Administrative healthcare claims databases are used in drug safety research but are limited for investigating the impacts of prenatal exposures on neonatal and pediatric outcomes without mother-infant pair identification. Further, existing algorithms are not transportable across data sources. We developed a transportable mother-infant linkage algorithm and evaluated it in two, large US commercially insured populations.We used two US commercial health insurance claims databases during the years 2000 to 2021. Mother-infant links were constructed where persons of female sex 12–55 years of age with a pregnancy episode ending in live birth were associated with a person who was 0 years of age at database entry, who shared a common insurance plan ID, had overlapping insurance coverage time, and whose date of birth was within ± 60-days of the mother’s pregnancy episode live birth date. We compared the characteristics of linked vs. non-linked mothers and infants to assess similarity.The algorithm linked 3,477,960 mothers to 4,160,284 infants in the two databases. Linked mothers and linked infants comprised 73.6% of all mothers and 49.1% of all infants, respectively. 94.9% of linked infants’ dates of birth were within ± 30-days of the associated mother’s pregnancy episode end dates. Characteristics were largely similar in linked vs. non-linked mothers and infants. Differences included that linked mothers were older, had longer pregnancy episodes, and had greater post-pregnancy observation time than mothers with live births who were not linked. Linked infants had less observation time and greater healthcare utilization than non-linked infants.We developed a mother-infant linkage algorithm and applied it to two US commercial healthcare claims databases that achieved a high linkage proportion and demonstrated that linked and non-linked mother and infant cohorts were similar. Transparent, reusable algorithms applied to large databases enable large-scale research on exposures during pregnancy and pediatric outcomes with relevance to drug safety. These features suggest studies using this algorithm can produce valid and generalizable evidence to inform clinical, policy, and regulatory decisions.The online version contains supplementary material available at 10.1186/s12874-023-02073-6. Pregnancy is characterized by distinct periods of embryonic development representing critical exposure windows for children’s health . ExposurCalls have been made to use real-world data (RWD) to study medication effects in pregnancy and are increasingly accepted by health authorities as part of post-authorization safety commitments , 17. LarTo assess prenatal exposures on infant outcomes in RWD requires implementing algorithms to define pregnancy episodes and to link live births to infant records, which is challenging in the United States where national health record identifiers are absent. Mother-infant linkage has been conducted using US administrative healthcare databases, including among Medicaid, commercially-insured, and Military Health System populations –24. OtheOur study builds on past efforts to create mother-infant linked cohorts in RWD. The objective of this work was to link mother and infant data using two large, US commercial insurance databases. We also sought to evaluate the algorithm through comprehensive characterization comparisons between linked and non-linked mothers and infants. In contrast to other linkage studies that use proprietary algorithms, our algorithm is publicly available. The algorithm was developed for use against the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) , 29, so The study used two health insurance claims databases, IBM® Marketscan® Commercial Database (CCAE)[2000–2022] and Optum’s de-identified Clinformatics® Data Mart Database (Clinformatics®)2000–2021]. Both contain de-identified, patient-level, encounter-based, longitudinal, employer-based US administrative health insurance claims records and include inpatient and outpatient diagnoses, procedures, and outpatient prescription dispensing records. Both databases use a unique insurance enrollment ID for identifying beneficiaries and their dependents under a single, primary insurance holder account. Both databases were transformed to the OMOP CDM, which provides a standardized representation of database structure and clinical content  to enabl. Both coThe linkage algorithm relies on and is distinct from an algorithm for identifying pregnancy episodes and outcomes . The preWe first identified candidate mothers as females whose pregnancy episode(s) ended with live birth and occurred during a period of insurance enrollment.Multiple periods of insurance enrollment were combined into a single observation period provided gaps between an enrollment period end and subsequent start date were ≤ 30 days. We identified candidate infants as persons whose year of birth was the same as their first observation period start year  and had an insurance enrollment ID shared with a candidate mother. Candidate infants’ date of birth (DOB) was set as year, month, and day. Year of birth was available for all persons in both databases. Month and day were unavailable in the data sources we used through the patient de-identification process, so we inferred these components from observation period start month and day. Most day of birth values were set as 1 because insurance enrollment typically begins on the first day of a month. We refer to this date as the inferred date of birth, rather than the true date of birth, which we assert is the delivery date of the corresponding linked mother, where links were established. The algorithm will use month and day of birth if available but will set these values to month and day of enrollment start otherwise. This supports algorithm transportability if used in other insurance claims databases where birth date information may or may not be redacted.We identified candidate links between mothers and infants where they matched on insurance enrollment ID and the candidate infant’s inferred DOB occurred during a candidate mother’s observation period.We identified probable links between mothers and infants by restricting to those where the candidate infant’s DOB occurred within ± 60 days of the candidate mother’s pregnancy episode end date. This correspondence window was varied in a sensitivity analysis  for each covariate in units of the pooled standard deviation, a metric uninfluenced by large sample sizes , and inthttps://data.ohdsi.org/MotherInfantLinkEval/. A reader can navigate to this web-based application to review the full characterization results set for each linked vs. non-linked comparison. By default, the table reports characteristic prevalence results for linked vs. non-linked cohorts sorted by largest to smallest standardized mean difference between characteristic prevalence. Additionally, a reader can search for characteristics of interest using the search bar.All source code and an interactive web application for viewing full results is available at Figure In CCAE, 3,064,263 candidate mothers and 2,942,216 candidate infants were identified in Step 1, of whom 26.8% and 1.4% were dropped respectively during Step 2, resulting in 2,915,538 candidate links. Links were reduced by 13.2% and 0.1% in steps 3 and 4 respectively, which resulted in 2,528,482 links: 2,146,726 linked mothers, and 2,528,482 linked infants. 31.3% of linked infant’s DOB were on the same day as their linked mother’s pregnancy episode end date and 58.3%, 71.5%, and 92.1% occurred within ± 7 days, ± 14 days, and ± 30 days, respectively. Linked infant’s DOB was on average 5.9 days  after the pregnancy episode end date. Linked mothers comprised 70.1% of all mothers  and linked infants comprised 51.2% of all infants   after the pregnancy episode end date. Linked mothers comprised 77.3% of all mothers  and linked infants comprised 47.0% of all infants . We also observed a greater prevalence of birth-related covariates among linked infants than non-linked infants . Despite these differences, we still observed absolute SMDs of < 0.1 for > 99% of covariates across all algorithm implementations of each linked vs. non-linked comparison in both databases where the number of covariate comparisons ranged from 58,611 (CCAE infants) to 68,368 (Clinformatics® mothers pregnancy end).Table Table Table The final person and record counts for each of the 9 cohorts constructed by the 3 linkage algorithm implementations in each database are reported in Additional file We developed and implemented an algorithm to infer mother-infant links in two large US commercial healthcare databases that exhibited high linkage coverage and similar characteristics across linked vs. non-linked persons. This signifies generalizability of linked mother-infant pairs to commercially insured source populations, which facilitates large-scale research on prenatal exposures and infant outcomes. This constitutes novel research by virtue of our emphasis on linked vs. non-liked characterization comparisons to support generalizability. Similarity of measured characteristics in linked vs. non-linked mother and infant records is supporting evidence that results produced by analyzing linked cohorts will generalize to the underlying source population, in this case commercially insured pregnant people and their infants. Our assessment of average linked-infant follow-up time  allows their inclusion in perinatal-exposure studies where outcomes of interested are not birth outcomes per se but longer-term infant conditions. Further, our linkage algorithm was implemented in the OMOP CDM, and the source code is publicly available. The utility of using standardized analytic routines against a standard data representation allows for transportable, complex algorithms to be implemented in other claims databases formatted to the OMOP CDM with no loss of fidelity .Our algorithm identified > 3.4 million linked mothers and > 4.1 million linked infants. Access to large, linked populations makes feasible the study of a wide range of prescription drug exposures, maternal and neonatal outcomes, and subgroups that are often unavailable in smaller linked populations , 41 and Across databases, linked mothers comprised 73.6% of all mothers with live births. In Clinformatics®, 77.3% of mothers were successfully linked to infants, which is lower but comparable to the 84% reported in a recent study using data from the same source with fewer linkage restrictions . DespiteIn our study, linked infants comprised 49.1% of all infants defined as persons 0 years of age at their observation period start. Contextualizing our linked infant coverage is difficult because most studies only report the proportion of linked pregnancies , 23. HowWhile our primary