable Weibull parametric model were fitted to identify predictors with 95% confidence interval of hazard ratio (HR) and p-value. P-value less than 0.05 in the multivariable model showed the presence of significant association between covariates and the dependent variable.The overall median length of recovery were 11 day with an interquartile range of  neonate-days. Being a product of multiple pregnancy ), vaginal mode of delivery ), and neonatal hypothermia at admission ) were found to be significant predictors of time to recovery.In this study the median time to recovery of preterm neonates with respiratory distress syndrome was slower than the clinical recommendations. Receiving bag and mask ventilation and hypothermia decreased the recovery whereas, vaginal delivery gestational age at birth, being multiple pregnancy, birth weight ≥2000grams were enhance the recovery of preterm neonates with RDS. World health organization defined preterm birth as birth after 28 weeks and before 37 completed weeks of gestation since last menstrual period of a woman . About 1Globally the leading cause for neonatal intensive care (NICU) admission is preterm and more than 60% of prematurity occurs in low- and middle-income countries (LMICs) , 5. StudThe United Nations of children’s fund reported that, in Ethiopia preterm is one of the main causes of neonatal hospital admission and death accounting for 23% of all other causes of neonatal death . Causal Even if preterm birth is not an acute disease, it is the major causes of infants’ death and continues to be significant public health problem by increasing the economic expenditure to health system of a developing nation .Among the complications of preterm neonates, respiratory distress syndrome (RDS) is the major one which is induced by the shortage or deficiency of surfactant in the lungs with the clinical manifestations of grunting, tachypnea, retractions, nasal flaring and increased the effort of inhalation at birth, or in a while subsequently and a necessity for complementary oxygen support . It is tThe overall incidence of respiratory distress syndrome is 10–15%, but the prevalence decreases with increasing maturity. It may occur among 60% of babies with 28–32 weeks of gestation, 15–30% of those between 32-36weeks, and in about 5% beyond 37 weeks of gestation , 14.A hospital-based studies conducted in India among neonates admitted to NICU due to respiratory distress syndrome reported that the recovery rate was account about 64.5 percent , 16. A cA retrospective cohort study conducted in NICU of a University Teaching and Referral Hospital in Southern Ethiopia reported that 34.04%  and in JStudies done in Johannesburg, South Africa , and JimStudies in different settings reported that the presence of neonatal clinical problems such as perinatal asphyxia (PNA), jaundice, hypothermia, hypoglycemia and neonatal sepsis were strong predictors for recovery of preterm neonates with RDS , 24, 26.Studies reported that Nasal continuous positive air pressure (NCPAP) and kangaroo mother care (KMC) were reported as determinant factors for recovery of preterm neonates with RDS , 22, 27.Findings addressing multiple risk factors aimed at reducing the risk of prematurity and address the survival gap of premature babies to achieve sustainable development Goal 3.2 entitled end preventable deaths of newborns and under-five children by 2030 .Though studies have been conducted on neonatal mortality in general, however no study has been done regarding preterm neonates with RDS and the complications following it in Ethiopia. Therefore, this study aimed to determine the time to recovery and predictors of preterm neonates with RDS and will serve as baseline for further research. This research will also help to evaluate the clinical service and be used to inform respective clinicians and stakeholders about the burden of prematurity, and its complications to assist in planning for the possible need of action.Facility-based retrospective follow up study was conducted among preterm neonates admitted with a diagnosis of RDS in NICU of the University of Gondar comprehensive specialized hospital Northwest Ethiopia from January 2017 to December, 2019. The hospital is one of the largest teaching hospitals in the Amhara region providing tertiary level care for more than seven million people in the northwest part of the country. It is located at 727 km and 180 km far from Addis Ababa and Bahir Dar, the capital city of Ethiopia and the Amhara region to Northwest respectively. Neonatology is a unit under the pediatrics and child health department. It provides an outpatient and inpatient medical service for neonates. Neonatal intensive care unit particularly offers intensive care for neonates on an inpatient basis.The source population were all preterm neonates who were admitted to the Neonatal Intensive Care Unit with a diagnosis of RDS at University of Gondar Comprehensive Specialized Hospital.The study population included all preterm neonates who were admitted to (NICU) with a diagnosis of RDS at University of Gondar comprehensive specialized Hospital from January 2017 to December 2019.α/2 and Zβ as 1.96& 0.842 at 95% confidence level respectively. Where q1 was probability of event in previous studies and q0 = 1- q1.The sample size was determined by using survival analysis formula based on the following assumptions; number of event (E), probability of the event (d) and values of ZHR2q1q0Then the sample sizes 42.78%  which gaBefore data collection, the records were reviewed and preterm neonatal cards were identified by their medical registration/card number. Then data collectors reviewed and extracted data from patients’ charts and registries using a structured check list. Data extraction check-lists was prepared in English from Health and Medical Information System (HMIS) registration format and patient’s card. Three BSc midwife professionals collected the data with the supervision of the principal investigator. The patients’ card clerks also supported them by identifying the cards of neonates. Training of the objective of the study and how to review the documents as per the data extraction format was conducted. The PI was supervise the overall process. The filled formats were checked for completeness by the PI supervisors.The data were entered in to EPI info version 7 and exported to Stata 14 statistical software for further analysis. Descriptive summary statistics like median survival time, Kaplan Meier survival estimation curve and Log rank test were computed. Proportional hazard assumption (PHA) was checked both graphically and hypothesis test called Schoenfeld residual test. At the same time Schoenfeld’s residual test was done for almost all variables and met proportional hazard assumption. Schoenfeld residuals test  showed that proportional hazard assumption PHA was satisfied.Then, parametric models were done for time to recovery of preterm neonates with respiratory distress syndrome to identify the potential determinants.Hazard ratio is used as a measure of probability of recovery, assuming that the Survival model is usually expressed in terms of hazard function.Once Cox regression model fitted, parametric survival analysis models were fitted by considering the baseline hazard with different