Expanding primary healthcare to urban poor populations is a priority in many low-and middle-income countries and is essential to achieve universal health coverage (UHC). Between 2008 and 2016 the city of Rio de Janeiro undertook an ambitious programme to rapidly expand primary care to low-income areas through the family health strategy (FHS). Infant health impacts of this roll out are unknown. This study examines associations between maternal FHS utilisation and birth outcomes, neonatal and infant mortality.A cohort of 75,339 live births (January 2009–December 2014) to low-income mothers in Rio de Janeiro was linked to primary care, birth, hospital and death records. The relationship between maternal FHS use and infant health outcomes was assessed through logistic regression with inverse probability treatment weighting and regression adjustment. Socioeconomic inequalities in the associations between FHS use and outcomes were explored through interactions. Primary outcomes were neonatal and infant death. Thirteen secondary outcomes were also examined to explore other important health outcomes and potential mechanisms.A total of 9002 (12.0%) infants were born to mothers in the cohort who used FHS services either before pregnancy or in the first two trimesters. There was a total of 527 neonatal and 893 infant deaths. Maternal FHS usage during the first two trimesters was associated with substantial reductions in neonatal  and infant mortality . Infants born to lower-income mothers and those without formal employment had larger reductions in neonatal and infant mortality associated with FHS use. Maternal FHS in the first two trimesters use was also associated with more antenatal care consultations and a lower risk of low birth weight and preterm birth.Expanding primary care to low-income populations in Rio de Janeiro was associated with improved infant health and health equity benefits.10.13039/501100002992DFID/MRC/10.13039/100010269Wellcome Trust/10.13039/501100000269ESRC. The World Health Organization (WHO) states that primary healthcare (PHC) is the main vehicle for achieving universal health coverage (UHC) and Sustainable Development Goal (SDG) target 3.2–reducing neonatal and early childhood mortality. However, many low-income urban populations lack access to quality primary care services. Limited knowledge on the impact of PHC on infant health and survival, especially in low-income urban populations, is hindering further investments in PHC.EMBASE, MEDLINE, Global Health, HMIC , and the Maternity & Infant Care Database via Ovid were searched in August 2022 for synonyms of “primary care”, “birth outcomes or infant health”, and “utilisation”. These were supplemented with internet searches (Google), searching of references in identified papers, and the authors’ own knowledge. Studies were restricted to those conducted in LMICs. Three recent systematic reviews highlight the relationship between antenatal care and reductions in neonatal and infant death, and improvements in birth outcomes (such a birth weight and risk of preterm birth). 32 studies examined the association between PHC services and infant health outcomes , with a consistent pattern of increasing PHC use or coverage associated with health improvements. There is a wealth of evidence from Brazil, demonstrating expansion of PHC was associated with improvements in birth outcomes and reductions in infant mortality. However, most studies relied on cross-sectional surveys or ecological data, used methods which limit causal inference, and health inequalities were infrequently explored. There has also been limited research on whether integrating antenatal care (ANC) into PHC delivers health gains.This study uses linked individual-level health records within a cohort of livebirths  born to low-income mothers to examine associations between PHC use and infant health outcomes in Rio de Janeiro. FHS use during the first two trimesters of pregnancy was associated with lower risks of neonatal or infant death, low birth weight or preterm birth and increases in ANC use. Lower-income mothers and those without formal employment had greater associated benefits from PHC use.PHC, including ANC delivered through PHC settings, is consistently associated with neonatal and infant mortality reductions–a finding supported by this robust, individual-level analyses. There is some evidence that more vulnerable and lower-income populations benefit more. PHC remains an essential platform for delivering health gains and is crucial for achieving UHC and the SDGs.Sustainable Development Goal (SDG) target 3.2 seeks to end preventable deaths of newborns and children under five years of age by 2030. In 2020, there were an estimated 3.79 million infant deaths , of which 63% (2.37 million) were neonatal deaths .,Strengthening primary healthcare (PHC) is central for making progress towards universal health coverage (UHC) and the SDGs.favelas.favelas,Estratégia de Saúde da Família ,Panel 1The 1988 constitution of Brazil guaranteed a right to health for all Brazilians and charged the government of Brazil with the responsibility for delivering healthcare to meet this obligation. This led to the creation of the unified health system  in 1990. The FHS began as a community workers primary care programme in the 1990s–aiming to expand basic services to underserved regions in the North and Northeast of the country. The FHS was later adopted nationwide and expanded to include higher-skilled health professionals and a comprehensive package of services.Today, the FHS is a multidisciplinary model of PHC including doctors, nurses and community health agents where each team covers ∼1000 local families and provides services including health promotion, health education, risk factor management, prevention of diseases, home visits, acute care, and referral.,,In Rio de Janeiro, PHC coverage was rapidly expanded beginning in 2008, with prioritised expansion in poorer areas. In 2008, the municipal government of the city of Rio de Janeiro spent the least on healthcare of any state capital, with over 80% of spending directed towards hospitals.Brazil is an internationally important setting for generating evidence on PHC and child health. The country has large socioeconomic inequities, with over 42 million people (20% of the population) living on less than US$5.50 a day and 20% of the urban population living in slums or ,This study uses a cohort of 75,339 live births to low-income mothers with linked welfare-claimant data, PHC registration records and mortality records to examine associations between maternal FHS utilisation and neonatal and infant mortality. We also explore effects on antenatal care (ANC), birth outcomes, and infant hospitalisations to assess potential mechanisms and other important health outcomes. The city of Rio de Janeiro was chosen for this research given the city-wide expansion of the FHS programme and investments in frontline services  during t,The cohort used for this study includes all births to low-income mothers in the city of Rio de Janeiro over the period 1st January 2009–31st December 2014, i.e., during FHS expansion. Associations between maternal FHS usage, birth outcomes and child mortality were analysed through regression modelling. Doubly robust inverse probability treatment weighting and regression adjustment (IPTW-RA) were employed to strengthen causal inference. This is a widely used approach to reduce bias from potential differences in control (FHS non-users) and ‘treated’ (FHS users) individuals in observational studies.Cadastro Único for government welfare. Cadastro Único is a national administrative database which includes approximately 25% of the population of the city of Rio de Janeiro who chose to apply for government welfare and contains individual- and household-level socioeconomic and demographic data. We obtained the 2015 Cadastro Único which included all individuals registered up until 31st December 2014. This original cohort contained 1,762,905 individuals, of which 95,093 (5.4%) were excluded due to duplicate Cadastro Único records, invalid registration, and if individuals that died before the start of the cohort. The mean observation period was 5.24 years. To obtain a cohort of infants born to mothers registered with the Cadastro Único, data linkage was undertaken. First, Cadastro Único was linked to SINASC (Sistema de Informações sobre Nascidos Vivos), Brazil’s national live birth database containing birth certificate data. Coverage and data quality for the city of Rio de Janeiro is high .,Cadastro Único including infants already registered in Cadastro Único and those who were not. Stillbirth records were not available for linkage. A total of 76,246 live births were identified, of which 846 birth records (SINASC) were identified as duplicate records and 61 had missing data on sex or race (1.2% excluded).Data for the cohort is based on linkage of administrative, health and mortality databases in individuals registered with Cadastro Único were linked to hospitalisation records as infant names are not recorded on birth certificates, inhibiting linkage. All datasets were linked via a combination of deterministic and probabilistic approaches  mother’s FHS electronic health records; ii) neonatal and infant mortality records for 2009–2015; and iii) both infant and mother’s public hospitalisation records. Only infants within the Cadastro Único: mother’s race/ethnicity, mother’s disability, mother’s employment status, household total income, household’s access to piped water, child labour in the household, formal employment in the household, number of household inhabitants, number of bedrooms in household, household expenditure on medicines, household Bolsa Familia payments , bairro (neighbourhood) of residence, and mother’s date of joining the Cadastro Único. From birth certificates: infant’s sex, infant’s month and year of birth, infant’s birth weight, mode of delivery, location of delivery, gestational age, number of ANC consultations , if the birth was single or multiple, mother’s age, mother’s marital status, mother’s educational attainment, if mother has other children, and if mother had lost other children. From mortality records: infant’s date of death. From hospitalisation records: dates of admissions for both mothers and infants. From FHS records: the dates of mother’s consultations with FHS clinics.The most relevant variables for child health were extracted from the datasets. From Cadastro Único.The two primary outcomes were: neonatal death (within 28 days of birth) and infant death (within one year of birth). Thirteen secondary outcomes were also examined to explore other important health outcomes and potential mechanisms of action covering prenatal care, delivery, birth outcomes, and hospital admission. The first nine secondary outcomes were binary variables–specifically: i) no ANC received; ii) 1–3 ANC consultations received; iii) 4–6 ANC consultations; iv) 7+ ANC consultations; v) caesarean delivery; vi) preterm birth (birth at less than 37-week gestation); vii) very preterm birth (less than 32-week gestation); viii) low birth weight (less than 2500 g); and ix) very low birth weight (less than 1500 g). We explore ANC as a secondary outcome measure to explore potential mechanisms of action. Four additional secondary outcomes were counts of hospital admissions: vii) hospitalisations of mother during pregnancy; viii) hospitalisations of mother 7–365 days since delivery; ix) hospitalisations of infant 7 days to 3 months since birth; and x) hospitalisations of infant during months 4–12 after birth. Infant hospitalisation