analysis used a ± 60-day window between infant DOB and mothers’ pregnancy episode end to identify candidate links, in sensitivity analyses, we observed high correspondence at 7, 14, and 30 days, including same-day correspondence of 31.3% in CCAE and 67.4% in Clinformatics®. Overall correspondence was greater in Clinformatics®, which may be due to more accurate and specific DOB information. Increasing the correspondence window to 90 days increased the proportion of linked infants by only 1.5% in CCAE and 0.2% in Clinformatics®, which we do not interpret as material because most of the correspondence occurred within ± 30 days.Characteristic comparisons between linked and non-linked mothers revealed similar demographic, clinical, and healthcare utilization profiles. Our linkage evaluation largely supports the generalizability of the linked mother population, having compared thousands of covariates between linked and non-linked mother cohorts and observing few differences. Of note, two of the differences we found in both CCAE and Optum were also detected in a recent study using the Sentinel network: non-linked mothers were younger and had shorter gestations than linked mothers . It is pDespite substantial similarity between linked and non-linked infants, we observed more differences than when comparing mothers. Of note, linked infants had greater total healthcare utilization and prevalence of individual clinical events, including birth and infant-care related claims. Because our algorithm linked mothers to infants by a shared insurance ID within a defined temporal interval, candidate infants whose inferred DOB fell outside of that interval would be non-linked and less likely to have their clinical events captured in the database. This suggests that some billing records may be attributed to family members on other insurance plans among the non-linked populations. Still, this evaluation supports the generalizability of the linked infant population. In cases of multiple pregnancies, linkages are made between maternal records and all live births from that pregnancy. In the event of a multifetal pregnancy ending in both a live birth and a stillbirth, codes associated with the still born infant may be observed on the live born infant record or on that of the linked mother. The occurrence of this scenario is expected to be very rare, with less than 0.5% of multifetal pregnancies experiencing a stillbirth in one study .Despite CCAE and Clinformatics® both consisting of administrative claims data from large US commercial insurance plans, data content heterogeneity between them still exists, which could contribute to results differences between them. In Clinformatics®, we observed more situations where multiple women of child-bearing age were associated with one candidate infant. This suggests that more extended family members may be included on the same insurance plan in Clinformatics® than in CCAE, which would increase the situations where one infant is associated with > 1 candidate mother on the same health plan. Regarding selection bias, by excluding multiple women of child-bearing age on the same insurance plan, we may be selectively decreasing representation of large, varied families covered in the Clinformatics® database.We note that several recent studies have established mother-infant linkage algorithms in claims databases with similar methods to the one described in this paper , 45, 48.A strength of our study is the rigorous linkage approach utilizing insurance ID in addition to delivery and birth procedure dates in large US claims databases representing the commercially insured population. Further, we provide open-source code and a web-application to interactively review characterization results, which provides valuable context for the external validity of future studies among linked populations. Lastly, developing a reproducible mother-child linkage algorithm in large administrative databases facilitates evidence generation in pregnant populations with improved rigor by avoiding recall, referral, and self-selection biases inherent to registry or other primary data collection studies of prenatal medication use .Using administrative healthcare claims databases in pharmacoepidemiologic research has limitations. Erroneously coded or missing diagnostic, procedure, and drug dispensing records results in misclassification which may under- or over-estimate exposures, covariates, health outcomes, other clinical events, and healthcare utilization . SubsequStill, developing reliable mother-infant linkages in large healthcare databases has increased the capacity to examine associations between rare prenatal drug exposures and infant outcomes with sufficient power. For example, prenatal use of antidepressants, stimulants, antihypertensive medications, and sulfonamides have been studied in relation to validated congenital anomalies –55. ThisWhile we found few differences between linked and non-linked populations suggestive of high internal validity to the underlying commercially insured US population, our results do not necessarily ensure external validity to those covered under other types of insurance or lacking coverage. The data in this study are representative of people with US-based, employer-sponsored health insurance, indicative of a higher socioeconomic status population. Given the established association between wealth and health , 57, carOur study reinforces the shift towards implementing pharmacoepidemiology studies on prenatal drug exposures utilizing large electronic healthcare data as a supplement to traditional pregnancy registries. Our algorithm and evaluation demonstrate the ability to assemble large mother-infant linked cohorts for investigating prenatal drug exposure effects on infant outcomes.Below is the link to the electronic supplementary material.Supplementary Material 1


Children of mothers with hypertensive disorders of pregnancy (HDP) have high rates of preterm-birth  and small-for-gestational-age (SGA), both of which are risk factors of autism spectrum disorder (ASD). This study tested the multiple-hit hypothesis that preterm-birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase childhood ASD hazards, and HDP might not be a major contributor. The propensity-score-matched cohort enrolled 18,131 mother–child pairs with HDP and 90,655 normotensive controls between 2004 and 2011. Children with siblings born to the same mothers were excluded for analysis to reduce the potential familial-genetic influence. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between HDP subgroups and the cumulative ASD risks were assessed with hazard ratios, and the effects of preterm-birth and SGA on the associations were examined. The HDP group had a higher cumulative rate of ASD (1.5%) than the normotensive group (1.2%). Preterm-birth and SGA exerted moderating effects to aggravate ASD hazards in children exposed to chronic-hypertension or gestational-hypertension. None of HDP types significantly contributed to ASD after adjustments. In conclusion, antenatal HDP exposure might predispose to ASD outcome through susceptibility to the impact of preterm-birth and SGA. Children with ASD may have not only behavioral problems and social incompetence requiring early intervention programs and special education, but also higher rates of comorbid medical conditions, such as intellectual disability and attention deficit hyperactivity disorder5. The co-morbidities in children with ASD may further negatively impact their mental health and social adaptation, leading to increased medical, educational and social expenses for special health care needs.Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social interaction, communication deficits and stereotyped behavior6. Among the prenatal events, hypertensive disorders of pregnancy (HDP), such as chronic hypertension or preeclampsia, complicate approximately 5–10% of all pregnancies leading to maternal and fetal morbidity and mortality7. As there have been increased trends of HDP and ASD during the past decades9, it is important to investigate whether HDP exert maternal–fetal influence upon offspring’s ASD outcome.The Developmental Origins of Health and Disease hypothesis suggests that prenatal events and maternal well-being during pregnancy may have long-lasting effects on children’s neurodevelopment10. Children born to mothers with HDP have high rates of preterm birth  and intrauterine growth restriction/small for gestational age (SGA)12, both of which are well-known risk factors of ASD14. Previous studies have reported children exposed to both preeclampsia and preterm birth/SGA had increased risks of ASD than those exposed to preeclampsia alone16, and the association between preeclampsia and ASD might be mediated through preterm birth or SGA18. There may be multiple hits of insults during the process leading to neuropsychiatric disorders19, and antenatal exposure to HDP may make the developing brain more susceptible to subsequent injuries associated with preterm birth and SGA in the perinatal and neonatal period. It remains unclear whether preterm birth and SGA may aggravate the impact of maternal HDP in early life to increase the risk of childhood ASD, and whether different types of HDP have independent contribution to ASD hazards under the confounding influence of preterm birth and SGA. Understanding the interrelationship between antenatal HDP exposure and the following preterm birth/SGA may help strategy making to reduce ASD hazards.Although meta-analysis studies have shown that children exposed to HDP, particularly preeclampsia, may have higher risk of ASD, it remains unclear whether the association is causal or attributed to residual or unmeasured confoundingUsing a propensity-score-matched cohort from the nationwide registry of mother–child database in Taiwan, this study tested the multiple-hit hypothesis that HDP might not be a major contributor for ASD outcome, and preterm birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase ASD hazards in childhood.p < 0.001) with low birth weights < 2500 grams , and higher incidence of neonatal intensive care unit (NICU) admission  than the normotensive group. Children in the HDP subgroups of preeclampsia with or without superimposed chronic hypertension had higher rates of preterm birth  and SGA (26–28%) than those in the subgroups of chronic hypertension and gestational hypertension   chronic hypertension, 3204 (17.7%) gestational hypertension, 7673 (42.3%) preeclampsia, and 1766 (9.7%) preeclampsia with superimposed chronic hypertension. The comparisons between the HDP and normotensive group are shown in Table p < 0.001). Among children exposed to maternal HDP, the crude cumulative incidences of ASD by 14 years of age were highest