distribution assumption. Under the parametric approach, the baseline hazard is defined as a parametric function and the vector of its parameters are estimated together with the regression coefficients.A more parsimonious hazard model was chosen by means of the log likelihood ratio (LR) test and Akaike Information Criterion (AIC). The best fitted model was chosen using AIC and those having the smallest AIC were considered as a best fitted model. Similarly, goodness of model fitness also checked using Cox Snell residual test.Ethical approval was obtained from Institutional Review Board (IRB) of Institute of Public Health, CMHS, University of Gondar. The IRB of Institute of Public health, College of Medicine and health Sciences (CMHS) has waved for informed consent of the medical records of participants. Permission letter was obtained from the hospital administration and names of patients were not be included during data collection.Among 386 preterm neonates with RDS 229 (59.3%) were males, 239 (61.9%) were singleton pregnancy. About 109 (28.24%) of neonates have Apgar score <4 with in the first five minute and 176(45.6%) required a bag and mask ventilation immediately after delivery .In this study the cumulative incidence of recovery of preterm neonates with RDS was 60.9 ) percent.The overall median length of hospital stay for preterm neonates under the study was 7 days, which gave a total of 3511 neonate-days observation and median length of recovery were 11 neonate-days with an interquartile range of  neonate-days.The cumulative probability of recovery at the end of seventh days was 79.6%, at twenty-eight days were 9.2% .Differences in all key variables between strata were determined using log rank (χ2) test and assessed the equality of hazard for the different explanatory variables.Similarly the plot Kaplan Meier survival by taking bag and mask ventilation (A), hypothermia (B) and birth weight (C) against survival time were done and the study indicated roughly parallel graphs for duration of follow up, thus proportional hazard assumption was met .The goodness of fit for the fitted model also performed using the Cox Snell residual test and the model was adequate .Univariable and multivariable Weibull parametric model was fitted to identify determinants of time to recovery for preterm neonates with RDS from admission to discharge in the neonatal intensive care unit.Findings from the bivariable analysis showed that gestational age, birth weight, neonatal hypothermia at admission, and neonate taking bag &mask ventilation were significantly associated with time to recovery of preterm neonates with RDS.However, in the multi-variable analysis type of pregnancy, mode of delivery, gestational age, birth weight, neonatal hypothermia at admission, and neonate taking bag &mask ventilation have remained statistically significant for time to recovery of preterm neonates with RDS .In this study the median time and cumulative incidence of recovery of preterm neonates with RDS was 11 days and 60.9% respectively.The median time to recovery of preterm neonates with RDS were 11 neonate-days with an interquartile range of  neonate-days. This finding shows slow recovery as compared with different medical resources like up todate 20.3 and Medscape which said that with good medical treatment they should recover within 72 hours or 3 days. This might indicate that the treatment given in the hospital was not satisfactory.The cumulative incidence of recovery of preterm neonates with RDS admitted in NICU of the University of Gondar comprehensive specialized hospital was 60.9% ). This finding is in line with the findings reported by a study done in Lautech Teaching Hospital, Osogbo, Nigeria 59.79% , in FaujOur study finding was higher than a study conducted in Jimma University Specialized Hospital, Jimma Ethiopia 42.78% , referraIn this study the recovery of preterm neonates with RDS who was delivered by vaginal delivery was 1.6 times more likely as compared with those delivered by cesarean delivery. This is clinically evidenced that, as the neonate is delivered through the vaginal birth canal, there is a pressure exerted on the chest to remove the fluid filling the neonatal lung leaving space for entry of air as well as better stimulate cardiorespiratory system.Here in this study gestational age was a predictor variable for time to recovery of preterm neonate with RDS. A week increase in gestational age enhances the recovery of preterm neonates with RDS by 1.26 times. This finding was in line with a study conducted in Fauji Foundation hospital, Rawalpindi , Jimma UThis is because as the gestational age increase the neonate has better capability of producing surfactants for maximizing lung maturity and maintaining their cardiopulmonary system.Preterm neonates with RDS who had comorbidity of hypothermia at admission had statistically significant effect on time to recovery and decreased by 45% as compared to those who had no hypothermia. The negative association between time to recovery of preterm neonates with RDS and hypothermia in our study is in line with studies conducted in Jimma University specialized hospital, Ethiopia  and Mt. A recovery of preterm neonate with RDS taking bag and mask ventilation has decreased by 46% as compared with those who hadn’t taking bag and mask ventilation. This might be due to the pressure exerted to the bag which may be beyond the capacity of the neonates’ lung and leading to alveolar damage causing life threatening complication.In this study being multiple pregnancy has 1.67 times higher recovery among preterm neonates with RDS as compared to singleton pregnancy. This might be due to the reason that multiple pregnancies matured earlier than singleton pregnancies since the intrauterine live becomes worse and compromised starting 30 weeks of gestation onwards.Birth weight greater or equal to 2000 grams among preterm neonates with RDS has 2.12 times higher recovery as compared with birth weight less than 2000grames. This is clinically evidenced that birth weight is another indicator for sign of maturity and copying life threatening complications.In this study the median time to recovery of preterm neonates with RDS was slow. In this study the cumulative incidence of recovery of preterm neonates with RDS was low as compared to clinical recommendations.Receiving bag and mask ventilation and hypothermia as a comorbid condition at admission decreased the hazards of recovery of preterm neonates with RDS whereas, vaginal mode of delivery gestational age at birth, being multiple pregnancy, birth weight 2000grams and above were enhance the hazards of recovery of preterm neonates with (RDS). It is better to access NICU infrastructures and skilled manpower at primary health care institutions  and give special attention for preterm neonates in the NICU to prevent comorbid complications like hypothermia.Since the data were secondary source it had missing information of some important variables which might have a significant association with outcome variable like maternal socio-demographic variables, obstetric conditions, immediate newborn care. Due to being secondary data it is unable to assess the quality of care provided which might have significant effect.S1 Data(DTA)Click here for additional data file.


