This cross-sectional study assesses the association of neighborhood-level characteristics  with birth weight outcomes in New York City. Is the healthfulness of the neighborhood food environment associated with birth weight outcomes?In this population-based cross-sectional study of 106 194 births in New York City, higher neighborhood density of healthy food retail establishments was associated with a reduced risk of delivering an infant classified as small for gestational age, while higher neighborhood density of unhealthy food retail establishments was associated with higher risk of having an infant born either small or large for gestational age.The findings suggest that urban design and planning guidelines to improve the healthfulness of neighborhood food environments are needed to promote healthy pregnancies and birth weights. Infants born with unhealthy birth weight are at greater risk for long-term health complications, but little is known about how neighborhood characteristics  may affect birth weight outcomes.To assess whether neighborhood-level characteristics  are associated with risk of unhealthy birth weight outcomes and to evaluate whether gestational weight gain mediated these associations.The population-based cross-sectional study included births in the 2015 vital statistics records from the New York City Department of Health and Mental Hygiene. Only singleton births and observations with complete birth weight and covariate data were included. Analyses were performed from November 2021 to March 2022.Residential neighborhood-level characteristics, including poverty, food environment , and walkability . Neighborhood-level variables categorized into quartiles.The main outcomes were birth certificate birth weight measures including small for gestational age (SGA), large for gestational age (LGA), and sex-specific birth weight for gestational age z-score. Generalized linear mixed-effects models and hierarchical linear models estimated risk ratios for associations between density of neighborhood-level characteristics within a 1-km buffer of residential census block centroid and birth weight outcomes.The study included 106 194 births in New York City. The mean (SD) age of pregnant individuals in the sample was 29.9 (6.1) years. Prevalence of SGA and LGA were 12.9% and 8.4%, respectively. Residence in the highest density quartile of healthy food retail establishments compared with the lowest quartile was associated with lower adjusted risk of SGA . Higher neighborhood density of unhealthy food retail establishments was associated with higher adjusted risk of delivering an infant classified as SGA . The RR for the association between density of unhealthy food retail establishments and risk of LGA was higher after adjustment for all covariates in each quartile compared with quartile 1 . There were no associations between neighborhood walkability and birth weight outcomes .In this population-based cross-sectional study, healthfulness of neighborhood food environments was associated with risk of SGA and LGA. The findings support use of urban design and planning guidelines to improve food environments to support healthy pregnancies and birth weight. Lower neighborhood SES has also been shown to be associated with infants born LGA11; however, research in this area is limited and some studies have shown no estimated association.6Prior studies19 assessing the association between neighborhood built environment features and birth weight outcomes is scant, there exists a robust body of literature demonstrating an association of neighborhood walkability and food environment with weight-related outcomes within the general population. Numerous studies16 have examined walkability features  or multicomponent indices of walkability and have found an association between living in areas of higher walkability and lower body mass index (BMI) or risk of overweight or obesity. There is evidence supporting an association between healthier food environments and weight-related outcomes; living both in closer proximity to healthy food retail establishments and in an area with a higher density of healthy food retail establishments have been associated with lower BMI.19 However, findings on the association between the food environment and BMI or overweight and/or obesity have not been as robust or consistent as the walkability literature.While the literature20 by our research team that used New York City (NYC) birth records from 2015 found that living in a neighborhood with a higher density of unhealthy food outlets was associated with lower odds of excessive gestational weight gain (GWG). However, higher density of unhealthy food outlets was associated with higher neighborhood walkability, which was also associated with lower odds of excessive GWG. Given the positive association between GWG and birth weight,22 we hypothesized that GWG would act as a mediating variable in analyses of associations between the density of unhealthy food outlets and birth weight outcomes. Therefore, to assess this possibility, analyses were conducted with and without adjustment for GWG, and formal mediation analyses were performed.A previous studySTROBE) reporting guideline.This cross-sectional study was classified as nonhuman participant research by the Columbia University Irving Medical Center institutional review board and thus was considered exempt from review, with a waiver of informed consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology . The DOHMH collects annual data on all births in NYC using medical records and self-report from the birthing parent. Only singleton births and observations with a plausible prepregnancy BMI  or child birth weight (defined as 500-6000 g) were included. Births with GA less than 22 weeks or greater than 42 weeks were excluded. Observations missing height or weight data for the pregnant individual either at the time of birth or before pregnancy were also excluded, as were observations missing primary exposure or outcome variables for neighborhood or birth weight.23 for defining residential neighborhood, a 1-km buffer was created around the geographic centroid of each census block. After removing areas of water, the land area of the radial buffers was characterized for sociodemographic and built environment characteristics.24 To preserve the confidentiality of the health records, the NYC DOHMH performed the linkage between census block of residence and neighborhood variables. The combined individual- and neighborhood-level data were then analyzed with neighborhood-level variables categorized into quartiles. Quartile cut points were established using the distribution of the neighborhood-level variables across all census blocks in NYC.The residential address of the pregnant individual was geocoded to the corresponding 2010 census block. Using a common metric in the literature26 Following methods developed for a prior study14 by our research team of neighborhood characteristics and obesity risk in NYC, we a priori grouped food retail establishments into healthy and unhealthy categories based on whether the types of food sold support a healthy weight and then calculated the density of healthy and unhealthy food establishments for each radial buffer. For example, we classified full-service supermarkets and fruit and vegetable markets as healthy and fast-food outlets, convenience stores, and candy stores as unhealthy. Categories were based on evidence in the literature31 reporting associations of different types of food retail establishments with energy density of foods sold, diet quality, and BMI. Prior work has shown that these food environment classifications are associated with residents’ BMI in NYC.33The locations of retail food establishments and walkable destinations were identified using the 2014 National Establishment Time Series data set, which provides a census of businesses and institutions in the US.34 The 2015 neighborhood walkability index (NWI) was calculated using residential density, street intersection density, land use mix for 5 types of land use , subway stop density, and the ratio of retail building floor area to retail land area.37 Each scale component was calculated for the land area inside each census block centroid’s 1-km radial buffer. The components were then z-score transformed and summed for each buffer. The proportion of residents whose income was below the federal poverty level (poverty rate) was calculated by applying tract-level US Census American Community Survey data (2012-2016) to the radial buffers using standard areal weighting interpolation methods.38 The data sets and methods used for calculating neighborhood exposure variables have been previously described in more detail.20Using National Establishment Time Series data, we also calculated density of walkable destinations, including businesses and municipal resources, for each radial buffer.5 SGA and LGA were defined as less than the 10th percentile and greater than the 90th percentile of sex-specific birth weight for GA z-scores, respectively. Gestational weight gain was the difference between prepregnancy weight (kg) and weight at time of delivery (kg). The GWG for GA z-score was calculated using z-score charts specific to prepregnancy BMI groups.41Birth weight was measured in grams and GA in weeks. Birth weight for GA z-scores were calculated using a 2017 birth weight for GA reference for US singleton births.2), which were extracted from the birth record in which these measures were primarily inputted from medical records . Other individual demographic variables were self-reported. The pregnant individual’s education level was a categorical variable ranging from less than high school to doctorate or professional degree. Age was included as a continuous variable. A dichotomous variable for nativity was defined as US born (including US territories) or born outside the US. Parity was defined as an ordinal variable using previous live births . A dichotomous variable for smoking status in the 3 months before or during pregnancy was included. A 3-level categorical variable for insurance type was used as a proxy for income . We included pregnant individuals’ race and ethnicity as a confounder not because we assumed there is a biological basis for difference in birth weight outcomes by race and ethnicity but because race and ethnicity may serve as a proxy for social factors  that influence birth weight and are not captured by other individual-level or neighborhood characteristics.42 Categories included Asian or Pacific Islander, Black non-Hispanic, Puerto Rican, White non-Hispanic, other Hispanic, other non-Hispanic, and non-Hispanic of 2 or more races  was calculated using weight (kg) and height (m43 Univariable and multivariable logistic (SGA and LGA) and linear (birth weight for GA) regression analyses were used to analyze the association between GWG and birth weight outcomes. To assess the association between neighborhood-level variables and SGA compared with appropriate weight for GA (AGA), we used generalized linear mixed-effects models with a Poisson distribution and robust SEs.45 Likewise, in separate analyses, generalized linear mixed-effects models were used to analyze associations between neighborhood-level variables and LGA compared with AGA. The models included a random intercept for NYC community district, which represents the most local unit of government in NYC and typically reflects well-known neighborhood areas.14 Due to high collinearity between neighborhood food environment and walkability variables, 6 separate models were fit; the first 2 assessed neighborhood density of healthy and unhealthy