for preeclampsia with superimposed chronic hypertension , followed by gestational hypertension , preeclampsia , and chronic hypertension , all of which were higher than those in the unexposed children   children who had ASD in the study cohort, with a higher rate in the HDP than in the normotensive group  of ASD , followed by those exposed to preeclampsia alone ; whereas children exposed to maternal chronic hypertension  or gestational hypertension  had no significantly increased hazards  and SGA on the association between different HDP types and ASD. Using the groups of normotension and GA > 36 weeks as the reference, preterm birth had little mediating influence (Supplementary Table p = 0.04), while preeclampsia with superimposed chronic hypertension became insignificant . After further adjusting for SGA in Model 2, the significant effect of preeclampsia disappeared . In Model 3 that included all covariates, none of any HDP had significant contribution to ASD outcome, while both the effects of preterm birth and SGA remained significant in Model 3 with high hazards for children born at GA < 32 weeks  or being SGA . For each HDP subgroup, the adjusted hazard ratio in the final Model 3 was less than the adjusted odds ratio estimated by E-value sensitivity analysis  in Model 1, and then incorporated Model 1 and SGA in Model 2, and finally included Model 2 and other covariates in Model 3  than those without exposure20, and early-onset or severe preeclampsia further increased the risks17. A few case–control studies showed children with ASD had higher rates of maternal preeclampsia than those with typical development, and preeclampsia had significant contribution to ASD (adjusted odds ratio ranged from 1.69 to 2.36)22. Recent studies have examined the confounding influence of familial genetic factors using the sibling pair analysis. After further adjusting for shared familial factors, two studies demonstrated preeclampsia or unclassified HDP was associated with ASD23, while another study did not15. Although most studies favored the association between preeclampsia and ASD, some important confounding factors may not always be considered or available to justify the causal relationship10. After reducing the potential sibling effects, we found that maternal preeclampsia had no significant association with ASD outcome after adjusting for preterm birth and SGA, and the findings were supported by the sensitivity analysis of unmeasured confounding.Previous studies examining the association between maternal HDP and childhood ASD often focused on preeclampsia17, while other studies did not24. When preeclampsia was superimposed on chronic hypertension, one study reported a higher risk of ASD in children exposed to both  than in those exposed to chronic hypertension  or preeclampsia  only17. Our study found no increased ASD hazards in children exposed to maternal chronic or gestational hypertension, and preeclampsia superimposed on chronic hypertension did not further increase ASD risk  than either preeclampsia  or chronic hypertension  alone.Few studies investigated ASD outcomes in children exposed to maternal HDP other than preeclampsia. One study showed children born to mothers with chronic or gestational hypertension had increased risks of ASD25. The antenatal detrimental events may sensitize the developing brain, making it more vulnerable to injuries from subsequent insults such as preterm birth and SGA26. Infants born very preterm often experience intertwining events of hypoxia/ischemia and infection in the perinatal and neonatal periods, which might have cumulative effects on the risk of neurodevelopmental impairment27. The higher rates of perinatal asphyxia and neonatal hypoglycemia in SGA infants might also predispose to unfavorable neurodevelopmental outcomes28. The early-life adverse events from the prenatal to neonatal period may not only damage the brain but also affect brain development through epigenetic modification of brain structure and function, leading to increased hazards of neuropsychiatric disorders29.Our study demonstrated that preterm birth and SGA exerted moderating effects to strengthen the association between HDP and ASD, implicating there might be multiple hits rather than single HDP exposure in the process leading to ASD outcome. Maternal hypertension during the pregnancy, particularly preeclampsia, may negatively affect the fetal environment by triggering insults such as uteroplacental hypoperfusion, oxidative stress, placental inflammation and nutrient insufficiency, resulting in intrauterine growth restriction/SGA or preterm deliveryUsing a large cohort of mother–child pairs with well-matched covariates in the inter-group backgrounds, this study demonstrated the potentiating effects of preterm birth and SGA on the association between maternal HDP and childhood ASD. The study cohort constructed by propensity score matching is not applicable for examining the potential familial genetic influence on ASD hazards. We therefore did not include children with siblings born to the same mothers for analysis in the propensity-score-matched cohort. The generalizability of our findings may be validated in another population-based cohort studies.In conclusion, our findings supported the multiple-hit hypothesis that preterm birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase ASD hazards in childhood. The associations between HDP and ASD were greatly attenuated after adjusting for preterm birth and SGA, suggesting that HDP might serve as a sensitizer rather than a major hitter on the developing brain. Adequate neonatal care for preterm and SGA infants and antenatal blood pressure control for HDP mothers, may help reduce the risks and complications of preterm delivery and SGA to diminish ASD hazards in offspring.30. We first obtained the mother–child data with birth registration between 2004 and 2011 from MCHD, and followed up these children until 31st December 2017 when they were at least 6 years old (range 6–13 years). The children’s data from 2012 to 2017 were extracted from NHIRD, which contains the medical claims data of more than 99.9% of the population in Taiwan covered by National Health Insurance Program31. Medical diagnoses were coded using the International Classification of Diseases, Ninth Revision (ICD-9) from 1998 to 2015, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) between 2016 and 2017.This cohort study used the Maternal and Child Health Database (MCHD) which link the data of offspring and their parents by integrating three nationwide databases in Taiwan, including Birth Registration Database, National Register of Death, and National Health Insurance Research Database (NHIRD). The MCHD contains perinatal records on 99.8% of all births in Taiwan from 1st January 2004 to 31st December 2011, and the data of medical claims and diagnoses during hospitalization and outpatient visits for mothers from 1998 to 2011, and for children from 2004 to 201133. Each HDP mother–child pair was propensity-score-matched with 5 control pairs without any maternal hypertension by maternal age at delivery, mode of delivery, birth year, GA, and children’s sex. The final study cohort consisted of 18,131 HDP and 90,655 normotensive control pairs , brain anomalies (n = 263), and congenital infection (n = 390). To reduce the potential familial-genetic influence on ASD outcome, mothers with multiple births  or more than one singleton births  were excluded from analysis. Among the remaining 1082,564 mother–child pairs, after excluding 8710 with incomplete data or unidentified maternal hypertension, there were 18,131 with HDP and 1,055,723 without any maternal hypertension. To diminish the imbalance of covariates and GA-related risks of neonatal morbidities between the HDP and the normotensive group, propensity score matching was used to construct an exposure-control cohort. The propensity score, which was calculated via the logistic regression model, provided matching criteria to make similar distribution of observed baseline covariates between the HDP-exposure and normotensive-control group34. Maternal chronic hypertension referred to the occurrence of hypertension before pregnancy or during the first 20 weeks of gestation, while hypertension (> 140/90 mmHg) arising de novo at or after 20 weeks included gestational hypertension (without complications), preeclampsia , and preeclampsia superimposed on chronic hypertension34. The diagnoses of HDP were identified with ICD-9 codes on at least one inpatient or at least three outpatient NHIRD records , and identified with ICD-9 or ICD-10 codes from NHIRD records of at least one hospital admission or at least three ambulatory clinic visits. The covariates that might have influence on ASD outcome were defined and recorded by ICD codes . Kaplan–Meier survival curves were plotted to compare the crude cumulative incidences of ASD among the normotensive group and HDP subgroups. Using the normotensive group as the reference, the associations between HDP subgroups and the cumulative risks of ASD were assessed with hazard ratios in the Cox proportional hazards regression models37. Potential predictors of ASD in the univariable analyses were fitted into a multivariable model by stepwise selection of variables, with estimation of adjusted hazard ratios and 95% confidence intervals.The differences in maternal and infant characteristics and the rates of ASD between the HDP and normotensive group were compared by 38, while mediation explores whether the observed relationship between a predictor and an outcome variable is transmitted through a third variable (or mediator) using a regression-with-residuals approach39. The sensitivity analysis of unmeasured confounding was performed using E-value estimation for the adjusted odds ratio, which denotes the degree to which one or more unobserved confounders would need to increase the risk of exposure and outcome to fully account for the observed associations40. All analyses were performed using the SAS v9.4 statistical software .The potential effects of preterm birth and SGA on the association between HDP subgroups and ASD outcomes were determined using moderation and mediation analysis. Moderation, also known as effect modification, examines the interacting effect of a third variable (or moderator) on the relationship between a predictor and an outcome variableThe study was conducted in accordance with the Declaration of Helsinki, and was approved by the Institutional Review Board of Taichung Jen-Ai Hospital in Taiwan (No. 108-83).The need for informed consent was waived by the Institutional Review Board of Taichung Jen-Ai Hospital in Taiwan due to encrypted and anonymous databases without personal identification.Supplementary Information.