The aim of this study was to determine a predictive index for the risk of anastomotic leak following esophageal atresia anastomosis,This article reviewed the clinical data of 74 children with esophageal atresia in Fujian Children's hospital. The risk factors for anastomotic leak were analysed, and a new predictive index was proposed.P = 0.033, OR = 0.273) was a protective factor for anastomotic leak, whereas gap length  was a risk factor for anastomotic leak. The ratio of gap length to birth weight had a positive predictive effect on the occurrence of anastomotic leak .The incidence of anastomotic leak was 29.7% after anastomosis in 74 children with esophageal atresia. Birth weight and gap length were risk factors for anastomotic leak. Logistic regression analysis showed that birth weight (Wald 2 = 4.528, Birth weight and gap length are important predictors of anastomotic leak in esophageal atresia. Measurement of the ratio of gap length to birth weight is a helpful predictive index for anastomotic leak following the anastomosis of esophageal atresia. Esophageal atresia (EA) is a congenital disruption of esophageal continuity with or without tracheal fistula (TEF). Up to 55% of affected infants may have other congenital malformations, especially complicated congenital heart disease (CHD), which is an important factor in poor prognosis . Great pAnastomotic leak is defined as esophageal rupture caused by poor anastomotic healing after esophageal reconstruction surgery, which is the most common complication after esophageal surgery and the main cause of death . AnastomThe study was approved by the ethics committee of our hospital and adhered to the tenets of the Declaration of Helsinki. All participants gave written informed consent to use their infant’s data for this study after being educated about the nature of the study, potential risks and how their data may be used. Patient and Public Involvement was not implemented in the design, conduct, reporting, or dissemination of our research.This study was conducted retrospectively in a provincial hospital along the southeast coast of China. From January 2016 to June 2020, we collected 74 infants with type III EA, including 51 males and 23 females. The inclusion criteria were infants with complete clinical data after successful surgical treatment. All infants were operated on by the same general thoracic surgeon. In this study, children who were underwent staged surgery  were excluded.Type III esophageal atresia is the most common clinical type in the classification of EA. The classification of EA classification comes from the Vgot classification. The 74 patients included in this study all had type IIIb esophageal atresia (according to the Vogt classification).For the selection of surgical methods, we believe that the criteria for the exclusion of thoracoscopic surgery are the cases with birth weight < 1500 g, unable to stabilize physiological parameters (circulatory failure and respiratory failure) or major cardiac abnormalities . For theGeneral data were collected through the medical record system, including sex, birth weight, gestational age, preoperative mechanical ventilation, and CHD status. The albumin data came from preoperative blood tests. The length of the EA defect was determined by measuring the distance between the two ends of the oesophagus after esophageal disconnection. The operative time, the amount of blood loss and the number of anastomotic lines were obtained by summarizing the operative records. A diagnosis of anastomotic leak was confirmed by the presence of contrast leakage on esophageal contrast studies. Preoperative mechanical ventilation was defined as ventilator assistance required before surgery due to the following: respiratory failure caused by tracheesophageal fistula, gastresophageal reflux and gastrointestinal flatulence.P value < 0.05 was defined as statistically significant.The data were analysed using SPSS Statistics, version 22.0 software . Univariate analysis was used for risk factors. ANOVA was used for continuous variables, and the chi-square test was used for discontinuous variables. Binomial regression analysis was used for logistic regression analysis, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to indicate associations. A P = 0.721).Table P = 0.031), birth weight  and length of EA defect . Factors that did not influence anastomotic leak formation included the following: operation time, blood loss, and stitch number required for anastomosis.Table P = 0.033, OR = 0.273) was a protective factor against anastomotic leak, while gap length  was a risk factor for anastomotic leak.Table P = 0.012). Using the receiver operating characteristic (ROC) analysis method, the area under the curve (AUC) of this indicator was found to be 0.732 . Nine of seventeen infants with CHD weighed less than 2.5 kg. Low birth weight is often associated with a history of premature delivery, foetal distress and heart malformation [Possible factors associated with its onset include a poor anastomotic technique, the use of woven sutures, a two-layer anastomosis, a long-gap EA, blood transfusion, anastomosis under tension and gastresophageal reflux . Factorsormation . Low birormation .P = 0.004) [P = 0.721). This is consistent with the conclusions of Japanese scholars, who believe that CHD has nothing to do with anastomotic leak or stenosis [Survival is directly related to birth weight and CHD status. Infants weighing over 1500 g with no major cardiac problems had nearly 100% survival, whereas the presence of one risk factor reduced survival to 80%, and when both risk factors were present survival was further reduced to 