counts were only available in the sub-set of infants that were registered within the i) any FHS utilisation prior to pregnancy; and ii) any FHS utilisation (for any reason) in the first two trimesters of pregnancy. Analyses did not focus on third trimester FHS usage as the most health benefits and risk reductions come from healthcare use during the first two trimesters.Two main exposure variables of interest were generated related to mother’s FHS utilisation before and during pregnancy. These were Other variables used in the analyses were grouped at household-, mother-, and child-levels. Household variables were: household per capita income quintile; household inhabitants per bedroom ; household per capita monthly expenditure on medicine 0–50; more than R$50); if there was formal employment in the household; if the household received Bolsa Familia; household with piped water; and child labour in the household. Mother variables were: self-identified race/ethnicity ; Asian, indigenous or other); marital status ; age category , educational attainment ; self-reported disability ; employment status ; if the mother had other children ; and if the mother had other children who died . Infant variables were: month of birth; year of birth; type of birth ; and sex .Additional variables that were derived for selected analyses: mother’s neighbourhood of residence; number of hospitalisations the mother had prior to pregnancy (2009–2015); if the birth was in a private hospital; and mother’s year of cohort entry.Weights for IPTW were constructed by conducting logistic regression on the likelihood of mother’s FHS use at any point before the third trimester of pregnancy (including consultations pre-pregnancy). The model was adjusted for all household- and mother-level variables noted above in addition to mother’s year of cohort entry, neighbourhood of residence, and pre-pregnancy hospitalisations. These variables aimed to capture factors predicting FHS usage in pregnancy including deprivation, maternal characteristics, neighbourhood factors, and earlier health needs. The model selection process initially included all relevant covariates with potential confounding effects that were available in the data and collinearity checked through variance inflation factors (VIFs). Given the low VIFs, no covariates were excluded. Predicted probabilities were used to generate stabilised weights for IPTW. Stabilised weights were used to weight all regression models. Doubly-robust estimators were obtained by using both IPTW and adjustment for potential confounders through regression models.The association between maternal FHS usage and our outcomes were assessed through multi-level regression models (See Heterogeneity in the association between FHS use and outcomes was assessed through interactions. FHS usage in the first two trimesters (binary) was interacted with key socioeconomic and demographic variables, and also a categorical variable denoting ANC use. Three measures of socioeconomic status were used: i) household income per capita quintile; ii) maternal race/ethnicity; and iii) formal employment status of the household. This allowed identification of inequalities in associations between FHS use and outcomes by socioeconomic groups.Analyses only examined FHS utilisation during the first two trimesters as this is the period when most health benefits and risk reductions are accrued.Comissão Nacional de Ética em Pesquisa (CONEP))–number 2.689.528.Approval for this study was obtained from Imperial College London and the Brazilian National Commission for Ethics in Research  for carrying out linkages and the generation of linkage keys to link the anonymised datasets.This study was supported by the UK’s Joint Health Systems Research Initiative (DFID/MRC/Wellcome Trust/ESRC) grant number MR/P014593/1. This funder had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.There were 75,339 live births to 66,034 mothers in the period 1st January 2009–31st December 2014 . Mean biCadastro Único registered infants), of whom 794 were hospitalised 7 days to 3 months post birth (1.5%) and 1480 were hospitalised 4–12 months after birth (2.8%).Mothers of 59.4%  births received seven or more ANC consultations throughout their pregnancy, 42.1%  of births were by caesarean, 1.7% (1340) were very preterm, 10.9% (8178) were preterm, 1.6% (1226) were very low birth weight, and 9.5% (7184) were low birth weight. 0.7% (527) died within 28 days of birth , and 1.2% (893) died within one year of life (infant death). There were 4525 hospitalisations of mothers during pregnancy (6.0% of births) and 1366 (1.8%) hospitalisations of mothers during 12 months post-delivery. For infant hospitalisations, 52,390 infants were included in the subgroup analysis : 0.345–0.806] and infant death  . In postFor secondary outcomes, maternal FHS utilisation both prior to pregnancy and during the first two trimesters were associated with reductions in no ANC, 1–3, and 4–6 ANC consultations with a concomitant increase in likelihood of having 7 or more ANC consultations . For exaFHS usage during pregnancy or the first two trimesters was not associated a risk of hospitalisation for either infants or mothers. However, the exceptions were maternal FHS use in the first two trimesters, which was associated with 23% lower risk of admission of infants 4–12 months post birth , and maternal or infant FHS use in the three months since birth which was associated with a 21% lower risk of admission of infants 7 days to three months post birth  .Table 3RAlthough imprecisely estimated with wide confidence intervals due to small numbers, there was evidence of heterogeneity in the associations between FHS usage in the first two trimesters and neonatal and infant mortality . MothersExamining FHS use in the third trimester of pregnancy found FHS use was not associated with neonatal or infant mortality, however improvements in ANC usage and birth outcomes were found . The resInfants born to mothers who utilised FHS services during the first two trimesters of pregnancy had large associated improvements in child health outcomes and survival. This included reductions in likelihood of neonatal and infant mortality, of low or very low birth weight, and of preterm or very preterm birth. Lower-income mothers appeared to benefit more from FHS usage than higher-income mothers.,,,,,,,,These findings underscore the vital importance of PHC during pregnancy and align with previous research on the infant and wider health benefits of PHC in Brazil,,,,,A second key set of findings relates to heterogeneity in the effects of FHS use. Generally, children born to more deprived mothers  had larger increases in ANC use and larger relative reductions in risk of death associated with FHS use than children born to more affluent mothers. This aligns with the inequality-reducing aspects of the FHS identified in Brazil,There was a notable finding that babies born to Black mothers did not experience the same improvements in birth and health outcomes from maternal FHS use as white or pardo mothers, except for increases in ANC use, where Black mothers differentially benefitted. These findings may stem from underlying racial/ethnic injustices in Brazil where individuals of darker skin colour have greater health needsCadastro Unico, and so the highest risk infants (who died before registering Cadastro Único) were not captured, potentially underestimating the associations found. Lastly, we tested multiple outcomes and although there could be concerns over multiple outcome testing, conservative Bonferroni adjustment would still have produced statistically significant findings for key outcomes.This study has limitations. The study is observational, and despite some randomness in the roll-out of the FHS in Rio de Janeiro and the use of IPTW-RA, selection bias relating to FHS use may remain. There could be unobserved factors associated with ANC use, FHS use, and health outcomes such as care seeking behaviours, health knowledge, self-care, and other socioeconomic factors that remained unaccounted for in our analysis. However, a large number of covariates were included in the models which likely acted, at least partially, as proxies for these factors. There are limitations from the data used. Unfortunately, updated data is not available due to changes in the electronic health records in Rio de Janeiro, limiting inference for the present day. Data on the timing of receipt of social welfare was also not available. The quality of delivery services in hospital was also not known and may bias the findings , although given the low-income focus of the whole cohort the variability in quality may not have been as large relative to the city of Rio de Janeiro as a whole. ANC use and birth weight were encoded categorically on birth certificates precluding the ability to analyse the timing of ANC care or to calculate birth weight centile. Some births (1.2%) were excluded due to duplicates or missing data. It was not known the reasons why women attended ANC and if a problematic pregnancy led to more ANC visits, this may have biased the results towards the null. It was also not possible in analyses to account for lower levels of ANC use for women who delivered preterm, but who may have higher levels of risk, which may have biased the findings. There may also be overlap between ANC and FHS usage, meaning the results on ANC use should be interpreted with caution. Despite the size of the cohort, small numbers precluded further inequality analyses and wide confidence intervals were present for many analyses. Data on stillbirths were not available and this remains an area for future research. Infant hospitalisation data was only available for infants in ,The study strengthens the evidence base supporting the benefits of the FHS systems in Brazil and re-enforces the importance of PHC-orientated health systems for all countries, especially for low-income populations. The infant survival and health benefits and reductions in inequalities in these outcomes identified serve as a timely reminder to policymakers of the need to invest in PHC. This evidence builds on the broad knowledge of the importance of PHC for achieving UHC and the SDGs.The expansion of PHC in Rio de Janeiro between 2008 and 2015 to poor urban populations was associated with improvements in infant survival and health outcomes, especially for lower-income mothers and those without formal employment. This evidence contributes to the understanding that PHC is an essential platform for strengthening health systems and delivering health gains to vulnerable populations in LMICs.This study was conceived by BD, CM, TH, and DR. Data acquisition and linkage were undertaken by VS and CMC. VS, CMC, and TH accessed and verified the data. TH undertook the analyses with inputs from AT, JB, and CM. TH wrote the first draft of the paper with inputs, revisions, and edits from all authors.The datasets generated and analysed during the current study are not publicly available due confidentiality of the linked data. They are available from the corresponding author on reasonable request and following approval from the Brazilian National Commission for Ethics in Research ) and the Municipal government of Rio de Janeiro.BD was Undersecretary of Health Promotion, Surveillance, and Primary Care at the Secretaria Municipal de Saúde, Rio de Janeiro when this project was conceived. VS is a Coordinator of Health Situation Analysis in the Health Surveillance Department, at the Secretaria Municipal de Saúde, Rio de Janeiro. All other authors declare they have no competing interests.


