Preterm birth is a significant contributor to newborns morbidity and mortality. Despite the availability of highly effective and powerful interventions, the burden of preterm birth has not decreased. Given the relevance of the topic to clinical decision-making, strong conclusive and supporting evidence emanating from the umbrella review is required. To this end, this umbrella review study sought to determine the association between intimate partner violence and obstetrics characteristics of women with preterm birth in Ethiopia.Six systematic review and meta-analysis studies searched across multiple databases were included in this umbrella review. The quality of the included systematic review and meta-analysis studies was evaluated using the Assessment of Multiple Systematic Reviews (AMSTAR-2) checklist. STATA version 18 was used for the statistical analysis. A random-effects model was used to calculate the overall effect measurement.A total of 114 observational studies in the six systematic review and meta-analysis studies involving 75,624 pregnant women were included in this comprehensive analysis. The preterm birth rate among mothers in Ethiopia was 11% . Preterm birth was significantly associated with intimate partner violence , multiple pregnancies , pregnancy-induced hypertension , anemia , and premature rupture of pregnancy .More than one out of ten pregnant women experienced preterm birth in Ethiopia. Intimate partner violence is significantly associated with preterm birth. Furthermore, multiple pregnancies, pregnancy-induced hypertension, anemia, and premature rupture of the membrane were significant predictors of preterm birth. Therefore, policymakers should consider further instigations and implementations of policies and strategies closely related to reductions of intimate partner violence. It is also crucial to the early identification and treatment of high-risk pregnancies.The online version contains supplementary material available at 10.1186/s12978-023-01716-7. Preterm delivery is a serious clinical issue that is linked to high newborn morbidity and mortality rates , 2. PretNumerous sociodemographic factors such as younger maternal age, rural residence, educational level, and marital status , 10; nutPreterm births have significant consequences for both neonates and mothers. Prematurity accounts for 35% of all neonatal mortality in the world . NeonataEthiopia has introduced various measures to reduce the burden of preterm birth. Preconception care, early detection and treatment of women at risk of preterm birth, antenatal corticosteroid provision, prevention of unintended pregnancy, prevention of pregnant women being exposed to cigarette smoke, and prudent use of fertility treatments are some of the strategies that help reduce preterm birth , 28. AddDespite these initiatives, the burden of premature birth remains unchanged. It is essential to review and reevaluate the current policies to improve the survival rate of premature newborns. Umbrella review is the strongest evidence that can help policymakers in developing novel measures that can reduce infant deaths associated with prematurity. To the authors' knowledge, no umbrella review done to investigated the relationship between intimate partner violence and obstetric characteristics of pregnant women and preterm birth in Ethiopia. Therefore, this umbrella review aimed to assess the overall state of preterm births in Ethiopia and explore the association between intimate partner violence and obstetric characteristics of pregnant women with preterm birth in Ethiopia.This umbrella review was established to provide decision-makers with a single, comprehensive source of information for use in formulating clinical recommendations, intervention strategies, and evaluating healthcare treatments following prior research . PreferrAll suitable systematic reviews and meta-analyses (SRMA) studies on preterm delivery, intimate partner violence, and obstetrical characteristics of pregnant women who gave premature birth in Ethiopia were included. The pre-established inclusion criteria were as follows: the population was pregnant mothers and their newborns; the study area was only studies carried out in Ethiopia; the study design was all SRMAs studies; the publication condition was both published and unpublished research; and language was studies reported in English. Finally, all full-text articles published before August 13, 2023, were included. SRMA studies without well-defined study questions, search strategies, or article selection procedures were excluded. We also excluded narrative reviews, editorials, letters, abstracts, methodological studies, and literature reviews.We used reliable databases like the Web of Sciences, CINAHL (EBOSCO), Science Direct, MEDLINE, EMBASE, SCOPUS, Google Scholar, and PubMed to conduct our electronic literature search. We also attempted to use direct Google searches to visit university repository websites.Two authors (AE and AD) searched for both published and unpublished SRMA studies using a combination of Boolean logic operators , Medical Subject Headings (MeSH), and keywords in the aforementioned databases: A thorough search was conducted using the PICOS questions. The PubMed search query was (("premature birth"[MeSH Terms] AND "pregnant women"[MeSH Terms]) OR "infant, newborn"[MeSH Terms]) AND ("systematic review"[Publication Type] OR "systematic reviews as topic"[MeSH Terms] OR "systematic review"[All Fields]) AND  AND "Ethiopia"[MeSH Terms].All search results were exported to the EndNote X8 citation system, and duplicate publications were removed to find systematic reviews and meta-analyses that met the inclusion criteria. The whole text of the papers was evaluated after the publications were screened by title and abstract. Duplicate authors (AE and AD) individually examined each paper. A discussion with a third reviewer (AA) was used to resolve any disagreements among the authors regarding the admissibility of certain studies.Duplicate extraction was conducted for data from the included SRMA studies to assess study quality and evidence synthesis. Microsoft Excel 2016 was used to extract information about the publication period, number of studies included in each SRMA study, study design, sample size, risk of bias assessment technique, and predictors.All pertinent systematic reviews and meta-analysis studies were evaluated for quality using the AMSTAR-2 (Assessment of Multiple Systematic Reviews) quality assessment method . The tooThe extracted data were exported to the statistical software STATA 18 to conduct statistical analysis. The overall estimates of the prevalence of preterm birth were presented using forest plots utilizing the random effects model and the Der Simonian Liard method. Furthermore, the association between different variables and preterm birth reported in each systematic review and meta-analysis study was presented using forest plots utilizing the random effects model and Hedges method. A narrative synthesis was used to present the findings of the included SRMA studies, followed by an overall meta-analysis. A meta-analysis of SRMA studies was conducted using the recommendations of Higgins et al.'s statistic  . Owing tWe were able to locate 685 articles with the aid of the major electronic medical and health databases and other relevant sources. Forty-nine articles from all identified studies were eliminated due to duplication, and 636 publications were retained for further review. Approximately 615 of these were removed after examination based on the titles and abstracts. For eligibility, 21 articles were reviewed. Approximately 15 studies were excluded because they could not show the intended result. Finally, this umbrella review comprised six systematic reviews and meta-analyses  and obstetric characteristics of pregnant women with preterm birth in Ethiopia. In the included six systematic review and meta-analysis studies there are 114 primary observational studies. Of these, 89 were cross-sectional studies, 16 were case–control studies, and nine were cohort studies. The median number of studies included in each SRMA with the primary outcome was 19.5, with a minimum of 9 studies . The medThe methodological quality of the included SRMA studies was evaluated using the AMSTAR-2 critical appraisal checklist . Quality2 = 98.08)  and preterm birth was studied by Muchie et al. . The stuTwo SRMA studies , 15 wereDespite extensive attempts by the Ministry of Health and non-governmental organizations, the burden of preterm births has not been reduced. This may be a result of a lack of solid and thorough data that could aid in rethinking and reevaluating the current approaches to increase the survival rate of premature neonates. Furthermore, an umbrella review of the SRMA study results must be conducted to draw more consistent conclusions, given the relevance of the topic to clinical decision-making. This umbrella review established that the overall pooled prevalence of preterm births among mothers in Ethiopia was 11% . Furthermore, there is a strong relationship between intimate partner violence, multiple pregnancies, pregnancy-induced hypertension, anemia, and premature rupture of pregnancy with preterm birth.The prevalence of preterm delivery among mothers in Ethiopia was 11% . This result is higher than those of studies conducted in Brazil (9.9% ), in UgaWe observed that there was a strong association between IPV and preterm birth. Pregnant women who experienced IPV were 2.32 times more likely to give preterm birth than women without IPV. This finding is supported by a study conducted in Zimbabwe and Australia , 41. A vIn this study, multiple pregnancies were associated with preterm birth. The odds of preterm birth among pregnant women with multiple fetuses in utero were 3.36 times higher than those among pregnant women with a single fetus. A possible explanation could be the multifactorial nature of multiple pregnancies, which may be associated with the mechanism of labor, large placenta, cervical insufficiency, increased uterine stretch, and intrauterine infection. Multiple pregnancies cause abdominal distension. This can initiate the occurrence of arachidonic acid, and then prostaglandin synthesis, and finally preterm birth . AdditioWe found that there is a strong association between pregnancy-induced hypertension (PIH) and preterm birth. The odds of preterm birth among pregnant women with PIH were 4.13 times higher than among women without hypertensive disorders of pregnancy. This could be explained by the fact that PIH can cause stress to the fetus and mother, which can contribute to the initiation of prostaglandins, which can cause preterm labor and preterm birth , 48.In this study, anemia is associated with preterm birth. Anemic pregnant women were 2.76 times more likely to give preterm birth compared to non-anemic pregnant women. This finding is supported by a meta-analysis study , 50. AneThis umbrella review could be a solution to the lack of adequate data that hampers visibility, effective policies, and research.More than one out of ten-tenth of pregnant Ethiopian women experienced preterm birth. Intimate partner violence is significantly associated with preterm birth. Furthermore, multiple pregnancies, pregnancy-induced hypertension, anemia, and premature rupture of membranes were significant predictors of preterm birth. Therefore, policymakers should consider further instigations and implementations of policies and strategies closely related to reductions of intimate partner violence. It is also crucial to early identification and treatment of high-risk pregnancies such as multiple pregnancies, pregnancy-induced hypertension, premature rupture of membranes, and anemias to reduce the impact of preterm birth. Additionally, it is preferable to design and strengthen policies and programs that aim to improve maternal nutritional status which all contribute to a decrease in the burden of preterm birth.Additional file 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement Checklist.Additional file 2: Table S2. Quality of assessment using AMSTAR-2Additional file 3: Figure S1. Umbrella review about the association between anemia and preterm birth in Ethiopia, 2023. Figure S2. Umbrella review about the association between premature rupture of membrane and preterm birth in Ethiopia, 2023. Figure S3. Umbrella review about the association between rural residency and preterm birth in Ethiopia, 2023.