30–50% . Folaran= 0.004) . Our stustenosis . Anotherstenosis . More instenosis .In clinical practice, we found that infants with anastomotic leak had lower perioperative albumin. Low albumin is an independent risk factor for postoperative anastomotic leak of the oesophagus . A low pThe treatment of long-gap EA is still difficult . There iUsing the receiver operating curve, the AUC of this indicator was found to be 0.732, which had a good predictive value. We believe the index can be used as a good predictor of anastomotic leak during the perioperative period. For infants with a preoperative evaluation of the ratio of loss length to birth weight greater than 0.7, esophageal extension and gastrostomy should be considered. Anastomosis can be attempted after the natural extension of the oesophagus within the chest reaches a gap length of less than 3 cm, therefore, delayed repair may be a better choice .As with any retrospective study, there is bias associated with data collection; this study was limited to one institution, and other institutions may have produced different results. A prospective study with a large group of patients and long-term follow-up is necessary.Birth weight and gap length are important predictors of anastomotic leak in EA. Our study shows that the ratio of gap length to birth weight index had a good predictive effect on the occurrence of anastomotic leak after anastomosis of EA.


Embryo quality may affect birth weight among neonates born through assisted reproductive technology. There are very limited studies assessing the adverse effect of transferring a poor-quality embryo with a good-quality one on neonatal outcomes.The aim of this study was to evaluate the effect of double embryo transfer (DET) with one good-quality embryo (GQE) plus a poor-quality one on the birth weight of newborns conceived by in vitro fertilization in both fresh and frozen-thawed embryo transfer cycles. This study was conducted at Yazd Reproductive Sciences Institute, Yazd, Iran. A total of 626 women were classified into three groups according to the embryo quality: single embryo transfer with a GQE (group A); DET using two GQEs (group B); and DET using one good-quality and one poor-quality embryo (group C). The primary outcome was singleton birth weight which was compared between the three groups among fresh and frozen-embryo transfer cycles. A comparative analysis was also performed regarding the effect of vitrification procedures on neonatal birth weight within each of the three embryo quality-based groups.The mean birth weight and the rate of preterm birth were similar between the three groups . There were also no significant differences found in the vitrification comparative analysis between and within the groups with regard to birth weight.Our results showed that a poor-quality embryo did not have a significant influence on a good-quality one regarding neonatal birth weight when transferred together. In vitro fertilization (IVF) has some unknown features which may adversely affect IVF-born babies. The risk of low birth weight (LBW), preterm birth (PTB), and being small for gestational age are increased among neonates born through assisted reproductive technology (ART) cycles in comparison with naturally conceived ones (1). Moreover, the laboratory procedures, including the method of insemination, culture medium and duration of culture period, influence the embryo quality, which has been shown to have a critical role in successful pregnancy .Even though transferring good-quality embryos (GQEs) is preferable, for a fairly large number of patients without GQEs, the transfer of poor-quality embryos (PQEs) is unavoidable. It has been previously reported that double embryo transfer (DET) may increase ongoing pregnancy and live birth rates and therefore, some IVF clinics transfer more than one embryo. In using the DET strategy with only one GQE available, the second embryo must be a PQE. There are very limited studies assessing the adverse effect of an additional PQE on the neonatal outcomes through DET.On the other hand, frozen-thawed embryo transfer (FET) has become a common ART procedure and so determining the effect of cryopreservation on embryo quality is crucial. In addition, it has been indicated that cryopreservation is strongly involved in the variation of neonatal birth weight . As LBW has been associated with the incidence of serious complications such as cardiovascular diseases, hypertension and Type 2 diabetes (6), it is important to know whether the combination of one GQE and one PQE transferred in a DET program might affect neonatal birth weight in both fresh and FET cycles. Thus, the aim of the current study was to evaluate the effect of DET with one GQE plus one PQE on the birth weight of newborns conceived by ART in both fresh and FET cycles.2, uterine anomalies, gestational diabetes, pregnancy-induced hypertension, preeclampsia and uncontrolled endocrine or immune disorders. Women with oocyte donation or surrogate cycles, women with preimplantation genetic testing or couples with severe male factor infertility were also excluded from all analyses. Women were enrolled only once in the study and if women had more than one treatment cycle during the study period, only the first cycle was considered.This retrospective cohort study assessing the effect of embryo quality on the neonatal birth weight after transfer of cleavage-stage embryos in both fresh and FET cycles was conducted at Yazd Reproductive Sciences Institute in Yazd, Iran. The data of 626 infertile women aged 20 to 44 yr, who had undergone IVF/intracytoplasmic sperm injection (ICSI) cycles and delivered an alive