Stress is a process that triggers various physiological, hormonal and psychological mechanisms in response to a threat, which significantly affects the health of an individual. The COVID-19 pandemic introduced a lot of social changes that required constant adaptation to unfavorable conditions. The aim of the study was to assess the impact of stress related to this pandemic on pregnant women, mothers of premature infants and their families, and on obstetric complications, particularly preterm birth. A comprehensive literature review was performed using electronic databases such as Pubmed, Science Direct and Google Scholar. Keywords such as: “prematurity”; “pregnancy”; “stress”; “COVID-19” and various combinations of the above were used. Maternal stress and anxiety increase the levels of corticotropin-releasing hormone (CRH) in the placenta, which in turn affects the incidence of preterm birth and many other related maternal and neonatal complications. In addition, it was found that SARS-CoV-2 infection may increase the risk of this phenomenon. The COVID-19 pandemic has adversely affected preterm birth rates and the mental health of mothers of preterm infants, exacerbating their negative experience of having a premature baby. More research is needed to demonstrate the long-term effects of COVID-19 stress on prematurity. The premature birth of a child, defined as birth before 37 weeks of gestation, is becoming increasingly common worldwide. More than 50% long-term morbidity and circa 75% of perinatal mortality is caused by premature birth. Survived preterm children are at increased risk of developing neurological, respiratory and gastrointestinal complications .According to the National Children’s Health Institute in Poland, every third child born before the completion of 32 weeks of gestation requires hospitalization in a neonatal intensive care unit [Data published between 2015 and 2023 by the European Centre for Disease Prevention and Control (ECDC) under the Euro-Peristant project indicates that 7.1% of all live births in European countries are premature. However, the prevalence of preterm birth varies among individual countries, with Romania having a rate of 11.1% and Iceland having a rate of only 5.5% .According to the World Health Organization (WHO), approximately 14.9 million premature babies were born worldwide in 2021, accounting for around 10.6% of all births ,5.Moreover, lockdown during the COVID-19 pandemic could have caused modifications in environmental and behavioral life, such as reduction of physical activity, employment, social support and the most common in this group, reduction of access to healthcare—especially gynecological and obstetric . HedermaThe comprehensive literature review was performed using the electronic databases: Pubmed, Science Direct and Google Scholar. Keywords such as: “prematurity”; “pregnancy”; “stress”; “COVID-19” and various combinations of the above were used. The search was limited by 2019 year for „COVID-19” and 2010 year for the others keywords. The aim of this review paper is to summarize the current state of knowledge about how experience of COVID-19 pandemic may have affected the stress of prematurity. Due to many research, the influence of COVID-19 pandemic in the adults is currently well-known. The importance of this review paper is focusing on the impact of stress caused by pandemic in the early, prenatal and postnatal (particularly premature) stage of life. Stress may affect the pregnancy course, or obstetric complications, as well as long-term maternal and offspring outcomes .Both the incidence of COVID-19 in pregnant women and the impact of this infection on pregnancy outcomes are still being investigated. Existing research suggests that SARS-CoV-2 infection may increase the risk of preterm birth and numerous pregnancy complications. There have also been reports of the potential placental transport of the virus and maternal-fetal transmission of the infection; however, the risk appears to be relatively low, and the number of reports confirming intrauterine transmission of the coronavirus is limited ,9,10.Conducted studies indicate that COVID-19 infection increases the risk of preterm birth compared to healthy women. This may be attributed to the inflammatory state resulting from the infection, which leads to the initiation of premature uterine contractions. The authors of one study conducted on a large population of pregnant women in the United States observed that COVID-19 increased the risk of preterm birth by 60% ,9.Coronavirus infection can adversely affect the overall health status of pregnant women, manifesting in various symptoms such as fever, cough, muscle aches, gastrointestinal disturbances (diarrhea and nausea), and respiratory difficulties. Pregnant women are also more susceptible to developing pneumonia and acute respiratory distress syndrome, which carries the risk of severe oxygen deprivation for both the mother and the fetus. Severe COVID-19 infection can also serve as an indication for the premature termination of pregnancy for the health of the mother and the fetus, thus warranting iatrogenic preterm delivery ,14,15,16Furthermore, COVID-19 infection increases the risk of gestational diabetes mellitus, gestational hypertension, preeclampsia, and intrauterine fetal demise .Maternal psychological stress, or prenatal stress, as well as major stressful events  during pregnancy, has been negatively associated with gestational age, weight and length of a child at birth. Furthermore maternal stress caused by psychosocial factors, such as single-parenting, food insecurity, or lack of physical activity, have been linked to lower birth weight .Fetal programming is a concept described by sensation, receivement and reaction of the fetus to the intrauterine environment. Sensitive periods of fetal programming may lead to structural and functional changes in cells, tissues and organs, and therefore, long-term consequences . CriticaIn conclusion the most common two factors, which influence on fetal programming are pregnancy nutrition and stress . HoweverThe consequences of perinatal stress, as preterm birth and low birth weight, affects also on brain development and reduction in regional brain volume, including the prefrontal cortex, the premotor cortex, the medial temporal lobe, the lateral temporal cortex and the postcentral gyrus, which are associated with a variety of cognitive functions . ThomasoMaternal stress mechanism, by excess exposure of glucocorticoids, may change in utero environment in association of adverse cardio-metabolic and cardio-vascular outcomes in their offspring, such as obesity and overweight, insulin resistance, diabetes, hypertension, hyperglycemia and metabolic syndrome . Van denMaternal stress-involved endocrine alterations may also affect maternal cognitive brain functions and behavior. Pregnancy contributes to changes in structure and function of the brain in regions involving recognition, spatial memory and stress responsivity, which persist via lifespan . MoreoveAnother major concern in the modern obstetrics, that affect maternal and fetal health, is the increase of pregnancy-related cancer prevalence. The most frequent malignant tumor diagnosed during pregnancy is breast cancer, although the occurrence of other types, such as hematological, skin, or ovarian cancer, have been reported. Medical multidisciplinary interventions, especially personalized and integrated treatment, may prevent iatrogenic pregnancy complications, such as impaired fetal growth or preterm birth. Nanotechnology, as the reaction in the structures on a molecular level, improves biocompatibility, pharmacokinetics, targeting of the tumor and reduces systemic toxicity or drug resistance. Nanomedicine, as a field of nanotechnology, offers the opportunity to safe and effective application of antiblastic agents during the pregnancy. However, fetal exposure on nanoformulation, by transplacental transport is still an issue of the debate in gynecological and obstetric profession. Hence, future research is necessary to development of rational, effective and safe treatment for pregnancy-associated cancers .Stress is a common problem among pregnant women. United States data from the Centers for Disease—Control Pregnancy Risk Assessment Monitoring showed that nearly 75% of postpartum women reported at least one major stressful event in the year prior to the birth of their child . It has The HPA axis can be overactivated by external stress-inducing factors. The consequence is an excessive release of endogenous cortisol and an increase of its concentration in the placenta, the process itself is regulated by metalloproteinase-1 (MMP-1), -2 (MMP-2), -3 (MMP-3) and -9 (MMP-9) . A case-Also remarkable is the fact that chronic and repeated acute stressors through modulation of the HPA axis can affect the epigenome and transcriptome, consequently causing changes related to receptors for glucocorticosteroids .Maternal stress as a risk factor for preterm birth remains a major cause of maternal morbidity and mortality worldwide . Beyond Due to the adverse effects of prenatal stress on pregnancy and perinatal outcomes, it is important to identify and mitigate pregnant women’s exposure to stress early in order to prevent premature births. For this purpose, routine prenatal care should include screening for behavioral health problems and potential intervention . Both unBoth the incidence of COVID-19 in pregnant women and the impact of this infection on pregnancy outcomes are still being investigated. Existing research suggests that SARS-CoV-2 infection may increase the risk of preterm birth and numerous pregnancy complications. There have also been reports of the potential placental transport of the virus and maternal-fetal transmission of the infection; however, the risk appears to be relatively low, and the number of reports confirming intrauterine transmission of the coronavirus is limited ,53,54,55Conducted studies indicate that COVID-19 infection increases the risk of preterm birth compared to women uninfected with the SARS-CoV-2 virus . The autCoronavirus infection can adversely affect the overall health status of pregnant women, manifesting in various symptoms such as fever, cough, muscle aches, gastrointestinal disturbances (diarrhea and nausea), and respiratory difficulties. Pregnant women are also more susceptible to developing pneumonia and acute respiratory distress syndrome, which carries the risk of severe oxygen deprivation for both the mother and the fetus. Pregnant women with COVID-19 are compromised and less able to cope with the disease in general, especially when it comes to the effects of delayed diagnosis and overdue referral to treatment, when compared to non-pregnant women. The main reason is that advanced pregnancy brings about physiological and metabolic changes that have an impact on the immune system, cardiovascular function and, essential in this context, respiratory system . BecauseSevere COVID-19 infection can also serve as an indication for the premature termination of pregnancy for the health of the mother and the fetus, thus warranting iatrogenic preterm delivery ,14,15,16Considering the mental health of pregnant women, depression is still at the first place among all mental illnesses in this population group . Stress The birth of a premature baby carries various consequences and implications for both the mother and the family of the preterm infant. Based on numerous scientific studies, it has been found that mothers of premature infants experience many health problems. These include infections, hypertension, increased postpartum bleeding, generalized infections, and genital tract infections. It has been demonstrated that patients who give birth before completing 37 weeks of gestation require longer hospitalization and rehabilitation ,71,72,73In addition to the physical consequences of preterm birth, it has been examined that mothers who are mothers of preterm infants experience significant and enduring emotional consequences. Numerous studies have shown that mothers experience high levels of stress and anxiety, which are associated with uncertainty about the future and the health of the child. Furthermore, the separation of the mother from the child in the neonatal unit generates strong feelings of worry and fear about their development and safety. This separation alters the experience of motherhood and poses difficulties in forming a bond with the child. The necessity of making difficult medical and ethical decisions contributes to elevated levels of anxiety and stress in mothers ,75,76,77Women who have experienced preterm birth are at increased risk of developing postpartum depression. The challenging experiences associated with traumatic preterm birth, separation from the child after birth, and the infant’s stay in the neonatal intensive