The Birth Center model of care is a health care delivery innovation in its fourth decade of demonstration across the United States. The purpose of this research was to evaluate the model's potential for decreasing poverty‐related health disparities among childbearing families.Between 2013 and 2017, 26,259 childbearing people received care within the 45 Center for Medicare and Medicaid Innovation Strong Start birth center sites. Secondary analysis of the prospective American Association of Birth Centers Perinatal Data Registry was conducted. Descriptive statistics described sociobehavioral, medical risk factors, and core clinical outcomes to inform the logistic regression model. Privately insured consumers were independently compared with 2 subgroups of Medicaid beneficiaries: Strong Start enrollees (midwifery‐led care with peer counselors) and non‐Strong Start Medicaid beneficiaries (midwifery‐led care without peer counselors).After controlling for medical risk factors, Strong Start Medicaid beneficiaries achieved similar outcomes to privately insured consumers with no significant differences in maternal or newborn outcomes between groups. Perinatal outcomes included induction of labor , epidural analgesia use , cesarean birth , exclusive breastfeeding on discharge , low Apgar score at 5 minutes , low birth weight , and antepartum transfer of care after the first prenatal appointment . Medicaid beneficiaries who were not enrolled in the Strong Start midwifery‐led, peer counselor program demonstrated similar results except for having higher epidural analgesia use  and significantly lower exclusive breastfeeding on discharge  than their privately insured counterparts.The midwifery‐led birth center model of care complemented by peer counselors demonstrated a pathway to achieve health equity. A CE form that includes the test questions is available in the print edition of this issue.Continuing education (CE) is available for this article. To obtain CE online, please visit The Strong Start for Mothers and Newborns Initiative (Strong Start), a joint effort between the Centers for Medicare & Medicaid Services, the Health Resources and Services Administration, and the Administration on Children and Families, tested enhanced approaches to prenatal care for beneficiaries of Medicaid.triple aim for improving population health as it improves quality of care, family experience of care, and value.Birth center care has been recognized as a driver of the Results of the Strong Start impact analysis demonstrated that outcomes depended on the type of prenatal care received  rather than the place of birth.Previous research has demonstrated that pregnant people who are recipients of Medicaid are at higher risk for poor outcomes than those with private health insurance.✦After controlling for medical risks and adjusting for social factors, birth center care resulted in similar perinatal outcomes for Strong Start Medicaid beneficiaries and privately insured populations.✦Strong Start Medicaid beneficiaries who received midwifery‐led care complemented by peer counselors showed no significant differences in core clinical outcomes when compared with privately insured beneficiaries.✦Non‐Strong Start Medicaid beneficiaries demonstrated similar health outcomes compared with privately insured consumers, except for higher epidural analgesia use and lower rates of exclusive breastfeeding on discharge.This is a secondary analysis of the American Association of Birth Centers (AABC) Perinatal Data Registry (PDR). The registry is one of the largest prospective data registries in the United States and is designed for quality assurance, quality improvement, and research of the midwifery‐led birth center model of care. All 10 public health regions of the United States were represented within the sample. The AABC PDR measures more than 900 variables throughout the perinatal episode of care, beginning with the first prenatal visit and stopping at 6 weeks postpartum. All childbearing people beginning care at an AABC PDR user sites were tracked through their disposition including antenatal, intrapartum, and postpartum transfers to higher levels of care if needed.Variables include sociodemographic descriptors, process, and outcome measures and were harmonized with nationally endorsed perinatal care measures as well as with the reVITAlize Obstetrics Data Definitions.t tests were used to evaluate significant variations between the privately insured population and each Medicaid group separately. The significance level was set at P < .05. Significant differences between groups during the preliminary analysis informed the risk adjustment model used in the logistic regression.This analysis included data on Medicaid and privately insured clients enrolled in care with the 45 CMMI Strong Start birth centers between 2013 and 2017. Descriptive statistics were used to evaluate the sociodemographic and medical risk factors across 3 groups . Strong Start enrollees were Medicaid beneficiaries who received midwifery‐led care complemented by peer counselors. Medicaid beneficiaries who did not enroll in Strong Start received midwifery‐led care without peer counselors. Statistical Sociodemographic variables included years of education, maternal age, gravidity, parity, marital status, and race and ethnicity (self‐attributed by the consumers). Core maternal clinical outcomes included use of medical induction of labor, preterm birth, mode of birth, postpartum hemorrhage, and exclusivity of breastfeeding on discharge. Core neonatal clinical outcomes included low birthweight (<5.5 pounds), 5‐minute Apgar score less than 7, and neonatal intensive care unit (NICU) admission. Transfers of care from birth centers to hospitals based on intention to treat were tracked by noting each client's preference for place of birth at the first prenatal visit, their location of initial admission in labor, and the place of birth.t test analysis between groups. The social adjustment factors included maternal age, educational level , race and ethnicity (Black and Latinx), and geographic location . Robust SEs were clustered at the birth center level. All data were analyzed using Stata 16. The AABC PDR is designated as exempt by the New England Institutional Review Board.Logistic regression was used to compare Strong Start Medicaid and non‐Strong Start Medicaid beneficiaries with privately insured consumers to evaluate if poverty was a driver of poor clinical outcomes in this sample. The main outcomes considered in the logistic regression included binary indicators for cesarean birth, induction of labor, epidural analgesia, breastfeeding at discharge, low Apgar score at 5 minutes, low birthweight, and any transfers . Within the logistic regression model, individuals were included in a control group to adjust for medical risk factors . Maternal characteristics were adjusted for based on Between 2013 and 2017, 26,259 childbearing people gave birth during the study time frame and met inclusion criteria . Privately insured people represented 57.8%  of the total sample. The total Medicaid sample was 11,072 (42.2%) and was further divided into 2 groups. Strong Start Medicaid beneficiaries  received midwifery‐led care with enhanced peer counselor services within the birth center model of care, and 5279 (47.6%) were non‐Strong Start Medicaid beneficiaries who received midwifery‐led birth center model care outside of the Strong Start program.Descriptive statistics for the sample are reported in Table Although exceeding national benchmarks across all groups, mean maternal outcomes differed between groups prior to adjustment for medical risk factors. Privately insured consumers had similar rates of cesarean birth to the Medicaid population, whereas the Strong Start Medicaid population had the highest rate of cesarean birth . Epidural analgesia use varied between groups, with privately insured consumers maintaining the lowest rates compared with Strong Start and Medicaid, respectively . Privately insured consumers had an 18.0% labor induction rate compared with those with Strong Start and Medicaid (16.0 and 19.8). Postpartum hemorrhage varied between private, Strong Start, and Medicaid . Exclusive breastfeeding on discharge varied between private, Strong Start, and Medicaid beneficiaries .Average newborn outcomes between payer groups also varied within this sample but exceeded national benchmarks across all payer groups. Compared with privately insured childbearing people, Strong Start and Medicaid beneficiaries had a higher prevalence of low birth weight, on average . Privately insured consumers had higher NICU admissions compared with Strong Start and Medicaid beneficiaries .Attrition throughout the perinatal episode of care  was tracked and also varied by group. Compared with privately insured consumers, the Strong Start group had the highest proportion of the sample lost to antenatal attrition, whereas Medicaid had lower attrition . The privately insured group had the highest proportion of intrapartum attrition compared with Strong Start and Medicaid . Compared with privately insured people, Strong Start beneficiaries had the lowest proportion of newborns transferred  and the lowest proportion of postpartum transfers . Variations in intrapartum, newborn, and postpartum transfer rates between groups may relate to variation in planned place of birth and place of admission. Compared with privately insured consumers, a smaller share of Strong Start and Medicaid beneficiaries intended to give birth at the birth center  and a smaller proportion of clients admitted to the birth center in labor . Compared with privately insured people, Strong Start and Medicaid beneficiaries had a higher proportion of the sample giving birth in the hospital by choice or for medical indications .Based on these average sociodemographic characteristics and clinical outcomes, logistic regression was used to test whether poverty was an independent driver of maternal and newborn outcomes in this sample Table . MedicaiIn this