Non-pharmaceutical interventions (NPIs), such as social distancing and hand washing, have been associated with a decline in the preterm birth rate worldwide. We aimed to evaluate whether the preterm birth rate in Korea during the coronavirus disease 2019 lockdown has changed compared to that in previous years.A birth registry from the Korea Statistical Information Service, which is a nationwide official database, was used to include all births claimed to have occurred between 2011 and 2020. Newborns with gestational age (GA) less than 22 weeks and birth weight less than 220 g were excluded. The pre-NPI period was designated as January 2011 to January 2020, and the NPI period was defined as February 2020 to December 2020. We assessed the effect of NPI on the incidence of prematurity per 100 births using an interrupted time-series quasi-experimental design and implementing an autoregressive integrated moving average (ARIMA) model.P < 0.001). The ARIMA model showed that in all singleton and multiple births, except those in July , September , and December , most observed values were within the 95% PI of the expected values and showed an increasing trend.From 2011 to 2020, a total of 3,931,974 live births were registered, among which 11,416 were excluded. Consequently, the final study population included 3,920,558 live births (both singleton and multiple births) among which 275,009 (7.0%) were preterm. The preterm birth rate was significantly higher during the NPI period (8.68%) compared to that in the pre-NPI period (6.92%) (In this nationwide observational study, the trend in premature birth rate did not significantly change due to NPI implementation in Korea, as it had been increasing since 2011. The trend of Korea's birth rate appears to be unaffected by the implementation of NPIs; however, further studies with a longer follow-up period are needed. After the first quarter of 2020, most countries decided to implement non-pharmaceutical interventions (NPIs) to prevent the spread of COVID-19 .Preterm labor is defined as labor that starts before 37 weeks of pregnancy. The estimated global preterm birth rate in 2014 was 10.6%, and this was similar in Asia, where a 10.4% preterm birth rate was reported . SeveralInvestigators in Tennessee first identified an association between NPI and preterm birth after the COVID-19 pandemic . Birth r2.2.1.Birth registry data from the Korean Statistical Information Service  was used to include information on all births between 2011 and 2020 . Parents2.2.This was a retrospective, observational study that evaluated the change in preterm birth rates after the implementation of NPI. After the first confirmed case of COVID-19 in Korea on January 20, 2020, the government imposed mitigation measures, such as social distancing and restricted overseas travel, in February 2020. In this study, the NPI period was defined as January 2011 to January 2020 and the pre-NPI period as February 2020 to December 2020. Although only live births are meant to be registered, we observed 11,416 cases in the categories of gestational age (GA) less than 22 weeks and birth weight less than 220 g . These c2.3.As per the World Health Organization's definition, in this study, preterm birth was defined as births with a GA < 37 weeks . Subgrou2.4.Categorical variables were expressed as frequencies (%) and compared using the Chi-square test. Odds ratios of preterm births by birth types, such as singletons and multiples, and GA subgroups were calculated using multivariable logistic regression analyses between the defined pre-NPI and NPI periods after adjusting for maternal age, sex, maternal education, and birth order.auto.arima in the forecast package in R  and R Statistical Software .We assessed the effect of NPI on preterm birth rates and prematurity incidence per 100 births using an interrupted time-series quasi-experimental design . To accoage in R . Using tAdditionally, to compare the results using different statistical methods, segmented regression analysis was performed for statistical modeling of interrupted time series to evaluate whether the trend changed during the NPI period , 18. The2.5.This research was conducted ethically, in accordance with the World Medical Association and Declaration of Helsinki, and the institutional review board (No. 4-2021-0416) approved the study.3.P < 0.001). Additionally, the proportion of low-birth-weight neonates, with birth weight under 2,500 g, especially in the subcategory of 1,500 g to less than 2,500 g , was higher in the NPI period compared to the pre-NPI period. Detailed demographic features of the study populations for both periods are shown in The final study population included 3,920,558 births, of which 275,009 (7.0%) were preterm . A sligh3.1.The observed and expected preterm birth rates were plotted in 3.2.P < 0.001) and a similar trend was observed in the multivariate analysis . (Preterm births (including both singletons and multiple births) increased in the NPI period when compared to the pre-NPI period (odds ratio (OR) = 1.25, 95% CI, 1.23–1.27,  0.001).  When pre3.3.We summarized and compared the results of previous international studies on whether there was a change in the preterm birth rate due to NPI implementation . Overall4.In this study, we aimed to establish whether a correlation exists between preterm birth rates and the NPI period in Korea in 2020. Our findings showed that the preterm birth rate was increasing in the pre-NPI period, and this continued to increase after the implementation of such measures, suggesting an unclear impact of NPI implementation on the preterm birth rate.Preterm births have been increasing in most developed countries, including South Korea. The percentage of preterm births in the United States increased from 9% in 1981 to 10.5% in 2021 , 32. SimThe etiology of preterm delivery can be broadly categorized into three main groups: (1) spontaneous preterm labor; (2) maternal or fetal infections; and (3) premature preterm rupture of the membranes . EtiologIn contrast to our findings, many international data-based studies supported a negative association between NPI and preterm birth that were investigated up to the first quarter of 2020. In the United States, Gemmill et al. reported a decline in preterm birth rate during the pandemic, especially during the early and late 2020 . Oakley 4.1.Owing to the lack of confirmed etiologies for preterm births, the decline in preterm births during pandemic lockdowns could simply be a coincidence. On the other hand, further investigating this potential association could lead to more effective measures to prevent preterm births. Cohort data from other countries with lockdown periods during the pandemic showed a potential decrease in preterm births during the pandemic; however, they only investigated a short period of time after the NPI, mostly the first three months of 2020. This contrasts with our study, with data collection over a large period, in which we found no significant relationships between NPI implementation and preterm birth. Another limitation to our study is the lack of individual patient data in our database. For instance, the database does not include information on the cause or type of preterm birth, such as an underlying maternal or fetal condition (“indicated preterm birth”) or preterm rupture of membranes or cervical dilatation (“spontaneous preterm birth”). Consequently, it is difficult to correlate NPI with a specific type of preterm birth. However, because NPI could affect the maternal or fetal environment in multifaceted ways, differentiating the type of birth in the analysis may not have necessarily provided additional helpful information. However, to improve the quality of the database, further collection of National Health Insurance Data and the Korean Developmental Survey Data is required in the future. As a result of these limitations, we cannot definitively conclude that a causal relationship between COVID-19 mitigation measures and preterm birth rate exists.5.In conclusion, we were unable to establish a significant relationship between the NPI and pre-NPI preterm birth rates in South Korea. The overall South Korean preterm birth rate continues to increase, and this contributes to the country's disease burden. Future research should ideally aim to investigate whether there are more significant variables that could affect preterm birth rates, as well as how clinicians can reduce these factors and ultimately decrease the rate of preterm births.


