Preterm birth is the leading cause of childhood mortality and morbidity. We aimed to provide a comprehensive systematic review on randomized controlled trials (RCTs) on progesterone, cerclage, pessary, and acetylsalicylic acid (ASA) to prevent preterm birth in asymptomatic women with singleton pregnancies defined as risk of preterm birth and multifetal pregnancies.Six databases  were searched up to February 2022. RCTs published in English or Scandinavian languages were included through a consensus process. Abstracts and duplicates were excluded. The trials were critically appraised by pairs of reviewers. The Cochrane risk-of-bias tool was used for risk of bias assessment. Predefined outcomes including preterm birth, perinatal/neonatal/maternal mortality and morbidity, were pooled in meta-analyses using RevMan 5.4, stratified for high and low risk of bias trials. The certainty of evidence was assessed using the GRADE approach. The systematic review followed the PRISMA guideline.n = 50).The search identified 2,309 articles, of which 87 were included in the assessment: 71 original RCTs and 16 secondary publications with 23,886 women and 32,893 offspring. Conclusions were based solely on trials with low risk of bias   thereby reducing neonatal mortality and respiratory distress syndrome. Cerclage probably reduced the risk of preterm birth <37 gestational weeks: 29.0% vs. 37.6% (RR 0.78 [95% CI 0.69 to 0.88]) . In addition, perinatal mortality may be reduced by cerclage. Pessary did not demonstrate any overall effect. ASA did not affect any outcome, but evidence was based on one underpowered study.Multifetal pregnancies: The effect of progesterone, cerclage, or pessary was minimal, if any. No study supported improved long-term outcome of the children.Progesterone and probably also cerclage have a protective effect against preterm birth in asymptomatic women with a singleton pregnancy at risk of preterm birth. Further trials of ASA are needed. Prevention of preterm birth requires screening programs to identify women at risk of preterm birth.https://www.crd.york.ac.uk/prospero/], identifier [CRD42021234946].[ Preterm birth, defined by the World Health Organization as a birth of a liveborn child before 37 gestational weeks, is the leading global cause of childhood mortality and morbidity. About 15 million children worldwide are born preterm each year, and one million will die due to preterm birth complications. Furthermore, 40% of children born preterm will be subjected to an increased risk of various short- and long-term complications, potentially reducing their quality of life and raising healthcare costs , 3.Preterm birth is either a spontaneous or a physician-initiated birth. Spontaneous preterm birth accounts for two-thirds of all preterm births and starts with either contractions or preterm prelabor rupture of membranes (PPROM). The underlying causes of spontaneous preterm birth are multifactorial, including infection, inflammation, vascular disease, or distention of the uterus, but the cause often remains elusive . AnotherBoth pharmacological and mechanical intervention strategies have been suggested to prevent preterm birth. Progesterone, vaginal cerclage, pessary, and more recently, acetylsalicylic acid (ASA) are examples of commonly studied such interventions.Progesterone is an essential hormone to maintain a pregnancy until term. It modulates the immune response  and is aCervical cerclage offers mechanical support to the cervix by placing a stitch around the cervix by a vaginal (most common) or transabdominal approach, requiring anesthesia and the resources of an operating theatre . CerclagThere are different techniques for cerclage where the two most commonly used are the McDonald and the Shirodkar technique. Both are applied vaginally. The McDonald cerclage is placed like a purse-string fashion and tied anteriorly. It requires no dissection into paracervical tissue. The Shirodkar cerclage starts with a transverse incision in the vaginal mucosa anterior and posterior to allow upward displacement of the bladder and rectum in order to achieve a higher insertion point of the cerclage. The knot is tied posteriorly, and the mucosa is sutured anteriorly and posteriorly. Complications associated with the procedure are iatrogenic rupture of the membranes, vaginal bleeding, and intraamniotic infection. The transabdominal approach is mainly used after a failed vaginal cerclage or in women who have undergone a trachelectomy  .The cervical pessary is suggested to change the position of the cervix to a more posterior angle and thus change the weight of the pregnancy towards the anterior lower segment of the uterus. Also, the pessary can prevent the cervix from dilating and prevent the amnion and chorion from dissociation from the uterine wall. It is placed and removed during outpatient visits . Thus, tAcetylsalicylic acid has an anti-inflammatory effect, and an impact on preterm birth might be due to decreasing uterine contractility through inhibition of the cyclooxygenase (COX)-dependent prostaglandin synthesis . ASA is There have been several contributions to preterm birth prevention in the last few years. The aim of this systematic review was to provide a comprehensive, up-to-date review on randomized trials on progesterone, cerclage, pessary, and ASA for the prevention of preterm birth in asymptomatic women with singleton pregnancies defined as having an increased risk of preterm birth or women with a multifetal pregnancy. The focus on a North European setting is based on the lack of guidelines in several countries in this region, and thus the need for a systematic review explicitly applicable to this population.The protocol for this review was registered at the International Prospective Register of Systematic Reviews  before data extraction. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) was followed .The research question was framed as the following:Will the interventions progesterone, cerclage, pessary, or ASA, alone or in combinations, decrease the risk of preterm birth, neonatal and maternal mortality/morbidity, and long-term child morbidity in asymptomatic women with a singleton pregnancy at risk of preterm birth or in asymptomatic women with a multifetal pregnancy with or without additional risk factor(s)?Asymptomatic women with previous preterm birth, previous spontaneous late miscarriage between 16 and 22 gestational weeks, short cervix, previous cervical surgical treatment for cervical intraepithelial neoplasia, or with other risk factors as defined by the trial authors were considered to be at risk of preterm birth.We used the PICO model to define the Populations, Interventions, Comparisons, and Outcomes.Populations (P) were asymptomatic (without symptoms indicating risk of preterm birth) women with a singleton pregnancy at increased risk of preterm birth <37 + 0 gestational weeks or asymptomatic women with a multifetal pregnancy, irrespective of other risk factors.Types of interventions (I) were:Progesterone, any type initiated in the second trimester, alone or in combination with the other specified interventions in the PICO. Comparisons between different dosage and administration routes were not included.Cerclage, any type applied before pregnancy, in the first or second trimester, alone or in combination with the other specified interventions in the PICO.Pessary, any type applied in the first or second trimester, alone or in combination with the other specified interventions in the PICO.ASA initiated in the first or second trimester, alone or in combination with the other specified interventions in the PICO.Types of comparisons (C) were no intervention, placebo, or other intervention .Main outcome (O) measures included preterm birth: Any preterm birth <37 weeks and early preterm birth <34 weeks. We assessed adverse neonatal outcomes associated with preterm birth: perinatal mortality , neonatal mortality <7, <28 days, serious neonatal morbidity , individually or as a composite outcome with or without peri/neonatal mortality, and long-term morbidity . We assessed maternal mortality and maternal morbidity .Other outcomes were any preterm birth <35, <33, <32, <28 gestational weeks, spontaneous preterm birth <37, <35, <34, <33, <32, <28 gestational weeks, gestational length, low birth weight , and very low birth weight .Peri/neonatal and maternal mortality and long-term child outcome were considered to be the most critical outcomes.Randomized controlled trials (RCTs) and systematic reviews of RCTs were eligible for inclusion. In addition, in a separate search addressing the intervention of progesterone and the outcome of cancer in the woman, cohort studies with any number of participants were included to support the discussion of long-term risk.Exclusion criteria were as follows: Studies not fulfilling PICO, trials not published in English, Swedish, Norwegian, or Danish, abstracts, posters, conference papers, or duplicates.Two authors  performed systematic searches in PubMed, Embase, Medline, and the Cochrane Library . In addition, the websites of the Swedish Agency for Health Technology Assessment and Assessment of Social Service (SBU) and The Norwegian Institute of Public Health (Folkehelseinstituttet) were searched, and reference lists of relevant articles were scrutinized for additional references. Search strategies and eligibility criteria are presented in A separate search was done , addressing the intervention progesterone and the long-term risk of cancer in the woman. Search strategies and eligibility criteria are presented in Two authors , independently, assessed the obtained abstracts and made the first selection of full-text articles for inclusion. The selected articles were sent to all authors, and at least two other authors independently read the articles. In a consensus meeting, the authors decided which articles to include. Any disagreements were resolved in consensus.A graphic presentation of the selection process is presented in At least two authors critically appraised the included trials independently regarding directness , risk of bias , and precision using a checklist for the assessment of RCTs from the Swedish Agency of Health Technology Assessment and the Assessment of Social Services (SBU) and modified by HTA-centrum .A detailed risk of bias assessment of each trial and its primary outcome was conducted using the Cochrane risk-of-bias tool . Studies2I statistics  with 95% confidence interval (CI) and as pooled weighted risk differences (RD) with 95% CI. In the case of trials with zero events in one arm, continuity correction by adding 0.5 in each cell was used in the meta-analysis. For three outcomes in there are discrepancies in significances between the presented RR and RD. This difference can occur when there is a borderline significance and is caused by (1) the difference in mathematical approximations when calculating CIs for RR and RD, respectively, and (2) the continuity corrections when calculating RR for trials with zero event-arms which is not done for RD. The latter occurred for two out of the three outcomes. Continuous data that were presented with median and interquartile range (IQR) were transformed to mean and standard deviation (SD), assuming a normal distribution. The heterogeneity of treatment effect was assessed with atistics . We asseSingleton and multifetal pregnancies are presented separately. Trials with mixed populations without separate reporting were included in meta-analyses of singleton pregnancies if twins constituted ≤2% of the study population. Trials with >2 and < 10% multifetal pregnancies were also included in meta-analyses of singleton pregnancies, followed by