singleton birth, were consecutively reviewed between July 2017 and September 2021. The women who planned to have one or two cleavage-stage embryos transferred were included in our study. The data were extracted from hospital electronic medical records and only women with complete hospital records were included. The exclusion criteria were body mass index (BMI) Women were stimulated with gonadotropin releasing hormone (GnRH) agonist, GnRH antagonist, or microdose flare protocols. In the GnRH agonist long protocol, 0.1 mg triptorelin acetate  was injected subcutaneously each day from the 21For women who were stimulated by the GnRH antagonist protocol, the starting dose of gonadotropin was adjusted in accordance with their ages, Anti-Mullerian hormone (AMH) level, antral follicle count, and ovarian response, which was assessed using serial transvaginal ultrasonography during ovarian stimulation. From 150 to 300 IU/day rFSH was administered subcutaneously for five days starting on cycle day two. Once a leading follicle In the microdose flare protocol, buserelin  was administered at the dose of 0.05 mg subcutaneously twice daily starting on cycle day two, which continued until the day of human chorionic gonadotropin (hCG) injection. Ovarian stimulation was started using a daily subcutaneous injection of 225 to 300 IU rFSH on cycle day four. Oocyte triggering was done when at least two follicles reached 17 mm in diameter in ultrasonography. Oocyte triggering was performed using either 10,000 IU hCG  or 0.2 mg of subcutaneous GnRH-a . However, in some cases, oocyte triggering was done using a dual-trigger method by administration of 1500-5000 IU hCG plus 0.2 mg of subcutaneous GnRH-a.Transvaginal ultrasound-guided oocyte retrieval was carried out 36 hr after hCG administration for all subjects. Oocytes were inseminated using conventional IVF or ICSI as standard protocols.Cleavage-stage embryos were graded according to the number of blastomeres and fragmentation degree from A  to D . Grade A: embryos with 7-9 blastomeres and a maximum of 20% cytoplasmic fragmentation; Grade B: embryos with 7-9 blastomeres and over 20% fragmentation; Grade C: embryos with 4-6 blastomeres and a maximum of 20% fragmentation; Grade D: embryos with 4-6 blastomeres and over 20% fragmentation (7). Embryo grading was done by a team of three highly experienced embryologists. In this study, we considered grade A and B embryos as good quality if they possessed 7-9 blastomeres on day three and contained Embryo vitrification and warming were performed as previously described . In short, embryos containing less than 30% fragmentation were cryopreserved via the vitrification method (9). Thawing was carried out at least two months after cryopreservation based on the VitroLife protocol  (8). Cryopreserved-thawed embryos with The best quality embryos were selected for fresh embryo transfer 48-72 hr after oocyte retrieval. Routinely, a maximum of two fresh or vitrified-warmed embryos of good quality were transferred using an embryo transfer Labotect catheter  in the fresh and FET group, respectively. In some cases, one GQE and one PQE were transferred as there was no alternative.For endometrial preparation, 6 mg per day oral estradiol valerate  was administered starting on cycle day two until the endometrial thickness reached 7.5 mm. After that, all women received 400 mg of vaginal cyclogest pessaries  twice daily. Both estradiol and progesterone were administered until observation of fetal heart activity by ultrasound.This study was approved by the Ethics Committee of Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran (Code: IR.SSU.RSI.REC.1399.043).The SPSS software  was used for data analysis. The primary outcome was singleton birth weight. The other neonatal factors, as secondary outcomes, included gestational age, LBW , of which, 258 women were in the fresh embryo transfer group, and FET was performed for 368 women. The patients' basic characteristics and ART cycle features along with neonatal outcomes were compared according to the quality of the transferred embryos in both the fresh and FET cycles. The demographic and treatment cycle characteristics in the fresh and FET groups are listed in table I and II, respectively. No differences were observed in terms of maternal or paternal age, maternal BMI, parity, gravidity, infertility cause or duration, insemination method, type of ovarian stimulation, or endometrial thickness between the groups. Nevertheless, the number of retrieved and mature oocytes and the number of 2PNs differed significantly among the embryo quality categories in the fresh group ; group B: DET using two GQEs (this included 181 fresh and 244 FET cycles); and group C: DET using one GQE plus one PQE (this included 40 fresh and 74 FET cycles). There were no significant differences between and within the groups with regard to birth weight .To adjust for the confounding factors, we carried out a logistic regression analysis to investigate the relationship between embryo quality, and birth weight and preterm delivery. No association was found between the embryo quality and birth weight and preterm delivery (Table V).Our results showed that neonates born after SET of a cleavage-stage GQE had a similar birth weight compared to those born after DET of two GQEs or DET of a GQE plus a PQE embryo during both fresh and FET cycles. Therefore, our research hypothesis that the addition of a PQE to a GQE, when transferred together, may decrease the neonate's birth weight was rejected.Previously, the association between embryo quality and pregnancy outcome had been investigated in several studies and the results showed