food retail establishments and neighborhood poverty rate simultaneously as exposures for (1) SGA vs AGA and (2) LGA vs AGA, models 3 and 4 assessed NWI scores and neighborhood poverty rate for (3) SGA vs AGA and (4) LGA vs AGA, and models 5 and 6 assessed density of neighborhood walkable destinations and neighborhood poverty for (5) SGA vs AGA and (6) LGA vs AGA .48 Specifically, higher density of unhealthy food outlets was negatively associated with GWG in previous studies, and GWG was positively associated with LGA.22 To test the role of GWG as a competitive mediating variable, we conducted a mediation analysis using Stata macro by VanderWeele49 to estimate the direct effect, indirect effect, and total effect of higher density of unhealthy food outlets on LGA  age of pregnant individuals in the sample was 29.9 (6.1) years, 59.1% were married, and 44.4% were nulliparous. Additional characteristics for the final analytic sample of 106 194 births are presented in In the first adjusted model, there was a positive association between the density of unhealthy food retail establishments and risk of LGA for the second quartile  and third quartile  compared with the first quartile, but there was no association for the fourth quartile compared with the first. After adjustment for all covariates including GWG z-score, the RRs for the association of higher density of unhealthy food retail establishments with LGA was higher for each quartile . The increase in the estimated effect size was consistent with GWG acting as a competitive mediating variable in the data. The formal mediation analysis examining GWG as a mediating factor between unhealthy food density and LGA , as has living in a neighborhood with greater density of healthy food retail outlets. Furthermore, numerous studies52 have shown that preconception and prenatal diets that are rich in fruits, vegetables, whole grains, legumes, and dairy are associated with reduced risk of adverse birth outcomes, including preterm birth and SGA.In this cross-sectional study, the risk of having an infant who was SGA was lower for pregnant individuals living in the highest density quartile of healthy food retail establishments, while an increasing density of unhealthy food retail establishments was associated with higher SGA risk. This association remained even after adjusting for GWG z-score, suggesting an association between healthfulness of the neighborhood food environment and healthy birth weight that was not solely influenced by weight gain during pregnancy. Living closer to healthy food retail establishments has been shown in some prior studies22 showing that GWG above the Institute of Medicine recommendations is associated with lower odds of SGA and higher odds of LGA and that, inversely, GWG below Institute of Medicine recommendations is associated with lower odds of LGA and higher odds of SGA.The present analyses found that an increase in GWG by 1 SD was associated with 23% lower odds of SGA, 51% higher odds of LGA, and a 0.18-SD increase in birth weight for GA. These findings align with previous literature20 by our research team found that higher density of unhealthy food outlets was associated with lower odds of excessive GWG. Given the high correlation between neighborhood walkability and unhealthy food density in NYC, we previously hypothesized that higher density of unhealthy food would be a proxy in our analyses for neighborhood walkability, which was associated with lower odds of excessive GWG.20 Unhealthy food outlets are commonly found near transit stops and in areas with higher population density and higher land use mix, which are all key components of neighborhood walkability. The previous findings,20 combined with results in the current study showing that higher density of unhealthy food outlets was associated with a higher risk of LGA only after adjusting for GWG z-score, suggests that GWG may have a competitive mediating effect in the unadjusted analyses of neighborhood food environment and LGA.46 That is, in the present analyses, higher density of unhealthy food outlets was associated with LGA through 2 pathways: one negatively associated with LGA through GWG and the other positively associated with LGA 36 However, many of these experiential qualities correlate with neighborhood socioeconomic conditions, which was captured by adjustment in the analyses for neighborhood poverty rate.36 Lastly, opportunities for causal inference are limited by the observational and cross-sectional nature of the study.The walkability measures used in the present study are based solely on urban form and planning concepts and do not include more experiential characteristics of the built environment such as aesthetic qualities or perceived safety.59 However, due to limited research on the implications of active design for health during pregnancy, few wellness-oriented urban design and planning guidelines explicitly consider pregnant individuals and their infants. Given the long-lasting benefits of healthy pregnancies for parental and child health, this research provides further impetus for the use of urban design to support healthy weight and reduce the risk of unhealthy birth weight. Supporting the health of young children should be factored into cost-benefit analyses of built environment interventions to improve healthy food access across neighborhoods.In this cross-sectional study, higher neighborhood density of healthy food retail establishments was associated with a reduced risk of delivering an infant classified as SGA, while higher neighborhood density of unhealthy food retail establishments was associated with higher risk of having an infant born either SGA or LGA. This research provides further evidence of a role of neighborhood environment features in pregnancy and birth outcomes. Well-established guidelines exist for improving perinatal health through diet and physical activity.


We describe an outbreak of echovirus 18 infection involving 10 patients in our neonatal intensive care unit (an attack rate of 33%). The mean age at the onset of illness was 26.8 days. Eighty percent were preterm infants. All were discharged home without sequelae. There were no differences in gestation age, birth weight, delivery mode, use of antibiotics, and parenteral nutrition between the enterovirus (EV) group and non-EV group, but the rate of breastfeeding was significantly higher in the EV group. Separation care and reinforcement of hand-washing seemed to be effective in preventing further spread of the virus. Visiting policy, hygiene practice, and handling of expressed breastmilk should be reinforced. Enterovirus (EV) infection, a common pathogen that causes an outbreak of nosocomial infections in neonatal intensive care units (NICUs), often occurs in summer and autumn, accounting for 15.6% of neonatal nosocomial infections caused by viruses. EV has been reported to be one of the top viruses to cause outbreaks of nosocomial infections in NICUs in the United States every year . An EV iIn July 2019, sepsis-like manifestations were observed in 10 neonates in the NICU of our hospital. At that time, our hospital had a Grade III NICU with 31 patients admitted. On 14 July, the conditions of three hospitalised preterm infants declined, including of two infants (40 days after birth) who were twins  born at a gestational age (GA) of 29 weeks and one infant born at a GA of 30+5 weeks , all having received full enteral feeding without any intravenous medication. Another preterm infant at a GA of 29+3 weeks (case 4) was re-admitted due to fever after 3 days of discharge. From 15 July to 19 July, six new cases were reported.There were two term infants and eight preterm infants. The mean GA was 31.7±4.0 weeks, and the mean birth weight was 1812.9±1025.1 g. The term infants showed significantly elevated body temperature, without anorexia or diarrhoea. However, one term infant developed rashes. Most preterm infants had mild fever or normal body temperature, apnoea, unstable oxygenation, and feeding intolerance, without diarrhoea or vomiting; two preterm infants developed rashes. Two preterm infants had early manifestations of shock such as tachycardia and poor peripheral circulation. One preterm infant had bloody stools. Convulsion, disturbance of consciousness, and involvement of limb movement were not observed . One infP < 0.05 was considered statistically significant. There were no differences in gestation age, birth weight, delivery mode, use of antibiotics, and parenteral nutrition between the EV group and non-EV group, but the rate of breastfeeding was significantly high in the EV group  were collected for bacterial culturing. On 18 July, the Administrative Department of the hospital and the Centers for Disease Prevention and Control were reconvened to assist in investigation and case handling. The affected infants were isolated before treatment start. On the day of onset, patients received 1–2 g/kg gamma globulin and antibiotics until EV positive result. One preterm infant born at a GA of 27 weeks was hospitalised for a long term due to bronchopulmonary dysplasia; the other nine infants were discharged 10 days after onset. Follow-up after discharge showed no abnormality. Upon recovery, all patients were discharged from isolation and symptomatic and supportive treatment.Further prevention and control measures were initiated against EV infection: (1) Admission of new patients was suspended and receipt of breastmilk was stopped. (2) The offices and care units were disinfected using a chlorinating agent twice a day and then using ultraviolet radiation. (3) The NICU staff washed hands before and after each nursing activity and used disposable gloves (previously rinse-free hand sanitiser was used instead of hand-washing). (4) Recordings of standard operating procedures like changing diapers were provided to all nursing staff (to avoid secondary contamination from excreta). (5) The excreta was sealed using double-layer medical garbage bags (and sprayed with a chlorinated disinfectant on both its inside and outside). (6) Interactions between nursing staff from different work stations of the NICUs were restricted. (7) Breastmilk collection was strictly managed and collection table promptly disinfected after each visit. (8) Telephonic follow-up was done for each discharged patient. Following the above procedure, no new cases of infection were reported.EV surveillance conducted by the US Centers for Disease Prevention and Control from 2007 to 2008 showed that the most common EV was Coxsackie B1, followed by echovirus types 18, 9, and 6 . The EV A case report has suggested that echovirus 18 can cause sepsis, aseptic meningitis, encephalitis, paralysis, and rashes in neonates and infants . In 1958The likelihood of an outbreak of EV infection in NICU is much high . It is o