a sensitivity analysis with the exclusion of the mixed population trial. Trials with ≥10% multifetal pregnancies were not included in any meta-analyses of singleton pregnancies.Pre-specified subgroup analyses were conducted according to risk factors (short cervix or history of preterm birth) in women with singleton pregnancies among trials with low risk of bias. Subgroup analyses according to the administration route of progesterone  were conducted as exploratory analyses comprising trials with low risk of bias. Subgroup analyses of women with multifetal pregnancies were exploratory according to additional risk factors.The certainty of evidence was defined according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system , 32. TheThe domain directness (applicability of evidence) was evaluated generally, i.e., considering proportion of eligible women who were randomized. Directness was also evaluated specifically, i.e., considering applicability to a North European health care setting, including inclusion/exclusion criteria and ethnical background affecting risk for preterm birth. At least three researchers in a joint evaluation determined the certainty of evidence for each outcome.The literature search in January 2021 and February 2022 identified 2,309 articles after removing duplicates . Two autA separate search in November 2021, addressing the intervention of progesterone and the outcome of cancer in the woman, identified 369 references . Two autThirty RCTs reporting on singleton pregnancies were included, and two long-term follow-up reports of RCTs , 91 in tOne secondary publication  reportedTen RCTs reporting on singleton pregnancies were included . Four trIn addition, one systematic review contributed to the meta-analyses with study data on singleton pregnancies . In totaSeven RCTs reporting on singleton pregnancies were included . All triOne RCT with low risk of bias comprising 387 women/babies was included in the analyses  Supplem.The RCTs were carried out in the USA (7), in the Netherlands (1), and in the Middle East (12), and the rest were conducted in Pakistan, India, Brazil, Japan, and Zambia. Five trials were multinational.The RCTs were carried out in the USA (4), United Kingdom (2), France (2), the Netherlands (3), South Africa (2), Brazil, Slovenia, Greece, Chile, Nigeria, Hungary, Norway, Italy, Japan, Israel, Belgium, Zimbabwe, Iceland, Ireland, and Canada. Two trials were multinational.The RCTs were carried out in the USA (1), China (1), Iran (1), Brazil (1), Italy (1), and Spain (1). One trial was multinational.The trial was conducted in 34 centers in the Netherlands.All trials included asymptomatic women with an increased risk of preterm birth, mainly a history of preterm birth , short cervical length , or both. In addition, two trials included women with pregnancies after assisted reproductive technology (ART) as a risk factor. Finally, one trial included women with HIV as a risk factor.The risk of preterm birth was assessed based on previous obstetric history , 80, 105Otsuki et al.  and To eAll trials included asymptomatic women with the specific risk factor for preterm birth and short cervical length. The cut-off for inclusion was cervical length ≤ 25 mm in all trials except for one that used ≤30 mm .The trial included women with a history of previous spontaneous preterm birth of a singleton between 22 and 37 gestational weeks.The interventions included different routes of administration: vaginal progesterone  , im injection of progesterone (17-OHPC) , or oral progesterone . Doses of vaginal progesterone varied between 90 and 400 mg per day. Doses of oral progesterone varied between 400 and 600 mg per day. Doses of 17-OHPC were similar across trials (250 mg 17-OHPC im per week), except in one small trial [Hauth et al.  which usThe included trials differed in inclusion criteria regarding gestational age at the onset of intervention (ranging from early to late second trimester) and treatment duration .Trials with low risk of bias reported adequate compliance or adherence to treatment (≥80% of prescribed medication) for >90% of participants in nine trials , 92, 96.All trials compared transvaginal cervical cerclage versus no cerclage. Blinding was not feasible due to the nature of the intervention. The intervention included either McDonald cerclage  or Shirodkar cerclage . One triFive trials compared pessary with no pessary. In one of the trials, a vaginal examination was performed in the control group to simulate pessary insertion . BlindinThe intervention was a daily oral intake of 80 mg ASA or a matched placebo, starting between 8 and 16 gestational weeks. Good medication adherence was defined as tablet intake ≥80%. Medication adherence was calculated by dividing the number of used tablets by the expected number of doses per participant. Good adherence was reported by 63.3% of participants. Other interventions for preventing preterm birth, such as progesterone, cerclage, or pessary, could be used alongside the studied intervention if deemed appropriate by the physician.Quality assessment  of the included trials is presented in the outcome tables in Some of the included trials had some problems with directness, which was affected by ethnicity . The study limitation in all trials on cerclage and pessary was the lack of blinding since blinding participants and personnel was considered impossible. The trials were generally underpowered for outcomes such as neonatal mortality and neonatal and maternal morbidity since these were not primary outcomes in most trials.Publication bias was not detected in any of the funnel plots, and thus not utilized as a reason for downgrading the certainty of evidence.In some studies, directness was affected by a high preterm birth rate in the control group.More than half of the included trials had no severe study limitations. Three trials were stopped early , 84, 116Some trials were old, conducted, and published before 2000 [low risk of bias: Macnaughton et al. ; high riDirectness was affected by an unusually high incidence of preterm birth in the control group in one study , 7.6% ofTwo trials were stopped early, affecting precision. The reasons were (1) a competing trial and (2) a lower enrolment than expected , 86.The trial had minor problems with directness since the number of eligible women was not presented. There was no serious study limitation, although there were some baseline differences. A greater proportion of participants in the intervention group had previously undergone cervical or uterine surgery, had a higher rate of previous second-trimester fetal loss and had a positive family history of preterm birth compared with the placebo group.The precision of the trial was affected by a lower rate of preterm birth than assumed in the sample size calculation. Typically, the certainty of evidence was downgraded two levels due to serious imprecision.Complete outcome tables are presented in A summary result per outcome and the associated certainty of the evidence for the main outcomes are presented in Low risk of bias trials showed an overall effect of progesterone to reduce the risk of preterm birth . A reducSpontaneous preterm birth was less frequently reported and thus yielded imprecise estimates for a reduction (low to moderate certainty of evidence) .Prespecified subgroup analysis of trials with women with previous spontaneous preterm birth as a risk factor demonstrated an effect of progesterone on any preterm birth <37 gestational weeks  and < 34 gestational weeks  . ExploriThe reduced risk of preterm birth was reflected in neonatal outcomes, in particular as reduced mortality within 28 days  (moderate certainty of evidence) . All neoOne trial from Zambia in a population of women with HIV reported one maternal death in the placebo group . MaternaNo study has been reported on maternal cancer.Three trials  examined long-term child outcomes in singletons  follow  [Triple n = 57 children [unpublished data), Norman et al. (n = 833 children) showed no difference in neurodevelopment assessed by the Bayley-III Cognitive Composite score at 2 years of age between children exposed to progesterone versus placebo   . Northento 0.19)  used theA summary result per outcome and the associated certainty of the evidence for the main outcomes are presented in Low risk of bias trials showed an overall effect of cerclage to reduce the risk of any preterm birth, assessed from <37 down to <28 gestational weeks, reaching significance for <37 gestational weeks  and < 34 gestational weeks  (moderate certainty of evidence) . The cerIn pre-specified subgroup analyses of women with short cervical length as a risk factor, cerclage significantly reduced the risk of any preterm birth <37 gestational weeks  and < 34 gestational weeks  .The risk of perinatal mortality was significantly reduced with cerclage  (low certainty of evidence) . ComposiMaternal morbidity outcomes were not significantly affected by cerclage (very low to low certainty of evidence) .No trial reported on long-term child outcome.A summary result per outcome and the associated certainty of the evidence for the main outcomes are presented in All women had short cervical length as a risk factor for preterm birth. Low risk of bias trials demonstrated no effect of pessary on the risk of any preterm birth <37 weeks  (moderate certainty of evidence), <34 gestational weeks  (low certainty of evidence), or for other assessed gestational weeks, apart from spontaneous preterm birth <28 weeks, where a reduced risk with pessary was shown  (low certainty of evidence) .Peri/neonatal mortality and neonatal morbidity was not affected by pessary   .Maternal morbidity was not affected by pessary (low certainty of evidence), except for an increase in vaginal discharge (moderate certainty of evidence) .No trial has been reported on long term child outcomes.Results per outcome and the associated certainty of the evidence for the main outcomes are presented in Any assessment of neonatal mortality and morbidity was uncertain (very low certainty of evidence), except for no difference in admittance to the neonatal intensive care unit (NICU) (low certainty of evidence).The maternal morbidity and mortality assessments were uncertain (very low certainty of evidence), except for no differences in gestational diabetes mellitus and PPROM (low certainty of evidence).Long-term child outcome was not reported.Two trials with low risk of bias, including singleton pregnancies, were identified . One triWomen with different risk factors for preterm birth and a cervical length ≤ 25 mm had a similar risk of spontaneous preterm birth <35 weeks (primary outcome) when treated with cerclage or 17-OHPC, RR 1.14 (95% CI 0.67 to 1.93) . The cerThe Cruz-Melguizo et al.  trial diEighteen RCTs, three subgroup analyses of RCTs , 75, 83 In addition, four systematic reviews   and im injection of 17-OHPC . Doses of vaginal progesterone varied between 90 and 600 mg per day. Doses of 17-OHPC were similar across trials (250 mg 17-OHPC im per week). All trials used placebo as a control and were double-blinded. The intervention started in the first trimester between 11 and 14 gestational weeks in one trial  and in tTrials with low risk of bias reported adequate compliance or adherence to treatment (≥80% of the prescribed medication) for >90% of patients participating in 10 trials. Three trials with low risk of bias reported compliance between 77 and 85% , 99, 109The trials compared McDonald cerclage versus no cerclage , 100. BlNo trial included adjuvant progesterone treatment in both groups as a routine. Roman et al.  reportedAll seven publications  compared pessary with no pessary. Blinding