study, national quality benchmarks were achieved across 45 AABC Strong Start birth centers for both privately and publicly insured populations. Both Medicaid groups included more birthing people who were living at the intersections of poverty, including unmarried, Black, and Hispanic people, with fewer years of formal education than the comparison group of privately insured birth center consumers. The birth center model demonstrated equitable outcomes between private and public payers, suggesting a potential role for the wellness‐based model in the mitigation of poverty‐related health disparities.Previous studies of birth center care have been limited by homogeneity of the sample and underrepresentation from populations living in poverty.This analysis demonstrated that the beneficial outcomes from birth center‐led prenatal care persist between payer groups and across sociodemographic categories for most of the variables evaluated. The Medicaid Strong Start group was able to achieve equitable outcomes compared with privately insured people on all measures analyzed, including socially mediated indicators and those requiring social support . The combination of midwifery‐led birth center care and peer counselors has a role in mitigation of societal risks and their impact on childbearing families.The results of this research further illustrate the potential impact of evidence based psychosocial support interventions, specifically peer counselors within a birth center model.Limitations to sustainability, scale, and spread of the birth center model have been noted in previous research, including lack of payment for enhanced care services, like peer counselors, doulas, and community health workers.The findings of this study support the call to expand access to birth center care as part of a national initiative to improve perinatal outcomes. The optimal outcomes of vaginal birth, spontaneous labor, and healthy term, normal weight newborns transcended payer status in this sample, suggesting that outcomes of midwifery‐led birth centers are robust at the population health level. Medicaid programs can achieve improved outcomes by aligning their policies with the current evidence on effective interventions for optimal outcomes among Medicaid participants. The processes of enhanced care service  require sustainable reimbursement by Medicaid.More research is needed to understand the high leverage components of the innovative Strong Start birth center model. Other variables of interest relate to the business structure of the birth center, for‐profit or not‐for‐profit, and whether there is a relationship to outcomes.The organization of the birth center practices within this sample vary, including whether midwives have privileges at a hospital and whether the practice offers midwifery‐led hospital birth. It was outside the scope of this research to explore these variables. More research is needed to understand these relationships, to further inform policy and move the model to scale in the United States. In this study, compared with privately insured birthing people, those in both Medicaid groups were significantly more likely to be admitted to the hospital in labor. Decisions regarding place of birth admissions were related to the birthing persons preferences, as well as medical risk factors in this sample.A notable limitation of this study is the lack of generalizability due to unquantifiable selection bias within the population and unique characteristics of the 45 Strong Start birth centers. There is an assumed selection bias of consumers who choose birth center care, although, to date, no research has been published quantifying the existence or impact of selection bias upon initiation of prenatal care within the birth center model. The Strong Start birth centers have been recognized for their culture of quality with a high percentage of sites accredited by the Commission for Accreditation of Birth Centers (CABC). These results are not generalizable in settings that do not follow AABC Standards and are not accredited by the CABC.The optimal outcomes achieved through birth center care were not limited to clients with private insurance; they extend to those living at the intersections of poverty. The increased risk for poor outcomes in Medicaid populations can be mediated by midwifery‐led care including enhanced care services with peer counselors. Birth center model care achieves care that is safe and above national quality standards for both public and private payer patients.The authors have no conflicts of interest to disclose.


Baseline characteristics and neonatal mortality and morbidities were compared between infants with PIH and non-PIH mothers. After adjustment for potential confounders, infants with PIH mothers had significantly higher odds of respiratory distress syndrome  and bronchopulmonary dysplasia , and severe bronchopulmonary dysplasia  than infants with non-PIH mothers, while there were no significant differences in severe intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or death during neonatal intensive care unit admission between infants with PIH and non-PIH mothers. This study showed that preterm infants with PIH mothers had an increased risk of neonatal respiratory morbidities, including respiratory distress syndrome and bronchopulmonary dysplasia.The association between maternal pregnancy-induced hypertension (PIH) and neonatal mortality and morbidities in preterm infants has not been consistent. This study aimed to evaluate the influence of maternal PIH on mortality and morbidities in singleton infants with very low birth weight born before 30 weeks of gestational age using the Korean Neonatal Network (KNN) database. A total of 5340 singleton infants with very low birth weight were registered in the KNN registry, who were born at 23 PIH is associated with severe complications such as placental abruption, HELLP  syndrome, preterm birth, intrauterine growth retardation, and even fetal or maternal death5. Of preterm births in particular, up to 20% are due to hypertensive disorders of pregnancy6. Moreover, recent reports have indicated rising rates of PIH as a result of changing maternal characteristics7. Treatment of PIH depends on blood pressure levels, gestational age (GA), presence of symptoms and associated risk factors5. Given the high risk of neonatal mortality and morbidity in preterm infants, finding the proper balance between delivery in the second trimester and continuation of pregnancy in mothers with PIH is crucial.Pregnancy-induced hypertension (PIH) affects approximately 5–10% of pregnancies17. However, the findings regarding neonatal mortality and morbidities in preterm infants born to PIH mothers have not been consistent. Some studies have demonstrated that preterm infants born to mothers with PIH have an increased risk of several morbidities, including respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD)11. Others have demonstrated a decreased risk of mortality, intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) in preterm infants with PIH mothers17.The association between maternal PIH and neonatal mortality and morbidities in preterm infants has been examinedThe purpose of this study was to evaluate the influence of maternal PIH on mortality and morbidities in singleton infants with very low birth weight (VLBW) born before 30 weeks GA using the Korean Neonatal Network (KNN) database.18. The singleton infants with VLBW registered in the KNN registry who were born at 23+0 to 29+6 weeks GA from January 2015 to December 2020 were enrolled. The infants with major congenital anomalies or infants born to mothers with chronic hypertension were excluded. Neonatal mortality, and morbidities between infants with PIH mothers or non-PIH mothers were analyzed.This study was based on an analysis of prospectively collected data from 70 neonatal intensive care units (NICUs) participating in the KNN. The KNN registry includes approximately 70% of all infants with VLBW (< 1500 g) born in South Korea18. The maternal data included age, PIH, diabetes, premature rupture of membrane (PROM), the use of antenatal corticosteroids, and delivery mode. The neonatal data included GA, birth weight, small for gestational age (SGA), sex, and Apgar scores at 1 and 5 min. The following clinical information was collected: RDS, BPD, necrotizing enterocolitis (NEC), sepsis, IVH, PVL, retinopathy of prematurity (ROP), duration of invasive ventilation, length of NICU admission, and survival to NICU discharge or death.The KNN is a nationwide multicenter registry of infants with VLBW that prospectively collects demographic and clinical data using a standardized operating procedure2. The definition of PIH included gestational hypertension, preeclampsia, and eclampsia. Chronic hypertension was defined as a persistent elevation of blood pressure before 20 weeks of gestation or prior to pregnancy. Antenatal corticosteroid administration was defined as the successful completion of a dexamethasone or betamethasone regimen within 7 days before delivery6. SGA was defined as the birth weight below the 10th percentile for a GA based on the 2013 Fenton growth charts19.PIH was defined as newly diagnosed hypertension in a pregnant woman after 20 weeks of gestation, with systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg20. NEC was defined as stage 2 or higher NEC according to the modified Bell’s staging criteria21. Severe IVH was defined as grade III or IV IVH according to the criteria of the Papile classification system, and the worst grading result during hospitalization was recorded22. PVL was diagnosed based on the results of brain ultrasound or magnetic resonance imaging findings before NICU discharge. ROP was defined as stage 3 or higher ROP according to the International Committee for the Classification of Retinopathy of Prematurity23. Invasive mechanical ventilation included conventional mechanical ventilation and high-frequency oscillatory ventilation.RDS was defined as the presence of acute