BACKGROUND:Evaluating the success of policies aiming to reduce early term birth (37+0-38+6 weeks' gestation) is analytically challenging. OBJECTIVES:Determine the best method of reporting temporal changes of early term birth rates. METHODS:We analysed 54,646 singleton births at Western Australia's main tertiary hospital (2009-2019). Using interrupted time series, segmented and nominal regression, we assessed how varying gestational age outcomes, denominator, or statistical method affected conclusions regarding temporal changes (pre and post-Initiative implementation) in the timing of birth. RESULTS:Interrupted time series showed yearly rates of birth at 37+0-38+6 weeks increased pre-Initiative, with no instant level change or change in the slope post-Initiative, regardless of denominator: all births (slope change -0.0, 95% CI -0.5, 0.5); births > 36+6 weeks (slope change: -0.4, 95% CI -1.0, 0.2), and no change to the number of early term births averted. Conversely, when examining births < 39+0 weeks, pre-Initiative rates increased by 0.9% (95% CI 0.5, 1.3) per year, then stabilised post-Initiative (slope change: -0.8, 95% CI -1.4, -0.3), with no change to the number of births < 39+0 weeks averted. Nominal logistic regression showed that pre-Initiative, the rise in the early term birth rate was driven by a reduction in births at ≥ 39+0 weeks, and post-Initiative by a reduction in preterm birth. Using segmented quantile regression, lengthening of gestational age at birth in days was observed more so at the lower percentiles, compared to the estimated counterfactual. CONCLUSION:Examining early term birth rates in isolation can mask changes in birth timing in the presence of a changing preterm or ≥ 39+0 birth rate. Researchers should examine all births < 39+0 weeks rather than just early term births, or use nominal logistic regression. For gestational age in days as the outcome, segmented quantile regression can be used.

Introduction Infants born before 28 weeks’ gestation account for approximately 75% of neonatal morbidity and mortality. Late-onset sepsis (LOS) affects around 25% of these infants and is associated with an increased risk of adverse long-term outcomes. The topical application of coconut oil has been used for centuries in newborn care. Coconut oil is rich in saturated fatty acids, several of which have demonstrated antimicrobial properties. It is considered safe for extremely preterm infants, improves skin condition and may reduce the incidence of LOS.Methods and analysis This is a pragmatic, cluster-randomised, two-arm, parallel-group, multicentre, phase III clinical trial evaluating the effect of topical coconut oil versus routine skin care on the incidence of LOS in extremely preterm infants. Participating neonatal units will be cluster-randomised, and all infants born at <28 weeks gestational age will receive either routine skin care or routine care with the addition of topical coconut oil. A minimum of 616 infants will be recruited into each treatment arm. Intention-to-treat and per-protocol analyses will be performed.Ethics and dissemination Following ethical approval, patients will be recruited at participating sites under a waiver of consent with opt-out framework. The trial results will be disseminated through conferences, media sources and publication in relevant peer-reviewed journals.Trial registration number ACTRN12620001332910.

Background Preterm birth is a major cause of death and disability. We evaluated a national preterm birth prevention programme in Australia, implementing clinical strategies including avoidance of unnecessary early birth, cervical length measurement in mid-pregnancy, and prescription of vaginal progesterone. Methods The study was implemented in two phases. Phase 1 (2018–21) was a whole-of-national-population, clinician-led education programme, analysed as a retrospective, population-level study. Official data from the Australian Institute for Health and Welfare were used to assess outcomes. Phase 2 (2022–24) added a Breakthrough Series Collaborative involving 59 maternity hospitals across all Australian states and territories and was analysed as a pre–post implementation study. For this phase, we used record-level data provided by Women's Healthcare Australasia to assess outcomes. Phase 2 encompassed a 21-month baseline pre-Collaborative programme period and a 21-month Collaborative period, further divided into three time periods for analyses. The outcomes for both phases were changes in the rates of preterm (20 weeks + 0 days to 36 weeks + 6 days) and early-term (37 weeks + 0 days to 38 weeks + 6 days), liveborn, singleton births of 20 weeks' or more gestation, estimated by Poisson regression with national aggregate data in Phase 1 and with record-level data of all births from participating hospitals in Phase 2. Findings In Phase 1 (Jan 1, 2018, to Dec 31, 2021), 1 479 125 births were included in the analyses. The national singleton liveborn preterm birth rate fell from 6·40% in 2017 to 5·97% in 2021 (6·83% reduction; incidence rate ratio 0·93, 95% CI 0·91–0·95; p<0·0001), with the reduction limited to the gestational age group 32 weeks + 0 days to 36 weeks + 6 days. The early-term birth rate (37 weeks + 0 days to 38 weeks + 6 days) increased from 30·58% in 2017 to 32·17% in 2021 (5·22% increase; 1·05, 1·04–1·06; p<0·0001). In Phase 2 (October 1, 2022, to June 30, 2024), 458 542 births were included for analysis. The early-term birth rate in participating hospitals decreased from 30·63% in the pre-Collaborative period to 27·69% in the third and final Collaborative time period (9·60% decrease; 0·90, 0·89–0·92; p<0·0001), with no further decrease in preterm birth rates. Interpretation The results of the national preterm birth prevention programme in Australia suggest that, in the context of a highly resourced setting, multifaceted preterm birth prevention projects applying existing knowledge and conducted at scale might produce meaningful benefits at a population level. Further investigation is required to more effectively prevent spontaneous preterm labour at early gestational ages. Funding Australian National Health and Medical Research Council, Health Department of Western Australia, Health Department of New South Wales, Health Department of Victoria, Western Australian Channel 7 Telethon Trust, and Commonwealth Government of Australia.