Antiphospholipid antibody (aPL)-associated thrombophilia has been implicated in various adverse pregnancy outcomes, including preterm birth and impaired fetal development. This systematic review aimed to elucidate the relationship between aPL-associated thrombophilia and these outcomes, as well as to identify potential modifiers of this relationship such as maternal age, coexisting maternal medical conditions, type of aPL antibodies involved, and the timing of thrombophilia diagnosis during gestation. We conducted a comprehensive literature search in PubMed, Web of Science, Cochrane, and Scopus in May 2023, covering literature published within the last 10 years. Eight articles, involving 2935 patients, were eligible for inclusion in the review. Single aCL was the most common type of aPL found in patients, with rates up to 61.0% in some studies, followed by single LA and single ab2GPI. Multiple aPL antibody positivity was found to be associated with a higher risk of preterm birth, with odds ratios ranging from 1.29 to 9.61. Patient characteristics and previous pregnancy history varied significantly across the studies. Risk factors such as diabetes mellitus, thrombosis, and systemic lupus erythematosus were also variable across the studies, but presence of these risk factors did not consistently affect the risk of preterm birth. Furthermore, although a triple positive aPL test was the most important risk factor for preterm birth, it was observed that thrombophilia treatment during pregnancy significantly reduced the risk by 2.44 times (95% CI = 1.18–6.20). This review supports the evidence for aPL-associated thrombophilia being a significant contributor to preterm birth and fetal developmental abnormalities. Further research is required to investigate the exact mechanisms and to determine the best clinical management for patients with aPL-associated thrombophilia during pregnancy. Preterm birth, defined as birth before 37 weeks of gestation, is a significant global health concern ,2. It isAPS is an autoimmune disorder characterized by thrombosis and pregnancy-related complications, including recurrent miscarriage, preeclampsia, and preterm birth . At the In pregnancy, APS is associated with an increased risk of adverse obstetric outcomes. The immunological responses and inflammatory state induced by aPL can interfere with placental function, leading to fetal growth restriction, stillbirth, preeclampsia, and preterm birth ,11. DespPrevious studies investigating the relationship between aPL-associated thrombophilia and preterm birth have reported mixed results, highlighting the need for a comprehensive review of the existing literature ,15. FurtThe primary hypothesis of this study is that aPL-associated thrombophilia significantly increases the risk of preterm birth. We hypothesize that this risk may be modulated by several factors, such as the specific type of aPL present, the patient’s history of thrombotic events, and co-existing autoimmune disorders. Additionally, it was assumed that the effect of aPL-associated thrombophilia on preterm birth may be mediated by complications such as preeclampsia and intrauterine growth restriction. By addressing these research questions, this systematic review aims to improve our understanding of APS’s impact on preterm birth, providing valuable insights for clinicians and researchers alike. Therefore, we conducted a systematic review focusing on the influence of aPL-associated thrombophilia on the risk of preterm birth, aiming to quantify the risk of preterm birth associated with aPL-associated thrombophilia. Secondly, we aimed to elucidate the effect of various clinical and demographic factors on this risk. Lastly, we also aimed to identify gaps in the current knowledge base, thus providing direction for future research.This systematic review was conducted in May 2023 and involved searching four electronic databases: PubMed, Web of Science, Cochrane, and Scopus. The review included literature published within the last 10 years. The search strategy utilized Medical Subject Headings (MeSH) keywords, such as “thrombophilia”, “antiphospholipid antibodies”, “anticardiolipin antibodies”, “lupus anticoagulant”, “anti-β2-glycoprotein”, “aPL”, “intrauterine growth restriction”, “preterm birth”, “preterm delivery”, “prematurity”, “IUGR”, “fetal development”, and “adverse fetal outcomes”. The search was limited to English-language journal articles.In adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria  and the The primary objective of this systematic review was to comprehensively explore and address research questions that assess the relationship between aPL-associated thrombophilia and preterm birth, as well as overall fetal development. The main research question was aimed at determining the impact of aPL-associated thrombophilia on the incidence of premature births and fetal developmental abnormalities. The review also sought to identify any significant modifiers that might influence this relationship. These modifiers included maternal age, coexisting maternal medical conditions, type of aPL antibodies involved, and the gestational age at which thrombophilia was diagnosed.Primary sources of information for the compiled material encompassed the text, tables, figures, and available data within the articles. The selection process began with study exclusion based on title and abstract. Duplicate studies were excluded during the screening part. This was followed by a thorough evaluation by two independent researchers of each abstract to assess its relevance to the research questions. Subsequently, a comprehensive review of the entire text was conducted for the remaining articles to ensure that they met the inclusion criteria. An in-depth analysis of the reference lists of the gathered papers was performed by two independent researchers, to identify any pertinent literature that may have been overlooked during the initial search, thereby enhancing the comprehensiveness of this systematic review.The inclusion criteria for studies in the systematic review were as follows: (1) the study should examine the association between aPL-associated thrombophilia and preterm birth or fetal development; (2) the study must have specifically measured the presence of aPLs; (3) the research must have detailed fetal outcomes; and (4) the study cohort must include pregnant women diagnosed with aPL-associated thrombophilia. Conversely, the exclusion criteria were: (1) studies where aPLs were not measured; (2) studies lacking relevant data on patients’ characteristics and medical history; (3) articles where preterm birth or fetal development were not mentioned; (4) studies where the preterm risk was not evaluated ; (5) antiplatelet therapy being used in the study groups; and (6) other exclusions were made for case reports, literature reviews, meta-analyses, letters to editors, and brief communications.The final analysis included a broad set of variables, encompassing both study characteristics and key findings. The study characteristics evaluated included the study number and first author’s name, the geographical location of the study, the year the study was conducted, the research design used, and a thorough assessment of the study’s quality. Key findings, such as the presence of aPLs, incidence and severity of prematurity, and measures of fetal development, were extracted from each study.The initial exploration yielded a total of 751 studies, of which 93 were recognized as duplicates. After eliminating 505 papers based on their title and abstracts, we scrutinized 153 full-text articles for relevance. Ultimately, eight articles were eligible for inclusion in the systematic review, as shown in p-value < 0.05 indicating significant publication bias. A sensitivity analysis was also conducted by removing one study at a time and recalculating the pooled odds ratios to evaluate the robustness of the results and to examine the impact of individual studies on the overall effect size.Publication bias was examined by creating a funnel plot, where the standard error of the log odds ratio was plotted against its corresponding log odds ratio. The symmetry of the plot was visually examined and further assessed using Egger’s regression test, with a The Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was used to evaluate the included studies . Each quIn the review, eight studies published between 2016 and 2022 were assessed that investigated the influence of antiphospholipid antibody-associated thrombophilia on the risk of preterm birth, and were evaluated for publication bias, as presented in Among the included studies ,26,27,28By comparison, the five retrospective cohort studies, conducted in various countries including Italy , Japan , Israel 2 [Patient characteristics were gleaned from eight diverse studies assessing the impact of antiphospholipid antibody-associated thrombophilia on preterm birth risk. This covered an aggregate of 2935 patients, with individual study sizes ranging from a low of 81  to a hig2 . However2 ,25,28.In terms of ethnicity, where reported, a predominant proportion of patients were identified as Caucasian, ranging from 72.5%  to 94.6%Patient’s previous pregnancy history differed significantly across the included studies. The proportion of patients with a history of live birth ranged from a low of 11.8%  to a higConcerning the presence of APL antibodies, the distribution of lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2 glycoprotein I (ab2GPI) antibodies demonstrated wide-ranging results. While some studies showed higher percentages of single LA, aCL, or ab2GPI positivity, others documented a notable proportion of patients with double or triple positivity. This indicates the diverse characteristics of the antiphospholipid antibody-associated thrombophilia in the included populations. The assessment of preterm birth risk associated with the presence of APL antibodies was diverse across the studies. While some studies found that single positivity for APL antibodies was associated with a lower risk of preterm birth compared to multiple positivity ,26, otheThe current systematic review aimed to investigate the impact of antiphospholipid antibody-associated thrombophilia on the risk of preterm birth and overall fetal development. We found overarching agreement across these studies, indicating a consistent association between aPL antibodies and an increased risk of preterm birth. There was a considerable variability in the prevalence of single and multiple aPL antibody positivity across the studies, illustrating the diverse nature of the antiphospholipid antibody-associated thrombophilia in the respective populations. While a number of studies indicated higher percentages of single lupus anticoagulant (LA), anticardiolipin (aCL), or anti-β2 glycoprotein I (ab2GPI) positivity, others noted a substantial proportion of patients with double or triple positivity. This variability could potentially reflect differences in the studied populations, diagnostic criteria, or clinical management.Patient characteristics, such as age, BMI, ethnicity, and smoking status, varied considerably across the studies and could potentially modify the relationship between aPL-associated thrombophilia and preterm birth. Age and BMI, which have been linked to obstetric complications, varied significantly between studies. Similarly, ethnicity, known to influence pregnancy outcomes, was predominantly Caucasian, but this varied between studies. Lastly, smoking status, a known risk factor for preterm birth, also exhibited significant differences across studies.The studies included in our review had a wide range of participants, varying from 81 to 1000, making it one of the most comprehensive reviews on this topic to date. Despite the diversity in study size, design, and quality, our findings consistently suggested an increased risk of preterm birth in the presence of aPL antibodies. Moreover, the studies were conducted in various geographical locations, encompassing both Western and Eastern populations, which enhances the generalizability of our findings.Our findings suggest an increased risk of preterm birth in the presence of aPL antibodies, with some variations noted, where Rezk et al.’s study  found a The significance of specific aPL antibodies on preterm birth risk varied between studies. For example, a study by Bouvier S et al.  noted thBesides the risk of preterm birth, other large studies investigated the