was not feasible due to the nature of the intervention. The Arabin pessary was used in five trials and the Biotech cup in one trial . Women wQuality assessment  of the included trials is presented in the outcome tables in Publication bias was not detected in any of the funnel plots, and thus not utilized as a reason for downgrading the certainty of evidence.Some of the trials had problems with directness, which was affected by ethnicity and the use of ART . Three of the 18 trials were conducted in European countries with an ethnicity similar to the Swedish population , 99, 109One old trial included only twin pregnancies after infertility treatment .The five trials and the two reports showed no major directness problem. However, it is also noted that the two reports on long-term outcomes had a significant loss to follow-up, which may have affected the results. The follow-up rate was 45%  and 83% Complete outcome tables are presented in A summary result per outcome and the associated certainty of the evidence for the main outcomes are presented in Exploratory subgroup analyses performed for the administration route  did not demonstrate any obviously more efficacious route . In addiPooled estimates from meta-analyses of low risk of bias trials reporting mortality and morbidity in neonates from multifetal pregnancies are summarized in Neonatal mortality within 28 days , respiratory distress syndrome, and admittance to NICU was not affected by progesterone (moderate certainty of evidence) , and neiPooled estimates from meta-analyses of low risk of bias trials reporting maternal morbidity are summarized in Long-term child outcome is presented in A summary result per outcome and the associated certainty of the evidence for the main outcomes are presented in Peri/neonatal mortality may be reduced by cerclage in a high-risk group of women with a twin pregnancy, dilated cervix, and visible membranes  (low certainty of evidence). However, neonatal morbidity outcomes were not significantly affected by cerclage (very low to low certainty of evidence) .Maternal morbidity outcomes were not significantly affected by cerclage (very low certainty of evidence) .No trial has been reported on long-term child outcomes.A summary result per outcome and the associated certainty of evidence for the main outcomes are presented in Low risk of bias trials demonstrated no effect of pessary on the risk of preterm birth, assessed from <37 down to <28 gestational weeks (low to moderate certainty of evidence) for all gestational weeks     examined long-term child outcomes in twins and triplets , 115 Su.Both articles are a follow up of the ProTWIN trial . The folOne trial with low risk of bias  includedThe Dang trial showed no difference in the primary outcome of preterm birth <34 weeks, comparing pessary with vaginal progesterone, RR 0.73 (95% CI 0.46 to 1.18) . The cerIn singleton asymptomatic pregnant women at high risk of preterm birth, progesterone and probably also cerclage have a protective effect against preterm birth. Neither pessary nor ASA showed any convincing protective effect.In the subgroup analyses, vaginal progesterone appears to be the best prevention for preterm birth <34 gestational weeks in asymptomatic women with a singleton pregnancy and the risk factor short cervix. Another subgroup analysis displayed that weekly 17-OHPC injections did not decrease the risk of preterm birth. Trials on oral progesterone were small but showed a protective effect.There were few trials on cerclage to prevent preterm birth in singleton pregnant women. The largest trial was old, including women with heterogeneous risk factors and no cervical length screening. Only two trials used universal cervical screening to identify women at high risk of preterm birth. Thus, the target population for treatment may differ between progesterone and cerclage. There is evident ambiguity regarding indications for cerclage. Cerclage is a more complex intervention compared with progesterone. It is an invasive procedure and considerably more costly than progesterone. In addition, by the nature of the intervention, it is not possible to blind participants and practitioners. Due to these disadvantages, cerclage has been less studied in recent years compared with progesterone. When comparing the trials, trials with progesterone are also more commonly funded by pharmaceutical companies. There is a gap in knowledge to which subgroup of women at risk of preterm birth that would profit from cerclage instead of progesterone. Suggested target population for trials on cerclage vs. progesterone may include women with clinically diagnosed cervical insufficiency, i.e., several late miscarriages or preterm births with painless cervical dilation. These women are today subject for cerclage but without convincing evidence in the literature. We did not find any trials comparing vaginal progesterone with cerclage. No trial reported clear harm with neither progesterone nor cerclage, an important result for women and caregivers.Multifetal pregnancies carry a much higher risk of preterm birth than singleton pregnancies, with an approximately 50% incidence of preterm birth in twins. In multifetal pregnancies, the impact of preventive interventions of progesterone, cerclage, or pessary is minimal, if any. In most trials on multifetal pregnancies, the only risk factor was the multifetal pregnancy. In an extreme high-risk population, cerclage may reduce the risk of perinatal mortality. There is no evidence to support the use of progesterone, cerclage, or pessary in unselected multifetal pregnancies to prevent preterm birth or to improve neonatal outcomes.In the literature search process, 39 recent systematic reviews relevant to our PICO and published between 2017 and 2022 were identified. Our results are generally consistent with previous systematic reviews. Two recent systematic reviews , 121 shoThis systematic review summarizes the most recent evidence on the effectiveness and safety of commonly used interventions for prevention of preterm birth. There is convincing evidence that progesterone but also cerclage are effective interventions in singleton pregnancies. However, except for short cervical length in asymptomatic women, the inclusion criteria in many trials are mixed. It is therefore unclear which women who will benefit the most from treatment. Preterm birth is also a heterogenous condition which requires individualized management. We encourage healthcare professionals to create new or update national clinical practice guidelines on these preventive strategies being aware of these limitations. Reliable clinical practice guidelines should be based on a systematic review, provide ratings of the certainty of evidence and the strength of recommendations, as well as consider patient values and economic aspects , 125. ThAll interventions for preterm birth prevention imply identifying women at high risk of preterm birth. Traditionally this is based on an accurate history of maternal and pregnancy-related risk factors. Unfortunately, available risk-scoring systems based on history have a low detection rate and a high false-positive rate , 127. AnIn preterm birth prevention, multiple areas are subject to debate, mainly due to lack of clinical evidence.Although vaginal progesterone has been studied extensively, there are still areas for further research. The effect of vaginal progesterone against preterm birth is best documented in women with a short cervix (≤25 mm) detected on ultrasound screening. The best cut-off for short cervical length has been debated, and a recent study has shown it to be 29 mm at 18–20 gestational weeks and 27 mm at 21–23 gestational weeks . HoweverRegarding cerclage, included trials were heterogenous regarding risk factors for preterm birth in the population. Therefore, additional trials are needed to clarify the proper indications for cerclage and its relation to preterm birth prevention by investigating specific subgroups of women at risk to target the population that would benefit the most from the intervention. This is a challenging area of research since it has been a common practice in many clinics for several decades . A recenRegarding pessary, the results from different research groups are conflicting , 86. ThuA large trial performed in low- and middle-income countries, including nulliparous women with singleton pregnancies and no other specified risk factors, found that low-dose aspirin initiated in the first trimester reduced the risk of any preterm birth <37 weeks and perinatal mortality . In addiFurther studies are also needed regarding different combinations of prevention strategies for preterm birth prevention. Some authors have suggested that using a placebo as a comparator in future trials is challenging and have indicated that the new golden standard for intervention to prevent preterm delivery should be vaginal progesterone . This miFinally, researchers should be encouraged to harmonize reporting of outcome data and use the recommended core outcome set that has been recommended for evaluations of interventions to prevent preterm birth . This win = 29). There are also a few limitations. Most trials used any preterm birth as the primary outcome. Spontaneous preterm birth is a more clinically relevant outcome than any preterm birth because it may be possible to identify women at risk  with subsequent treatment and prevention. Still, few trials reported on spontaneous preterm birth. Many of our meta-analyses included several trials with sparse data, yielding low precision with wide CIs and uncertainty of results. Meta-analyses on long-term children follow-up data were not feasible due to the heterogeneity of data. Some early trials were not registered or registered after trial completion, and some did not report the predefined primary outcome. These trials may be biased by selective outcome reporting  and distortion of results , Forskning och utbilding (FoU) Södra Älvsborg. LB the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-942685). The Wallenberg Center for Molecular and Translational Medicine (WCMTM). BJ the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-965353). The funding sources had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.LB board member and responsible for the biobank in the IMPACT study where PlGF reagents have been donated by Roche, Perkin Elmer, and Thermo Fischer. Course leader for the course in Preeclampsia in Sweden with sponsorship by Thermo Fischer and Roche. Obtained reimbursement for lecture by iLab Medical and reimbursement as expert opinion from Homburg and Partner. Board member in intervention trials where the trial drug is donated by Merck. Associate member in FIGO for the working group of maternal longterm health. Chair of the Swedish Preeclampsia Working Group. Board member in CoLab. Author of the chapter about preeclampsia in “Obstetrik” and about pulmonary hypertension in “Internetmedicin.” Research grants from the Swedish Research Council, STINT, Märta Lundqvist stiftelse, Swedish Society of Medicine, Gothenburg Society of Medicine, SSMF, Jane and Dan Olssons Stiftelse, Swedish Brain fund, Jeanssons stiftelse and Wallenberg Center for Molecular and Translational Medicine. BJ Research grants from Swedish Research Council, Norwegian Research Council, March of Dimes, Burroughs Wellcome Fund and the US National Institute of Health. During the last years performed clinical diagnostic trials on NIPT with Ariosa (completed), Natera (ongoing), Vanadis (completed), and Hologic (ongoing) with expenditures reimbursed per patient. Also performed clinical probiotic studies with the probiotic product provided by FukoPharma  and BioGaia . Previously (2018–2020) a collaborator in IMPACT study where Roche, Perkin Elmer and Thermo Fisher provided reagents to PLGF analyses. No lectures, presentations, travel or personal reimbursement has been financed by any company. Division Director of Maternal and Neonatal Health of the International Federation of Gynecology and Obstetrics (FIGO), Board member of the European Association of Perinatal Medicine and chair the EAPM special interest group of preterm delivery. Steering group member of Genomic Medicine Sweden and is in charge of the Genomic Medicine Sweden complex diseases group. Swedish representative in Nordic Society of Precision Medicine. U-BW, BJ, and PK declare being co-investigators in the OPPTIMUM trial, an included trial in this review.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fmed.2023.1111315/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