IntroductionAround the world, rates of induction of labour (IOL) among nulliparous mothers have increased in the last 10 years. In Australia, rates have increased over the last decade by 43%, from 32% to 46%. There is growing concern about the rapid rise in IOL before 41 weeks for nulliparous women without medical complications because of the associated increased rates of caesarean section, reduced satisfaction with birth, and birth trauma. Melatonin potentiates the action of oxytocin and may promote the spontaneous onset of labour; therefore, we will test the hypothesis that exogenous melatonin supplementation in late pregnancy will reduce the rate of labour induction by 30% or more.Methods and analysesThis is a double-blind, randomised, placebo-controlled trial in nulliparous pregnant women to reduce IOL rates. We will randomise 530 women to receive either 3 mg oral melatonin or placebo daily from 39+0weeks’ gestation until they give birth. The primary endpoint will be IOL rate after 39 weeks post enrolment. Secondary endpoints will include the following: interval between administration of trial medication and birth; a range of maternal and neonatal outcomes, including birth outcomes; breastfeeding on discharge, at 10 days and at 2 months; maternal satisfaction; child developmental outcomes at 2 months of age; and cost-effectiveness of melatonin compared with standard care. All data will be analysed by intention to treat.Ethics and disseminationThe study is approved by the Western Australia Health Central Human Research Ethics Committee (RGS0000006283). Trial findings will be disseminated through conference presentations and peer-reviewed publications.Trial registration numberThe trial has been prospectively registered on the Australian New Zealand Clinical Trials Registry as ACTRN12623000502639 on 17/05/2023.

AbstractObjectiveTo provide data on maternal levels of estradiol and progesterone in the second trimester of pregnancy with a live foetus and those complicated by a spontaneous foetal demise.MethodsWithin a randomised trial to assess efficacy of mifepristone in termination following foetal demise from 14 to 28 weeks of gestation, we measured progesterone and estradiol levels in trial patients and in women undergoing termination with a live foetus. Women admitted to King Edward Memorial Hospital (Western Australia) from 2013 to 2016 were considered for eligibility and enroled. Scatter plots with 95% confidence intervals were generated for hormone levels by gestation. Generalised linear models were used to estimate mean values of estradiol and progesterone, accounting for maternal age, gestation and parity.ResultsOverall, women with a foetal demise had lower estradiol levels compared to women with a live foetus, (mean difference of 10 460 pmol/L). With a live foetus, higher levels of estradiol were observed with increasing gestations: with a mean of 17 010 pmol/L at 14 ≤ 17 weeks, 31 180 pmol/L at 23–28 weeks and similarly progesterone with a mean of 113 nmol/L at 14 ≤ 17 weeks and 183 nmol/L at 23–28 weeks. Progesterone levels in women with foetal demise were 37 nmol/L higher than women in the live foetus group. In all women, each unit increase in parity was associated with a decrease of 10nmol/l of progesterone (95% confidence interval: 4–16, p = 0.001).ConclusionsEstradiol and progesterone levels in the second trimester vary between pregnant women with a live and demised foetus.

BackgroundTo minimise the risk of perinatal mortality, clinicians and expectant mothers must understand the risks and benefits associated with continuing the pregnancy.ObjectivesReport the gestation-specific risk of perinatal mortality at term.MethodsPopulation-based cohort study using linked health data to identify all singleton births at gestations 37-41 weeks, in Western Australia (WA) from 2009 to 2019. Lifetable analysis was used to combine the risk of each type of perinatal mortality and calculate the cumulative risk of perinatal mortality, termed the perinatal risk index (PRI). Rates of antepartum and intrapartum stillbirth and neonatal death, as well as the PRI, were examined for each gestational week at term by non-Aboriginal and Aboriginal ethnicity. For non-Aboriginal women, rates were also examined by time-period (pre- vs. post-WA Preterm Birth Prevention Initiative (the Initiative) rollout), primiparity, and obstetric risk.ResultsThere were 332,084 singleton term births, including 60 perinatal deaths to Aboriginal mothers (3.2 deaths per 1000 births to Aboriginal mothers) and 399 perinatal deaths to non-Aboriginal mothers (1.3 deaths per 1000 births to non-Aboriginal mothers). For non-Aboriginal women, the PRI was at its lowest (PRI 0.80, 95% CI 0.61, 1.00) at 39 weeks gestation. For Aboriginal women, it was at its lowest at 38 weeks (PRI 2.43, 95% CI 0.48, 4.39) with similar risk at 39 weeks (PRI 2.68, 95% CI 1.22, 4.14). The PRI increased steadily after 39 weeks gestation. The risk of perinatal mortality was higher among Aboriginal women. The gestation-specific perinatal mortality rates were similar by the time-period, primiparity and obstetric risk.ConclusionsThe gestational ages at term associated with the lowest risk of perinatal mortality reinforce that the recommendation not to deliver before 39 weeks without medical indication is applicable to both Aboriginal and non-Aboriginal women giving birth in WA. There was no increase in the perinatal mortality rate associated with the introduction of the Initiative.