respiratory insufficiency  with typical radiologic finding after birth and that required surfactant replacement therapy. BPD was diagnosed on the basis of oxygen dependence or respiratory support at 36 weeks of postmenstrual age (PMA) or at NICU discharge, corresponding to moderate to severe BPD using the severity-based definition of BPD in the National Institutes of Health consensusp value < 0.05 was considered statistically significant.Continuous variables are expressed as the means ± standard deviations, and categorical variables are expressed as numbers and proportions. Comparisons of continuous variables between the groups were performed using Student’s t test for normally distributed variables and the Mann–Whitney U test for variables with non-normal distributions. Categorical variables were compared using Pearson’s chi-square test. Multivariable logistic regression analysis was performed to adjust for potential confounding variables, and adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) were calculated. The potential confounders adjusted in the multivariable analyses were those identified from the comparison of baseline characteristics. These factors included maternal age, PROM, antenatal steroids, mode of delivery, GA, SGA, and sex. Statistical analyses were performed using SPSS software, version 27.0 . A This study was approved by the institutional review board of CHA Bundang Medical Center, CHA University (IRB No. CHAMC 2013-08-082) and the Korean Neonatal Network (2021-058). All methods were performed in accordance with the ethical standards of our institutional research committee and with the 1964 Helsinki declaration and its later amendments.The Korean Neonatal Network registry was approved by the institutional review board and informed consent was obtained from parents of each infant before participation in the KNN registry.+0 ± 1+5 weeks, and mean birth weight was 970 ± 269 g. Of these 4990 infants, 855 (17.1%) infants were born to PIH mothers, and 4135 (82.9%) infants were born to non-PIH mothers.Information on the study population is presented in Fig. The baseline maternal and neonatal characteristics were compared between infants with PIH mothers and infants with non-PIH mothers Table . The motThe numbers and rates of neonatal mortality and morbidities between infants with PIH and non-PIH mothers are shown in Table p = 0.002), BPD , and severe BPD  than infants with non-PIH mothers. No significant differences in severe IVH, PVL, ROP, or death during NICU admission were observed between infants with PIH mothers and infants with non-PIH mothers in an adjusted comparison.The multivariable logistic regression analyses evaluating the effect of PIH on mortality and neonatal morbidities are shown in Table In this population-based study of singleton VLBW infants born before 30 weeks of gestation, infants with PIH mothers had significantly higher odds of RDS, BPD, and severe BPD than infants with non-PIH mothers after adjusting for potential confounders, while there were no significant differences in severe IVH, PVL, ROP, or death during NICU admission between infants with PIH mothers and infants with non-PIH mothers.24. Inadequate placental implantation leads to uteroplacental ischemia. As a consequence of uteroplacental ischemia, angiogenic or antiangiogenic factors, reactive oxygen species and inflammatory cytokines in the bloodstream of mothers with PIH can cross the placenta, reach the fetus and possibly affect the developing lungs26.Although the pathophysiology of PIH remains uncertain, inadequate placental implantation and abnormal vascularization may play certain roles in the development of PIH29. A cohort study in the Netherlands reported the protective effect of preeclampsia on RDS in late preterm infants28. Another single-center cohort study including preterm infants born at 23–28 gestational weeks demonstrated that preeclampsia increased the risk of RDS29. We can infer that different study populations and different onset of maternal PIH could be a reason for these discrepancies among the studies. Similar to several studies examining the association between maternal PIH and RDS in preterm infants, we also showed a twofold increased risk of RDS in infants born to mothers with PIH, after adjustment for confounding factors29. Wang et al. suggested that the antiangiogenic state in PIH contributes to surfactant dysfunction10. Considering RDS is secondary to surfactant insufficiency, and the association between PIH and RDS might be biologically plausible.The association between maternal PIH and RDS in preterm infants remains controversial9. In particular, infants with PIH mothers had significantly higher odds of severe BPD than infants with non-PIH mothers in this study. Because angiogenesis and alveolar development are interactive in the fetal lung, BPD has been recently recognized as a manifestation of vascular disease of the lungs30. Impaired pulmonary vascular growth by altered signaling of angiogenic or antiangiogenic factors derived from mothers with PIH may play a role in the pathogenesis of BPD31. However, conflicting results on the effect of maternal PIH on BPD in preterm infants have been reported33. An international cohort study specifically examining preterm infants born at 24 to 28 weeks of gestation reported that the risk for BPD increased in infants born to mothers with PIH8. A meta-analysis demonstrated that PIH was associated with BPD in preterm infants born at < 29 weeks of gestation9. By contrast, a meta-analysis of Australian cohorts showed that maternal preeclampsia did not influence the risk of BPD in extremely low-birth-weight infants32. Another large population-based study also reported that maternal preeclampsia was associated with a decreased risk of BPD in VLBW infants33. In that study, a negative association between maternal preeclampsia and BPD was shown only in a subgroup with a GA greater than 31 weeks. Considering that the study populations in these reports comprised data from birth weight-based registries, not GA-based registries, these discrepancies might be attributable to different study populations. A high number of SGA infants born at a relatively later GA would be preferentially included in birth weight-based registries. To minimize this bias in the KNN cohort, we only included VLBW infants born earlier than 30 weeks of GA in this study.After adjustment for confounding factors, we found that the increased risk of BPD in infants with PIH mothers is in accordance with previous studies34. Some studies have demonstrated that PIH is associated with an increased or decreased risk of mortality17. Another study has reported no association between PIH and neonatal mortality in preterm infants, similar to our study34. Conflicting results can be accounted for in part by differences in statistical approaches, differences in GA and birth weight ranges, and differences in sample sizes.No difference was found in mortality before NICU discharge between infants born to PIH mothers and infants born to non-PIH mothers. The association of maternal PIH and mortality in preterm infants has not been consistent13. They suggested that PIH may serve some adaptive role for the fetus in the face of uteroplacental dysfunction35. However, despite the suggested protective mechanisms, no significant differences were observed after adjusting for confounding factors in the rate of severe IVH and PVL between infants born to PIH mothers and infants born to non-PIH mothers in our study. This finding is in accordance with a previous meta-analysis showing that the rate of IVH and PVL in infants with PIH mothers was comparable to that in infants with non-PIH mothers9.Several reports have noted a lower incidence of severe brain injuries, such as IVH or PVL, among preterm infants born to mothers with PIH36. Considering that the worldwide incidence of PIH is increasing with the rising prevalence of predisposing factors, such as increasing maternal age, obesity, assisted reproductive technologies and diabetes, PIH deserves significant attention7.In this study, the overall rate of PIH was 17.1%. The maternal PIH rates in our study were comparable to those in previous studies14. Our study has some limitations. One limitation of the current study lies in the KNN definition of PIH. The KNN definition of PIH does not discriminate between gestational hypertension, preeclampsia, and eclampsia. It is important to know that a subgroup of PIH, such as gestational hypertension, preeclampsia, and eclampsia, may result in different adverse outcomes for infants. Moreover, the KNN database does not include information regarding aspects of the management of maternal PIH, including fetal monitoring and usage of medications such as magnesium sulfate, that may have affected outcomes for the infants37.There are several strengths to our study. Our data were derived from a large national cohort prospectively collected in Korea. The KNN database is reliable and has been validated with a high degree of precision. In consideration of the bias that may exist in birth weight-based registries, as mentioned above, we excluded infants with a GA of 30 weeks or more from the study population. Additionally, we only included infants born as singleton in this study, which may have influenced the results by pluralityIn conclusion, the present study demonstrated that preterm infants with PIH mothers had a higher risk for RDS, BPD, and severe BPD than infants with non-PIH mothers among singleton VLBW infants born before 30 weeks of gestation after adjustment for potential confounding factors, while we found no significant differences in severe IVH, PVL, ROP, or death during NICU admission between infants with PIH and non-PIH mothers. Our data showing the increased risk of neonatal respiratory morbidity will improve the care of preterm infants with PIH mothers. Moreover, further research is required to understand the biological mechanisms that shed light on differences between infants born to mothers with and without PIH.