Polycystic ovary syndrome (PCOS) has unusual levels of hormones. The hormone receptors in the endometrium have a hostile effect and make the microenvironment unfavorable for embryo implantation. The use of gonadotropin stimulation during in vitro fertilization (IVF) may have an impact on embryo implantation and live birth rate. According to recent data, the clinical results of day 4 embryo transfer (D4 transfer) were on par with those of day 5 embryo transfer (D5 transfer) in IVF-ET. There are few studies comparing the outcomes of transplants with various etiologies and days. The purpose of this study was to determine which transfer day had the best result for PCOS patients undergoing IVF.This retrospective cohort study was conducted in the Xingtai Infertility Specialist Hospital between January 2017 and November 2021. A total of 1,664 fresh ART cycles met inclusion criteria, including 242 PCOS transfers and 1422 tubal factor infertility transfers.PCOS individuals had the highest live birth rate on D4 transferred. It was not need to culture embryos to blastocysts to optimize embryo transfer for PCOS women. This could be a novel approach to transplantation for PCOS. Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects many facets of fertility. It is the cause of 18–25% of couples’ infertility. More patients with PCOS than those without the condition need assisted reproduction techniques (ARTs) therapy [Several reports have shown that gonadotropin stimulation in IVF treatment may change the endometrium and embryo quality, which may affect the live birth rate and embryo implantation , 4. HorcAccording to recent data, elective single blastocyst and single morula embryo transfer (ET) during in vitro fertilization embryo transfer (IVF-ET) produced similar clinical results –10. In aThis retrospective cohort study was conducted in the Xingtai Infertility Specialist Hospital between January 2017 and November 2021. A total of 1,664 fresh ART cycles met inclusion criteria, including 242 PCOS transfers and 1422 tubal factor infertility transfers. We used the Rotterdam diagnostic Revised 2003 criteria (2 out of 3) in adults revised: (1) Oligo-or anovulation; (2) Clinical and/or biochemical signs of hyperandrogenism; (3) Polycystic ovaries and exclusion of other etiologies  . The selThe primary endpoint of this research was the fresh cycle clinical live birth rate, and the secondary endpoints were implantation rate, pregnancy rate, and miscarriage rate. There was no missing data in the study. Written approval for this study was obtained from the Ethics Board at Xingtai Reproduction and Genetics Specialist Hospital.All patients received GnRH agonist pituitary down-regulation protocol. 1.0 to 3.75 mg of long-acting Duffelin  were administered. Subsequently, recombinant follicle stimulating hormone  was administered from 100 to 225 IU/d. Transvaginal ultrasonography was used to regularly measure follicle size, and blood levels of progesterone, LH, and E2 were used to measure follicle growth. When at least two leading follicles were ≥ 18 mm, 6000-10,000 IU of human chorionic gonadotropin  was injected. 36–37 h later, the oocytes were taken out.2, and 5% O2 incubators.The oocyte collection and embryo culture system media used G-series . All procedures were performed in standard incubators using 37℃, 6% COAfter selective fertilization, one to two embryos were transplanted on D3/D4/D5 in accordance with the development of the embryos on D3 after fertilization. In our center, we grade embryos according to the 2011 ESHRE Istanbul Consensus and Ryh-sheng Li’s system , and blaD3 embryos were assessed based on the number and blastomeres, the degree of fragmentation, and the presence of multinucleated cells. High-quality embryos were determined to have 7–8 cells, with 10% fragmentation. The available embryos were 6–10 cells, uneven blastomeres, and ≥ 10% fragmentation. They were both absence of multinucleated blastomeres.D4 embryos, which lose all of the boundaries of the blastomere were classified as grade 1. Embryos with less than 100% but more than 50% of compaction will be rated as grade 2 . The graThe inner cell mass and trophectoderm quality of D5 embryos, whose growth and hatching status were assessed from grade 1 to grade 6, were both rated as A, B, and C . The 4/5Women with overt ovarian hyperstimulation syndrome (OHSS) and thrombosis were not allowed to have embryo transplantation; The number of available embryos on the third day following fertilization determined which day to transfer. If the number of available embryos was equal to the number of transplants, the embryos were transplanted on D3. If the number of available embryos was higher than that of transplants, the early blastocysts or morulae were selected for transplantation on D4. The blastocysts were chosen and transplanted on D5 if there were more than four high-quality embryos available.Serum β-hCG was detected 12–14 days after transplantation to determine whether it was a biochemical pregnancy. About four weeks after transplantation, the beat of the gestational sac and the cardiac canal were observed by transvaginal ultrasound. The gestational sac was confirmed as a clinical pregnancy feature, and the number of gestational sacs was recorded.P < 0.05 was considered statistically significant.SPSS 27.0 (IBM) was used for statistical analyses. Continuous variables distribution was expressed as mean ± standard deviation and categorical variables were expressed as frequencies and percentages. Comparisons between groups were performed using one-way ANOVA, chi-square test, Fisher’s exact test, and nonparametric test. Logistic regression, presented as unadjusted odds ratio (crude odds ratio (OR)) or adjusted odds ratio (aOR) with a 95% confidence interval (CI), was performed. P = 0.009) and AMH (P = 0.000) of the tubal group transferred on D3, D4, and D5 were different.This retrospective cohort study was conducted in the Xingtai Infertility Specialist Hospital between January 2017 and November 2021. A total of 1,664 fresh ART cycles met inclusion criteria, including 242 PCOS and 1422 tubal factor transfers. Only patients who underwent fresh embryo transfer were included. The flowchart is shown in Fig. P = 0.001), number of oocytes (P = 0.003), E2 of HCG (P = 0.014), number of embryos per ET cycle (P = 0.000), and endometrium thickness (P = 0.000) were different among D3, D4, and D5 of PCOS. The E2 of HCG was lowest, while the endometrium thickness was thickest in the D4 PCOS group . The outcomes of PCOS were different in pregnancy rate (P = 0.001), implantation rate (P = 0.000), miscarriage rate (P = 0.011), and live birth rate (P = 0.000) among D3, D4, and D5; It is apparent from this table that the pregnancy rate and live birth rate of D4 were higher than D3 and D5 transferred patients with PCOS . From this data, we also could see that the number of oocytes (P = 0.000) and E2 of HCG (P = 0.000) of tubal on D5 was highest in the three group days; The implantation rates of tubal on D4 and D5 were both higher than D3 .As can be seen from Table P < 0.05). Although there was no statistically significant difference in live birth rates of the > 30 years group patients with PCOS, a similar trend was presented; When the number of oocytes was less than or equal to 20, the live birth rate was different among D3, D4, and D5 . The implantation rates of tubal (P = 0.006 and P = 0.027) were different in the two age stages (≤ 30 years and >30 years groups). In the different oocytes from tubal groups, the implantation rates were different among D3, D4, and D5 in numbers between 11 and 15 (P = 0.014) and more than 20 oocytes (P = 0.009) groups. With between 11 and 15 tubal oocytes, D5 had a greater implantation rate than D3 and D4 ; With more than 20 tubal oocytes, D4 and D5 had a higher implantation rate than D3  ; The situation on D4 was the contrary, PCOS has a higher live birth rate than tuble (P = 0.031). There was no difference between them on D5  had a positively and significantly increased effort for live birth.The associations of different transferred days and live birth rates of PCOS and tubal were shown in Table According to this study, D4 transplanted patients had the highest live birth rate of PCOS patients. It might be not necessary to culture to blastocyst to optimize embryo transfer for PCOS women. This could be a novel way for PCOS patients to schedule their transplantation.The primary goal of IVF-ET is the delivery of a healthy baby. ART has advanced over 40 years, yet the live birth rates remain poor . PCOS paP < 0.05), which was consistent with before report [P < 0.05). However, there was no statistically significant difference in live birth rates among D3, D4, and D5 of tubal. The live birth rate of tubal was greater than PCOS on D3 and a lower live birth rate than PCOS on D4 of the same-day transferred groups in subgroup analysis by selecting high-quality embryos from women aged 30 years or younger (P < 0.05). The rate of live births differed between the tubal and PCOS. Recently, Wang et al. [To select the most developing embryos, blastocyst culturing was used in IVF-ET. According to certain findings, transferring blastocyst-stage embryos increases the likelihood of a live delivery compared to transferring cleavage-stage embryos , 24. Howe report . We alsog et al.  found thSuccessful implantation requires endometrial receptivity status for embryo localization, adhesion, invasion, and implantation. Notably, whether its tolerance synchronous alteration with the growth of the embryo is key to determining implantation. Synchronous coordination of the endometrial receptivity status and embryonic development is necessary for successful implantation.In this study, we found the tubal and PCOS have differences in live birth rates undergoing IVF-ET. This may reflect the differences between the endometrial receptivity of tubal and PCOS during COH. It was reported that COH might negatively affect endometrial receptivity  for implEmbryo-endometrium synchronization is important in embryo transfer. A study demonstrated abnormal gene expression in human PCOS oocytes. These genes included processes such as maternal effect genes and the mitotic cell cycle . It has P < 0.05). Since estrogen matched with the number of oocytes retrieved, we chose the number of eggs collected for group analysis to avoid statistical errors. Our results showed that the implantation rate of tubal oocyte numbers between 11 and 15 were different in three transferred days (P = 0.014). D5 had a higher implantation rate than D3 and D4 of tubal oocytes between 11 and 15 ; The live birth rate of PCOS was higher on D4 than D3 when oocytes number between 11 and 20 . The results of this study showed that D4 of PCOS  had a positively and significantly increased effort for live birth. Those might imply that PCOS transferred on D4 were better, especially the live birth rate.A study thought that serum E2 levels on the day of trigger were not a good predictor of live birth rate or perinatal and obstetrical outcomes . HoweverThe outcomes of PCOS were different from tubal. The reasons for this conclusion may be: First, it should be noted that PCOS had a lower endometrial receptivity than tubal. Additionally, ovarian stimulation changed how the endometrial luteal phase developed and appeared to affect receptivity for implantation. The premature appearance of the NCS and hence maturation of the endometrium following COH . Also, iP ≤ 1.5 ng/mL (99.28% of the entire cycle). This resulted in a high multiple pregnancy rate. We have now been able to reduce the number of transplant as well as the multiple pregnancy rate since realizing this problem. Moreover, we cannot exclude bias due to different ethnicities. Further multi-center randomized clinical trials would be needed for confirmation. In addition, due to the nature of the study unknown confounding factors cannot be excluded. Prospective randomized control trials should be addressed in the future to investigate the best day for transfer.The main benefit of our study was that it investigated the outcomes of PCOS and oviduct factor infertility in different transferred days of D3, D4, and D5. This study does, however, have some limitations since it was a retrospective single-center study. Efforts to boost the patients’ pregnancy rate at the time, we transplanted more embryos than now when In conclusion, the current study showed that live birth rates of PCOS were different on various transferred days. The highest live birth rate of PCOS patients was on D4 transferred. These results suggested that it was not need to culture embryos to blastocysts to optimize embryo transfer for PCOS women. This may be a new transplantation strategy for PCOS.