that transfer of PQEs could adversely affect clinical pregnancy and live birth (10-12). Throughout recent years it has been stated that this adverse effect may not be limited to live birth, and may in fact extend to neonatal outcomes such as birth weight (2). The earlier studies evaluated the effect of embryo quality on perinatal outcomes in fresh cycles and reported that the transfer of either GQEs or PQEs in the cleavage or blastocyst stages did not affect the neonatal birth weight, or the risk of PTB or being small for gestational age (13-15).On the other hand, with improvement in ART, the transfer of frozen-thawed embryos has become an option for women undergoing IVF, especially for those who are at risk of developing ovarian hyperstimulation syndrome. However, it has been shown that freezing-thawing procedures can negatively affect perinatal outcomes of singleton pregnancies (5). Regarding birth weight, it has been claimed that there is a strong correlation between embryo cryopreservation and birth weight variations (4). Two studies involving FET cycles compared neonatal outcomes after transferring PQEs or GQEs. They found decreased birth weight among neonates born following the transfer of PQEs in comparison with GQE transfer, regardless of cleavage or blastocyst stage .All of the above-mentioned studies compared the perinatal outcomes following the transfer of either PQEs or GQEs. Only five studies have examined the impact of adding one PQE to a GQE on ART outcomes and two of these investigated the effect of transferring a PQE and a GQE together on neonatal birth weight (17-21). Similar to our findings, Li and colleagues examined fresh cycles in which one cleavage-stage PQE plus one GQE were transferred, and compared these cycles with those in which two GQEs were transferred, in terms of ART outcomes. They did not find any significant differences regarding pregnancy, miscarriage or live birth rates between the two groups. Moreover, according to their results, an additional PQE did not negatively affect the neonatal birth weight, gestational age or risk of PTB (19). Likewise, another recent study reached the same conclusion. The study evaluated ART outcomes among women who received either DET with a PQE and a GQE or SET with only a GQE during FET of blastocysts. The results showed that the neonatal birth weight was similar between both groups. However, the women in the double blastocyst transfer group comprising one PQE plus one GQE achieved significantly higher pregnancy and live birth rates (20). In line with the two aforementioned studies, our findings indicated that adding a PQE to a GQE did not adversely affect preterm birth or birth weight either in fresh or in FET cycles.The mechanism by which embryo quality could influence birth weight remains unknown. It has been proposed that epigenetic changes during the culture period may be involved in this process and could affect fetal growth (22). Moreover, the methylation levels and any altered homeostasis or impaired metabolism may have consequences for normal fetal growth and could affect neonatal birth weight .It should be noted that DET with a GQE accompanied by a PQE usually means that there were no more GQEs for transfer and therefore the transferred GQE had to have come from a poor cohort. Theoretically, a cohort of PQEs may negatively affect the GQE potential during the co-culture period. However, the adverse effect of the PQE on the GQE, when those two are transferred together in a DET procedure, is highly debatable. Published data have suggested that embryo growth and development can be positively affected by group culturing .Nevertheless, it has been indicated that the presence of PQEs in the culture medium may have a detrimental effect on the developmental process of GQEs (24). On the other hand, the evidence shows that the endometrium plays a selective role and prevents PQEs from implantation (17). It should also be noted that morphology is not the only predictor for embryo quality and other factors such as embryo ploidy status or mitochondrial issues should be considered.Other studies have focused on either fresh or FET cycles; however, for the first time in this study we compared the effect of adding a PQE to a good-quality one on neonatal birth weight between fresh and FET cycles. It should be noted that twin pregnancies and other pregnancy-linked problems triggering intrauterine fetal growth retardation such as gestational diabetes, pregnancy-induced hypertension and preeclampsia were excluded from the study. In addition, parental basic characteristics associated with embryo quality and neonatal outcomes including age, BMI and poor ovarian reserve were considered for further analysis. However, our results did not change after adjusting for these confounding variables.The main limitation of this study was its retrospective design. The data were extracted from electronic medical records with some missing information. Patients' follow-up was done using a phone questionnaire, which was less accurate than the medical records. Another limitation may be the subjectivity in the embryo grading process. However, the procedure was performed in a single center where embryos were graded by the same group of trained embryologists. The study was also limited by the small sample size, preventing more subgroup analysis.In conclusion, our results showed that a PQE did not have a significant influence on a GQE regarding neonatal birth weight when transferred together. This study was a retrospective one and naturally a randomized controlled trial would be more persuasive.The authors declare that there is no conflict of interest.