influence of aPL antibodies in other pregnancy conditions such as low birth weight or being born small for gestational age, which can be correlated with premature labor. Concordant with preceding reviews was the association among prior conditions such as thrombosis and triple aPL positivity with diverse unfavorable pregnancy outcomes  ,30. RegaMoreover, the nature of the antibodies or association of antibodies that were identified in other studies as negative predictors for low birth weight, neonatal mortality, and preterm birth remained indeterminate. The EULAR  categoriIt is noteworthy that, while placental infarction is more prevalent in aPL-positive women compared to those without aPL, this is not the universal feature in cases of fetal loss . In addiTo evaluate the risk factors for preterm birth, our review also considered the history of previous miscarriages and thrombosis across the included studies. While a significant variation was observed in the rates of previous pregnancy loss and thrombosis among the subjects, a direct statistical relationship between these factors and preterm birth was not established in our analysis. Specifically, previous pregnancy loss ranged from 18.2% to 74.4% across studies, and thrombosis prevalence varied from 0.0% to 33.3%. Although these factors were comprehensively described, they were not quantified in relation to preterm birth risk. Our findings suggest that these factors may play a role in understanding the complex landscape of preterm birth, but they do not directly implicate a causal relationship. Future studies focusing on these specific parameters might provide a more nuanced insight into the multifactorial influences on preterm birth in the context of antiphospholipid antibody-associated thrombophilia.In the context of our investigation into the association between aPL antibodies and preterm birth, it is essential to highlight the difference between the presence of these antibodies and the clinical diagnosis of APS. While our study found a consistent relationship between aPL antibodies and an increased risk of preterm birth, we did not specifically differentiate between the impact of clinically diagnosed APS and mere antibody positivity. The presence of aPL antibodies is a characteristic feature of APS, but the syndrome’s diagnosis also involves other clinical manifestations such as thrombosis. The comparative impact of APS versus only antibody positivity on preterm birth risk remains an area that warrants further exploration. A nuanced understanding of this relationship could yield more targeted clinical interventions and inform future research about the underlying mechanisms linking APS with adverse pregnancy outcomes. Future studies that separate these two aspects might uncover more precise information about how APS as a whole, compared to the presence of the antibodies alone, influences the risk of preterm birth.The current systematic review provides a solid foundation for further research on the impact of aPL-associated thrombophilia on preterm birth and fetal development. These findings clearly indicate a relationship between the presence of aPL antibodies and an increased risk of preterm birth. Future studies should aim to better understand the potential underlying mechanisms, evaluate the effect of different types of aPL antibodies on preterm birth risk, and investigate potential interventions to mitigate this risk. Additionally, more research is needed to explore potential modifiers, such as maternal age, coexisting maternal conditions, and gestational age at thrombophilia diagnosis, to provide a more comprehensive understanding of the impact of aPL-associated thrombophilia on pregnancy outcomes.The strengths of this systematic review lie in its comprehensive and structured approach. A rigorous search strategy was implemented, which was inclusive of four major databases, ensuring the capture of a wide range of relevant studies. The diversity of the studies, both geographically and methodologically, broadens the scope and generalizability of the review’s findings. Our review also took into account various study designs (cohort and case–control), which contributes to a more rounded picture of the impact of aPL-associated thrombophilia on preterm birth and fetal development. Further, by evaluating both study characteristics and key findings, our review provided a detailed and thorough analysis of the relationship between aPL-associated thrombophilia and preterm birth.However, certain limitations also need to be acknowledged. Although most studies agreed on the association between aPL antibodies and preterm birth, there was considerable variability in the presence of specific aPL antibodies and the reported risk of preterm birth. Furthermore, there were inconsistencies across the studies in reporting key patient characteristics such as BMI, smoking status, and ethnicity, which could have potentially modified the observed relationship. Not all studies reported on the same risk factors or patient characteristics, which may have affected the comparison and synthesis of results. Finally, despite our thorough search strategy, our review was limited to English-language publications, which may have resulted in missing relevant studies published in other languages.Based on the comprehensive analysis of the selected studies, it is evident that antiphospholipid (aPL) antibodies significantly impact preterm birth and, potentially, fetal development. The review consistently noted an association between aPL-associated thrombophilia and preterm birth, regardless of the geographical location or study design. The findings also suggest that the type and number of aPL antibodies present can influence the risk of preterm birth, highlighting the complexity of antiphospholipid antibody-associated thrombophilia in pregnancy. This systematic review underscores the necessity for thorough screening and monitoring of pregnant women with aPL antibodies to mitigate adverse fetal outcomes. Future research should aim to clarify the precise mechanisms through which aPL antibodies impact fetal development, to further refine therapeutic strategies and improve outcomes for this patient group.


Syphilis during pregnancy remains an important global health concern causing miscarriage, stillbirth, preterm birth and neonatal death. As part of the fetal infection, placental changes occur which may include a heavier placenta than expected.A cohort of 50 neonates with symptomatic congenital syphilis has previously been described. This cohort was admitted to Groote Schuur neonatal unit in Cape Town South Africa from 2011 to 2013. For this study, the placental weights of the neonates were analyzed and compared to population based placental centiles.There was data for 37 placentae. Heavy placentae (>90th centile) occurred in 76% of placentae in the study. All 6 infants with birth weights ≥2,500 g had heavy placentae. There was no correlation between placental centile and death.Heavy placenta are an important and frequent finding with symptomatic congenital syphilis, especially in the larger neonates. Despite effective antenatal screening and treatment, syphilis remains one of the commonest congenital infections globally and a serious public health concern , 2. In 2Syphilis can infect the fetus at any stage of gestation, invoking a marked inflammatory response and widespread spirochaetal dissemination in fetal organs including the placenta . The risDuring uncomplicated pregnancy, the placental weight increases with gestational age but decreases in relation to fetal weight . Due to South Africa is a middle-income country where syphilis prevalence is not declining as evidenced by an antenatal syphilis prevalence rate of 2% in 2015 . We prevThe index study was a retrospective record review of neonates with symptomatic congenital syphilis admitted to the GSH Neonatal Unit (NNU) from the 1st January 2011 to the 31st December 2013. The study was approved by the University of Cape Town, Health Sciences Faculty, Human Research Ethics Committee. The GSH NNU is a tertiary referral unit in Cape Town with 75 beds including 20 intensive care beds. It is the referral center for the Metro West Area of Cape Town, which has approximately forty-thousand deliveries per annum .Neonates who had a positive rapid plasma reagin (RPR) with a titer >1:1 were identified from the National Health Laboratory Service database and symptomatic neonates were identified by folder review. Neonates were deemed to have symptomatic congenital syphilis if they had a positive RPR, signs which could be attributed to congenital syphilis  and received penicillin as treatment. The birth weight, gestational age at birth, placental weights and neonatal outcome data were extracted. The Chi square or Fisher's exact tests were used for categorical comparisons, depending on the expected values. The student's t and Wilcoxon rank sum tests were used for comparison of parametric and non-parametric continuous variables respectively. All statistical tests were 2-sided at alpha = 0.05.There were 50 neonates with symptomatic congenital syphilis admitted over the three-year study period. Most (68%) of these neonates required intensive care and 19 neonates (38%) demised . FurtherPlacental weights were recorded for 37 (74%) of neonates. The weights were missing in 13 (26%) cases; three infants were born at home and the remaining missing data were related to health worker omissions. The birth weight and gestational age characteristics of the 37 neonates compared to the whole cohort are shown in p = 0.691).The placental weights were plotted on a placenta for birth weight centile graph redrawn from the data published by Malan et al.  Figure . Twenty-Placental weights were available for 74% of the cohort with symptomatic congenital syphilis. The majority of placentae (76%) were above the 90th centile for birth weight while the frequency of normal sized placentae decreased with increasing birth weight. There were no significant differences in birth weight and gestation between the neonates with placental weights recorded compared to the whole cohort. We did not find a universal association between hydrops fetalis and heavy placentae.Heavy placentae occurred in our cohort at almost double the frequency compared to the 38% described in Malan's cohort, despite their similar proportions of low birth weight (83%) and preterm neonates (61%) . The plaBirth and placental weights can differ between populations, and it is important to obtain current population-specific nomograms which are not often available, especially in LMICs. Similarly, there should be standardization of placental weight/birthweight assessment—some placental centile charts include only birthweight whilst others incorporate gestational age . Some ceSyphilis is the most common congenital infection associated with heavy placentae but other infections such as cytomegalovirus have also been reported . InclusiThe limitations with this study were the retrospective nature, missing data on 13 placentae and the lack of histological correlation. The strengths were the well described neonatal characteristics and the relatively large case series.Heavy placentae occurred in 76% of neonates with congenital syphilis. The frequency of heavy placentae increased with increasing birth weight with neonates with a birth weight ≥2,500 g all having a heavy placenta.If placental weight is greater than the 90th centile for birth weight, neonates should be evaluated for congenital infection, hydrops fetalis and syndromes. Placental histopathological evaluation should be considered when the diagnosis is not clear.