The relative age effect (RAE) has been the subject of many studies, but no relevant literature has discussed the phenomenon of RAE in Chinese tennis. Numerous studies have demonstrated that RAE significantly contributes to brain drain and other occurrences that create inequity. This paper analyzes the birth dates and year-end rankings of all male players (N = 2697) who participated in China’s junior tennis tournaments  between 2014 and 2019 and who were selected for China’s National Junior Team in 2019 and 2020; the paper classifies the birth dates into quarters and semesters. One of the research objectives of this study is to analyze whether RAE exists in Chinese junior men’s tennis and whether RAE exerts an effect on athletes’ performance. Differences between the observed and expected birthdate distributions were tested using chi-square statistics, and subsequent calculations were tested using odds ratios. The study found that RAE was present in all Chinese junior male tennis sports groups (p<0.001). The percentages of athletes born in the first half of the year were 56.4% (U12), 60.4% (U14), and 60.4% (U16), and the percentages of those born in the first quarter were 34.1% (U12), 36.4% (U14), and 37.1% (U16). Athletes with birth dates closer to the beginning of the year had a higher probability of achieving excellent athletic performance as a result of RAE, whereas those who were born near the end of the year had a more difficult time achieving strong athletic performance. For exaAccording to sports science research, RAE makes athletes born in the selection year or early in the competition year more mature in terms of their physical, emotional, cognitive, and performance advantages than athletes born later in the same year –12. ThisThe impact of RAE has been researched in relation to sports –4, educaNumerous studies regarding the impact of the RAE have been published in the past ten years, including those concerning soccer , 13, 26,In tennis, RAE has been uncovered in both young players and elite athletes. The skewed birthdate distribution of 12-to-16-year-old tennis players in the Dutch youth league rankings was initially discovered by Dudink et al. . GiacomiBased on various studies regarding elite tennis players, Edgar, O’ Donoghue  found thStudies have also specifically examined young tennis players. Pacharoni et al.  analyzedThe RAE in sports has been the subject of substantial research and discussion, but there is still minimal relevant research in China. A large number of studies have demonstrated that RAE can cause many unfair phenomena, such as talent loss , 46, 47;This study recorded the birth date and year-end ranking results of all the 2590 male athletes who participated in the Chinese junior tennis tournaments  from 2014 to 2019. The 107 male athletes chosen for China’s National Junior Tennis Team and Junior Reserve Team in 2019 and 2020 were listed with their birth year and year-end ranking.www.Tennissport.org.cn). Data extraction included each player’s name, birthdate, and Year-end ranking results. Due to the study data being in the public domain, no informed consent and approval by an Ethical Committee were required.Rankings and birth months for the research participants was downloaded through the open-access online data-bases provided by the China Tennis Association’s official website  and two semesters (S) to calculate the RAE of the different age categories . The cutTo examine RAE, the distribution of the participants’ birth months across Q1–Q4 was examined using Chi-square t (X²) goodness of fit test. The theoretical (expected)frequency distribution was Q1 = 90.25/365.25, Q2 = 91/365.25, Q3 = 92/365.25, Q4 = 92/365.25, which is in relative values: Q1 = 24.71%, Q2 = 24.91%, Q3 = 25.19%, Q4 = 25.19% . The effAs is evident in There is an evident relative age effect among Chinese U12 male tennis players. The birth dates of athletes from 2014 to 2019 exhibited a skewed distribution every year, and there were statistically significant differences (p < 0.05); based on the Q1/Q4 (OR) values, 2019 was the only year with no obvious impact; all other years had different degrees of impact. In general, the date of birth skew of the U12 athletes displayed a statistically significant difference (p < 0.01). Among U12 male tennis players between 2014 and 2019, there was a trend of exacerbation followed by a steady decline in the RAE; overall, there was neither a notable improvement nor an exacerbation.It is evident from Among Chinese U14 male tennis players, with the exception of 2016 and 2017, the date of birth skews in other years were statistically significantly different, even for athletes born in the first half of 2016 or 2017; they were also significantly higher than for those born in the second half of the year. Judging from the S1/S4 (OR) value, only the impact of 2016 was negligible, and other years had varying degrees of impact. In terms of the total number of U14 players, the date of birth was more skewed, and the impact on the statistical significance was highly significant (p < 0.01). Therefore, among U14 Chinese U14 male athletes, the RAE was evident. Overall, there was no significant trend of improvement or exacerbation of the RAE among U14 male tennis players from 2014 to 2019.For the older group of Chinese junior tennis players (U16), the degree of skewness in the players’ dates of birth was still evident; the years of age were not statistically significant for only 2017 and 2018. In terms of the Q1/Q4 (OR) values, only the impact of 2017 was negligible, and other years had varying degrees of impact. The date of birth skew of the total number exhibited a highly significant difference (p < 0.01), and the RAE was clear among Chinese U16 junior men’s tennis players. Overall, there was no significant regular change in the impact of the RAE among U16 male tennis players between 2014 and 2019.As is evident in In general, the dates of birth among the Chinese men’s national junior tennis team players were highly skewed, and there was a statistically significant difference in each group (p < 0.05); the overall degree of skewness was highly significant (p < 0.01), with the OR value as high as 2.8 and the proportion of births in the first half of the year as high as 65.4%. The relative age effect is thus evident in the Chinese national men’s junior tennis team.We evaluated and compared the total numbers for each group with the total numbers for the top 30 ranked at the end of the year and the total numbers of the bottom 30 ranked at the end of the year to more clearly understand the influence of relative age on the performance of young tennis players.The skewed distribution of birth dates among the top 30 athletes displayed an extremely significant difference, while the bottom 30 athletes exhibited no difference or a significant difference, according to the data in Meanwhile, the percentages of the total number in each group whose birth dates were in the first quarter were 34.1% (U12), 36.4% (U14), and 37.1% (U16), and the percentages of people whose birth dates were in the first half of the year were 56.4% (U12), 60.4% (U14), and 60.4% (U16); the ORs were in order: 1.49, 1.66, and 1.76. In general, the degree of birth date skew between the top 30 and bottom 30 athletes varied widely across all groups, with more top-ranked athletes having birth dates closer to the start of the year and more bottom-ranked athletes having birth dates closer to the end of the year. Therefore, athletes with birth dates closer to the start of the year were more likely to achieve greater athletic performance, while those with birth dates closer to the end of the year were less likely to do so.The key purpose of this study was to examine the RAE among Chinese youth men’s tennis players. The study found that there was a skewed distribution of the birth dates of the athletes in each group. These results are consistent with earlier studies , 43–45 tThere was a significant RAE among all groups of Chinese junior male tennis players, with a skewed distribution of birth dates in each group, and the difference was statistically significant (P < 0.05). The percentages of the total number of athletes in each group whose date of birth was in the first quarter were 34.1% (U12), 36.4% (U14), and 37.1% (U16), and the percentages of athletes whose date of birth was in the first half of the year were 56.4% (U12), 60.4% (U14), and 60.4% (U16); the ORs were 1.49, 1.66, and 1.76, respectively. As the level of play continued to increase, there was a gradual upward trend in the percentage of births in the first quarter and first half of the year from the U12 to the U14 and U16 divisions, and the extent of the impact of the RAE continued to deepen. This trend supports several theoretical models demonstrating the existence of RAE. The Matthew effect is explained by the fact that the rich become richer and the poor become poorer; the Pygmalion effect posits that the greater the expectations of a person, the greater the outcome that person will achieve; and the Galatea effect indicates that once expectations are imposed on a person, that person’s behavior is typically consistent with those expectations . As a reThe findings mentioned above could be attributed to the selection process used for Chinese youth tennis players as well as the fact that tennis is a sport with numerous youth competitions. Tennis has a more competitive atmosphere due to its early competitive activity and the abundance of youth tournament events throughout the junior years. As a result, those players who were born towards the early end of a particular group are more likely to have superior skills and physical fitness, giving them an advantage over their peers in