To what extent are birth defects associated with child mortality?In this cohort study of 1 037 688 children younger than 14 years, birth defects were associated with more than 23 times the risk of mortality from circulatory, respiratory, and digestive causes compared with no defect. Risk of death was elevated for children with central nervous system, heart, and chromosomal defects, and between 28 and 364 days of life.These findings suggest that children with birth defects have a high risk of postneonatal mortality, including mortality from cardiorespiratory and digestive causes. This cohort study uses the Maintenance and Exploitation of Data for the Study of Hospital Clientele data set to examine mortality rates by cause of death in children with and without birth defects. Causes of death in children with birth defects are poorly understood.To determine mortality rates by cause of death in children with and without birth defects.This longitudinal cohort study included a population-based sample of 1 037 688 children and was conducted in all hospitals in Quebec, Canada, with 7 700 596 person-years of follow-up between birth and age 14 years .Presence or absence of a birth defect.Outcomes were all-cause and cause-specific mortality. Hazard ratios (HRs) and 95% CIs were computed for the association between birth defects and mortality with Cox proportional hazards models adjusted for patient characteristics.Among the 1 037 688 children in the cohort, 95 566 had birth defects (56.5% boys). There were 532 542 boys in the cohort (51.3%), and mean (SD) age at the end of follow-up was 7.42 (3.72) years. There were 918 deaths among children with defects, and the mean (SD) age was 0.93 (2.07) years at death; there were 1082 deaths among the 942 122 children without defects, and the mean (SD) age at death was 0.50 (1.51) years. Mortality rates were higher for children with birth defects compared with no defect . Girls  and boys  with birth defects had an elevated risk of death before 14 years compared with unaffected children. Birth defects were associated with mortality from circulatory , respiratory , and digestive causes , but anomalies were rarely listed as the cause of death. Compared with children with no defect, those with birth defects were at greatest risk of death between 28 and 364 days of life.This cohort study of 1 037 688 children suggests that birth defects were strongly associated with mortality owing to circulatory, respiratory, and digestive causes. This finding suggests that the contribution of birth defects may be underestimated in mortality statistics. Birth defects account for 20% of infant deaths in the United States.2 Preventing mortality is challenging because causes of death in children with birth defects are often poorly understood. Although it is easy to identify defects that are incompatible with life, severe anomalies are rare and account for only a fraction of deaths.4 For the majority of children with birth defects, mortality may not be directly due to the anomaly.6 Improved understanding of cause of death is needed to improve the survival of children with birth defects.Children with birth defects have high mortality,9 and may underestimate mortality due to congenital anomalies.6 Cohorts of children with birth defects frequently lack a comparison group.10 In a systematic review of 55 studies of long-term survival, only 7 studies of children with birth defects had a comparison group.1 The review confirmed that children with birth defects had an elevated risk of mortality, but causes of death were not investigated.1 The only study that assessed specific causes of mortality attributed deaths primarily to perinatal conditions and the underlying anomaly.5 However, the study assessed births from the 1970s and 1980s.5 It is likely that the findings are outdated because recent advances in the management of birth defects may have improved survival since then. To provide updated data, we studied the association between birth defects and cause-specific mortality in a longitudinal cohort of children with 14 years of follow-up between April 1, 2006, and March 31, 2020.Most studies of child mortality rely on death certificates or cross-sectional data with incomplete information on birth defectsSTROBE) reporting guideline for cohort studies  ; cancer (C00-D48); blood (D50-D89); endocrine, nutritional, and metabolic (E00-E90); nervous system (G00-G99); circulatory (I00-I99); respiratory (J00-J99); digestive (K00-K93); musculoskeletal (M00-M99); genitourinary (N00-N99); and perinatal (P00-P96). We included causes relating to congenital anomalies (Q00-Q99), shock and ill-defined conditions (R00-R99), injury and external causes (S00-T98 and V01-Y98), and health status and contact with health services (Z00-Z99).We categorized deaths by cause, following chapters in 13 including maternal age , parity , multiple birth, preterm birth , sex, socioeconomic deprivation , and period at birth . Data on socioeconomic deprivation were missing for 4.0% of children; we placed this variable in a separate category because there was no difference in the distribution between exposed and unexposed children.We adjusted for potential confounders associated with child mortality in the literature,We calculated mortality rates and used Cox proportional hazards models to compute hazard ratios (HRs) and 95% CIs for the association between birth defects and mortality in boys and girls separately. We ran models for each type of defect and examined both all-cause and cause-specific mortality. The time scale was measured as the number of days between birth and the date of death or study end on March 31, 2020. We censored children who survived to the end of the study. We adjusted the models for maternal age, parity, multiple birth, preterm birth, socioeconomic deprivation, and period. We accounted for children with the same mother by using robust error estimators and examined the proportionality of hazards with log  curves.In secondary analyses, we stratified the analysis by age at death . In sensitivity analyses, we restricted the data to term births to rule out any association with prematurity. We performed the analysis in SAS version 9.4 (SAS Institute Inc) and assessed statistical significance with 95% CIs.Among 1 037 688 children in the cohort (532 542 boys [51.3%] and 505 146 girls [48.7%]), 95 566 had at least 1 birth defect (9%), and there were 2000 deaths (0.2%) during 7 700 596 person-years of follow-up . Mean S. There wChildren with birth defects had a high risk of mortality between birth and age 14 years . CompareSeveral specific defects had particularly strong associations with mortality . HypoplaAmong the 918 children with birth defects who died, the most common causes of death were perinatal conditions  . PerinatBirth defects were associated with an increased risk of death from most causes . CompareChildren with birth defects had a high risk of mortality at all ages, especially the postneonatal period . CompareIn sensitivity analyses, excluding preterm births strengthened the associations. Relative to that of children with no defect, risk of death for boys with birth defects was 14.66 times greater ; and for girls, 18.44 times greater .In this study of 1 037 688 children in Canada, birth defects were associated with more than 4.7 times the risk of death before age 14 years. Nearly half of children who died had a birth defect. Central nervous system defects were associated with more than 10 times the risk of death; heart defects, with more than 8 times the risk; and chromosomal