All of the participants provided blood samples twice (in their first and third trimesters). Inductively coupled plasma mass spectrometry (ICP-MS) was used for the laboratory analysis, and unconditional logistic regression was used for the statistical analysis. We found that the maternal Mn levels were significantly higher in the third trimester than those in the first trimester (median: 1.23 vs. 0.81 ng/mL). The SPB risk was increased to 1.65  in the highest Mn level (third tertile) in the third trimester, especially in normal-weight women  or non-premature rupture of membrane (PROM) women . Moreover, a dose-dependent relationship exists between the SPB risk and maternal Mn concentration in non-PROM women (P trend < 0.001). In conclusion, dynamic monitoring of maternal Mn level during pregnancy would be helpful for SPB prevention, especially in normal-weight and non-PROM women.We performed this study to clarify the dynamic changes in maternal manganese (Mn) concentration during pregnancy and its association with spontaneous preterm birth (SPB). A nested case–control study was conducted based on the Beijing Birth Cohort Study (BBCS) from 2018 to 2020. Singleton pregnancy women aged 18–44 ( Preterm birth, defined as a live birth between 28 and 37 weeks of gestation, is the leading cause of perinatal death and the death of children under five years old worldwide, with an incidence of 6.4% ,2. PreteManganese (Mn), as one of the essential trace elements, may play a vital role in fetal growth and development ,4,5,6. ASeveral studies have discussed the relationship between Mn concentration and preterm birth. However, no consistent conclusions were made. Studies conducted in different countries suggested a positive correlation between Mn levels and preterm birth ,14,15. HTherefore, this study explores the relationship between the maternal plasma Mn level and SPB through repeated measurement data to discover SPB’s underlying drivers in micronutrient views. The measurement is carried out in the first and third trimesters of pregnancy. We aim for this study to be helpful for clinical prevention and intervention measures for preterm birth to reduce the occurrence of preterm birth and improve the quality of the birth population.A nested case–control study was conducted based on a prospective maternal and child health cohort, the Beijing Birth Cohort Study (ChiCTR2200058395), in Beijing, China. In total, 32,496 pregnant women were recruited in the cohort from 2018 to 2020 at Beijing Obstetrics and Gynecology Hospital, Capital Medical University. We recruited women with the following inclusive criteria: aged 18–44 years old, with gestational weeks ≤ 14 weeks during recruitment, with no mental illness, and who could provide signed informed consent. Participants were examined and followed up until delivery. We collected maternal and fetal information prospectively when participants came to the hospital for an antenatal examination, and the information was recorded in the electronic clinical system. The ethics committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, approved the study (2018-ky-009-01).n = 946), stillbirth (n = 46), fetal defects (n = 968), multiple pregnancies (n = 1030), and cervical insufficiency (n = 203), a total of 29,303 live singleton pregnant women with complete medical records remained, including premature births (n = 1599) and term births . Among the preterm birth group, a final amount of 244 pregnant women were included in the SPB group after excluding iatrogenic preterm birth (n = 982) and a lack of plasma samples in the first or third trimester (n = 373). In the full-term birth group, women were excluded if they met the following criteria: gestational weeks were <39 weeks or >41 weeks (n = 8008), if they experienced pregnancy complications , or if there was a lack of plasma samples in the first or third trimester (n = 2567). Then, the control group was randomly selected according to the blood sampling time (1:1).2; normal: 18.5 ≤ BMI < 23.9 kg/m2; and overweight: BMI ≥ 24 kg/m2.In our study, preterm birth was defined as a live birth during the gestational ages of 28–36 + 6 weeks. SPB was defined as the spontaneous onset of labor at a gestational age of 28–36 + 6 weeks, including premature birth with a partial premature rupture of membranes and intact membranes. Iatrogenic premature birth refers to cases that require a medical intervention to give birth at 28–36 + 6 weeks. One reason for premature birth may be the mother’s or fetus’ poor health status that did not allow for pregnancy to continue . The gestational week was checked according to the last menstrual period (LMP), the course of pregnancy, and ultrasound measurement data in the first trimester. The first trimester referred to gestational weeks < 14 weeks, and the third trimester referred to gestational weeks ≥ 28 weeks. Body mass index (BMI) was classified into three grades based on expert consensus on medical nutrition treatment for overweight/obesity in China (2016) . The crig for 10 min within 1 h after collection, and plasma samples were extracted and stored at −80 °C until analysis. Inductively coupled plasma mass spectrometry  was used to detect plasma Mn concentration. A plasma sample of 0.1 mL was added to a 2 mL centrifuge tube. Then 0.1 mL of internal standard indium (In)  and 1.8 mL of 1% nitric acid (UPS grade (68%), Suzhou Crystal Clear Chemical Co., Ltd., Suzhou, China) were added into the 2 mL tube. All of the samples were shaken sufficiently before determination. The median measured concentration of standard plasma samples  was 15.3 ng/mL, which was within the range of the reference value: 15.2 (12.2–18.3) ng/mL. The detection limit of Mn was 0.008 ng/mL. We conducted the quantitative analysis in the Central Laboratory of biological elements of the Health Science Center of Peking University. The program has passed the China metrology certification system. Specific detection methods have been described in previously published studies [Plasma samples were chosen for Mn level determination to reflect nutrition intake to a certain degree. We collected plasma samples from the same pregnant women in their first and third trimesters. Maternal venous blood samples were collected by healthcare workers after 8–10 h of fasting. Then they were placed into vacuum blood collection vessels lined with sodium ethylene diamine tetraacetic acid (EDTA). All blood samples were centrifuged at 1680×  studies .According to a previous search of the literature, the exposure rate of high-level Mn in the term birth group was about 50%. The SPB risk was significantly increased to 2.46 (95% CI: 1.08–5.62) at the highest level of Mn in the first trimester . Assumint-tests or Pearson’s chi-square test were used for the comparison of the maternal baseline information. As a result of the skewed distribution of Mn concentration, the median with an interquartile range (IQR) was used to describe Mn exposure level. The Mann–Whitney U test was used to compare the two groups’ differences. Wilcoxon’s signed-rank test was used to compare the difference in Mn concentrations between the first and third trimesters. In the dose–response analysis, we divided all women into three equal groups based on the Mn concentration: low, medium, and high. Unconditional binary or multiple logistic regression was used to analyze the relationship between Mn level and SPB risk in different populations with or without adjusting for confounders. The odds ratio (OR) and a 95% confidence interval (CI) were used to quantify the SPB risk. Adjusted confounders included age, BMI, education, economy, nationality, gravida, parity, sampling time, and fetal gender. All the confounders involved have been reported to have effects on preterm birth [n = 9 in the SPB group and n = 16 in the term labor group) were excluded from the sensitivity analysis. Spss26.0  was used for data analysis, and a two-tailed p-value < 0.05 was considered statistically significant. Regarding multiple testing by analyzing various subgroups, Bonferroni correction was used here to adjust the significant p-value [Student’s rm birth ,20,21. A p-value .p = 0.003). The SPB group had a lower proportion of nulliparous than the controls . All of the women in the SPB group were late preterm (34–36 + 6 weeks), and the cesarean section rate was higher than that in the term labor group . There was a similarity between the two groups in terms of education, economy, nationality, sampling time (8 weeks in the first trimester and 34 weeks in the third trimester), and fetal gender. All women were not antibiotic-treated during pregnancy.In this study, a total of 488 women were included in the final analysis, including 244 cases (SPB) and 244 controls (term birth). The primary characteristics of the mothers and fetuses are summarized in p = 0.441 in the first trimester; 1.27 vs. 1.20 ng/mL, p = 0.119 in the third trimester). When comparing Mn levels between the first and third trimesters, a cumulative effect during pregnancy was found, as the Mn concentration in the third trimester was significantly higher than that in the first trimester (p < 0.001)  in the first trimester, and it was 1.23 ng/mL (IQR: 0.67 ng/mL) in the third trimester. Despite the fact that there was a slightly higher Mn median concentration in the SPB group than that of the controls, it was not statistically significant  see .p = 0.052) in the highest Mn concentration in the third trimester. After adjustment for clinical confounders, including age, BMI, education, economy, nationality, gravida, parity, sampling time, and fetal gender, the association became significant .p = 0.032; OR: 1.65, 95% CI: 1.04–2.62, p = 0.035).As inflammation may affect SPB, we conducted univariate logistic regression to analyze the relationship between inflammatory factors and SPB. The results are summarized in p = 0.043; see p = 0.014). After adjustment for the clinical confounders, the SPB risk increased to 1.96 . Moreover, a combined adjustment for clinical and inflammatory confounders made the risk association