care unit are factors that significantly elevate the levels of perceived stress, sadness, discouragement, and helplessness. It has been observed that mothers of preterm infants often blame themselves for the premature birth. They frequently experience negative thoughts and question whether the preterm birth could have been avoided or if something could have been done differently to prevent it. They also ask why it happened to them and their child. Feelings of guilt and uncertainty hinder the emotional adjustment process for women in the situation of preterm birth. It has been proven that preterm birth increases the risk of anxiety disorders and heightens the level of anxiety experienced by mothers. The stress associated with caring for a preterm child and the experience of anxiety are more prevalent in mothers of preterm infants compared to women who gave birth at term ,77,78,79Another factor that disrupts the emotional stability of mothers is social isolation, which results from the time spent in the hospital with their child. Devoting oneself entirely to the care of the preterm infant separates and limits the mother’s contact with family and the community.The issue of prematurity also affects other members of the family. It brings about changes in roles and responsibilities within the family. Siblings of preterm infants require increased attention and support during this time when parents focus on caring for the preterm infant. The issue of prematurity also disrupts the relationship and closeness between the father and the mother of the preterm newborn. This is a consequence of mutual blame for the preterm birth, as well as the disruption of the mother’s experience of sexuality due to the trauma of preterm birth. The family also experiences financial burdens associated with long-term medical care, including transportation to the hospital where the preterm infant is receiving care, treatment, hospitalization, and rehabilitation, which require significant financial resources. Around-the-clock care for the preterm infant, hospital visits, uncertain prognosis, and frequent stressful situations can lead to significant emotional exhaustion in the family. This has a negative impact on relationships and the well-being of the family ,81,82,83The COVID-19 pandemic has increased the risk of vitamin D deficiency among pregnant women due to reduced sunlight exposure, particularly during periods of isolation and quarantine. This article examines the association between vitamin D deficiency and the heightened risk of preterm birth. Although the link has been studied, the underlying mechanisms remain the subject of ongoing scientific research. Potential factors that closely correlate with vitamin D deficiency and may contribute to preterm birth include the impact on the immune system, hormonal regulation, inflammatory state, and vascular function. This paper also highlights recent scientific studies conducted in different regions that explore the relationship between vitamin D levels during pregnancy and the severity of COVID-19, as well as the risk of preterm birth.Vitamin D is an essential nutrient that has profound implications for human health, influencing various physiological processes, especially during pregnancy and reproductive health. However, the COVID-19 pandemic has raised concerns about vitamin D deficiency in pregnant women, mainly due to reduced exposure to sunlight as a result of isolation and quarantine measures. This deficiency has been linked to an increased risk of preterm birth, but the exact mechanisms underlying this association are yet to be fully understood and require further scientific investigation ,85.Impact on the Immune System:Vitamin D plays a pivotal role in the proper functioning and regulation of the immune system. Deficiencies in this vitamin can lead to an altered immune response, making individuals more susceptible to infections, inflammations, and conditions that heighten the risk of preterm birth. Calcitriol, the activated form of vitamin D, directly affects immune cells such as T lymphocytes, B lymphocytes, and macrophages, as these cells express vitamin D receptors on their surface. A 2021 study conducted by Turkish scientists aimed to assess the levels of vitamin D in pregnant women and its association with the severity of COVID-19. The study revealed a significant difference between vitamin D levels and the severity of COVID-19 in pregnant women, suggesting that maintaining adequate vitamin D levels may reduce the severity of inflammation caused by COVID-19 ,86,87.Regulation of Hormonal System:Vitamin D influences the production of hormones, including steroid hormones crucial for maintaining pregnancy. Insufficient vitamin D levels can disrupt hormonal processes and directly impact the uterus’s ability to sustain a pregnancy for its full term. The vitamin D pathway is intertwined with calcium and phosphorus metabolism and also influences the production and action of progesterone, a key pregnancy hormone. A study conducted in Bangladesh in May 2023 examined the impact of vitamin D deficiency on the course of pregnancy and found a potential link between low vitamin D levels and an increased risk of preterm birth .Inflammatory State:Research has extensively investigated the association between vitamin D deficiency and inflammatory conditions within the body. In response to infections and inflammation, the body produces pro-inflammatory substances like cytokines, which trigger an immune response and increase the risk of preterm birth. Chronic inflammatory states accompanying vitamin D deficiency may interfere with fetal development and uterine health, leading to an elevated risk of preterm birth. A 2022 laboratory study conducted in Turin, Italy, on a group of 160 women, explored genetic variants related to vitamin D and their potential impact on vitamin D levels during pregnancy. The study found a significant correlation between vitamin D levels and a positive result in one of the SARS-CoV-2 tests, indicating that vitamin D deficiency may influence preterm birth ,86.Impact on Vascular Function:Vitamin D influences the proper functioning of blood vessels by affecting the production of nitric oxide and endothelin. Nitric oxide relaxes blood vessels and enhances their elasticity, while endothelin constricts blood vessels. Vitamin D deficiencies can disrupt these mechanisms, affecting the vasodilation and vasoconstriction processes in blood vessels, leading to impaired uterine function and reduced capacity to maintain pregnancy. A study conducted in Spain in 2020 explored the impact of vitamin D on preeclampsia and the risk of preterm birth. The findings suggested that higher vitamin D concentrations in pregnant women might decrease the risk of preterm birth and preeclampsia .The COVID-19 pandemic has highlighted the potential impact of vitamin D deficiency on the risk of preterm birth among pregnant women. Although scientific studies have demonstrated the association between vitamin D levels and preterm birth risk, the precise underlying mechanisms necessitate further investigation. Understanding these mechanisms could aid in the development of preventive and therapeutic strategies to mitigate the risks associated with vitamin D deficiency during pregnancy, particularly during pandemics like COVID-19 ,85,86,87The COVID-19 pandemic has had a significant impact on various aspects of social life and the mental health of people worldwide. A review of studies has shown that in the case of mothers of premature infants, COVID-19 has had a significant effect on exacerbating the already challenging situation of premature birth. This is a consequence of strong emotions and anxiety related to the risk of coronavirus infection for both the mother and, most importantly, the premature baby. Based on the conducted scientific research, it has been demonstrated that the COVID-19 pandemic has contributed to an increased level of anxiety and stress.Physical and emotional stress: Mothers of premature infants experience both physical and emotional stress, resulting from the need to adapt to new requirements related to caring for a premature baby in conditions of an epidemiological threat. In a published Italian study from 2021 that focused on the impact of the COVID-19 pandemic on parental stress, breastfeeding, and lactation success among mothers of premature infants whose children were in the neonatal intensive care unit (NICU), it was found that the availability of breast milk and breastfeeding decreased drastically . However, it was noted that the rate of breastfeeding was similar before and during the pandemic after the premature baby’s discharge from the hospital. Another study conducted by the University of Liverpool and the School of Health in Australia examined experiences related to the stress of prematurity using the social media platform Twitter. A total of 3161 tweets from parents of premature infants were analyzed. It was found that the COVID-19 pandemic and the associated restrictions, which affected parents’ contact with preterm infants, imposed significant emotional burdens on the studied group ,93,94,95p > 0.05). The result of this study highlights the importance of kangaroo care for the mental health of mothers, which was often impossible or limited during the COVID-19 pandemic. According to WHO, Kangaroo mother care has been demonstrated to reduce baby mortality by as much as 40%, hypothermia by more than 70%, and severe infections by 65% in infants delivered preterm or at low birthweight [Health safety concerns: Mothers of premature infants have heightened concerns about their children’s health in the context of the pandemic. These concerns primarily revolve around the risk of coronavirus infection, especially in the case of premature babies who are more susceptible to infections. This leads to increased anxiety and fear in women who have given birth before the due date. Spanish scientists from Torrecardenas University Hospital (between 2020 and 2022) focused on assessing the kangaroo mother care method in reducing anxiety and stress in women after preterm birth in the context of the COVID-19 pandemic. A cohort study was conducted on recruited mothers whose children were in the neonatal intensive care unit and participated in kangaroo mother care, and their stress levels were measured using the Parental Stressor: Neonatal Intensive Care Unit (PSS: NICU) scale and the STAI E/R questionnaire before and after implementing kangaroo care. It was proven that mothers in the group where kangaroo care had not yet been applied obtained higher scores on the PSS: NICU scale and the STAI E/R questionnaire compared to women who practiced kangaroo care. However, no statistically significant differences were found  had to be modified to ensure the safety of both healthcare staff and patients. These changes, such as the use of personal protective equipment (PPE) and limitations on visitation, created additional challenges and emotional strain for parents, particularly mothers of premature infants ,92,93,94The main factors determining this phenomenon include:In summary, the COVID-19 pandemic has had a profound impact on mothers of premature infants, exacerbating their experiences related to premature birth. The interrelationships between stress, the COVID-19 pandemic and prematurity are presented in The physical, emotional, and practical challenges faced by these mothers have been further complicated by the pandemic, resulting in increased levels of stress and anxiety. Certainly there is a significant impact of limited access to health service, hospitalization and deferred diagnostic, treatment or rehabilitation of premature children on their future outcomes.The limitation of this study is primarily the structure of the narrative review with a more descriptive and subjective view of the topic. Another limitation is the relatively short time that has elapsed since the beginning of the COVID-19 pandemic. For this reason, the long-term consequences for mothers and their offspring of premature delivery during the pandemic are currently unknown. However, an in-depth analysis of the literature allows us to summarize the current state of knowledge in many aspects of the subject. The article characterized the general impact of the COVID-19 pandemic on maternal and fetal health during pregnancy. In addition, stress is presented as a reaction at the physiological and molecular level, its impact on the prenatal and postnatal period of children. Furthermore, the study described a possible consequence of stress and the COVID-19 pandemic, caused by, among others, vitamin D deficiency, which is premature birth and the impact of prematurity on the future development of offspring.More research is needed to investigate and observe how the stress of prematurity during the COVID-19 pandemic influences the long-term impact.