Introduction: Bronchopulmonary dysplasia (BPD) is the most common complication associated with extreme prematurity. Although several criteria defining severity were developed over time, there are a few studies describing the differences in BPD phenotype and neonatal morbidities and complications between severity groups. We aimed to describe these differences in BPD patients of a neonatal intensive care unit (NICU).Methods: We conducted an observational retrospective cohort study through a medical record review over a five-year period. Participants were newborns admitted to an NICU who were diagnosed with BPD. We performed a descriptive statistical analysis of gestational complications and the use of antenatal corticosteroid therapy, birth-related data, and complications throughout the NICU stay, as well as the respiratory support used. We also compared different severity groups across these variables. The patients were divided into severe and non-severe BPD using the severity criteria of the 2001 NICHD/NHLBI/ORD consensus workshop.p-value=0.012, p-value<0.001, and p-value=0.012, respectively). Infants with severe BPD had a longer duration of invasive ventilation than those with mild or moderate BPD . Late sepsis, necrotizing enterocolitis, severe brain injury, and retinopathy of prematurity were more frequent in severe BPD .Results: A total of 101 newborns with BPD participated in the study and 73 had data on BPD severity. The median gestational age was 27 weeks, ranging from 23 to 32 weeks. Of these 73 newborns, 36 had mild BPD (49.3%), 10 had moderate BPD (13.7%), and 27 had severe BPD (37.0%). When comparing severe and non-severe BPD, we found that extreme prematurity, extremely low birth weight, and small size for gestational age were more frequent in the severe BPD group (Discussion: Previously published evidence describing causal links between BPD development and comorbidities exists but data on their impact on BPD severity are scarce. In our study, severe BPD seemed to be associated with a higher frequency of comorbidities and complications. Further studies are needed to ascertain the impact of each morbidity on the severity of BPD and if measures to prevent them could lead to potentially milder BPD disease. Premature birth affected an estimate of 8.7% to 13.4% of all live births in the world, in 2014 . RespiraOver the years, advancements in perinatal medicine such as antenatal corticosteroids and exogenous surfactant therapy have significantly reduced neonatal morbidity and mortality ,4. InterFrom 2001 to 2017, BPD was defined as a requirement for supplemental oxygen for at least 28 days at a postmenstrual age of 36 weeks  . This deDespite the several criteria developed over time, there are a few studies describing the differences in BPD phenotype and risk factors between severity groups and, specifically, differences in neonatal morbidities and complications. As such, we aimed to describe these differences in a retrospective cohort of BPD patients in a neonatal intensive care unit (NICU).Study designWe conducted a retrospective cohort study through a medical record review.Inclusion and exclusion criteriaParticipants in this study were all the newborns admitted to the NICU of a level 3 hospital between January 1st, 2015, and December 31st, 2019 (five years), who were diagnosed with BPD. BPD was diagnosed using the 2001 NICHD/NHLBI/ORD consensus workshop criteria. No participants were excluded from this study.Data collectionWe collected relevant data from the electronic medical record of each participant on the peripartum period, as well as the gestational period, and from admission into the NICU until discharge (or transfer) or death.Birth weight lower than 1000 g was defined as extremely low; birth weight between 1000 and 1499 g as very low; and birth weight between 1500 and 2499 g was defined as low. Size for gestational age was defined as follows: birth weight below the 10th percentile was classified as small (SGA), birth weight between the 10th and 90th percentile was classified as appropriate (AGA), and birth weight above the 90th percentile as large (LGA). Respiratory distress syndrome was categorized according to radiological criteria: Grade I for mild diffuse reticulogranular opacities, grade II for ground-glass opacities and air bronchogram, grade III for generalized air bronchogram and poorly defined cardiac silhouette, and grade IV for generalized loss of lung transparency and loss of cardiac silhouette. We acknowledged the diagnosis of sepsis in any infant manifesting systemic signs of infection for whom antibiotics were administered. Sepsis was classified as early or late depending on whether the onset of symptoms was in the first 72 hours of life or afterward, respectively. Severe brain injury was defined as having grade III or IV germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) or grade II or higher periventricular leukomalacia (PVL). No data on the use of vitamin A were collected since no formulation for intramuscular use was available in Portugal at the time of this study. Also, no data on caffeine usage were used as it is routinely administered to all infants with less than 34 weeks of gestational age.Statistical analysisp-values ≤0.05.Statistical analysis was done using the IBM® SPSS® Statistics version 22 software . We performed a descriptive statistical analysis of gestational complications and the use of antenatal corticosteroid therapy, birth-related data (including the presence of respiratory distress syndrome and surfactant administration), and complications throughout the NICU stay , as well as the respiratory support used. We also compared different severity groups across these variables. For this, the patients were divided into severe and non-severe (mild or moderate) BPD using the severity criteria of the 2001 NICHD/NHLBI/ORD consensus workshop. When the assumptions for parametric tests were met, we used the t-test for comparing continuous variables and the chi-square test for categorical variables. Otherwise, we used the Mann-Whitney U and Fisher tests, respectively. Statistical significance was set at During the study period, 1218 newborns were admitted to the NICU. One hundred and one newborns were diagnosed with BPD and were thus included in the study. Most newborns had extremely low birth weight , 34 had a very low birth weight (33.7%), and only four had a low birth weight (4.0%) (Table Prematurity was spontaneous in 45 newborns (44.6%), induced due to fetal illness in 42 cases (41.6%), and 14 due to maternal illness (13.9%). Cesarean was the most frequent mode of delivery (82.2%). Antenatal corticosteroids were given for fetal maturation in 95.0% and, in 73 (72.3%), it was possible to administer all the corticosteroid doses before delivery.The most frequent gestational complications were premature rupture of membranes , fetal growth restriction , hypertension , early pregnancy bleeding , and chorioamnionitis .Most newborns required invasive mechanical ventilation ; the median duration of ventilation was 16 days and the maximum was 100 days. Surfactant was administered in 79 newborns (78.2%). Almost all BPD newborns  needed noninvasive positive airway pressure, either as a first respiratory support modality or for ventilator weaning.During the stay at the NICU, 82 (81.2%) newborns were diagnosed with early sepsis and 75 with late sepsis (74.3%). Thirty newborns had a hemodynamically significant PDA (29.7%); most underwent pharmacologic therapy  and 17 needed surgical closure (56.7%). NEC was found in 13 newborns (12.9%) and five underwent surgical treatment (38.5%). Neurologic complications were also found in these newborns: 59 had intraventricular hemorrhage (58.4%) and 16 had grade II or higher PVL (15.8%). Four infants had no data on the ophthalmology exam. Of the 97 remaining, 43 newborns were diagnosed with ROP and 12 were submitted to surgery.The mortality rate among newborns with BPD in this study was 6.9% (n=7). At birth, these newborns had a median weight of 650 g (minimum of 475 g) and a median gestational age of 26 weeks (minimum of 23 weeks). The median age at death was 98 days.p-value=0.012, p-value<0.001, and p-value=0.012, respectively). No difference was found concerning the complete administration of antenatal corticosteroids . Infants with severe BPD had a longer duration of invasive ventilation (median 42.5 days) than those with mild or moderate BPD (median 7.5 days) .We were able to collect data on BPD severity grading in 73 newborns . Of these 73 newborns, 36 had mild BPD (49.3%), 10 had moderate BPD (13.7%), and 27 had severe BPD (37.0%)  but late sepsis was more frequent in newborns with severe BPD .Early sepsis was equally frequent among severe and non-severe disease . No difference in the frequency of hemodynamically significant PDA was found between severe and non-severe BPD . However, 38.9% (seven out of 18) of infants with a hemodynamically significant PDA ended up needing supplemental oxygen at discharge; only 10.4% (five out of 48) of those without a hemodynamically significant PDA needed supplemental oxygen at discharge .NEC was also more frequently present in the severe disease group . ROP was more frequently found in severe BPD infants  and they needed surgery for ROP more frequently .Infants with severe BPD had a higher proportion of severe brain injury (37.0%) than infants with mild or moderate BPD (15.2%) , including a full-course administration in 72%. We could not find any difference in BPD severity with antenatal corticosteroid therapy, but this might be the result of a lack of statistical power due to the low number of newborns who had not received antenatal corticosteroids.Severe respiratory failure was prominent among these newborns. Most required respiratory support with invasive mechanical ventilation, even though the surfactant was administered to 78.2%. These are not surprising results as our cohort is exclusively composed of infants with BPD and three-quarters had less than 29 weeks of gestational age. Probably for the same statistical reason as the use of antenatal corticosteroids, we could not find a difference in the surfactant use between severity groups.The long duration of ventilation we encountered (median 15.5 days) seemed to be in association with more severe BPD. In fact, severe BPD infants had a median duration of ventilation more than five times longer than that of non-severe BPD. Although, by definition, more severe BPD is associated with higher respiratory support, this relation also reflects a more damaged lung. Besides this, the neonatal lung is immature and underdeveloped, and, therefore, more prone to ventilator-induced injury.Perhaps in relation to risk factors for preterm labor, most of the BPD newborns were diagnosed with early sepsis. Surprisingly, late sepsis was present in almost three-quarters of the newborns and seemed to be more frequent in severe BPD patients. The inflammatory response associated with sepsis contributes to lung injury and the subsequent need for higher respiratory support and is already established as a risk factor for developing BPD ,11. FurtDespite being a respiratory condition, BPD is frequently encountered in extremely premature newborns with multiple comorbid conditions and complications affecting several organ systems. These include