much more apparent   see . However011) see .p = 0.023) and 3.48  for the second and third tertile, respectively. Additionally, there was a clear dose-dependent relationship (p trend < 0.001) (see p = 0.031) and 3.93  for the second and third tertile, respectively.001) see . After an = 9 in the SPB group; n = 16 in the term labor group). The results did not change significantly . They are absorbed in the form of Mn2+ or Mn3+, and Mn2+ is the most common form in the body ,24. In tBlood Mn concentration, including whole blood and plasma/serum samples, is an effective and representative biomarker of Mn exposure ,27. PlasStratified by BMI grade, it showed a relationship between the two groups only in the normal weight layer. The reason may be that being overweight or thin is a risk factor for premature birth and would modify the effect of Mn on SPB. Researchers should fully evaluate these confounders when conducting further research. All the above findings suggested that the plasma Mn level in the third trimester may be associated with SPB, and the effect is significant in specific populations.Several previous studies have reported that an excessive Mn concentration was associated with a higher preterm birth risk. Most studies did not strictly distinguish SPB from iatrogenic preterm birth, and most sampling times were at the time of delivery. Only one study conducted in a Shanxi cohort study estimated the relationship between the serum Mn level and SPB in the first and second trimesters. However, their serum samples in the first and second trimesters were from different populations. They reported a positive risk association between serum Mn levels and SPB in a positive dose-dependent manner in the first trimester, not the second trimester . HoweverConsidering that a vaginal GBS infection may impact SPB, we performed a sensitivity analysis after excluding women with the infection. The results showed that the relationship between the Mn concentration and SPB risk was still significant, further confirming the aforementioned results that a high Mn concentration is a risk factor for SPB.The current understanding of the SPB mechanism is related to inflammation and oxidative stress , such asThere are some advantages to our study. First, we are the first to use a repeated measurement design to clarify the dynamic changes in plasma Mn during pregnancy in the related studies. Second, iatrogenic preterm birth would confuse the study results with a specific reason for preterm birth. In this study, only SPB cases were selected for analysis and strictly distinguished from iatrogenic preterm birth. Third, the sampling time was similar in the two groups, which could reduce the effect of the gestational week on element concentration. Fourth, this nested case–control study relied on a prospective cohort study conducted in Beijing; the same exposure backgrounds helped to reduce confounding in the region. Additionally, we were able to obtain the accurate information we required in the survey, which minimized recall bias.Still, several limitations should be considered when explaining our results. First, we included no information on diet and nutrient supplementation, and we could not evaluate the pregnant women’s dietary Mn exposure level and its relationship with the plasma Mn concentration. Second, when the stratified analysis was carried out according to specific factors, some subgroups’ relatively small sample size may have affected the power to determine an association between the Mn level and SPB. Third, in this study, all cases were late-preterm (labor week ≥34 weeks), meaning they were close to full-term. The pathological condition related to SPB may be too small to observe a meaningful difference between the two groups. In future studies, it will be helpful to include early preterm women to clarify the relationship between plasma Mn levels and SPB. Fourth, parameters of oxidative stress were not assessed. As Mn may play an important role in SPB through oxidative stress, it would be better if the oxidative stress parameters were evaluated in our study. In future studies, we could further optimize the experimental design and try to assess related parameters of oxidative stress.The increased plasma Mn concentration in the third trimester of pregnancy is associated with higher risks of SPB. The effect is much more significant in normal-weight women and non-PROM women. Our results provide a unique insight into SPB prevention in terms of monitoring and managing essential micronutrient elements during pregnancy. In addition, as the functioning of micronutrients especially tends to be in groups, further studies should be conducted to identify whether it is Mn alone or another compound that accompanies it that is associated with an increased risk of SPB.


Premature progesterone (P) rise during IVF stimulation reduces endometrial receptivity and is associated with lower pregnancy rates following embryo transfer (ET), which can influence provider recommendation for fresh or frozen ET. This study aimed to determine whether change in P level between in IVF baseline and trigger (𝚫P) is predictive of pregnancy outcome following fresh ET, and whether the ratio of gonadotropins influences P rise and, as a result, clinical pregnancy outcomes: clinical pregnancy rate (CPR) and live birth rates (LBR).Retrospective cohort study at a single fertility center at an academic institution. The peak P level and 𝚫P were modeled in relation to prediction of CPR and LBR, and the ratios of hMG:rFSH were also modeled in relation to prediction of peak P level on day of trigger, 𝚫P, and CPR/LBR in a total of 291 patients undergoing fresh embryo transfer after controlled ovarian hyperstimulation-IVF (COH-IVF).𝚫P correlates with CPR, with the most predictive range for success as 𝚫P 0.7–0.85 ng/mL . The optimal range for peak P in regard to pregnancy outcome was 0.15–1.349 ng/mL . A multivariable logistic model for prediction of CPR and LBR using either peak or 𝚫P supported a stronger association between 𝚫P and CPR/LBR as compared to peak P. Furthermore, an hMG:rFSH ratio of > 0.6 was predictive of lowest peak P  and smallest 𝚫P  during COH-IVF cycles. Highest CPRs were observed within hMG:rFSH ratios of 0.3–0.4 . Highest LBRs were seen within the range of 0.3–0.6 hMG:rFSH, [LBR of 55.4% vs. 41.4% ].Our data supports use of 𝚫P to best predict pregnancy rates and therefore can improve clinical decision making as to when fresh ET is most appropriate. Furthermore, we found optimal gonadotropin ratios can be considered to minimize P rise and to optimize CPR/LBR, emphasizing the importance of luteinizing hormone (LH) activity in COH-IVF cycles. The serum progesterone (P) level on the day of trigger for final oocyte maturation in controlled ovarian hyperstimulation-in vitro fertilization (COH-IVF) cycles has been studied extensively, with the majority of evidence supporting lower implantation rates in cycles with elevated late follicular phase P levels due to asynchrony of the embryo and the endometrium . PrematuMoreover, modifiable factors such as the choice of gonadotropin regimen may affect the progesterone rise and can be addressed prior to cycle start to minimize the risk for premature progesterone elevation. In a retrospective cohort study of over 10,000 COH-IVF cycles, Werner et al. demonstrated that cycles using gonadotropin medications with a balanced activity of both luteinizing hormone (LH) and follicle stimulating hormone (FSH) resulted in the lowest rates of premature progesterone rise. However, in this study, the relationship between P elevation and pregnancy or live birth rates was not evaluated , as theiA retrospective cohort study was conducted for all patients who underwent fresh ET at Yale Fertility Center from January 2017 to December 2018 (n = 291). Collected information included all demographic, laboratory, medication regimen, ultrasound, and embryologic as well as consequent pregnancy outcome data. For each COH-IVF cycle, the following variables were collected: BMI, age, infertility diagnosis, baseline P, peak P (at time of trigger), anti-Müllerian hormone (AMH), final estradiol (E2), gonadotropin medication (types and dosages), endometrial thickness, total follicle count, follicle number greater than 15 mm, number of retrieved oocytes, embryo grade/stage, number of embryos transferred, initial human chorionic gonadotropin level, gestational sac identification, fetal heart rate detection, live birth occurrence, and number, gender(s) and neonatal weight(s) of live births. The 𝚫P was calculated by subtracting the baseline P level from the peak P level within a COH-IVF cycle. Gonadotropin stimulation regimens were chosen by each patient’s primary infertility specialist, accounting for the patient’s medical history and provider preference, with the majority of cycles completed as gonadotropin-releasing hormone (GnRH) antagonist cycles. Serum P levels were measured via the Roche Cobas e411 analyzer, which measures P4 levels using enhanced chemiluminescent technology in a competition assay format. Exclusion criteria included patients using donor oocytes, gestational carriers, and patients who had preimplantation genetic testing of embryos. Logistic regression was used to model peak P and 𝚫P in relation to clinical pregnancy rate (CPR), defined as detection of a fetal heart rate, and live birth rate (LBR), controlling for age, body mass index (BMI), number of embryos transferred, follicle count and size, and endometrial thickness. Data were analyzed using the Python Statsmodels library to build a multivariable logistic regression model after standard scaling of the data. A secondary analysis was performed to identify optimal hMG:rFSH ratios in relation to 𝚫P. For this analysis, the hMG:rFSH ratio was calculated by totaling the dose of hMG over the entire ovarian stimulation cycle in relation to the total dose of rFSH. The ratio of hMG:rFSH was modeled in relation to peak P and pregnancy outcomes . This secondary analysis also controlled for age, BMI, number of embryos