Tests of this prediction must use indirect indicators of fetal loss in birth cohorts because vital statistics systems typically register fetal deaths at the 20th week of gestation or later, well after most have occurred. We argue that tests of selection in utero would make greater progress if researchers adopted an indicator of selection against slow-growing fetuses that followed from theory, allowed sex-specific tests and used readily available data. We propose such an indicator and assess its validity as a dependent variable by comparing its values among monthly birth cohorts before, and during, the first 10 months of the COVID-19 pandemic in Sweden.Selection We apply Box–Jenkins methods to 50 pre-pandemic birth cohorts  and use the resulting transfer functions to predict counterfactual values in our suggested indicator for selection for ten subsequent birth cohorts beginning in February 2020. We then plot all 60 residual values as well as their 95% detection interval. If birth cohorts in gestation at the onset of the pandemic lost more slow-growing fetuses than expected from history, more than one of the last 10 (i.e. pandemic-exposed) residuals would fall below the detection interval.Four of the last 10 residuals of our indicator for males and for females fell below the 95% detection interval.in utero, Swedish birth cohorts in gestation at the outset of the COVID-19 pandemic included fewer than expected infants who grew slowly in utero.Consistent with selection  Itsin utero in stressed populations must use indirect indicators of fetal loss in birth cohorts because vital statistics systems typically register spontaneous abortions at the 20th week of gestation or later, well after most have occurred. These bespoke indicators have typically assumed that selection in utero requires faster growth of males than of females [Tests of selection  females , 18–20.  females .in utero than currently found in the literature. Such testing would presumably use indicators of the depth of selection in birth cohorts as either a dependent [in utero would make greater progress if the field adopted an indicator of the depth of selection in conception or birth cohorts that (i) faithfully followed from theory, (ii) allowed for sex-specific tests and (iii) used data readily available across many populations. We propose such an indicator below. To encourage and inform consideration of the indicator, we also assess its association with a known population stressor. We compare the indicator’s values among monthly birth cohorts before and during the first 10 months of the COVID-19 pandemic in Sweden—a time when women of reproductive age, like most other Swedes, feared they and close others would encounter a lethal exogenous stressor.We assume that scholars interested in how evolutionary mechanisms measurably affect the health of contemporary populations would want more definitive tests of selection ependent  or prediependent . Here wein utero raised the standard of growth needed to continue gestation. If the onset of a lethal pandemic deepened selection in utero in Sweden, residuals for cohorts born from February through November 2020 would be significantly negative.Any indicator of selection against slow-growing fetuses in birth cohorts should reflect the fact that low birthweight varies over time with the incidence of births before 39 complete weeks of gestation. Although these ‘early’ infants weigh less as a group than infants born later in gestation, most also appear at or near the correct size for their gestational age. To ensure that our indicator faithfully reflects the theory of selection against slow-growing fetuses, we adjust the number of low-weight births for the number born preterm and early term. More specifically, we derive our indicator of tolerance for slow growth in historical birth cohorts from the regression of cohort counts of low-weight infants (i.e. birthweight less than 2500 g) on the count of preterm infants (i.e. <37 weeks of gestation) as well as on the count of early-term births (i.e. 37 to <40 weeks of gestation). The fitted value of this regression estimates the number of low-weight infants expected from the size of the cohort and the number of short gestations. Subtracting the fitted from observed values yields residuals from which we then remove ‘autocorrelation’ or patterns in time such as trends, seasonality and the tendency to remain elevated or depressed after high or low values. We reason that negatively signed residuals, which imply unexpectedly few low-weight infants in birth cohorts, occur, at least in part, because selection Using data from the Swedish National Medical Birth Register , we consin utero predicts that these cohorts would have yielded fewer lower-weight live births than expected from history and from the number of preterm and early-term births in the cohorts. Virtually all gestations end by their 44th week . The first exposed monthly conception cohort would, therefore, have been conceived in April 2019 and all its live-born members would have been delivered by the end of February 2020. The last exposed conception cohort would have been conceived in January 2020 and all its live-born members delivered by the end of November 2020. We did not include Infants delivered after November 2020 in our test because they would have been conceived after the onset of the pandemic and, therefore, could have had heritable risks for fetal death different from cohorts conceived earlier. The difference arises because risk-averse persons of reproductive age would have contributed fewer gestations to post- than to pre-January 2020 conception cohorts.We defined ‘exposed’ monthly birth cohorts as those in gestation when Swedish authorities reported the country’s first COVID-19 case (i.e. 31 January 2020). Selection We applied an interrupted time-series design by proceeding through the following steps . First, we regressed monthly low-weight (i.e. less than 2500 g) births on monthly preterm (i.e. <37 weeks of gestation) and early-term (37–39 weeks of gestation) births for 50 months (December 2016 through January 2020) prior to the onset of the pandemic in Sweden. Fifty months provide sufficient study power to detect and model autocorrelation.Second, using the methods of Box and Jenkins  we inspet as a function of values observed at time t − n. Seasonality in a monthly time series, for example, would yield an n of 12 in t − n. Box and Jenkins modeling uses ‘moving average’ and ‘autoregressive’ parameters to gauge how far into the future a high- or low-value influences subsequent observations. Moving average parameters efficiently describe short ‘memory’ of high or low values while autoregressive parameters better fit longer memory.Box and Jenkins  offered Third, we estimated equations (i.e. Box–Jenkins ‘transfer functions’) specified by adding moving average and autoregressive parameters, indicated by the results of step 2, to the regression equation estimated in step 1. The residuals of these estimations have a mean of 0, appear normally distributed, and exhibit no autocorrelation.Fourth, we applied the transfer functions estimated in step 3, with parameters fixed to those fitting the 50 pre-pandemic cohorts, to all 60 cohorts born in the test period (i.e. December 2015 through November 2020).in utero predicts, cohorts in gestation in February 2020 yielded fewer low-weight infants than expected, more than 1 of the last 10 residuals would fall below the lower detection interval.In step 5, we plotted all 60 residuals of the step 4 estimation as well as their 95% detection interval. If, as selection Steps 1–3, in which we identified and estimated Box–Jenkins transfer functions for the 50 months prior to the onset of the COVID-19 pandemic in Sweden, yielded the following transfer functions, in which all estimated parameters exceeded twice their standard errors.Ymt = 32.266 + 0.288X1t + 0.018X2t + (1 − 0.530B)(1 − 520B9)/(1 − 0.258B3)etMales: Ymt is the number of low-weight males born live in month t. 32.266 is a constant. X1t is the number of preterm males born live in month t. X2t is the number of early-term males born live in month t. et is the residual of the transfer function at month t. Bn are backshift operators or the value of et at months t − 1, t − 9 and t − 3. 0.530 and 0.520 are moving average parameters and 0.258 is an autoregressive parameter.Yft = 76.895 + 0.211X1t + 0.011X2t + etFemales: Yft is the number of low-weight females born live in month t. 76.895 is a constant. X1t is the number of preterm females born live in month t. X2t is the number of early-term females born live in month t. et is the residual of the transfer function at month t.t persisted into t + 1 and ‘echoed’, although diminished, at t + 3 and t + 9 months.The transfer function for females includes no moving average or autoregressive parameters because we detected no autocorrelation in the residuals of the regression estimated in step 2. The residuals for males, however, showed autocorrelation in which high or low values in month in utero, 4 of the 10 male  and four of the female  birth cohorts in gestation at the onset of the pandemic yielded fewer low-weight births than expected. ‘Missing’ low-weight male births for the 4 cohorts summed to 65, or about 11% of the 600 expected in those cohorts. The 118 missing low-weight females equalled about 20% of the 598 expected.in utero follows faithfully from the theory describing selection in utero [Our cohort indicator of the depth of selection in utero , 22, 28,We acknowledge that the accuracy of birth certificate reports of gestational age, particularly before 36 weeks of pregnancy, may vary over time and across places. We note, however, that we attempt to compensate for this problem by suggesting an indicator inferred primarily from birth weight, which appears more dependably measured than gestational age. Our indicator uses gestational age only to identify births before 40 weeks gestation—a relatively less controversial, although likely imperfect, determination.in utero increases spontaneous abortion during stressful times. Our observational test cannot rule out that some non-adaptive mechanism induced the association we found. We note, for example, that our finding of less ‘tolerant’ male and female birth cohorts in October 2020 could arise if the onset of the COVID-19 pandemic somehow impeded reproduction among individuals with traits that increase the likelihood of fetal growth retardation. Under this circumstance, conceptions in February 2020 would be ‘scheduled’ for a term birth in October 2020. We expect that the rapidly expanding literature on effects of the pandemic on reproductive choices will shed light on the characteristics of the October 2020, and subsequent, birth cohorts in Sweden and elsewhere.We do not offer our findings as strong evidence that selection Unlike its neighboring countries, Sweden imposed relatively few COVID-19-related restrictions. Gyms, schools, restaurants and shops all remained open throughout the pandemic . This stbirth cohorts with fewer than expected low-weight births appeared near in time to the onset of the pandemic  while female cohorts with fewer than expected low-weight births generally appeared later . Further testing of this patterning will require difficult-to-obtain 2020 data describing the sex and timing of pregnancy losses before 20 weeks. Clinical registers in Scandinavia may provide an opportunity to pursue this important avenue of research [Although fetuses of both sexes spontaneously abort throughout gestation, early losses appear dominated by females and later losses by males . The onsresearch .Strengths of our analysis include the use of a large population with consistent and high-quality data collection protocols. Our methods also control for well-documented autocorrelation in birth outcomes that could induce spurious results.in utero [We offer our indicator as an aid for testing the prediction of greater selection in acutely stressed populations. Theory regarding selection in utero  does notin utero produces ‘culled’ cohorts with relatively improved infant health and survival would better consider cohorts stressed by non-infectious shocks [The next logical step in this line of research would test whether our indicator correlates with, as theory predicts, cohort infant morbidity and mortality. We note, however, that COVID-19 cohorts may not be appropriate for such a test given the possibility that their members may have suffered unusually high rates of infectious illness, and its related morbidity, in infancy. A test of whether selection s shocks .


Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital.Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age.p ≤ 0.001).We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds : NCT00063063 Follow-up assessments of extremely preterm (EP) infants are difficult to perform and interpret for multiple reasons. As for other assessments , the expAnother issue is the appropriate comparison group of term infants. One approach is to compare EP infants to term infants matched for maternal age, ethnicity, income, education, marital status, insurance status, etc. This approach has been used in efforts to identify the independent effects of perinatal factors on outcomes. However, matching is logistically difficult, quite likely to be incomplete, and precludes assessment of how adverse socioeconomic factors and their interactions with biological or medical factors compromise the outcomes of EP infants. A better understanding of all these factors is needed to develop improved methods to reduce rates of impairment among EP born children. For these reasons, a comparison to healthy term infants may be preferred in deciding which EP infants should be considered to have a developmental impairment based on the child’s capabilities irrespective of the extent to which these impairments result from medical, socioeconomic, or other factors .Additional issues include the choice of the developmental test and whether its norms are fully appropriate in designating which EP infants should be considered impaired , 7–11. WFor all these reasons, the NICHD Neonatal Research Network (NRN) undertook the study described below to assess EP and a concurrent sample of healthy term reference (TR) infants examined by the same blinded and certified examiners in the same centers at two years corrected age. We hypothesized that the proportion of EP infants with developmental impairment based on standard deviations (SDs) from the mean for the TR sample would be higher than that based on Bayley III norms. If so, we hoped to identify threshold values for Bayley III scores based on our term reference infants that would be more appropriate than those based on the Bayley III norms for categorizing EP infants as impaired in NRN centers.The study was conducted in 15 NRN centers between January 2017 and March 2020. The addition of the TR infants to the follow-up assessments was approved by each center’s Institutional Review Board (IRB). Consent was obtained in accordance with each study site’s IRB requirements.To augment the reliability of the assessments and reduce the likelihood that examiner expectations would affect the scores, the TR and EP infants in the study were assessed concurrently by examiners not informed of their gestational age at birth or their prior clinical or developmental findings.The eligible EP infants were inborn at NICHD NRN centers and <27 weeks gestation by best obstetric estimate. Infants with at least one Bayley III composite score at the 24-month follow-up visit were included in the analysis.Eligible TR infants met the following criteria assessed using the medical record: singleton birth at 39 0/7-40 6/7 weeks gestation by best obstetric estimate; birth weight appropriate for gestational age; no resuscitation at birth; absence of congenital anomalies or other abnormalities on physical examination; benign neonatal course with all care given in a low risk nursery and no neonatal problem delaying discharge home; and parent(s) willing and able to come into the clinic. Exclusion criteria included major central nervous system disorder , child protective services custody, parental incarceration, and parental psychosis.Our goal was to assess one healthy term infant for every fifth EP survivor at 22–26 months corrected for prematurity in the same center to evaluate 180 total TR infants in a one-year study. (See Sample Size and Power.) Recruitment of each healthy TR infant began shortly (e.g. 1–2 months) before the corresponding EP infant’s scheduled assessment. If the EP infant was lost to follow-up, the TR infant was still to be assessed.Center coordinators used medical records to identify and attempt to recruit the first healthy term infant born on or after the expected due date of the index EP infant. The potential value of developmental testing was emphasized in recruiting. The methods of contact  and incentives used to promote participation (e.g. up to $100 plus parking or $50 plus cab fare) varied as allowed by the individual site’s IRB. When a parent or guardian declined participation or missed two scheduled clinic visits, the coordinator contacted the next eligible infant’s parent or guardian by delivery time and date until one agreed for her child to participate within the testing window.To assess the representativeness of the TR sample with all term births in the NRN centers we requested the information for all term infants born in NRN hospitals during the study period. To further characterize the sample of TR infants we qualitatively contrasted the estimates on available data from the Bayley-III normative data.Certified Bayley III examiners, trained to reliability and re-evaluated annually, provided assessments at each NRN center , 16. TheGeneralized linear multilevel models compared the proportion of infants in each category using the norm-based vs. TR thresholds, accounting for clustering of infants within centers. Levels of impairment were analyzed using an ordinal logistic model and dichotomous variables  were analyzed using a binomial model. Analyses were conducted using SAS version 9.3.N = 180 provided 91% power to detect a 10% absolute difference in impairments > 2 S.D.’s below the mean with alpha = 0.05. Given prior, annual rates of enrollment for EP infants we anticipated that recruiting EP to TR in a 1:5 ratio would result in N = 180 within one year.Assuming a 5% rate of impairment based on Bayley III manual norms, a 15% rate of impairment based on thresholds derived from the reference group , and an A total of 1452 EP infants (86% of survivors at 2 years) were evaluated during the time required to accrue and successfully assess 183 TR infants . The TR sample differed from the Bayley normative sample with respect to percent who were Hispanic (20 vs 16%), African-American (28% vs 14%) and parents with ≥ 16 years of education (51% vs. 29%). Surprisingly, the Bayley III Technical Manual did not characterize the normative sample in terms of marital or insurance status, did not report the proportion of children approached for inclusion who did not participate, or indicate any measures to blind the evaluators to any unfavorable social, medical, or biologic factors that might influence scores [The data for our TR sample were compared with the data provided for the normative Bayley III sample at age two years gathered by the test company  for Cognitive and Motor Composites were thus were 5-6 points higher than for the Bayley normative sample. However, the Language Composite threshold was approximately 3 points lower.any one of the Cognitive, Motor or Language Composites Scores)  Table  bottom. s) Table . As evidWe assessed Bayley III scores at two years adjusted age for EP infants and TR infants born in the same NRN centers and examined by the same assessors who had been trained to reliability  and wereThe mean Bayley III composite scores for our TR group were lower than for term control infants in some other studies , 3, 12 dMore EP infants had moderate or severe cognitive and motor impairments  using the scores for TR sample (SD = 10.9–11.3) than the Bayley III normative sample (SD = 15.0). These differences are likely due in part to the different referent populations assessed. To avoid under-identification of impaired EP children, children with major congenital anomalies, perinatal problems, or postnatal insults likely to affect development  were sysp < 0.01)). The difference was particularly marked for severe impairment . An unexpected finding was that the proportion of EP infants with composite language scores lower than 1 SD below the mean based on our TR sample was not higher than for the Bayley normative sample. This finding reflects a relatively high SD (16.0) for the TR language scores which may well be due to a high proportion of Hispanics and marked heterogeneity in parental education among the TR parents and a greater influence of education on language than on cognition or motor scores.As hypothesized, the overall proportion of EP infants with a cognitive, motor, or language impairment based on a composite score at least 1 SD below the mean for our TR group was higher than that based on Bayley III normative population (68 vs. 57%, The approach in most follow-up studies to assessing EP infants and designating their impairment rates involves some uncertainty about the reliability and inadvertent bias of the examiners as well as the appropriateness of the Bayley normative sample. While our study facilitated blinded Bayley III assessment of EP and TR infants by the same carefully trained and certified examiners, our sample of healthy TR infants was not sufficiently representative of healthy term infants in NRN centers to establish clear impairment thresholds for outcomes in the NRN. Our findings for insurance coverage and parental education indicate that attempts to recruit such infants two years or more after birth are difficult and prone to selection bias. Caregivers who had concerns about their child’s development may have been more likely to participate, a problem that would cause us to underestimate the degree to which impairment rates were underestimated using Bayley norms. Future efforts to recruit a representative sample of healthy term infants may be more successful if these infants are enrolled in the neonatal period with special measures to maintain rapport with the parents and achieve high follow-up rates through the age of assessment .The need to minimize bias in assessing EP infants may be achieved more simply by including a convenience sample of term reference controls and blinding the evaluators to gestational age, medical history, and any prior follow-up assessments. However, it is unclear whether the Bayley IV Scales address the need emphasized by Sharp and DeMauro  among otAccurate identification and monitoring of impairment rates in EP infants is critical for multiple reasons, including provision of appropriate services and parental counselling for individual infants, planning their long term education and rehabilitation, testing perinatal interventions in proper clinical trials, and evaluating care and outcomes within and across different perinatal centers over time. The impairment rates identified among EP and other high-risk infants have been almost always assessed by examiners well aware of the infants’ risk factors and prior assessments. Yet,the need for blinded assessors and concurrently assessed control patients should not be assumed to be less important to assure unbiased assessments in follow-up clinics than in other settings. High priority should be given in neonatal follow-up programs to developing effective methods to meet this need and to define appropriate impairment thresholds for EP infants.