hemodynamically significant PDA, NEC, GMH-IVH, PVL, and ROP. PDA has long been associated with BPD, with frequencies varying between studies according to the inclusion of all PDA (72.2%) or only the hemodynamically significant PDA 10.3%) ,24,25. O.3% ,24,2NEC is more frequent in infants with risk factors for developing BPD (prematurity and low birth weight). Besides having common risk factors, there might also exist a causative role of NEC in the development of BPD, at least indirectly. A recent Spanish study found that infants with NEC had a higher risk of developing BPD . InfantsThe frequency of NEC among infants with BPD in our study (12.9%) was in line with the recent data from the United States . In our Neurologic injury is one of the most dreaded complications in premature infants. In our study, we found GMH-IVH and PVL in 58.4% and 49.5%, respectively. Severe brain injury was present in 25.7% and was more common among infants with severe BPD. Jensen et al. (2021) also observed a higher frequency of severe brain injury in grade III BPD infants than in grade I or II BPD infants (23.4% vs 13.1%) .Another risk factor for neurodevelopmental impairment in premature infants is ROP, particularly when severe. In our study, 44.3% of the infants were diagnosed with ROP and 27.9% of those underwent surgery. Our results are similar to the recently published data on DBP newborns . The etiInfants with BPD require more days of invasive mechanical ventilation and have higher oxygen needs than non-BPD infants; as such, it is only natural that BPD patients have more severe forms of retinopathy . PotentiOur study contributed to filling the gap in the literature regarding factors associated with BPD severity. Most published studies focus on differences between BPD and non-BPD infants but there is a paucity of studies comparing clinical characteristics of infants with BPD across different severity groups. Data comparison between published evidence is also challenging as different classifications for BPD and different severity gradings are used.In our study, we did not compare a BPD and non-BPD sample and, thus, we are unable to state which factors are associated with both the development and severity of BPD. However, multiple studies have already been published documenting risk factors for the development of BPD.The small sample size and the difficulty in ascertaining causality are the most important limitations of our study. It is possible that some differences between groups were not found due to a lack of statistical power. However, even with this sample size, the two severity groups had differences in several clinical factors, probably translating to strong associations. Unfortunately, the retrospective nature of our study does not allow us to firmly affirm the causality of the associations we found, specifically because prematurity and low birth weight are important confounders. It would be interesting to conduct an observational prospective study to determine how much each clinical characteristic contributes to the severity of BPD, as well as understanding the impact that more severe disease has in the development of complications.In the future, precision medicine may play an important role in the care of BPD patients and hopefully improve outcomes. A more individualized approach to ventilation strategies using novel monitoring techniques such as electrical impedance tomography and electromyography of the diaphragm may provide additional benefits beyond the currently used ventilatory strategies . UnderstAlthough the risk of developing BPD is largely associated with extreme prematurity and extremely low birth weight, both nonaddressable by the neonatology care team, prevention of severe BPD must be a priority. Besides the usual care with the appropriate choice of ventilation and the use of surfactant, caffeine, and corticosteroids when appropriate, we highlight the importance of instating measures to prevent late sepsis and NEC, both morbidities associated with more severe disease with a probable role in the development of more severe BPD. Additionally, special focus on preventing severe neurological injury and ROP should be given to infants with severe BPD, as both conditions seem to be more prevalent in this group of patients and can potentially contribute to a worse neurodevelopmental prognosis and quality of life.


To evaluate the association between second trimester plasma cytokine levels in asymptomatic pregnant women and preterm births (PTB) in an attempt to identify a possible predictor of preterm birth.The study design was a nested case–control study including women with singleton a gestational age between 20–25(+ 6) weeks from two Brazilian cities. The patients were interviewed, Venous blood samples were collected. The participants were again evaluated at birth. A total of 197 women with PTB comprised the case group. The control group was selected among term births (426 patients). Forty-one cytokines were compared between groups.p < 0.05). Logarithmic transformation was performed for cytokines with discrepant results, which showed increased levels of IL-2 in the group of spontaneous PTB (p < 0.05). In both analyses, the incidence of maternal smoking and of a history of preterm delivery differed significantly between the case and control groups. In multivariate analysis, only serum GRO levels differed between the case and control groups.When only spontaneous PTB were analyzed, GRO, sCD40L and MCP-1 levels were lower in the case group (Lower second trimester serum levels of GRO in asymptomatic women are associated with a larger number of PTB. This finding may reflect a deficient maternal inflammatory response. Preterm birth (PTB) is defined as birth before 37 weeks of gestation, which may or may not be preceded by labor, and is independent of the newborn’s weight . Its incThe physiopathology of PTB is not fully understood but appears to be the result of a multifactorial process in which the interaction of numerous factors transforms the quiescent uterus into an effectively contracting uterus . PretermSeveral studies have reported a strong association of high concentrations of inflammatory biomarkers with a short cervix  and consCytokines are hydrosoluble glycoproteins or polypeptides that are synthesized and released by different cell types in the organism in response to different stimuli. They can be divided into interleukins (IL-1 to IL-35), chemotactic cytokines (chemokines), tumor necrosis factors, mesenchymal growth factors, and interferons . During The well-established relationship between inflammation and myometrial contraction that underlies the mechanism of contractions and subsequent progression to labor (preterm or term) allows us to question whether the early emergence of inflammatory markers in maternal venous blood an indicator of PTB may be and whether these markers may be used for population screening because of the easy application of this method and noninvasive sample collection. In view of this association, studies have attempted to determine the role of cytokines in the diagnosis of labor by measuring their levels in vaginal secretions, amniotic fluid, and/or maternal blood. However, these studies are conflicting since their results are variable and inconsistent .The aim of this study was to establish the relationship between serum cytokine levels in asymptomatic women in the second trimester of gestation and PTB, and to identify cytokines that could be used as risk indicators of prematurity in asymptomatic patients in the second trimester.The study design was a case–control study nested within a convenience cohort that is part of a project entitled “Etiological factors of preterm birth and consequences of perinatal factors in child health: birth cohorts in two Brazilian cities” (BRISA project). The BRISA project was approved by the Ethics Committee under number 4116/2008.The participants were recruited through the municipal health system in Ribeirão Preto (SP) and São Luís (MA) between February 2010 and February 2011. The patients were invited to participate in the project during regular prenatal consultations and those who showed interest were asked to come to the hospitals responsible for data collection in their respective cities: University Hospital of the Ribeirão Preto Medical School (HCRP) in Ribeirão Preto, State of São Paulo, and three maternity units in São Luís, State of Maranhão, Brazil.Exclusion criteria were multiple pregnancies and fetuses with congenital malformations or chromosomal syndromes diagnosed before 20 weeks or at the time of prenatal data collection (confirmed with ultrasound). The inclusion criteria are only pregnant women with a single fetus and a gestational age between 20–25(+ 6) weeks (confirmed by obstetric ultrasound performed at less than 20 weeks of gestation) were included and term of consent and clarification of the study that the participant signed for anonymous use of the data collected. All patients who agreed to participate in the study signed the free informed consent form. Women with multiple pregnancies and fetuses with congenital malformations or chromosome syndromes diagnosed before 20 weeks or on the occasion of prenatal data collection (confirmed by ultrasound) were excluded.The pregnant women eligible for the study answered a standard questionnaire and underwent an interview and examinations, including gynecological examination, morphological and transvaginal obstetric ultrasound for the measurement of cervical length (except for pregnant women from São Luís where the uterine cervix is not measured routinely), and collection of a venous blood sample. The team responsible for the collection and processing of the data was adequately trained to ensure homogeneity and applicability of the assessment.The study involved 2,864 pregnant women from Ribeirão Preto and São Luís. Based on the responses of the birth cohort in the BRISA project, it was possible to identify and exclude from the case.n = 82), constituting a new group (n = 115) of cases that contained only spontaneous PTB (spontaneous PTB group). Spontaneous PTB was defined as that resulting from preterm labor or chorioamniorrhexis. A premature (PTB) baby is a child who was born preterm, that is, before completing 37 weeks of gestation [Group patients who progressed to PTB because of obstetric indications  were measured using a high-sensitivity assay  according to manufacturer recommendations. The analytes were quantified in a Luminex 200 analyzer  using the Analyst Software and the results are expressed as pg/ml.The seven most studies cytokines associated with PTB were measured: TNF, IFN-γ, IL-1, IL-6, IL-17 (proinflammatory), and TGF-ß and IL-10 (anti- inflammatory), added to the 41 markers available in the commercial kit used in the study.Variables that could influence the number of PTB were also analyzed : maternan = 82), constituting a new group (n = 115) of cases that contained only spontaneous PTB (spontaneous PTB group). Spontaneous PTB was defined as that resulting from preterm labor or chorioamniorrhexis.Statistical analysis was performed in two steps. First, all women with PTB that had their cytokines measured in the prenatal cohort of the BRISA project were included and comprised the case group (PTB group). The following variables were compared between the