transferred, follicle count and size on day of trigger, and endometrial thickness. This analysis was performed using the Python Statsmodels library to build a multivariable logistic regression model after standard scaling of the data. This study was approved by the Yale University Institutional Review Board.2 undergoing fresh IVF cycles with a GnRH antagonist protocol. Patient demographics including infertility diagnosis, age, BMI, AMH, E2 level, total number of follicles, follicles > 15 mm, and total number of oocytes retrieved is shown in Table Our single-center cohort included a total of 291 patients, 21–42 years of age, and average BMI of 26.6 kg/mTo determine whether peak P or 𝚫P was more predictive of birth outcomes, we used a multivariable logistic model for prediction of CPR and LBR using either peak P or 𝚫P. The coefficient in the model for peak P was 2.025 and for 𝚫P was 2.1351. Thus, 𝚫P was slightly more predictive of CPR and LBR than peak P. The optimal range for peak P in regard to pregnancy outcome was 0.15–1.349 ng/mL  and 0.7–0.85 ng/mL for 𝚫P .With respect to the optimal hMG:rFSH ratio, secondary comparative models identified an hMG:rFSH ratio of greater than 0.6 as predictive of both lowest peak P  and lowest 𝚫P  during COH-IVF cycles. When the relationship between hMG:rFSH ratio and birth outcomes was analyzed by classifying hMG:rFSH as “within” versus “outside” the “optimal” ranges identified, the highest CPR was observed at an hMG:rFSH ratio between 0.3 and 0.4 ; Table Progesterone is essential for the development of a receptive endometrium for implantation, but high circulating progesterone levels at the end of the follicular phase in COH-IVF cycles accelerate the secretory transformation of the endometrium and negatively affect pregnancy rates . An incrMoreover, the infertility specialist may intervene to prevent an unwanted rise in progesterone level by considering the ratio of gonadotropins used in the COH-IVF cycle. Our study highlights the importance of balanced use of hMG and rFSH, and specifically the incorporation of LH activity in COH regimens in regard to not only the subsequent progesterone rise but also pregnancy outcomes , which has not been previously described. Within the ovarian follicle, LH stimulates theca cells to produce androgens by the induction of genes involved in steroidogenesis, including cytochrome P450 CYP 17 hydroxylase and 17–20 lyase, which convert progesterone and pregnenolone to 17-hydroxylated products and androgens via the 𝚫4 and 𝚫5 pathways, respectively . FurtherA strength of our study’s design is its clinical utility, as its observational design demonstrated values determined from women who ultimately chose to undergo fresh ET. Given the average age of 35 with BMI 26 and 44% had tubal or male factor infertility, our cohort represents patients with a generally good prognosis. Of note, or sample did include a broad range of infertility diagnoses including 10% having DOR and 12% having PCOS. Thus, these findings are reflective of a representative patient sample who indeed elect for fresh ET, and may serve as a guide for clinical decision making for similar eligible patients who prefer to proceed with fresh ET. Additionally, our observational design and resulting exclusion of patients who did not undergo fresh ET resulted in a more conservative threshold for progesterone level, as our levels of peak and calculated 𝚫P are likely lower than what would be seen across all patients who underwent COH-IVF cycles. There is unlikely to have been selection bias for fresh embryo transfers unique to our clinic, as our clinic performed approximately equivalent proportions of fresh and frozen embryo transfers in the time period of this study (2017–2018): 50.1% fresh ETs and 49.9% FETs.A more robust, prospective study with an interventional design, assigning stratified ratios of gonadotropins and then having all participants proceed with fresh ET despite regardless of peak or 𝚫P, would not be feasible in a typical infertility patient population due to the potential for adverse effects on pregnancy rates.Moreover, previous studies have demonstrated that the adverse effects of progesterone rise are of most significance for women with low and intermediate ovarian response to COH as opposed to high response; these women are considered to be particularly susceptible to the negative effects on implantation from a premature progesterone rise . Our stuIn conclusion, our findings suggest that it would be advantageous to consider each patient’s change in progesterone level (𝚫P) during IVF stimulation in the decision to proceed with fresh ET versus deferral. While FET using embryos created from oocytes retrieved in the setting of premature progesterone rise appear to be successful , 17, fre


A workflow including a transcriptome-wide association study, pathway enrichment analysis with a meet-in-the-middle approach, and mediation analysis was performed to characterize the biological pathways and intermediate gene expressions of the MDC–birth weight relationship. Among 26,170 transcriptomic features, we successfully annotated five overlapping metabolism-related gene expressions associated with both an MDC and birth weight, comprising BCAT2, IVD, SLC25a16, HAS3, and MBOAT2. We found 11 overlapping pathways, and they are mostly related to genetic information processing. We found no evidence of any significant mediating effect. In conclusion, this exploratory study provides insights into transcriptome perturbations that may be involved in MDC-induced altered birth weight.Prenatal exposure to metabolism-disrupting chemicals (MDCs) has been linked to birth weight, but the molecular mechanisms remain largely unknown. In this study, we investigated gene expressions and biological pathways underlying the associations between MDCs and birth weight, using microarray transcriptomics, in a Belgian birth cohort. Whole cord blood measurements of dichlorodiphenyldichloroethylene ( Metabolism-disrupting chemicals (MDCs) have been defined as natural or anthropogenic endocrine-disrupting chemicals (EDCs) that can promote metabolic changes and ultimately lead to obesity, type 2 diabetes and/or non-alcoholic fatty liver disease (NAFLD) . In linep,p’-DDE), polychlorinated biphenyl-153 (PCB-153), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS)] and birth weight  was linked to p,p’-DDE; three  were linked to PFOA, two  were linked to PFOS, and five  were linked to birth weight.The MDC- or birth weight-associated pathways at FDR < 0.05 with at least five genes involved are represented in p,p’-DDE, PCB-153, PFOA, and PFOS, respectively  are associated with the progression of obesity-related metabolic disorders  and expressed as ng/g lipids for subsequent analyses [2-transformed in order to reduce the potential influence of extreme values.Several classes of environmental chemicals were measured in cord blood samples. Here, we have focused our analyses on MDC exposures that could be detected in at least 60% of the cord blood samples : p,p’-DDescribed ,56. All omarkers ,57. LipiCombat to eliminate possible batch effects related to different hybridization dates (28 dates from 14 September 2011 to 11 January 2012) [As previously described ,58, totary 2012) ,60. Lastry 2012) .2), and gestational age (weeks). Birth weight and child sex were collected from maternity medical records. Other covariate data was obtained from questionnaires. Missing data in covariates and exposures that were completely missing  were singly imputed using the R package mice [We considered birth weight (g) as our outcome of interest. DAGs were used to guide the selection of covariates . The setage mice .i indexes the study subjects and Model (1) describes the association between a single transcriptomic feature and a single MDC, while Model (2) describes the association between birth weight and a single transcriptomic feature. Parameters 0β and 0γ are the model intercepts, while 1β and 1γ refer to the effect estimates (slopes) for a single MDC on a single transcriptomic feature, and for a single transcriptomic feature on birth weight, respectively. Parameters 2–8β and 2–8γ are coefficients corresponding to other covariates in the model, and 1iε and 2iε represent the residual errors, which are assumed to follow a normal distribution.TWASs were conducted in order to investigate the association of global transcriptomics with (1) MDCs and (2) birth weight. We used the following multivariable linear models to evaluate the effects of MDC exposures and potential predictors of birth weight, for each feature and MDC separately:p-values for 1β and 1γ, we estimated FDR using the method of Benjamini and Hochberg to correct for multiple testing and to select significant features [According to observed features .2-fold change) in cord blood in relation to MDCs and birth weight, i.e., 1β and 1γ obtained from Models (1) and (2) [In order to find pathways associated with MDC exposures and birth weight, we carried out Gene Set Enrichment Analyses (GSEA) using the WEB-based GEne SeT AnaLysis Toolkit  tool with pathway gene sets from the KEGG database ,64,65. F and (2) ,67. Subs and (2) . We restmediation [ediation  to exploediation ,72. ACMERecognizing that gestational age could be associated with MDC exposure and impact transcriptome levels , combineAll statistical analyses were performed in R version 4.1.0 .In summary, we integrated cord blood TWASs in order to identify gene expressions and pathways associated with MDCs and birth weight. Taken together, our study suggested five gene expressions associated with at least one MDC and birth weight. This provides insight into the etiology of higher and lower birth weight and possible later metabolic disorders, but again, this is an exploratory study with weak signals. In order to validate our results and further understand the potential link between MDC exposures and birth weight, and to elucidate the underlying mechanisms, studies with larger sample sizes and prospective study designs combined with advanced omics techniques are warranted.