Antioxidant capacity and lipid peroxidation also decrease during lactation. Neonatal sex did not influence any of the cytokines, but BM from mothers with male infants had a higher antioxidant capacity. Gestational age was associated with male sex and NAO, being inversely correlated with the BM proinflammatory cytokines IL-8, MCP-1, and TNFα. From days 7 to 28 of lactation, BM from women with NAO infants increased MCP-1 levels and had a larger drop in antioxidant capacity, with the opposite trend in lipid peroxidation. MCP-1 was also significantly higher in women undergoing C-section; this cytokine declined in women who decreased mDII during lactation, while IL-10 increased. Linear mixed regression models evidenced that the most important factors modulating BM cytokines were lactation period and gestational age. In conclusion, during the first month of lactation, BM cytokines shift towards an anti-inflammatory profile, influenced mainly by prematurity. BM MCP-1 is associated with maternal and neonatal inflammatory processes.Breast milk (BM) cytokines support and modulate infant immunity, being particularly relevant in premature neonates with adverse outcomes (NAO). This study aimed to examine, in a cohort of Spanish breastfeeding women, changes in BM cytokines in the first month of lactation, their modulation by neonatal factors , maternal factors , and their relationship with oxidative status. Sixty-three mother-neonate dyads were studied at days 7 and 28 of lactation. Dietary habits were assessed by a 72-h dietary recall, and the maternal dietary inflammatory index (mDII) was calculated. BM cytokines  were assessed by ultra-sensitive chemiluminescence. Total antioxidant capacity was assessed by the ABTS method and lipid peroxidation by the MDA+HNE kit. From days 7 to 28 of lactation, the levels of IL-10 and TNFα remained stable, while IL-13 increased (β = 0.85 ± 0.12,  Cytokines play an important role during intrauterine and extrauterine development and are also present in breast milk (BM), being essential for the normal development of the neonatal immune system, epithelial barrier function, and microbiome . BM cytoBM cytokine profile changes during lactation can be modulated by both maternal and neonatal factors . BM pro-The aims of this study were to examine, in a cohort of Spanish breastfeeding women, changes in BM cytokine levels in the first month of lactation, evaluating the modulation by maternal and neonatal factors. We have also analyzed if there is an association between BM cytokine pattern and oxidative status.In this observational, longitudinal, and non-interventional study, the women were enrolled within the first 72 h postpartum, from September 2019 to March 2020, at the Obstetrics and Gynecology and Neonatology Departments of Hospital Clínico San Carlos . Maternal inclusion criteria were: ≥18 years old, good understanding of the Spanish language, and undiagnosed disease at the time of study. Mothers with specific dietary restrictions, such as those following a diet for competition sports, vegetarians, and vegans, were excluded from the study. The mothers who agreed to participate in the study signed an informed consent form.Since prematurity is associated with an underdeveloped immune system and neonatal adverse outcomes (NAO) with an inflammatory component, we were particularly interested in the assessment of preterm delivery as a possible factor affecting BM cytokines. Therefore, a sample size was calculated considering the rate of premature births in Spain is 6.3% , with a The present study was performed following the Declaration of Helsinki for studies on human subjects and was approved by the Ethical Committee of the HCSC (Ref. 19/393-E). Additionally, the study follows the STROBE statement and checklist criteria for cohort design .Close to enrollment day, the women filled out a sociodemographic questionnaire, including maternal age, educational level, employment situation, and nationality.The following obstetrical and labor clinical data were collected from medical records: number of gestations, spontaneous pregnancy (yes/no), gestational anemia (hemoglobin levels < 11 g/dL), gestational diabetes , preeclampsia (blood pressure > 160/110 mmHg with proteinuria or thrombocytopenia after 20 weeks of gestation), C-section (yes/no), and gestational age (completed weeks of gestation). Women undergoing C-section had antibiotherapy during the first 24–48 h postpartum. Women who gave birth before 37 weeks of gestation were categorized as premature delivery, and those who gave birth after 37 weeks were categorized as full-term gestation.The neonate parameters collected from medical records were sex, Apgar score at 5 min, antibiotherapy (yes/no), and presence of NAO. According to the neonatologist guidelines of the HCSC, NAO was considered if neonates were diagnosed with any of the following comorbidities: cardiac alterations ; neurological alterations  defined according to Volpe’s classification ,29); ChrMaternal dietary pattern was evaluated using the 72-h dietary recall (72hDR), which involved open-ended questions to obtain women’s food intake ,33. The In the records, the portion size of food was also recorded, and the resulting data were converted into daily units of macronutrients, micronutrients, vitamins, and minerals using the DIAL software . The data provided information about: energy , proteins (g), fats (g), saturated fatty acids , monounsaturated fatty acids , polyunsaturated fatty acids , total cholesterol , carbohydrates (g), fiber (g), vitamin A , vitamin B1 , vitamin B2 , vitamin B3 , vitamin B6 , vitamin B9 , vitamin B12 , vitamin C , vitamin D (μg), vitamin E , and iron . The dietary variables were scaled by typification for the data analysis.The 72hDR was used to calculate a maternal dietary inflammatory index (mDII) based on the global composite data set from the Dietary Inflammatory Index Development Study of Shivappa et al., linking diet with plasma high-sensitivity C-reactive protein values . BrieflyThe mDII was categorized as low or high considering the median of the variable, using previously described methodology , with sl® Medela, Barcelona, Spain). Women were instructed to wash their hands and clean their breasts with a gauze with soap and water before self-expressing milk and to obtain the milk always after neonate feeding. BM was collected between 10:00 a.m. and 11:59 a.m. from both breasts, pooled, transferred to a glass bottle, and stored in the freezer. The time between extraction and processing took a maximum of 3 h. The BM samples were then centrifuged three times (2000× rpm for 5 min at 4 °C) to obtain the defatted phase. Glass serological pipettes were used to extract the aqueous layer, placed in a clean tube, and stored at −80 °C until use.One mL of BM was collected at 7 ± 2 and 28 ± 2 days of lactation by each woman using an electric breast pump (Symphonyv/v).The levels of IL-10, IL-13, IL-8, MCP-1, and TNFα were measured in the defatted phase of BM using the Human U-Plex Ultra-Sensitive MSD Kit , following the manufacturer’s protocol. Briefly, each linker vial was conjugated with 200 μL of biotinylated antibody and incubated for 30 min at room temperature. Then, 200 μL of the stop solution was added to each linker vial and incubated for 30 min at room temperature. To prepare the multiplex coating solution, the linker-conjugated antibodies were mixed in a clean tube, obtaining a total volume of 6 mL. A 50 μL volume of the multiplex coating solution was added to each well. The plate was covered and placed on a shaker for 1 h at room temperature. Thereafter, the plate was washed three times with 150 μL of 0.05% Tween-20 PBS 1X solution (v/v). A 50 μL volume of the detection antibody was added to each well, and the plate was incubated under shaking conditions for 1 h at room temperature. Thereafter, the plate was washed three times with 150 μL of 0.05% Tween-20 PBS 1X solution (v/v). Afterwards, 150 μL of MSD-Gold read buffer was added to each well. This is a highly sensitive method, given the detection limits (LLD) of the analyzed cytokines: IL-10 = 0–3720 pg/mL (LLD = 0.14 pg/mL); IL-13 = 0–1920 pg/mL (LLD = 3.10 pg/mL); IL-8 = 0–2210 pg/mL (LLD = 0.15 pg/mL); MCP-1 = 0–6560 pg/mL (LLD = 0.74 pg/mL); and TNFα = 0–3650 pg/mL (LLD = 0.51 pg/mL).The standard curve was prepared according to the manufacturer’s guidelines, and the BM defatted samples were diluted 1.2-fold. A 50 μL volume of the standard curve or the diluted samples was added to the plate in duplicate. Thereafter, the plate was incubated under shaking conditions for 2 h at room temperature. Then, the plate was washed three times with 150 μL of 0.05% Tween-20 PBS 1X solution , and the data were extracted by MSD discovery workbench analysis software. The cytokines were reported in pg/mL and then transformed into natural logarithms. Additionally, a BM inflammatory index (BM-II), based on anti- and pro-inflammatory cytokines, was calculated as follows:The scale typification of the individual cytokines and of the inflammatory index was used for the data analysis. In addition, the change (△) in the cytokine levels during the first month of lactation was calculated as follows:∙+) method, as previously reported  and qualitative variables as relative frequency and sample size . 44.9% of the cohort had a university degree, and 55.1% had a high school degree. 71.4% of the women were employed.χ2 = 0.018; p = 0.89).With respect to obstetric parameters, the participants had a median of 2 previous pregnancies , and 94.0% of the women had a spontaneous gestation. Gestational diabetes was present in 24.5% of the cohort; 20.8% of the women had anemia; and preeclampsia was observed in 9.4% of the cohort. A C-section was performed on 29.1% of the women. 