anomalies, with more than 17 times the risk. Children with birth defects had an elevated risk of death from circulatory, respiratory, and digestive causes. Risk of death between 28 and 364 days of life was considerably elevated, although there was an elevated risk at other points as well. The findings demonstrate that in children with birth defects, the cause of death is frequently a reason other than the anomaly itself. The contribution of birth defects may be underestimated in mortality data.9 Birth defects are ascertained only if the anomaly is the obvious cause of death.14 A study of 83 183 children with death certificates in Michigan found that underlying birth defects accounted for only 18% of deaths.6 The proportion increased to 34% when the authors used longitudinal data, suggesting that death certificates may underestimate the contribution of defects to mortality.6 An analysis of death certificates revealed that birth defects were the underlying cause of death in less than 83% of children with known anomalies.14 In our longitudinal cohort, nearly half of children who died had birth defects, but only 22% had an anomaly recorded as the cause of death.In current statistics, deaths owing to birth defects are frequently captured with vital statistics or other cross-sectional information.5 The majority of children with birth defects in our cohort ultimately died from causes potentially related to the birth defect, including complications arising in the perinatal period. Up to 38% of deaths among children with birth defects were due to perinatal conditions. Improvements in early neonatal life support may have been associated with an increased number of deaths from these causes over time.18Birth defects were less often recorded as the cause of death in our data, contrasting with birth cohorts from the 1970s and 1980s, in which anomalies accounted for two-thirds of deaths.19 In another study of children with birth defects, circulatory disorders ranked as an important cause of death before age 10 years.6 Circulatory disorders are common in children with heart defects, diaphragmatic hernia, and lung hypoplasia.19 Infections such as respiratory syncytial virus can be common in children with spina bifida, lung malformations, cleft palate, and biliary atresia.20 Prematurity can also exacerbate risks of mortality because of circulatory, respiratory, and digestive complications,21 although birth defects were associated with these causes even when we excluded preterm births.Risk of death was high for circulatory, respiratory, and digestive causes. Compared with no defect, birth defects were associated with more than 23 times the risk of mortality from these causes. In Texas, a study of 8000 infants with birth defects found that deaths owing to circulatory, respiratory, and digestive causes were frequent before 1 year of age.13 These defects were associated with more than 160 times the risk of death in a study of 262 352 children from New York.13 They were also fairly lethal in our cohort, although the magnitude of association was lower. However, our data covered a later period, and improvements in clinical management may have been associated with increased survival of children with hypoplastic left heart syndrome and chromosomal anomalies.23 Most children with anencephaly die by 1 month of age, although survival past 2 years has been documented.24Defects such as hypoplastic left heart syndrome, trisomy 13 and 18, and anencephaly are known for causing high mortality.25 Displaced deaths may ultimately be unavoidable owing to a high prevalence of morbidities.26 Deaths are less likely to be displaced in children without defects, in whom the majority of deaths are concentrated in the earliest days of life.Children with birth defects had a markedly greater risk of death in the postneonatal period, or between 28 and 364 days of life. Birth defects were associated with 6.6 times the risk of death between 1 and 27 days, but 21.2 times the risk between 28 and 364 days. This pattern suggests that deaths of children with birth defects who would otherwise die without life-sustaining interventions may be displaced to the postneonatal period.27 In our data, children with heart, respiratory, and chromosomal anomalies continued to be at risk of death in infancy and childhood, although mortality rates decreased after the postneonatal period. Children with heart defects had nearly 40 times the risk between ages 1 and 4 years and 20 times the risk between 5 and 14 years compared with those with no defect. Children with respiratory or chromosomal anomalies had 33 to 87 times the risk of death between ages 5 and 14 years. Many children with lung malformations are initially asymptomatic before presenting with infections later in infancy.28 Prophylactic lobectomy is possible, but the association with survival remains uncertain.28 Careful monitoring may be needed, especially for cardiorespiratory and chromosomal anomalies, because in our cohort these children had a high prevalence of mortality from circulatory and respiratory causes.Today, most children with heart defects are expected to reach adulthood. Survival may depend on severity of the defect, age at surgery, and other prognostic factors.29 Complications related to surgery or medical devices, motor or sensory deficiency, or bladder, bowel, and cognitive impairment are common with spina bifida.30 Sepsis, pneumonia, and respiratory failure can account for more than one-third of hospitalizations that lead to death.30 In our data, respiratory disorders were a common cause of death in children with central nervous system defects.For central nervous system defects, mortality rates did not improve substantially with age. Risk of death was higher after age 1 year and peaked between 5 and 14 years. A longitudinal study of 117 infants with surgically treated spina bifida found that mortality rates remained high into adulthood.This cohort study had a large sample size and included birth defects that were detected later in childhood, but there are limitations. We used administrative data in which coding errors may have misclassified exposures or outcomes and attenuated results toward the null. We lacked data on birth defects diagnosed in ambulatory clinics, and potential confounders such as race and ethnicity. We had limited statistical power to examine associations for rare birth defects and uncommon causes of death. We used data that provided the immediate cause of death, information that is important for mortality prevention but may not reflect the sequence of events that lead to death. Finally, the results may not be generalizable to settings without a high standard of health care because the cohort comprised children with publicly funded health insurance in Canada.This longitudinal cohort study of 1 037 688 Canadian children suggests that birth defects are associated with a high risk of mortality in the postneonatal period, especially mortality due to circulatory, respiratory, and digestive causes. Among children with birth defects, perinatal conditions were the most common cause of death, whereas birth defects were recorded for a smaller fraction of deaths. The findings suggest that birth defects are substantially associated with child mortality despite medical advances. Better management of cardiorespiratory and digestive causes of mortality may be needed to improve long-term survival of children with birth defects. More accurate mortality statistics are required to inform guidelines for prevention of mortality in children with birth defects.