the same age group , 51–53. It is critical that equal opportunities are available to all players. However, many of the procedures that are currently used for selecting athletes do not ensure such fair opportunities. The performance of young players accounts for the majority of the selection criteria for Chinese young tennis players, which undoubtedly increases the probability of this unfair phenomenon. Children who mature later may experience discrimination under the existing selection process. The first group of talented athletes who withdraw from the selection process are frequently those who are temporarily less physically and psychologically mature –53. The RAE is most plainly present in the Chinese national men’s junior tennis team due to the aforementioned potential causes. The proportion of athletes born in the first half of the year reached as high as 65.4% in the Chinese national junior tennis team’s birth date distribution, which was markedly skewed . Therefore, Duarte et al.  suggest Studies regarding the relationship between the RAE and sports performance in different sports have reached different conclusions. Although studies have demonstrated a relationship between the RAE and performance among young alpine skiers , other sFrom the perspective of the sustainable development of sports and the reduction of brain drain, competition organizations, coaches, athletes, and their parents should fully understand the negative factors influencing the relative age effect on the growth and success of athletes. To mitigate the temporary disadvantage of younger players, the talent selection and deselection process should consider and favor player potential development rather than current performance. Some studies have thus suggested that coaches must keep all players to some extent and avoid selecting only the best athletic performers. As a result, late-born players should continue to be involved with the club and be given the same possibilities for playing and training as early-born players . This miSome limitations should be underlined when interpreting this study. Firstly, we have considered the quarterly distribution of birth dates as being equal. The distribution of birth dates for the overall population in the studied nations was not taken into consideration when executing this investigation. Secondly, only quantitatively collected data were used in our study, which slightly limited our ability to fully understand the RAE issue. Ultimately, the study’s findings contributed to a deeper understanding of RAE-related issues among coaches, athletes, and administrators. However, our study did not offer any suggestions regarding how to lessen the effect of the RAE in sports practice.The study found that there was a skewed distribution of the athletes’ birth dates in each group. Athletes born in the first quarter were significantly were prevalent than those born in the fourth quarter, and those born in the first half of the year were also significantly more common than those born in the second half of the year. The phenomenon of the RAE exists in all groups of Chinese young men’s tennis players. The RAE has a tendency to gradually strengthen its influence among young Chinese men’s tennis players as they become older.A deeper impact of the RAE was discovered in the examination of athletes selected for the national junior tennis team and the training reserve team, and in some years, the percentage of players born in the first quarter might reach 50%. This also further suggests that RAE has different degrees of influence on young male tennis players, with a tendency for that influence to increase with the level. In general, the RAE exerts an impact on the athletic performance of athletes participating in Chinese youth tennis competitions. This demonstrates that athletes with birth dates closer to the start of the year have a higher probability of achieving excellent sports performance, whereas athletes with lower rankings have a more difficult time achieving strong outcomes.S1 Data(XLSX)Click here for additional data file.


Preterm birth is a major maternal complication that has a great impact on perinatal and neonatal health, with consequences suffered during childhood and adulthood. Little is known about its etiology and development, resulting in poor screening, prediction and preventive methods. The present integrative review discusses the current knowledge regarding some risk factors for preterm birth, the differences between screening and prediction methods, the limitations of some current preventive interventions, the importance of applying standardized concepts for exposures and outcomes, and why it is important to develop more accurate and reproducible methods to predict preterm birth. In addition, the authors introduce the concept of metabolomics and the technology involved in this technique, and discuss about how it has become a promising approach to identify biomarkers for spontaneous preterm birth. The birth of a preterm baby may have diverse negative consequences for the baby him/herself, (his or her) neonatal life, childhood and adulthood, the family, the healthcare system/service, and society as a whole. The present manuscript focuses on the factors associated with preterm birth, the perinatal outcomes and the ways to predict them, supported by the hypothesis that it is possible to better understand and predict the preterm birth process, creating opportunities for increased effectiveness in the prevention of this condition.It took several decades to consolidate the definition of preterm birth. At the beginning of the 20th century, newborns weighing less than 2,500 g at birth were considered preterm, based primarily on neonatal behavior and progression to neonatal mortality, intracranial hemorrhage and other morbid conditions.Preterm birth may be classified according to the clinical presentation or the motivator: spontaneous, when due to spontaneous preterm labor  or preterm premature rupture of the membranes (P-PROM); and therapeutic, when theoretically there is a condition that poses a risk to the mother and/or the fetus, generating sufficient motivation for resolution at a preterm gestational age.Therefore, at least the distinction between spontaneous and therapeutic preterm birth is highly recommended when studying the determinants and consequences of preterm birth. The recognition that not every preterm birth occurs because of the same determinants was an early step to study the causes and develop preventive strategies. Preterm birth is also categorized according to gestational age at birth, and is divided into: late preterm (between 34 weeks + 0 days and 36 weeks + 6 days), moderately preterm (from 32 + 0 weeks to 33 + 6 weeks), very preterm (from 28 + 0 weeks to 31 + 6 weeks) and extremely preterm (< 28 weeks).Pregnancy of a singleton or multiple fetuses (twins) confers great differences not only in terms of the incidence of preterm birth, but also concerning its associated factors and the maternal and perinatal outcomes.A studyComplications due to preterm births account for more than 1/3 of neonatal deaths worldwide, representing over 1 million newborn infants who died in the first month of life in 2010. The impact of complications due to preterm birth also has repercussions regarding childhood health indicators. It is the second cause of death until age 5 globally, and the first cause of death in mid-income and high-income countries.Since the 1950s, many advances have been made in the number of options and in the level of scientific evidence-based preventive measures for neonatal complications due to preterm birth. Among those are measures of tertiary prevention, such as the use of tocolytics and corticotherapy for the prevention of hyaline membrane, intraventricular hemorrhage and necrotizing enterocolitis; magnesium sulfate for the prevention of cerebral palsy in cases of imminient preterm delivery; and antibiotic therapy for the prevention of neonatal sepsis and to prolong the latent phase in cases of P-PROM.There were also advances in the identification and institution of early therapies for neonatal complications such as neonatal sepsis, hypothermia, visual, cerebral (intra- and periventricular hemorrhage), auditory and/or neuropsychomotor impairments, providing the newborn with the possibility of earlier neonatal follow-up and better long-term results.Risk factor is a term used to designate conditions, characteristics, habits or markers that, when present, increase the probability of occurrence of a specific injury. Risk, therefore, is related to the onset of a condition.2), normal (BMI between 18.5 kg/m2 and 24.9 kg/m2), overweight (BMI between 25.00 kg/m2 and 29.9 kg/m2) and obesity (BMI ≥ 30.0 kg/m2).An example of a combination of factors is BMI and gestational weight gain. The National Academy of Medicine (NAM), in the United States, formerly known as the Institute of Medicine (IoM), categorized BMI into low weight  and the phosphorylated isoform of insulin-like growth factor binding protein (phIGFBP-1), binding proteins present between the chorion of the amniotic membrane and the maternal decidua, and cervical length measurement in the second trimester of pregnancy by transvaginal ultrasound. Systematic reviews have concluded that those markers are not sufficiently accurate to be useful in the clinical prediction of preterm birth, especially in asymptomatic women.A Dutch prospective cohort studyFetal fibronectin in the vaginal secretion does not show much superior results in asymptomatic women. A cohort studyOther propositions have attempted to address the association between multiple factors involved in the development of preterm birth. A group of expertsThe aforementioned