45.5% of the cohort had preterm births, and the median gestational age of the population was 37.3  completed weeks. No association between C-section and prematurity was detected . The median Apgar score was 10.0 . The neonatal antibiotherapy was not associated with C-section  or prematurity . NAO was diagnosed in 42.9% of the cohort, 22.2% for CLND, 12.7% for cardiac alterations, 7.9% for neurological alterations, 4.8% for IVH, 3.2% for LOS, and 1.6% for NEC. Premature birth was associated with NAO . However, NAO was not associated with neonatal sex .During the period of study, all infants had exclusive BM feeding, and 46.9% received antibiotic therapy. Males represent 43.6% of the cohort. Neonatal sex and prematurity were associated  and lipid peroxidation (by MDA+HNE) also decreased significantly during the first month of lactation .There were no differences in the levels of any of the studied cytokines between women with male or female infants, neither at day 7 nor at day 28 of lactation .At day 7, the total BM antioxidant capacity of women with male neonates was significantly higher compared to women with female neonates, and no differences were detected at day 28. There were no sex differences in BM lipid peroxidation levels at day 7 or day 28 .p = 0.019), MCP-1 , and TNFα . However, there was no correlation between gestational age and IL-10, IL-13, ABTS, or MDA+HNE.Gestational age was significantly and negatively correlated with IL-8 , and maternal factors  on BM cytokines. We also evaluated the oxidative status and its relationship to the cytokine profile. The main findings from the present study are that, during the first month of lactation, BM progresses towards an anti-inflammatory cytokine profile. Among the neonatal factors, prematurity and NAO modulated BM cytokines with a higher proinflammatory profile. Regarding the influence of maternal factors, women who decreased mDII during lactation tended to improve the anti-inflammatory cytokine profile in BM. Instead, C-section increased BM MCP-1 levels, while obstetric complications did not have an influence on the cytokine profile. Regarding BM oxidative status, we found a quicker depletion of antioxidant capacity in women with NAO neonates. Linear mixed regression models evidenced that the most important factors modulating BM cytokines were lactation period and gestational age.It has been reported that BM cytokines vary throughout the lactation period, with the highest levels found in colostrum ,7. HowevWe analyzed the impact of premature birth on BM cytokine content since preterm infants have an underdeveloped immune system and the immune response mostly relies on non-specific innate immunity . The plaCytokines are important for immune system regulation. However, an uncontrolled immune response results in excessive production, the so-called “cytokine storm”, with subsequent activation of immune cell populations . The cytAnother common finding is the impact of fetal sex on preterm birth, with males at higher risk of prematurity , as obseWe also evaluated the influence of several maternal factors as modulators of BM cytokines, including obstetric complications, type of delivery, and nutrition. Our study provided evidence that MCP-1 was higher in women with C-sections, but no influence was observed with obstetric complications. Therefore, inflammatory maternal conditions related to gestation and delivery influence BM cytokines, similarly to chronic conditions such as asthma or celiac disease ,11,56.The influence of maternal nutrition on BM macronutrients has been extensively studied ,58,59. EInflammation and oxidative stress are closely associated with many diseases, including those in the perinatal period. Obstetric complications, like gestational diabetes and preeclampsia, exhibit both an inflammatory and an oxidative stress component ,25. FurtThe present work is a comprehensive study assessing relevant maternal and neonatal factors affecting BM cytokines. One of the strengths of our study is the use of mDII in the context of maternal nutrition since it is a global parameter. Our data support that maternal nutrition has a direct influence on BM cytokines and, therefore, diet modification can be a feasible way to promote an anti-inflammatory pattern, which may be beneficial for premature neonates with several comorbidities associated with inflammation, particularly respiratory diseases.Regarding the limitations of the study, we did not evaluate the mechanisms through which maternal factors modulate BM cytokine levels, particularly the role of the microbiota. BM is a source of bioactive molecules, such as human milk oligosaccharides (HMO), which are able to increase anti-inflammatory cytokines through interaction with the microbiota . In turnThe main factors affecting BM cytokines were the lactation period, gestational age, and diet. During the first month of lactation, the cytokine pattern evolves towards an anti-inflammatory profile. Preterm delivery and C-section have an influence on BM with higher levels of pro-inflammatory cytokines. Using mDII, we provide evidence of the influence of diet as a modulating factor to improve the anti-inflammatory profile in BM, supporting the relevance of maternal nutritional counseling, particularly important in women with preterm deliveries or C-sections.


Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is mainly used for the treatment of type 2 diabetes mellitus. The study's objective was to assess empagliflozin's effects and impacts on post-myocardial patients to highlight its worth in comparison to alternative therapies. Only studies evaluating the effects of empagliflozin on individuals who have undergone a myocardial infarction (MI) are included in this review of the literature, which employed PubMed, Google Scholar, and Embase. To compare the advantages of empagliflozin for individuals who have recently experienced a myocardial infarction, abstracts from pertinent articles were retrieved, and complete publications were reviewed. A total of four articles were reviewed, which showed that in patients who suffered from a recent MI, empagliflozin caused a significant decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP). Additionally, it was shown that these individuals had better echocardiographic results for both structural and functional metrics. With studies showing a significantly larger median NT-proBNP decrease with empagliflozin compared to placebo among patients hospitalised with an acute big MI when empagliflozin was started early and administered in addition to the post-MI care suggested by guidelines, it is safe to say that the benefits outweigh the risks. There are currently larger double-blind trials in progress to prove the hypothesis of the benefits of empagliflozin for post-MI patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent heart failure hospitalisation in high-risk diabetics who typically do not have heart failure . It has SGLT2 inhibitors primarily affect kidney SGLT2, which eliminates extra glucose .SGLT2 inhibition has cardioprotective effects such as diuresis and natriuresis, blood pressure reduction, erythropoiesis, improved cardiac energy metabolism, reduced inflammation, suppression of the sympathetic nervous system, prevention of unwanted cardiac remodelling, and prevention of ischemia and reperfusion ,5.Recent clinical studies showed that SGLT2 inhibitor class of anti-diabetic medications had positive cardiovascular effects, including a decrease in cardiovascular death, non-fatal myocardial infarction (MI), heart failure, and non-fatal stroke, as well as all-cause mortality .The study's objective was to assess empagliflozin's effects and impacts on post-myocardial patients to highlight its advantages. Empagliflozin received FDA clearance for an indication that includes lowering the risk of cardiovascular mortality in individuals with type 2 diabetes and existing cardiovascular disease. The study is a review of published cases of empagliflozin treatment in post-myocardial patients. We are aware of very little research on humans, with two large blind studies in progress.Materials and methodsThis is a literature review where articles were searched and reviewed using PubMed, Google Scholar, and Embase. The keywords "empagliflozin" or "SGLT2 inhibitors" were used along with the Medical Subject Headings (MeSH) "post myocardial infarction". To compare the advantages of empagliflozin in post-MI patients, abstracts from every paper were retrieved, and the entire texts of each were read and taken into consideration. Six authors searched English titles and abstracts for pertinent studies. Our review included data that were abstracted from each study and linked to the use of empagliflozin after MI. Our article does not include any animal experiments. A total of 9.030 items in all were found. Between the various databases, 27 duplicate articles were eliminated. Only 27 papers remained after the screening, which involved looking through the titles, abstracts, and entire articles. A total of 23 more papers were disregarded because they either originated from the same research or concentrated mostly on other illnesses, including diabetes and the heart. Only case reports and case reviews were used in our study. We eliminated all literature reviews from the analysis. Following an extensive examination, four pertinent studies were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart supplied shows that a literature search was done and the results are presented in Figure ResultsAfter excluding secondary sources from the database search and eliminating duplicates, the initial search turned up 27 pertinent articles. After removing 23 records due to their lack of relevance to the issue after screening titles and abstracts (n = 27), the complete texts of four publications were evaluated. The studies in total had 669 patients with post-myocardial, of which 328 were given empagliflozin and 341 were given a placebo .Significant reductions in body weight, systolic blood pressure, and uric acid were seen in the empagliflozin group -10. The It has been proposed that higher mortality after MI and aberrant heart rate turbulence (HRT) are related . ConsequDiscussionExperimental evidence shows empagliflozin can lead to a reduction in infarct size and therefore reduced remodelling and development of HF following MI . The reaHF incidences reduce among those using empagliflozin for a short period of time who have diabetes and cardiovascular disease, yet the precise mechanism through which SGLT-2 inhibitors have a discernible beneficial effect on cardiovascular events is uncertain ,5,13,14.The influence of SGLT2 inhibitors on NT-proBNP concentrations in HF studies is variable among different cohorts, indicating a 13% substantially decreased NT-proBNP concentration after 52 weeks compared with placebo in patients with HF. This is despite a significant improvement in LV mass -23. The From our knowledge, there are also two major clinical trials to be published soon on this topic, which should give a better idea and prove the use of empagliflozin post MI.LimitationsThis study's primary limitations include the retrospective examination of the case studies. Control case studies have to be conducted as well to support and strengthen our findings. To evaluate the long-term outcomes, more clinical trials and meta-analyses are required. Our publication highlights current research, but there are two double-blinded clinical trials upcoming soon.Studies show that in patients who recently experienced a myocardial infarction, empagliflozin was linked to a much larger NT-proBNP decrease as well as a significantly improved set of structural and functional echocardiographic measures. A substantially larger median NT-proBNP decrease was shown with empagliflozin than with placebo among patients who were hospitalised with an acute big MI when empagliflozin was started early and administered in addition to the post-MI care suggested by guidelines. Empagliflozin also reduces ejection fraction, as well as renal function. Empagliflozin significantly decreases a person's body weight, systolic blood pressure, and uric acid. Empagliflozin is effective in treating HF connected to a recent MI, according to the EMMY research. Empagliflozin shows notable attenuations in the changes in protein levels, soft lean mass, and skeletal muscle index. Overall, empagliflozin decreased functional decline in those with acute MI and type 2 diabetes mellitus, especially in those whose baseline eGFR was 60 mL/min/1.73 m2. Empagliflozin have positives on patients with post MI but upcoming trials would prove or would show the efficacy and benefits of taking empagliflozin post MI.