Short Birth Interval negatively affects the health of both mothers and children in developing countries. Studies conducted in Ethiopia on the spatial variation and determinants of individual and community-level factors about short birth intervals were limited. Thus, this study was intended to assess the spatial variation of the short birth interval and its determinants in Ethiopia.This study is a secondary analysis of the Ethiopian Demographic and Health Survey (mini EDHS 2019). A total of 1784 reproductive-age women were included in the analysis. The global spatial autocorrelation  and the Getis-Ord statistics tool were used to detect the presence of clustering and the high/low hotspot areas of SBI respectively. Ordinary kriging was used to interpolate short birth intervals, and spatial scan statistics were employed to identify spatial clusters with high and low SBI. A multilevel multivariable model was used to identify predictors of a short birth interval.The prevalence of SBI was 62.89%  in Ethiopia. High clustering of SBI was observed in all parts of Somali, in Afar , Oromia , and northern Tigray. The most likely significant primary cluster was observed in the Somali region. Women who lived in the primary cluster were 24% more likely to have a short birth interval than those who lived outside the window. In the multilevel mixed-effect analysis age 25–34 , 35–49 , Muslim religion follower , no formal education , primary education, and secondary education , middle , rich wealth status , female sex children , and two or fewer ideal number of children  were found to be significant predictors of SBI.Overall, SBI was high and significantly clustered across the region of Ethiopia. Age, religion, education, wealth status, the sex of the indexed child, and the ideal number of children were found to be significantly associated with short birth intervals. Hence, the government should design a health promotion strategy and public health awareness in the identified hotspot areas of SBI and should scale up family planning and the wealth status of reproductive-age women. According to the World Health Organization (WHO), a short birth interval (SBI) is defined as the time of less or less than 24 months between births and the next pregnancy , or a peShort birth interval has become a public health and demographic concern and is associated with several adverse health outcomes, such as: poor maternal nutritional status and folate depletion, suboptimal lactation for the newborn, cervical insufficiency, infections, sibling competition, incomplete healing of the uterus, and abnormal remodelling of endometrial blood vessels , 4. It iStudies done using the Demographic and Health Survey indicate the high prevalence of SBI in African countries such as Uganda 25.3%), Rwanda (20%), and Cameron 21.3%) . In Ethi.3%, Rwan.3% . In When we comes to Ethiopia, most of the previous studies conducted in Ethiopia did not examine the extent of the spatial variation within and between regions, zones (districts), and predictors of short birth intervals to make specific area-based evidence-based decisions. The previous studies done in Ethiopia using DHS data were focused purposefully on selected areas expected to have high SBI. This lacks the generalizability of the result across the country to design and implement an evidence-based medicine public health intervention. Besides, the previous studies used a less advanced model to identify factors that influence SBI. This lacks the ability to identify which level of factors affect SBI and further limits policymakers and program managers areas of focus to reduce the risks.Hence, a spatial multilevel analysis will help to understand significant high-risk areas and predictors of short birth intervals and will also help to evaluate the quality of maternal health service. Therefore, this study aimed to assess the spatial distribution and predictors of short birth intervals in Ethiopia. The findings of this study will help policymakers, program planners, and other stakeholders in guiding health investment and developing prevention and intervention programs. In addition, mapping or exploring short birth interval hot spots will provide a deeper understanding of the impact of past intervention strategies, including family planning services in each region.This study used data from the Ethiopian Demographic and Health Survey (DHS), collected using across-sectional study design. Ethiopia, the second most populated nation in Africa with 114.96 million population. Ethiopia is located in the Horn of Africa between latitudes 3 and 15 degrees north and 33 and 48 degrees east. Nine regional states , Gambella, and Harari) and two city administrations make up its administrative organization (Addis Ababa and Dire Dawa). These are subdivided into administrative Woredas and further divided into Kebele, which is the smallest administrative unit in the country.http://www.dhsprogram.com).Our data source was the mini-EDHS survey, which was collected in 2019. EDHS is collected every 5 years by the Ethiopian Central Statistical Agency (CSA) along with ICF International and funded by USAID. The data sets for EDHS were downloaded in Stata format with permission from the Measure DHS website (https://africaopendata.org/dataset/ethiopia-shapefiles). The survey was conducted from March 21, 2019, to June 28, 2019. The census frame is a complete list of the 149,093 EAs created for the 2019 EPHC. An EA is a geographic area covering an average of 131 households. It employed a two-stage stratified selected sample. In the first stage, a total of 305 EAs  were selected with probability proportional to EA size (based on the 2019 EPHC frame) and with independent selection in each sampling stratum.The shape file of the map of Ethiopia has been accessed as an open source without restriction from the Open Africa website (https://www.dhsprogram.com). In this study, all reproductive aged women 15–49 were a source population. Women who had at least two consecutive live births in the 5 years preceding the survey were the study population. All women of childbearing age [In the second stage of selection, a fixed number of 30 households per cluster were selected with an equal probability of systematic selection from the newly created household listing. All women aged 15–49 who were either permanent residents of the selected households or visitors who slept in the household the night before the survey were eligible to be interviewed. The detailed sampling procedures were presented in the 2019 EMDHS report from the DHS website , i is for the individual level factors, and j is for the community level factors.The independent variables were classified into individual-level variables and community-level variables. Individual-level variables were the sex of the index child, age at marriage, mother’s age at first birth, parity (number of live births), women’s education level, husband’s education level, wealth index, respondents’ occupation, religion, survival status of the index child, the ideal number of children, preferred waiting time to birth, number of living children, duration of breastfeeding (in months), and contraceptive utilization. The community-level variables included in this study were region and residence. Region and residence were directly obtained from EDHS.Data cleaning, labelling, processing, and coding were done using the SATA 15 version. The EDHS dataset was weighted using sampling weights, a primary sampling unit, and strata before any statistical analysis to restore the representativeness of the survey and to take into account the sampling design and get reliable statistical estimates. The descriptive analysis was performed and presented using tables.ArcGIS 10.8 and SaTScan 9.6 statistical software were employed to explore spatial distribution and determine the geographical locations of statistically significant spatial windows for short birth intervals.p < 0.05) results in the rejection of the null hypothesis  and indicates the presence of spatial autocorrelation [p-value statistics were calculated to identify the significant clustering. A Z-score near zero indicates perfect randomness within the study area. A positive Z-score with a P-value of > 0.05 indicates statistical clustering of the hotspots of short birth intervals. Thus, the null hypothesis cannot be rejected. Whereas a negative Z-score with a p-value of < 0.05 indicates statistical clustering of reproductive age women who have no short birth intervals.Spatial autocorrelation  is used for detecting the geographical distribution of short birth intervals. The spatial autocorrelation coefficient is statistically significant when tested against the null hypothesis. Moran’s I value ranges from − 1 to 1. The Moran’s I value is close to − 1 indicating “dispersed short birth intervals”, 1 indicating “clustering of short birth intervals”, and zero indicating a “perfect random pattern of short birth intervals”, respectively . If Morarelation . The GetThe spatial interpolation is used to predict the un-sampled measurement areas in Ethiopia from the observed spatial pattern of short birth intervals in reproductive-age women. The current short birth interval data is used as an input to predict un-sampled areas of the country. Among the different interpolation techniques are: The ordinary Kriging spatial interpolation method was used in this study setting to predict un-sampled areas of short birth interval since they optimized the weight and had a small mean square error and residual . Based oThe Bernoulli-based model was employed to identify statistically significant spatial clusters of short birth intervals using Kuldorff’s SaTScan software version 9.6 . A circup-value were used to determine if the number of observed short birth interval cases within the potential cluster was significantly higher than expected for each potential clusters. The cluster that performed best according to the scanning window’s maximum likelihood was chosen. Each cluster’s p-value was assigned using Monte Carlo hypothesis testing by comparing the rank of the maximum likelihood derived from real data with the maximum likelihood from the random datasets. The primary and secondary clusters were identified and assigned p-values. Finally, the clusters were ranked based on their likelihood ratio test, based on 999 Monte Carlo replications [A Likelihood Ratio (LR) test statistic and a ications .The spatial autocorrelation  is used to measure the overall spatial autocorrelation of short birth intervals. It used to indicate “dispersed”, “Clustered,” and “random pattern” of short birth intervals. The Getis-Ord G index were used to identify the spatial heterogeneity (location and variation) of significant prevalence areas of high or low short birth intervals for each cluster.The spatial interpolation was used to predict the