case and control groups: maternal age, parity, history of PTB, smoking and presence of genitourinary infection, as well as the 41 inflammatory markers. Second, based on the responses of the birth cohort in the BRISA project, it was possible to identify and exclude from the case group patients who progressed to PTB because of obstetric indications . First, exploratory analysis was performed using measures of central tendency and dispersion and box plots. The Student t-test was used to compare mean values of the variables of interest between the two groups. The level of significance was set at 5%. The proc t test procedure of the software was used for all tests. For variables showing wide variability whose distribution was not symmetrical, logarithmic transformation was performed and the results were compared to those obtained with the tests without transformation to evaluate the influence of outliers. Variables that differed between the case and control groups were then submitted to multivariate analysis.n = 2,757). Forty-five PTB were excluded from the study because of insufficient data or the impossibility of analyzing inflammatory markers . Spontaneous PTB group was n = 115 of cases. The control group  was selected by simple random drawing without replacement at a proportion of 2:1 in their respective cities (426 patients). Thus, the total sample of the study consisted of 623 patients. In the group that included only spontaneous PTB (spontaneous PTB group), the mean age at birth was 239.8 days.A total of 2,864 pregnant women from Ribeirão Preto and São Luís were included in the study. There were 242 women with PTB  and the control group revealed no expressive changes in relation to those observed in the PTB group as a whole. A significant difference was only observed for maternal smoking and a history of preterm delivery in previous pregnancies. Maternal age, parity or infections did not differ between the two groups , whose levels were also lower in the spontaneous PTB group Table .Table 2Cp = 0.03)  and the results were compared with those obtained by tests without transformation to identify the possible influence of these outliers. Among the reevaluated cytokines, a significant difference was observed for Log IL-2 in the group involving only spontaneous PTB . As the measurement unit of GRO increased, the risk of PTB decreased. Since the marker-related variables are continuous, the estimates were very close to 1  in asymptomatic pregnant women in the second trimester and compared them between patients with PTB and a group of patients who delivered at term. Among the 41 cytokines analyzed, only GRO was a risk factor for spontaneous prematurity. The mean level of this cytokine was lower in the PTB group, although the literature shows an association between increased serum proinflammatory cytokines and PTB .GRO is a chemokine that consists of three subunits: GROα/CXCL1, GROβ/CXCL2, and GROγ/CXCL3. This chemokine is produced by different cell types such as synovial cells, monocytes, fibroblasts, and endothelial cells. Its production is directly influenced by 7 IL-8, which is responsible for neutrophil activation and chemotaxis of inflammatory cells . Some stOur findings are biologically plausible. Laudanski et al.  also fouThe analysis of this study may be compromised by the fact that it was not possible to assess changes in the plasma concentrations of the inflammatory markers throughout pregnancy, which would allow to identify critical periods during which cytokine levels would reflect the real increase in the risk of prematurity. Another limitation of the study is the impossibility of evaluating cervical characteristics and their association with serum levels of the inflammatory markers since the patients from São Luís did not undergo specific ultrasound examination to measure cervical length in the prenatal cohort, and another limitation is the use of corticosteroids during pregnancy, which can cause lung or neurological damage in the neonate, future randomized clinical trials will bring more evidence for this indication. Normal cut-off values for the cytokines are not available in the literature for direct comparison with the outcome (prematurity). The results of different studies are still insufficient to indicate the serum concentration of inflammatory markers in asymptomatic patients in the second trimester as a parameter to predict PTB or to identify at-risk populations.


High-throughput sequencing measurements of the vaginal microbiome have yielded intriguing potential relationships between the vaginal microbiome and preterm birth . However, results across studies have been inconsistent.L. crispatus and PTB that was consistent across almost all studies. The presence of the majority (18 out of 25) of genera was associated with a higher risk of PTB, with L. iners, Prevotella, and Gardnerella showing particularly consistent and significant associations. Some example discrepancies between studies could be attributed to specific methodological differences but not most study-to-study variations in the relationship between the vaginal microbiome and preterm birth.Here, we perform an integrated analysis of previously published datasets from 12 cohorts of pregnant women whose vaginal microbiomes were measured by 16S rRNA gene sequencing. Of 2039 women included in our analysis, 586 went on to deliver prematurely. Substantial variation between these datasets existed in their definition of preterm birth, characteristics of the study populations, and sequencing methodology. Nevertheless, a small group of taxa comprised a vast majority of the measured microbiome in all cohorts. We trained machine learning (ML) models to predict PTB from the composition of the vaginal microbiome, finding low to modest predictive accuracy (0.28–0.79). Predictive accuracy was typically lower when ML models trained in one dataset predicted PTB in another dataset. Earlier preterm birth  was more predictable from the vaginal microbiome than late preterm birth (34–37 weeks), both within and across datasets. Integrated differential abundance analysis revealed a highly significant negative association between We believe future studies of the vaginal microbiome and PTB will benefit from a focus on earlier preterm births and improved reporting of specific patient metadata shown to influence the vaginal microbiome and/or birth outcomes.The online version contains supplementary material available at 10.1186/s12915-023-01702-2. Lactobacillus species and overgrowth of typically strict anaerobes  32 weeks) and early or moderate PTB ([MYLT] 34 weeks) subgroups. Table S5. Summary of key reported genera/species in original studies. Table S6. Estimate of the odds ratio between genus is present relative to absent.Additional file 2: List S1. Results of Lactobacillus species BLAST against sequences from cultured Lactobacillus strains.Additional file 3: Figure S1. The relative abundance (A) and prevalence (B) of 34 genera/species either in common or top feature tables for both V1-V2 and V4 groups. The red number in the up-left shows the number of datasets that have relative abundance greater than 0.1% or prevalence greater than 10%. After filtering the genera using the following criteria (1) at least 5 datasets have the average relative abundance [MYGT] 0.1%; (2) at least 5 datasets have the average prevalence [MYGT] 10%, we excluded Prevotella_7, Haemophilus, Lactobacillus.delbrueckii, Alloscardovia, Lactobacillus.amylovorus, Fusobacterium, Peptostreptococcus, DNF00809, Parvimonas and kept another 25 genera/species for further analysis. Figure S2. The summary statistics of the population characteristics and gestational age at sampling. Figure S3. A: Distribution of gestational age delivery; B: Preterm birth type included in each dataset. Figure S4. The average prevalence and relative abundance of 25 core taxa across datasets. Figure S5. Assessment prediction performance of data transformation methods using the genus features. For intra-analysis, the area under the receiver operating characteristics curve (AUC) is obtained based on cross-validation within a dataset. For cross-analysis, the AUC value for a given dataset is the average of the AUCs using other datasets in V1-V2 or V4 group as the training set, and the dataset as the testing set. For LODO analysis, the AUC value for a given dataset is obtained using the combined dataset in V1-V2 or V4 group except the dataset as the training set and the study as the testing set. Rank row is calculated using the following steps (1) for each dataset, rank each method among all methods based on AUC values ; (2) calculate the average of the ranks across datasets for each method. Figure S6. Assessment prediction performance of classifiers using the genus features with CLR transformation. Rank row is calculated using the following steps (1) for each dataset, rank each method among all methods based on AUC values ; (2) calculate the average of the ranks across datasets for each method. Figure S7. Assessment of prediction performance for different preterm birth groups using intra-dataset analysis (A), combined-dataset analysis (B) and cross-dataset analysis (C) using proportional abundance data. Figure S8. SHAP summary plots for each study for random forests trained on genus-level proportional data. The five most important features for each study are shown. The data points are colored by the relative abundance of the taxa. Positive SHAP values indicate a higher likelihood of preterm birth and negative SHAP values indicate a lower likelihood of preterm birth in comparison to the average prediction. Figure S9. Average AUC with and without Aerococcus included as a feature for ten random forest models trained on genus-level CLR data from the Ro study and tested on all other studies. Figure S10. Dataset-specific differential abundance analysis for each genus/species using a one-sided Wilcoxon rank-sum test. A cell is in red color if the average relative abundance of a genus/species in term birth is larger than the average relative abundance in preterm birth, otherwise in blue color. The unadjusted p-value significant code: ‘***’: 0.001, ‘**’: 0.01, ‘*’: 0.05. Figure S11. Cross-dataset differential abundance analysis using a generalized linear mixed model with covariates. The genus and race effects were estimated using 11 datasets with a model including race covariate. The BMI and age effects were estimated using 8 datasets with a model including race, BMI and age. Point estimates less than 0 are shown as blue points and greater than 0 are shown as red points. Confident intervals less than 0 are shown as blue bars and greater than 0 are shown as red bars. Figure S12. Average estimates of log odd ratio for each PTB subgroup versus late term birth using the generalized linear mixed model. The asterisk shows the significant level of the combined p-values: *: p-value< 0.05; **: p-value< 0.01; ***: p-value< 0.001. Figure S13. Posterior distribution of log odds ratio using a Bayesian approach stepwise method. Maximum a posteriori (MAP) estimates less than 0 are shown as blue lines and larger than 0 are shown as red lines. The 95% credible intervals are shown in the left top corner.Additional file 4: Supplementary Methods. Details about classifiers used in the meta-analysis and the Bayesian approach.