To examine the association between gestational age at birth and hospital admission costs from birth to 8 years of age.Population-based, record linkage, cohort study in England.National Health Service (NHS) hospitals in England, UK.1 018 136 live, singleton births in NHS hospitals in England between 1 January 2005 and 31 December 2006.Hospital admission costs from birth to age 8 years, estimated by gestational age at birth .Both birth admission and subsequent admission hospital costs decreased with increasing gestational age at birth. Differences in hospital admission costs between gestational age groups diminished with increasing age, particularly after the first 2 years following birth. Children born extremely preterm (<28 weeks) and very preterm (28–31 weeks) still had higher average hospital admission costs (£699 (95% CI £419 to £919) for <28 weeks; £434 (95% CI £305 to £563) for 28–31 weeks) during the eighth year of life compared with children born at 40 weeks . Children born extremely preterm had the highest 8-year cumulative hospital admission costs per child (£80 559 (95% CI £79 238 to £82 019)), a large proportion of which was incurred during the first year after birth (£71 997 (95% CI £70 866 to £73 097)).The association between gestational age at birth and hospital admission costs persists into mid-childhood. The study results provide a useful costing resource for future economic evaluations focusing on preventive and treatment strategies for babies born preterm. Most previous research on the economic consequences associated with gestational age focused on the costs of initial birth admission or costs incurred during the first few years after birth.A small number of studies have examined the association between gestational age at birth and hospital costs over the longer term, but were based on regional data, decision-analytic models synthesising summary evidence from multiple sources, cross-sectional assessments at specific ages, or focused on narrow categories of the gestational age range.Using a large national cohort with hospital records linked from birth until mid-childhood, our study quantifies hospital admission costs from birth up to 8 years of age across the full range of gestational age at birth.The results should act as a useful resource for clinical and budgetary service planning, and as data inputs for economic evaluations of preventive and treatment strategies for babies born at different gestational ages.The rates of preterm birth (<37 weeks’ gestation) have increased or remained stable over the past few decades in most countries,Most previous research on the economic consequences associated with gestational age focused on the costs of initial birth admission or costs incurred during the first few years after birth.In this study, we conducted an evidence synthesis exercise to examine the association between gestational age at birth and hospital admission costs from birth to 8 years of age using a population-based, record-linkage study that included all live, singleton births occurring in England in 2005/2006 as part of the TIGAR study .In this study, we synthesised data from three data sources: TIGAR, National Neonatal Research Database (NNRD) and Paediatric Intensive Care Audit Network (PICANet) databases. Access to individual patient-level data was available for the TIGAR dataset, whereas aggregate data were available from the NNRD and PICANet datasets.The TIGAR cohort was built through a population-based data linkage using data from the Office for National Statistics (ONS) birth registration records linked to death registration records, birth notification records and Hospital Episode Statistics Admitted Patient Care (HES APC) records.The NNRD is a national resource holding quality-assured real-world clinical data captured during the course of care for all admissions to NHS neonatal units in England, Wales, Scotland and the Isle of Man.The main source of information for our economic analysis was the TIGAR dataset. However, although in the HES APC records the length of stay for admissions includes any time spent in critical care units, the information did not reliably indicate the level of care the child received on a day-to-day basis . Therefo10.1136/fetalneonatal-2022-324763.supp1Supplementary dataWhether a child was admitted to a neonatal or paediatric critical care unit during the birth admission.The number of days that were spent in a neonatal or paediatric critical care unit during the birth admission by level of care.Any difference between the total birth admission days observed in the TIGAR cohort and the critical care days estimated from the NNRD and PICANet was considered non-critical care ward days. More details about the methods used to simulate neonatal and paediatric critical care days and calculate non-critical care ward days in birth admission can be found in We estimated direct costs from a healthcare perspective in England. In the HES APC, each data record indicates a Finished Consultant Episode, which represents a continuous period of care under one clinical consultant. Costs were estimated at episode level. The 2018–2019 Casemix Grouper Software (HRG4+) was used to allocate each episode to a Healthcare Resource Group (HRG), primarily based on any procedures performed, diagnoses, hospital admission type, episode length of stay and patient characteristics.Neonatal and paediatric critical care costs during the birth admission were calculated on a per diem basis using the NHS 2017–2018 reference costs based on level of care. Birth admission ward costs were adjusted accordingly by extracting days spent in critical care units from the total hospital stay .We used descriptive statistics to estimate the average total length of stay and average costs for the birth admission and for subsequent hospital admissions by year of follow-up among children alive at the beginning and not censored by the end of each follow-up year. Comparisons were made between the following groups by gestational age at birth (weeks): <28, 28–29, 30–31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42. Gestational ages were grouped <28, 28–29 and 30–31 following ONS policy about reporting of small numbers.We used the Kaplan-Meier sample average estimator to calculate the total 1-year, 5-year and 8-year costs for each gestational age group.In the baseline analysis, we calculated the birth admission non-critical care ward days and costs according to aggregated data from the NNRD and PICANet. We conducted a sensitivity analysis to investigate the results when allocating all the estimated non-critical care ward days to neonatal critical care for children born at ≤33 weeks to reflect an scenario where these babies spent most of their stay in a neonatal unit as previously indicated.All analyses were conducted using Stata V.14 . Costs are presented in 2018 UK pounds (£).A total of 1 018 136 children were included in this study, with a total of 9 372 105 person years of follow-up and 1 315 338 admissions that occurred between 1 January 2005 and 31 March 2015. The baseline characteristics of the TIGAR cohort are presented in The proportions of children admitted to neonatal or paediatric critical care during the birth admission are presented in Full details on estimated lengths of stay for admissions subsequent to the birth admission, by year of follow-up, can be found in the The mean cumulative hospital admission cost over 8 years after birth among children born extremely preterm was estimated at £80 559 (95% CI £79 238 to £82 019) per child, with most of the cost incurred during the first year after birth (£71 997 (95% CI £70 866 to £73 097)) . ChildreIn this study, we have investigated hospital admission costs from birth to mid-childhood in England across the full range of gestational age at birth. We found that gestational age at birth is associated not only with birth admission hospital costs but also subsequent hospital admission costs up to age 8. The most common cause of subsequent admissions was infection.et al reported similar birth admission hospital costs for 32–33 week moderately preterm born (£13 168) and 34–36 week late preterm born (£5463) children (2017–18 prices), based on a cohort in the East Midlands region of England.et al estimated the costs to the public sector over the first 18 years after birth using a decision-analytic model and reported neonatal care costs of £109 860 (2017–2018 price) for extremely preterm children.Our cost estimates are in line with other studies of the costs of preterm birth in England. Khan This is, to our knowledge, the first study that uses a large national cohort to examine the association between gestational age at birth and hospital admission costs across the full spectrum of gestational age. The results of this study provide comprehensive estimates of hospital admission costs from birth to mid-childhood by gestational age at birth, which can act as a useful resource for clinical and budgetary service planning, and as data inputs for economic evaluations of preventive and treatment strategies for preterm birth.The main strength of this study is the large sample size available for analysis, which provided a sufficient sample to estimate costs across the full spectrum of gestational age. The national coverage of the TIGAR cohort contrasts with the regional-based or clinic-based populations that provided a focus for previous studies.The main limitation of the study is that we were not able to estimate more granular neonatal and paediatric critical care costs for the TIGAR cohort as such estimation is not supported by the HES APC data; notably, critical care information was collected with insufficient quality in HES APC before 2008. A separate HES dataset covers adult critical care from 2008/2009, whereas data relating to neonatal or paediatric intensive care are collected through systems external to NHS Digital, which collects HES data.It is also worth highlighting that the TIGAR cohort excluded children who died before discharge from their birth admission, which means that we have excluded a small group of extremely ill babies from our study. This suggests that our cost estimates should be viewed as conservative, particularly for the purposes of planning of neonatal services.In conclusion, this study provides estimates of the association between gestational age at birth and hospital admission costs from birth to mid-childhood and disaggregates those estimates by gestational category and chronological year. The study results should act as a useful resource for future economic evaluations that focus on preventive and treatment strategies for preterm birth and inform resource allocation decisions.