un-sampled measurement areas in Ethiopia from the observed spatial pattern of short birth intervals of reproductive-age women. Furthermore, spatial SaTScan statistical analysis and Bernoulli-based model were employed to identify statistically significant spatial clusters of short birth intervals.p-values < 0.2 were included in the multilevel analysis. In the final model, variables with p-values< 0.05 were declared to be factors associated with the outcome variable, and the result was presented using an adjusted odd ratio (AOR) with 95% CI.Since the DHS data are hierarchical in nature, women are nested within a cluster, and we expect that women within the same cluster may be more similar to each other than women in another cluster. To account for this cluster effect, we consider a variability test across a cluster since this violates the assumption of the traditional regression model. Due to this, a multilevel logistic analysis was used to determine the effect of the predictors of short birth intervals. Four models, such as: Model 0 or (the empty/null model) was fitted without explanatory variables to test the random variability of short birth intervals in the intercept and to estimate the intra-class correlation coefficient (ICC) and proportional change in variance (PCV), Model 1 , Model 2 (community-level factors), and Model 3 . Akaike Information Criteria (AIC) and Bayesian Information Criteria (BIC) were used in the design and comparison of models. Each successive AIC and BIC value was compared, and the model with the lowest AIC and BIC value was considered the most suitable model. Variables from the first bivariate logistic regression analysis with https://www.dhsprogram.com). For this particular study, a brief description of the protocol was submitted to the MEASURE DHS program to access and analyze the data. As a result, we obtained permission to access the EMDHS 2019 data through (https://www.dhsprogram.com/Date/terms-of-use.cfm) for statistical analysis and reporting. During EDHS data collection, informed consent was obtained from each participant, all identifiers were removed, and the confidentiality of the information was maintained.The data were obtained by requesting it from the Demographic and Health Surveys (DHS) Program and can be freely accessed from the program website   women have experienced SBI. Women with SBI aged 15–24 years comprised 238 (21.21%), 635 (56.59%) ranged from 25 to 34 years, and 249 (22.19%) were over 35 years.p-value of 0.0003), indicating that the observed clustering is less than 1% likely to be the result of random chance. The spatial autocorrelation analysis revealed the presence of statistically significant clusters at a 0.01 level of significance  across a study area  and cold spots . The hot spots  were significantly clustered in almost all areas of the Somali region, the Oromia region in Bale, Guje, and West Harerge Zones, in the Afar region, specifically in Zone 1, Zone 3, Zone 4, and Zone 5, and southern Tigray. Hence, an evidence-based public health intervention and designing health awareness and promotion should focus on this area to limit the fertility rate of women. Conversely, a cold spot area of the short birth interval was observed in the northern and southwest and central parts of Amhara region, Addis Ababa, the north and northwest of SNNPR, the central and northern parts of Gambella, and some parts of Oromia region  of 1.24 and Log-Likelihood Ratio (LLR) of 18.17373 at a P-value < 0.001); . Women whose age was [The SaTScan spatial analysis identified one statistically significant SaTScan cluster area. A total sampled population of 494 was found in the primary cluster area using SaTScan analysis with  age was , 27–49 aAccording to the null model, the variance of the random factor was 0.22 at a 95% CI , indicating the presence of heterogeneous areas since the variance estimate of short birth intervals is greater than zero. This shows there are enumeration (cluster) difference in short birth intervals among reproductive-age women in Ethiopia. Thus, multilevel analysis should be considered an appropriate approach for identifying both the individual or community-level predictors. The intra-cluster correlation coefficient (ICC), which indicated that 8% of the total variability of short birth intervals is due to differences across cluster areas, with the remaining unexplained 92% attributable to individual differences  and 0.44  times less likely to have a short birth interval than their counterparts. This study revealed that those women who are Muslim religion followers were 3.5  times more likely to have short birth intervals than those who are Orthodox religion followers. Keeping other variables constant, women who have no formal education, who attended primary and secondary education were 0.5 , 0.4 , and 0.3  less likely to have short birth intervals compared to women who have higher education.Besides, we have identified that the wealth status of the study participants was significantly associated with short birth intervals. Respondents, women who have middle and rich wealth status, were 1.3  and 1.4  times more likely to have short birth intervals than their counterparts. The odds of SBI among women who have female sex children was 1.2  times more likely to have SBI than those among women who have male sex children. Finally, in this study, women who wanted to have two or fewer children were 0.2  times less likely to have short birth intervals than those who wanted more than two ideal numbers of children  among women of this age group , 27–49 wThis discrepancy could be due to the inconsistent definition of SBI. Those previous studies considered SBI if the birth interval was less than 24 months, whereas our study defined it as less than 33 months. Besides, this might be due to socio-cultural barriers across the study areas and sample size differences. Moreover, the desire to have more children, which are rooted in the community, has changed due to economic concerns and changes in lifestyle.p-value of 0.0003). The hotspot analysis  and  were observed in some geographical areas. The spatial clustering of hot spots  was observed in the most parts of Somali in the Afar region such as: Zone 1, Zone 3, Zone 4, and Zone 5, and Northern Tigray, followed by Oromia region in West Harerge, Guje, and Bale zones. Hence, an evidence-based public health intervention and designing health awareness and promotion should be focus on these areas to limit the fertility rate of women. A cold spot area of the short birth interval was observed in the northern and southwest and central parts of Amhara region, Addis Ababa, the northern and northwest parts of SNNPR, the central and northern parts of Gambella, and some parts of Oromia region.In this study, the spatial analysis, spatial autocorrelation, hotspot, and SaTScan analysis were reported to access the spatial distribution of the short birth interval. The spatial autocorrelation analysis in this study confirmed the distribution of short birth intervals was clustered (global Moran’s I test was 0.190089 and the Z-score was positive with a The SaTScan spatial scan statistical analysis identified the most likely primary significant cluster of short birth intervals. The most likely primary SaTScan cluster of high short birth interval areas was detected in Somali and revealed that women aged women , 27–49 aIn multilevel analysis, the age of the mother, religion, education, wealth status, sex of the indexed child, and the ideal number of children were found to be significant factors in short birth intervals. Participants who follow the have more SBI when compared to Orthodox Christians. This study’s finding is supported by a study done in Ethiopia, Bangladesh, and Nigeria , 52. ThiA study done in Bahir Dar, Ethiopia, reported 63.9% of Orthodox Christian followers versus 36.1% of Muslim followers using modern contraceptives . The FMOThe maternal age was found to be a significant predictor of short birth intervals, with younger women having shorter birth intervals than older women. This finding is supported by a study done in Ethiopia. Younger women have a high rate of fertility as compared to older women. Another reason might be younger women wants to build their desired family size, which could probably decrease their birth spacing.Surprisingly, this study found that women with no formal education, primary, and secondary education had a low risk of short birth intervals compared to women having higher educational status. Most studies reported women who attained higher education had longer birth intervals as compared to women with low education or no formal education. This could be the hypothesis: that women who attained higher education get married later in life and subsequently wants to make a family. Additionally, this might be due to the fact that educated women may wish to compress or limit childbearing into fewer years and focus on educational activities. However, further qualitative and quantitative study may be required to investigate the evidence, especially in developing countries.The current study suggests that women who wanted to have fewer children had a lower risk of short birth intervals than those who wanted more. This could be due to, women may have achieved their desired family size and may feel less pressure or be in less of a hurry to get pregnant again. The wealth status of the women was found to be a predictor of birth interval spacing. Respondents, who have middle and rich wealth status, were 30 and 40% more likely to have short birth intervals than women with poor wealth status. Which is inconsistent with a study reported in Ethiopia , 35. AccThe prevalence of short birth intervals in Ethiopia is still optimally high. This study also observed a clustered pattern of short birth intervals in Ethiopia. Statistically significant local primary clusters of high SBI areas were detected in the Somali region. The individual-level characteristics of women’s educational level, age, religion, wealth status, the sex of the indexed child, and the ideal number of children were statistically significant factors of SBI. Therefore, the federal ministry of health and other concerned maternal and child health program managers give a concern about the areas with high SBI coverage identified in this study. It is also better to consider the individual determinant factors that may help planners, policymakers, and decision-makers with an evidence-based health intervention.This study used a multilevel mixed effect model and EDHS national datasets to examine the effects of clustering, which is considered the strength of this study. This study shares recall bias since the data were collected retrospectively and the 2019 EDHS data sets were not observed since some important variables that determine short birth intervals were not included in this study.