group of experts, with the aid of other collaborators, applied this concept through a secondary analysis of an international multicenter cohort study named INTERGROWTH 21st.According to Geoffrey Rose,The identification of factors associated with a higher risk of developing spontaneous preterm birth may be useful to help physicians understand its pathophysiology and identify women at higher risk who might benefit from prevention strategies. In the latter case, it may also possible to distinguish between screening for risk and prediction of preterm birth. Although both methods use risk factors as the basis for their models or algorithms, their practical application may be quite distinct.For example, women with transvaginal ultrasound assessment of cervical length between 20 mm and 25 mm, which was measured in the second trimester by a standardized technique, had an incidence of preterm birth ranging from 22% to 32%.p-value of 0.0009) and in cerebral alterations on ultrasound . The authors of this study concluded that the subgroups of women who might benefit from progesterone are not easily identified by the current screening strategies. This should encourage studies on new prevention strategies as well as those aimed at identifying women that may be potentially eligible to undergo this treatment.The OPPTIMUM study,Another technique that has been studied for decades is cerclage, which is primarily based on suture of the uterine cervix or isthmus-cervical region to prevent early effacement/dilatation of the cervix. The Shirodkarversus expectant management) to prevent preterm birth. Selecting pregnant women at high risk based on cervical length measurement in the second trimester, with slightly more than 190 women per group, the study showed that the incidence of preterm births before 34 weeks decreased by 80%. Subsequent studies demonstrated conflicting results, and did not confirm such a reduction in the incidence of preterm births observed by Goya et al.It is also worth mentioning that another intervention was studied for the prevention of preterm birth in high-risk women. A pessary, a device made of firm silicone in the shape of a convex ring, is inserted into the posterior vaginal fornix and fastened to the cervix. The theoretical mechanism for the prevention of preterm birth is based on: 1) a change in the axis of forces resulting from the uterine body and isthmus that act on the cervix; and 2) a potential closure of the cervix with consequent strengthening of the cervical canal and the immunologic barrier of the cervix, preserving the amniotic membranes from contact with the vaginal environment.Despite the advances/benefits resulting from a combination of screening for risk and interventions, such as, progesterone, the pessary and cerclage in women selected based on risk factors, there still seem to exist limitations and heterogeneity in screening. Better results from the use of these measures may be potentially hindered. Which women might actually benefit from the use of progesterone during prenatal care? Which women might not benefit from any preventive intervention? Furthermore, there is no consensus over which level of risk estimate determines that a woman should in fact be considered at high risk. Improved identification of women at high (or low) risk of having a preterm birth with the development of prediction models that have good discriminatory performance may be quite relevant to advance the investigation of the benefits of using (or not) progesterone, the pessary or any other form of preterm birth prevention.The description of these prevention studies and their interpretations are important to highlight the fundamental role of the adequate screening of women who may benefit from prevention strategies. Distinctions must be made regarding the risk assessment model and a predictor model for an outcome. This distinction may actually help physicians understand the clinical application of a screening strategy for women at high risk of having a preterm delivery.As an example of a risk marker, the cervix is known to be independently associated with a higher risk of having a preterm birth.A prospective observational studyIn summary, systematic reviews have concluded that there are no markers in the literature that can be applied in the clinical practice to predict spontaneous preterm birth with a good performance, and that enable new preventive approaches and studies in this area.The term “omics sciences” is applied to the field of knowledge that focuses on genomic studies, gene identification, DNA sequence polymorphisms, genes and the genome; transcriptomics, which is focused on the study of gene expression – RNAs; proteomics, the large-scale study of proteins; and metabolomics, the scientific study of chemical processes involving metabolites.Metabolomics is the science that studies metabolites, small molecules present in different chains of the metabolism of an organism.By identifying and quantifying metabolites, this technique is capable of showing the fingerprint of the metabolic interactions of the organism in a certain sample at a certain time. Metabolomics is a technique known as hypothesis-free, that is, it does not require an initial hypothesis. Instead of testing a certain hypothesis, the technique may generate novel hypotheses through its results when elucidating the markers and biological pathways involved in the process of disease development, which may not have been clarified.Metabolomics has been applied in biological samples for the investigation of processes ranging from embryogenesis to the emergence of complex diseases such as cancer, Parkinson disease, diabetes and depression.After identifying 45 metabolites significantly associated with preclampsia in serum samples collected at 15 weeks of gestation from a group of ∼ 39 nulliparous pregnant women with a history of preeclampsia (compared with 40 pregnant women without complications), 14 metabolites were selected to compose the final model . The model resulted in an area under the ROC curve of 0.92, and an OR of 23 .p-value according to the number of variables (metabolites) analyzed. The false discovery rate (FDR) method may also be applied to control the number of false-positive conclusions, and significance is only assigned to the “most promising” variables.Many aspects regarding the most effective method to investigate preterm birth using metabolomic markers should be discussed. First, there is the type of sample used . Then, there is the time for sample collection . Furthermore, metabolomics demands a high methodological rigor in the collection and storage of biosamples, since this is a highly sensitive method to identify small low-weight molecules; various types of “noise”, or interference in data acquisition, may hinder the identification of these molecules. Heterogeneity in sample collection and storage may be the cause. In addition, a well-delineated study design, with well-defined outcomes, following clear classifications, associated with sequential validations of findings is crucial for the reliability and reproducibility of this technique. Finally, still in the phase of data analysis, caution regarding some important considerations is emphasized. For example, hundreds or even thousands of metabolites are usually analyzed at the same time in a sample. Since the number of variables (metabolites) is much higher than the number of samples , the analysis is very susceptible to significantly false results. To correct this effect, the Bonferroni correction may be used, attenuating the significance of the Many questions need to be answered concerning the mechanisms involved in the development of preterm birth: why do some women have early cervical remodeling  and others do not? Which and how are the interactions between different risk factors, including infection, vaginal bleeding and body mass index, and how can they determine preterm birth? In theory, metabolomics depicts the final pathway resulting from these interactions, and it seems to be a useful approach not only to predict spontaneous preterm birth, but also to elucidate the many mechanisms involved.In order to adequately address the investigation of preterm birth, its associated factors and perinatal outcomes, a robust methodological approach is required, using judicious and standardized definitions of exposures and outcomes. Based on this premise, a multifaceted comprehensive approach, albeit integrated, was proposed for data exploration on the factors associated with preterm birth, its prediction and the perinatal outcomes, which may be capable of generating new knowledge regarding this issue. It is expected that the results of this approach may contribute to the prediction of the most effective performance and better understanding of the factors associated with spontaneous preterm birth and consequent adverse perinatal results, collaborating with the development and application of public policies to prevent preterm birth and its perinatal consequences. We acknowledge the fact that the present is an integrative review based on a biased search in the literature and on the interpretation of the studies and respective findings. Although we have not used the standard tools and strategies to measure and report these biases, we consider that it is a great opportunity to raise the discussion about some of the risk factors associated with sponteaneous preterm birth, how preventive strategies based on these factors have been implemented, and the results so far. We expect that, despite the limitations of the present integrative review, it may contribute to the discussion about recognizing women at a higher risk of having sponteaneous preterm birth and how to prevent it.