Small for gestational age (SGA) neonates are often born to mothers with pregnancy-induced hypertension (PIH). Here, we aimed to explore the morphometric characteristics of the placenta during the perinatal period associated with SGA risk in mothers with PIH and identify the risk factors related to SGA.The medical records of 134 neonates born between 28- and 32-weeks’ gestation to PIH mothers were retrospectively analyzed. Placental morphology and umbilical cord (UC) length were compared between the SGA and appropriate for gestational age (AGA) groups.z = −6.04, p < 0.01) and minor placenta axes , lower weight , smaller volume , and smaller area  than the AGA group. The UC was significantly shorter . Short placental major axis  and low placental weight  were independent risk factors for SGA in premature newborns of PIH mothers.The placenta of the SGA group had a shorter major (15.00 vs. 18.00 cm; A major axis shorter than 15.5 cm or placental weight lower than 347.50 g at birth was related to a greater risk of SGA infants born to PIH mothers. As a predictor in prenatal ultrasound, the major axis is more helpful for precise prenatal pre-evaluation of vulnerable SGA preterm neonates with PIH mothers. SmalPregnancy-induced hypertension (PIH) is a common and serious perinatal complication often leading to the birth of premature SGA neonates , 9. PIH The placenta supports intrauterine life and fetal development through its nutritional, immunologic, and endocrine functions . Existin2.2.1.This preliminary retrospective case-control research was performed in the neonatal department of a level 3 hospital in Beijing from January 2018 to December 2020. Ethical clearance (2021-KY-106-01) was obtained from the institutional ethical committee. Preterm SGA neonates with a gestational age (GA) of 28–32 weeks, born to mothers with PIH, were enrolled in the SGA group. Preterm AGA infants without intrauterine growth retardation, also born to mothers with PIH, were consecutively enrolled in the control group till two groups showed an even distribution for GA at birth. The exclusion criteria included (a) multiple pregnancies; (b) family history of inherited metabolic diseases; (c) abnormal test results in non-invasive detection of fetal chromosomal aneuploidy in maternal blood; (d) chromosomal or metabolic gene abnormalities diagnosed by chorionic villus sampling; (e) abnormality in deafness gene and hearing screening; (f) congenital malformation in the newborn; and (g) incomplete clinical records.SGA is defined when a newborn's birth weight is less than two standard deviations or below the 10th percentile of the mean for GA based on defined standards  for males and females –14. Pret2.2.Neonatal gender, length, weight, GA at birth; placental weight, length (major axis), width (minor axis), thickness, and length of the umbilical cord (UC); and mother's age at birth, mode of delivery, number of pregnancies and deliveries, perinatal complications  were obtained from the patients’ medical records. Methods of these measurements were referenced to the description by Barker et al. . Briefly2.3.a priori sample size was calculated and all the eligible participants during the study period were included.No 2.4.U test was used to compare non-normally distributed continuous variables  between SGA and AGA groups. Dichotomous data was compared between the two groups using the Chi-square or Fischer's exact test. Correlations between neonatal birth weight and the placental major axis, minor axis, area, volume, weight, and UC length were detected using Spearman rank correlation analysis. Potential risks and independent risk factors for growth retardation in preterm neonates with mothers of PIH were detected by univariate and multivariate logistic regression analyses, separately. The predictive accuracy of placental weight or major axis to estimate SGA preterm neonate birth to a mother with PIH was determined using receiver operating characteristic (ROC) curve analysis. Data was analyzed using SPSS Statistics for Windows, Version 21.0 . A two-sided p-value of <0.05 was considered statistically significant.Median (interquartile range) was used to show quantitative data. Absolute frequency (percentage) was used to show dichotomous data. Mann − Whitney 3.3.1.Between January 2018 and December 2020, 2,143 premature infants were hospitalized in the neonatal department of our hospital. Eighty-nine preterm neonates born between 28- and 32-weeks’ gestation to mothers with PIH were diagnosed with SGA. Sixty-five premature SGA infants were included in the SGA group according to the exclusion criteria. Sixty-nine premature AGA infants with matched GA, born to mothers with PIH were enrolled into the AGA (control) group, until GA of neonates in each group was evenly distributed. Hospitalization records of 134 premature Chinese infants and their mothers were complete for retrieval.p > 0.05). The neonatal birth length and weight in the SGA group were significantly lesser than in the AGA group . The rate of fetal distress was higher in the SGA preterm neonates than in the control neonates . The natural childbirth rate in the SGA group was significantly lower than in the AGA group . Other data regarding maternal information, such as age, gravidity, parity, primiparity, composition of subtype hypertension, gestational complications , and occurrence of abnormal amniotic fluid, showed no marked difference between both groups.z = −7.21, p < 0.01), smaller volume , smaller area , shorter major axis , shorter minor axis , and shorter UC length   and perimeter  showed no statistical difference between the SGA and control groups  . Placentl groups .3.2.ρ = 0.52, p < 0.01) and minor axes , area , volume , weight , and UC length .Spearman’s test  showed tp < 0.01; odds ratio (OR) = 1.84; 95% confidence interval (CI): 1.65 − 2.09), minor axis , weight , and UC length  were risk factors for growth retardation in premature infants of mothers with PIH. Multivariate regression analysis showed that short major axis  and low placental weight  were independent risk factors for SGA in premature newborns of PIH mothers . The median birth weight increased from 1,020 g for a placental weight of 200 to 2,047.80 g for a placental weight of 810 g. R2 = 0.303, p < 0.01). The median birth length increases with advancing placental weight from 37.15 cm at a placental weight of 200 g to 49.35 cm at a placental weight of 810 g. R2 = 0.278, p < 0.01). The median birth weight increased from 969.10 g for a placental major axis of 10 cm to 2071.30 g for a placental major axis of 30 cm. PIH mothers with shorter placental major axis at birth have a higher risk of giving birth to newborns with lower birth weight. R2 = 0.201, p < 0.01). The median birth length increases with the advancing placental major axis from 36.05 cm at the placental major axis of 10 to 45.45 cm at the placental major axis of 30 cm. PIH mothers with shorter placental major axis at birth have a higher risk of giving birth to newborns with shorter birth length.3.3.p < 0.01). With the optimal cut-off of 15.50 cm for the placental major axis, a sensitivity of 88.40% and specificity of 61.50% were achieved in the detection of SGA risk for preterm neonates born to PIH mothers. According to the cut-off value, we divided the subjects into two groups . The short placental major axis group tended to have a higher prevalence of SGA [83.33% (40/48) vs. 29.07% (25/86)] and a low percentage of AGA [16.67% (8/48) vs. 70.93% (61/86)] compared to the long placental major axis group.ROC curves were used to quantify marker  performance  in the pp < 0.01). The optimal cut-off value of placental weight for predicting the presence of SGA was 347.50 g, with a sensitivity of 84.10% and specificity of 76.90%. According to the cut-off value, we divided the subjects into the two groups . The light placental weight group tended to have higher prevalence of SGA [81.97% (50/61) vs. 20.55% (15/73)] and low percentage of AGA [18.03% (11/61) vs.79.45% (58/73)] compared to the heavy placental weight group.Areas under the ROC curve (AUC) indicated a good discriminatory power of placental weight , not the minor axis, was an independent risk factor for SGA in premature newborns of mothers with PIH in this study. These differences may be attributed to the placenta collected in these studies, which were from hypertension-complicated pregnancies in our study and from pregnancies without comorbidities in the above two studies .Furthermore, the surface area is also a critical placental parameter for fetal development because it determines nutrient transport and oxygen diffusion . In thisPlacental thickness is a controversial placental morphological parameter that has been widely investigated in many studies for its correlation with neonatal birth weight. An examination of 561 normal singleton pregnancies throughout pregnancy demonstrated that thick placentas are related to light birth weight and poor perinatal and infant outcomes . HoweverAmong the above parameters, short placental major axis and low placental weight were independent risk factors for SGA in premature newborns of mothers with PIH, which were associated with higher SGA delivery risks by 2.16 times and 2.68 times, respectively. As a diagnostic capability, the placental major axis for the prediction of SGA neonates has a sensitivity of 88.40% and specificity of 61.50%, while the placental weight for the prediction of SGA neonates is 84.10% and 76.90% for sensitivity and specificity, respectively. A placental weight lower than 347.50 g or a placental major axis shorter than 15.5 cm at birth was related with a greater risk of delivery of SGA premature infants to mothers with PIH. Our data showed that the placental major axis and low placental weight were reliable clinical indicators for SGA prediction. SGA neonates are more likely to experience adverse outcomes after delivery and even upon reaching adulthood . Early rThe UC is an important link between the fetus and the placenta. Compared with AGA term newborns, thinner (maximum diameter <0.8 cm) UCs were noted in SGA term newborns . Other UIn this study, we demonstrated the detailed morphometric characteristics of the placenta in a study of SGA preterm neonates of mothers with PIH. Furthermore, we revealed that lower placental weight and shorter major axis length were independent risk factors for SGA in premature newborns of mothers with PIH. The predictive value of these two parameters in predicting PIH-related SGA risk was also preliminarily explored. Since the length of the major axis is an easily obtainable ultrasonographic parameter and shows its potential to improve the prediction of the risk of SGA delivery, this research could be useful for monitoring the women with PIH. Furthermore, it could be helpful for the earliest possible intervention and management, not only during pregnancy but also after childbirth, and could prevent adverse neonatal outcomes as much as possible.Despite its potential clinical importance, this study has several limitations. The results were based on medical records obtained from one institution, and all neonates were Chinese. Due to the limited sample size, a classification study on the placental morphological characteristics of different subtypes of PIH-related SAG was not conducted. Furthermore, owing to the retrospective nature of this study, placental morphological parameters at different pregnancy stages were not collected. This research could be regarded as a preliminary exploration. Prospective multi-center larger cohort studies including neonates of various races should be conducted globally. The findings of this study should also be validated in larger cohorts. Further studies could also precisely determine when placental size and shape start to get affected during pregnancy in mothers with PIH who deliver SGA preterm neonates.