Thyroid autoimmunity and polycystic ovary syndrome (PCOS) are the most common endocrinopathies and have close relationships based on common etiology and pathogenesis, including genetic susceptibility, metabolic disorders, hormonal dysregulation, immune response, and inflammatory activation. The co-occurrence of both diseases is associated with adverse reproductive outcomes, but its effect on neonatal outcomes remains largely unknown. We aim to explore the effect of thyroid autoimmunity on neonatal birth weight in PCOS women undergoing IVF/ICSI.This is a retrospective analysis of 486 PCOS women who underwent the first IVF/ICSI cycles and gave birth to 361 singletons and 125 twins during 2018 – 2020 at a reproductive center. The associations between maternal preconception serum thyroid function and autoimmunity indicators and birth weights of the singleton and twin groups were evaluated using generalized linear models (GLMs) and generalized estimate equations (GEEs), respectively. Analyses were further stratified by neonatal sex, maternal age, and maternal preconception BMI to assess the possible interaction effects.P for trends = 0.03). Compared with women in the first tertile of TPOAb, women in the third tertile had a change in singleton birth weight of − 119.72 g . Maternal preconception serum TPOAb had a significant positive association with twin birth weight (P for trends = 0.01). Compared with women in the first tertile of TPOAb, women in the third tertile had a change in twin birth weight of 138.62 g . Besides, maternal preconception serum TPOAb had a specific association with increased twin birth weight for female neonates, a specific association with decreased singleton birth weight for PCOS women under 35 years, and a specific association with decreased twin birth weight for overweight PCOS women .Maternal preconception serum TPOAb had a significant negative association with singleton birth weight (Maternal preconception thyroid autoimmunity may affect the birth weights of both singleton and twin neonates. Further large cohorts and experimental studies are required to confirm these findings and explore the underlying mechanisms.The online version contains supplementary material available at 10.1186/s13048-023-01208-z. Polycystic ovary syndrome (PCOS) and autoimmune thyroid disease (AITD), are both commonly occurring endocrinopathies in women of reproductive age since the close correlation between the hypothalamic-pituitary-ovarian (HPO) axis and hypothalamic-pituitary-thyroid (HPT) axis –3. The pBoth AITD and PCOS can result in a wide range of metabolic syndrome features, including impaired glucose tolerance, insulin resistance, and dyslipidemia, which can result in diabetes, obesity, and cardiovascular disease over a lifetime –12. It hThis study aims to clarify the effects of maternal preconception serum thyroid function and autoimmunity indicators on the birth weight of neonates conceived by PCOS women undergoing IVF/ICSI treatment.The study was approved by the institutional ethics board of Peking University Third Hospital (No. 2021SZ – 011), and all participants signed written consent forms.n = 15), 2) history of autoimmune disease or recurrent spontaneous abortion (n = 1), 3) history of iatrogenic ovarian injury (n = 1); 4) chromosomal abnormalities in either of the spouses (n = 19); 5) receiving in vitro maturation (IVM) or preimplantation genetic testing (PGT) (n = 27); (6) missing information (n = 202). Finally, a total of 1550 participants were involved in this study.We retrospectively involved participants from the Reproductive Center of Peking University Third Hospital from January 1, 2018, to December 30, 2020. PCOS women aged between 20 – 45 years who underwent their first fresh IVF/ICSI cycles with autologous oocytes were informed of the purpose of our study. According to the Rotterdam criteria, PCOS is diagnosed by at least two of the three symptoms: hyperandrogenism , oligo- or anovulation, and/or polycystic ovary morphology . The excn = 1064), 486 women who successfully gave birth to a total of 361 singletons and 125 twins were included in the current analysis. The baseline reproductive characteristics, cycle characteristics, and birth outcomes  were extracted from electronic medical records. According to the American College of Obstetricians and Gynecologists (ACOG) guidelines for IVF/ICSI-based conception, the gestational age was calculated as (outcome date – date of transfer) + 14 + development days of the transferred embryo ) or n (%) when appropriate. The differences in clinical characteristics between the singleton and twin groups were analyzed by chi-square or Fisher’s exact test for categorical variables and Kruskal–Wallis tests for continuous variables. Generalized linear models (GLMs) were performed to investigate the associations between maternal preconception serum thyroid function and autoimmunity indicators and birth weight in the singleton group. Generalized estimate equations (GEEs) were performed to investigate the associations between maternal preconception serum thyroid function and autoimmunity indicators and birth weight in the twin group. The normal distribution and identity link were applied for neonatal birth weight. The linear trend tests across tertiles were conducted using an ordinal number .The potential covariates were chosen if their associations with either birth outcomes or thyroid function were reported , 26, or 2) to evaluate the possible modification effect. To test the robustness of our results, three sensitivity analyses were conducted as follows: 1) restricting the analyses to women with BMI ≥ 18.5 kg/m2; 2) restricting the analyses to women diagnosed with primary infertility; 3) only analyzing women with normal testosterone; 4) only analyzing women who had Day 3 embryo transfer. P-values < 0.05 was considered to be statistically significant.To better interpret the results, the total study population's results were also presented as marginal means adjusted for covariates using the R package “emmeans” (version 1.6.2 – 1). Analyses were further stratified by neonatal sex , maternal age (< 35 vs. ≥ 35 years), and maternal preconception BMI , applied GnRH antagonist protocol for COS , and underwent conventional insemination . Almost all of them had embryo transfers three days after oocyte retrieval  with two embryos . Significant differences were observed in transferred embryos number, gestational age, delivery mode, and birth weight between the singleton and twin groups .The clinical characteristics of 361 mothers with singletons and 125 mothers with twins are presented in Table P for trends = 0.03); the estimated mean difference in birth weight when the extreme tertiles were compared was − 119.72 g . However, we observed an association between maternal preconception TPOAb and increased neonatal birth weight in the twin group (P for trends = 0.01); the estimated mean difference in birth weight when the extreme tertiles were compared was 138.62 g . We further assessed the associations between maternal preconception thyroid autoimmunity positivity and neonatal birth weights of the singleton and twin groups. However, no significant association was observed between maternal preconception positive TGAb or TPOAb and neonatal birth weight (Table STable P for interactions = 0.03). The associations between maternal preconception thyroid function and autoimmunity indicators and neonatal birth weights of the singleton and twin groups stratified by maternal age are presented in Fig. P for interactions = 0.02). The associations between maternal preconception thyroid function and autoimmunity indicators and neonatal birth weights of the singleton and twin groups stratified by maternal preconception BMI are presented in Fig. 2 (P for interactions = 0.03).The associations between maternal preconception thyroid function and autoimmunity indicators and neonatal birth weights of the singleton and twin groups stratified by neonatal sex are presented in Fig. 2  for neonatal birth weight by maternal preconception serum thyroid function and autoimmunity indicators among PCOS women undergoing their first IVF/ICSI cyclesa.Additional file 2: Table S2. Associations between maternal preconception thyroid autoimmunity positivity and neonatal birth weight among PCOS women undergoing their first IVF/ICSI cyclesa.Additional file 3: Table S3. Associations between maternal preconception serum thyroid function and autoimmunity indicators and neonatal birth weight among PCOS women with preconception BMI ≥18.5kg/m2 undergoing their first IVF/ICSI cyclesa.Additional file 4: Table S4. Associations between maternal preconception serum thyroid function and autoimmunity indicators and neonatal birth weight among PCOS women with primary infertility undergoing their first IVF/ICSI cyclesa.Additional file 5: Table S5. Associations between t maternal preconception serum thyroid function and autoimmunity indicators and neonatal birth weight among PCOS women with normal testosterone undergoing their first IVF/ICSI cyclesa.Additional file 6: Table S6. Associations between maternal preconception serum thyroid function and autoimmunity indicators and neonatal birth weight among PCOS women undergoing their first IVF/ICSI cycles with Day 3 embryos transferreda.