No difference was found in median absolute systematic error (p = 0.450), random error, or sEFW evaluations that were within 10% of the birth weight between the fetuses . Reliability analysis demonstrated an excellent correlation between the sEFW and the birth weight for both twins; however, the Euclidean distance was slightly higher for the first twin (12.21%). For SGA prediction, overall, there was a low sensitivity and a high specificity for all fetuses, with almost no difference between the first and second twins. We found that sEFW overestimated the birth weight for the second twin, with almost no other difference in accuracy measures or SGA prediction.Accurate sonographic estimation of fetal weight is essential for every pregnancy, especially in twin gestation. We conducted a retrospective analysis of the sonographically estimated fetal weight (sEFW) of all twin gestations performed within 14 days of delivery in a single center that aimed to evaluate the accuracy of sEFW in predicting neonatal weight and small for gestational age (SGA) by comparing the first fetus to the second. A total of 190 twin gestations were evaluated for the study. There was no statistically significant difference in the sEFW between the first and the second twins, but the second twin had a statistically significant lower birth weight (2434 vs. 2351 g,  Twin pregnancies are associated with a high incidence of pregnancy complications. One of the most prevalent risks is preterm delivery, which accounts for most of the increased perinatal morbidity and mortality. Additionally, higher rates of fetal growth abnormalities and congenital anomalies contribute to adverse outcomes in twin pregnancies .It has been suggested that neonatal morbidity and mortality tend to be higher for the second-born twin (as compared to the first-born). In a systematic review of observational studies, overall neonatal morbidity, defined as pH < 7.0, Apgar score < 7 at 5 min, or any neonatal birth trauma, was 3.0 and 4.6 percent, respectively , and overall neonatal mortality, defined as death within 28 days, of the first and second twins was 0.3 and 0.6 percent, respectively . The increased risk of adverse neonatal outcomes in the second-born twin was most likely related to a lower birth weight, a higher frequency of malpresentation, cord prolapse, placental abruption, and the need for obstetric maneuvers at delivery ), representing the geometric average of the systematic and random errors. For every twin fetus, the sEFW was evaluated and compared to the neonatal birth weight. Accuracy was evaluated for every twin and compared between the 1st (closer to the cervix) and 2nd fetus. Measures of accuracy included the systematic error ; the random error (the standard deviation of the systematic error), reflecting the random component of prediction error; and the proportion of estimates within 10% of the birth weight. To further compare the accuracy of EFW between the 1st and 2nd twins, we utilized the Euclidean distance , negative predictive value (NPV), positive likelihood ratio ), and negative likelihood ratio /specificity). Overall accuracy was defined as (true negative + true positive cases)/all cases.p < 0.05 was considered significant. Categorical data were analyzed using Fisher’s exact test, and continuous variables were compared using the Mann–Whitney–Wilcoxon test as appropriate. Reliability analysis was used to calculate the Cronbach’s α value, which measures the power of correlation between sEFW and the neonatal birth weight . Statistical analysis was performed using SPSS version 28.0 software . Overall, 28,834 women delivered in our institution during the study period, of which 1064 had twin gestations. After consolidating the database, 190 women with twin gestations had sonographic fetal evaluations performed within 14 days of delivery and were thus eligible for our analysis.The demographic and obstetrical characteristics of the cohort are shown in p = 0.028), as shown in Although there was no statistically significant difference in the sEFW between the first and second twins, the second twin had a statistically significant lower birth weight of 2434 (900–3750) vs. 2351 (775–3610), grams, Overall, sEFW overestimated the actual neonatal birth weight. Specifically, there was almost no difference between the sEFW and birth weight for the first twin but a large overestimation for the second twin. p > 0.05 for both). The random error was 8.54% for the entire cohort. Unlike the systematic error, the random error was slightly lower for the first twin (8.39 vs. 8.71 %). For all twins, there was wide variation in the absolute systematic error . The median absolute systematic error and the proportion of estimates within 10% were similar between the first and the second fetuses (Reliability analysis demonstrated a good correlation with a Cronbach’s α value of 0.896 for the entire cohort with a slightly better correlation for the second twin. The Cronbach’s α value of the second twin was 0.911, suggestive of an excellent correlation, and the Cronbach’s α value of the first twin was 0.883, suggestive of a good correlation. The Euclidean distance was calculated to be 12.21 for the first twin and 12.27 for the second twin. The lower distance for the first twin reflects a higher prediction of neonatal birth weight.Accuracy measurements for SGA prediction for the first and second twins are demonstrated in Ultrasonographic estimation of fetal weight is routinely used in the management of multiple pregnancies and affects clinical decision-making regarding timing and mode of delivery. In this study, we aimed to evaluate the accuracy of sEFW in twin gestation. Specifically, we endeavored to assess the differences in accuracy between the first and second twins. Additionally, in order to evaluate the clinical impact of sEFW accuracy, we investigated the prediction of SGA at birth for both twins. Our study has several findings: 1. Overall, for the entire cohort, there was a good correlation between sEFW and birth weight; 2. the sonographic weight estimation of the second twin overestimated the actual birth weight; 3. the prediction of SGA was similar for both twins, however, with low sensitivity. The specificity and PPV were higher for the second twin. 4. There was no difference in the accuracy of predicting SGA between the first and second twins. The accuracy of sonography in predicting fetal weight has been studied in numerous studies ,19,20. OOur study confirmed the previous reports showing a good correlation between sEFW and birth weight ,23 and nOur results matched previous studies showing a tendency to underestimate the weight of the first twin and overestimate the weight of the second twin ,22.For sEFW prediction of SGA, overall we found high accuracy for both twins, as shown in previous studies . We founCognitive biases are unconscious mental shortcuts or patterns that can influence how people perceive, interpret, and make decisions about information. Although diagnostic errors arising from cognitive biases are well studied in the radiology field, there remains a lack of research in the obstetric ultrasound field . Our stuThe strength of our study relies on the selection of cases for sonographic evaluation within 14 days of delivery, with the majority performed up to 7 days before delivery. Additionally, sonographic evaluation was undertaken by highly experienced ultrasound technicians or physicians who were ultrasound specialists. Our study is not free of limitations. First, this study is limited by its retrospective design. For this reason, no data was available regarding patients’ body mass index, demographics, or ethnic origin. Additionally, fetal data regarding gender was unavailable, which potentially could have affected the sonographic weight estimation prior to delivery and should have been evaluated as a confounding variable. Secondly, our study included a relatively small sample size of twins at all gestational ages, which could have affected our results. The inclusion of preterm deliveries that are potentially related to placental insufficiency complications during pregnancy may have influenced the proportion of SGA or growth-restricted fetuses. Therefore, future studies are needed to further study and validate our findings. Thirdly, chorionicity was evaluated sonographically without validation using postpartum placental examinations. Lastly, although care was taken to correctly name the first and second twins, we could not retrospectively validate that the presenting twin in ultrasound was always the first delivered, particularly in cases of cesarean section. In conclusion, twin gestations are prone to growth abnormalities, and fetal weights are typically smaller at term than in singleton pregnancies. Our study shows that sEFW has no difference in predicting birth weight for first and second twins, with high accuracy in predicting SGA but low sensitivity.