We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis . However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP  = 2.14, 46.4% females) and 265 adolescent healthy controls  pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen’s  A recent meta-analysis from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium ( = 0.39) . EmerginThe term EOP covers rare and heterogeneous psychotic disorders, affecting 0.05–0.5% of the world’s population , 4, and Microstructural properties of white matter are commonly modelled using diffusion tensor imaging (DTI), which maps the Brownian movement of water molecules in the brain in vivo. Common DTI measures include FA and mean, axial, and radial diffusivity . While FA is a summary measure that reflects the degree of diffusion directionality, AD describes diffusion along the primary axis, and RD characterizes diffusion perpendicular to it . MD is aSeveral studies have used DTI to compare white matter microstructure in youth with EOP to healthy controls, predominantly focusing on early-onset schizophrenia (EOS ). Most sThe ENIGMA-EOP Working Group aims to address some of the methodological issues in prior MRI studies and increase statistical power by pooling data for the largest coordinated analysis on brain white matter in EOP to date . The prin = 180), affective psychosis , and other psychosis (n = 46). Diagnoses were determined using either the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV or the International Classification of Diseases (ICD)−10. To assess the presence and severity of symptoms, five cohorts used the Positive and Negative Syndrome Scale , and twe (PANSS /SAPS [31http://enigma.ini.usc.edu/ongoing/dti-working-group/) and on the ENIGMA GitHub page (https://github.com/ENIGMA-git/). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were obtained for 25 bilateral  regions of interest (ROI) from the Johns Hopkins University ICBM-DTI-81 white-matter labels atlas , MD, RD, and AD data were obtained from eight sites .Case-control differences in FA, MD, AD, and RD across all ROIs were examined using multiple linear regression analysis, correcting for age, age , sex, anTo examine global vs. regional white matter effects between diagnostic groups, the main DTI analyses were re-run either co-varying for (i) average, (ii) core, and (iii) periphery DTI measures. For instance, average FA constitutes FA averaged across the entire white matter skeleton, excluding gray matter. However, average FA is not only comprised of the JHU atlas regions, but also FA in white matter outside of these regions. Therefore, we separately calculated average FA for the “core”, which is defined as the region within the skeleton labeled by the JHU white matter atlas, and the “periphery”, outside of the JHU atlas regions. The average FA in the standard ENIGMA-DTI template consists of 112,889 voxels, while the core consists of 31,742 voxels, less than a third of the average FA. The remaining 81,147 voxels surrounding the core comprise the periphery (non-JHU). Detailed formulas to calculate core and periphery DTI measures have been published in Kelly et al. 2018 [For each DTI measure  as dependent variable, separate multiple linear regression models were fitted with diagnostic subgroup as fixed factor  and age, age , sex, anTo explore white matter microstructural differences between diagnostic groups across age and sex, we performed follow-up sex-stratified as well as sex-by-diagnosis and age-by-diagnosis interaction analyses. Separate multiple linear regression models for each DTI measure as dependent variable were fitted either including a sex-by-diagnosis or age-by-diagnosis interaction terms. The same covariates as above apply. The sex-stratified case-control models  were covaried for age and age .http://www.scottwilliamwoods.com/files/Equivtext.doc) on DTI measures. Current medication use included antipsychotics, lithium, antidepressants, and antiepileptics. As age and age at onset are highly correlated (r = 0.70), this linear model was only adjusted for sex, whereas the other models were adjusted for age, age [In adolescents with EOP, we tested for effects of duration of illness, age at onset, PANSS scores (negative/positive subscores), current medication use (user vs. non-user) and antipsychotic chlorpromazine equivalents . The corresponding p-value was calculated using (two-tailed test):d values for the adult schizophrenia sample were retrieved by SK [d values for EOP . To allow for such a comparison, the same covariates were used in both studies, namely age, age [To assess whether the effect sizes of the case-control differences in tract-specific FA differed between adolescents with EOP and adults with schizophrenia , we condmentclass2pt{minimd effect sizes for tract-specific FA from the current study with the meta-analytically derived Cohen’s d values from the adult schizophrenia study [To further test whether brain alterations in EOP resemble the pattern observed in adult schizophrenia, we correlated the meta- and mega-analytically derived Cohen’s ia study .https://www.R-project.org/). All continuous variables were mean-centered before entered into the analyses. We computed the Cohen’s d effect sizes ± standard error across all 25 ROIs from the t-statistics for categorical variables [All statistical tests were conducted in R, version 4.1.0 . Follow-up analyses showed higher MD in the FX and UNC; higher RD in Average RD, CGC, FX, PCR, SLF, and UNC; and higher AD in the FX in adolescents with EOP relative to healthy controls . We observed no significant white matter microstructural alterations in adolescents with other psychosis relative to healthy controls.When stratifying EOP by diagnostic subgroup, only adolescents with EOS showed significantly lower FA in 14 ROIs relative to healthy controls, including: Average FA, ALIC, BCC, CC, CR, FXST, GCC, IC, PCR, PTR, RLIC, SCC, SFO and SLF (p ≤ 0.002). Sex-stratified analyses showed that only male adolescents with EOP showed widespread lower FA relative to healthy male controls . Tract-specific AD was not significantly different in EOP vs. healthy controls. In females, FA, MD, RD and AD did not differ significantly between EOP and healthy controls after correction for multiple comparisons . A sex-stratified diagnostic subgroup analysis showed that the male-specific effects were again driven by the EOS group. No significant age-by-diagnosis interactions were found for FA, MD, RD, and AD . However, longer duration of illness was associated with significantly lower MD in the ALIC and IC . Furthermore, higher AD of the ALIC was associated with later age at illness onset . In contrast, the same effect sizes in adult schizophrenia were not correlated with the meta-analytically derived Cohen’s d values in EOP . Scatterplots for the effect size correlation are displayed in Fig. Mega-analytically derived Cohen’s d = 0.37), posterior corona radiata , and superior fronto‐occipital fasciculus . Regions of the corpus callosum (CC), internal capsule (IC), and posterior thalamic radiation (PTR) also showed significant effects with Cohen’s d > 0.25. Lower FA in EOP was accompanied by widespread higher RD, and more localized higher MD of the fornix (FX) and uncinate fasciculus (UNC). Higher AD for EOP individuals was observed in the FX. Case-control differences in brain white matter microstructure were driven by individuals diagnosed with EOS, who represent the majority of the EOP sample.We found widespread lower FA in individuals with EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus , resulting in a higher variance between tracts and diagnostic groups in the meta- relative to the mega-analysis  and CC (d = 0.39) [d = 0.37), PCR (d = 0.32), and SFO (d = 0.31). Furthermore, FA differences in the SLF remained significant after controlling for periphery FA, unlike the effects observed in adult samples that were found to be driven by peripheral regions [In the present study, no regional FA differences remained significant after covarying for global effects. However, lower FA in the SLF was still significant after adjusting for periphery FA, suggesting that the effects observed in the SLF are being driven by differences in core white matter, as opposed to periphery white matter. Overall, the findings suggest that lower FA across the entire white matter skeleton is driving the difference in FA across almost all ROIs. Similar effects were observed for MD, RD, and AD. These findings reflect a pattern of globally lower DTI measures, commonly observed in adults with schizophrenia . While t = 0.39) . In EOP,O d = 0.3. FurtherThe diagnostic subgroup analysis showed that widespread lower FA was limited to EOS. No case-control differences in FA were found for AFP and other psychosis. This finding is not in line with previous studies in adolescents , 49 and No significant age-by-diagnosis interactions were observed. However, MD in the ALIC and IC were negatively associated with duration of illness. Similarly, average RD and AD in the BCC and CC were negatively associated with the duration of illness. Furthermore, AD in the ALIC was positively associated with age of onset. These findings suggest that the white matter differences in these regions may be linked to disease progression, as opposed to developmental factors. However, as EOS is associated with a longer duration of illness, these findings may also reflect an effect of the diagnostic subgroup.We found no significant sex-by-diagnosis interaction for DTI measures, except for RD in the SCC. However, a sex-disaggregated analysis showed that male adolescents with EOP had widespread lower FA relative to healthy male controls, whereas females with EOP did not significantly differ from healthy female controls. Plotting average FA by sex and diagnostic group against age further highlighted consistently lower FA values in male individuals with EOP compared to healthy male controls across the studied age range Fig. . AverageThere were no significant differences between medication users and non-users and impact of CPZ on white matter microstructure, which is similar to findings observed in adult schizophrenia . In addiThis study is subject to some limitations. Firstly, the cross-sectional design of this study does not allow for a more thorough investigation of the effects of sex, duration of illness, and medication exposure. Secondly, FA is a summary measure of white matter microstructure that does not map perfectly onto the microstructural properties of the underlying tissue. The observed differences in FA may be influenced by a number of neurobiological processes, including changes in fiber organization such as packing density and axon branching, as well as alterations in myelination , 55, 56.Finally, tract-based spatial statistics (TBSS) is commonly used to perform voxel-based analysis of white matter . HoweverIn the largest analysis of white matter differences in EOP to date, we found widespread lower FA and higher RD with more localized differences in MD and AD for EOP relative to healthy controls. In contrast to what has previously been reported in adult samples, the largest effects for EOP were observed in the SLF and PCR, followed by interhemispheric and thalamo-cortical regions. Differences were most pronounced in male individuals with EOS relative to same-sex healthy controls. The global pattern of widespread microstructural alterations observed in EOP solidifies the hypothesis that schizophrenia may be a disorder of global brain structural connectivity. Future analyses of longitudinal data will allow for a more in-depth investigation of brain maturation in EOP and for further explorations of the effects of sex, duration of illness, and medication exposure.Supplemental Material