Background Heat-inactivated probiotics (HPs) may provide an effective alternative to live probiotics (P) by avoiding their risks (eg, probiotic sepsis) while retaining the benefits. We assessed the safety and efficacy of a HP in very preterm (VP: gestation <32 weeks) infants. Methods VP infants were randomly allocated to receive a HP or P mixture ( Bifidobacterium breve M-16V, Bifidobacterium longum subsp. infantis M-63, Bifidobacterium longum subsp. longum BB536, total 3×10 9 CFU/day) assuring blinding. Primary outcome was faecal calprotectin (FCP) levels were compared after 3 weeks of supplementation. Secondary outcomes included faecal microbiota and short chain fatty acid (SCFA) levels. Results 86 VP infants were randomised to HP or P group (n=43 each). Total FCP and SCFA were comparable between HP and P groups within 7 days (T1) and between day 21 and 28 (T2) after supplementation. At T2, median (range) FCP was 75 (8–563) in the HP group and 80 (21–277) in the P group (p=0.71). Propionate was significantly raised in both groups, while butyrate was significantly raised in the HP group (all p<0.01). Bacterial richness and diversity increased but was comparable between HP and P (p>0.05). Beta diversity showed similar community structures in both groups (all p>0.05). Changes in faecal Actinobacteria, Bacteroidetes and Bifidobacteriacae levels were comparable in both groups at T1 and T2. There was no probiotic sepsis. Conclusions HP was safe and showed no significant difference in FCP as compared with a live probiotic. Adequately powered trials are needed to assess the effects of HP on clinically significant outcomes in preterm infants. Trial registration number ACTRN12618000489291.

BackgroundPreterm birth (PTB) is a major pregnancy complication. There is evidence that a short cervical length in mid‐pregnancy may predict women at increased risk of PTB.AimsTo evaluate the utility of population‐based, transabdominal cervical length (TACL) measurement screening in mid‐pregnancy for PTB prediction in women.Materials and MethodsA transabdominal approach was initially performed, with a transvaginal (TVCL) approach offered when the TACL was <35 mm, could not be accurately measured, or the pregnancy had risk factors for PTB. TACL was compared to the directly related TVCL, when both were performed at the same assessment. Women with risk factors of PTB were included when they had both TACL and TVCL measurements performed at the same visit.ResultsData were provided for 9355 singleton pregnancies from 13 participating imaging centres. A transabdominal approach was used in 9006 (96.3%), including 682 (7.3%) TVCL combined with TACL. There were 349 (3.7%) women who had TVCL only. The median TACL was longer (40 mm) than the TVCL (38 mm). In 682 paired TACL and TVCL measurements, TACL <35 mm correctly identified 96.2% of pregnancies with TVCL <25 mm, compared with 65.4% of cases when using a TACL <30 mm. A TVCL <25 mm occurred in 59 (0.6%) women. A TACL <35 mm was associated with birth <37 weeks of gestation in 12.1% of women and birth <32 weeks of gestation in 3.9%.ConclusionsUniversal TACL is a feasible option for population screening of cervical length in a low‐risk population, progressing to TVCL if the TACL is <35 mm or the cervix cannot be transabdominally accurately measured.

Abstract Study question How effective and user-friendly is a non-invasive, patient-operated urine test (Kinder) in tracking reproductive hormone levels during ovarian stimulation (OS) treatment in an IVF cycle? Summary answer Urinary E1-3G correlates well with blood E2 levels and ovarian follicle development. Patients found it easy and stress-free to perform the urine test at home. What is known already Monitoring blood reproductive hormone levels during OS is a widely accepted practice to ensure the optimal ovarian response to gonadotropin treatment, timing of oocyte maturation triggering and mitigating hyperstimulation risk. However, conventional blood testing is invasive, necessitating patients to travel to clinics for blood sampling, adding to their overall burden. Previous studies have revealed a robust correlation between blood E2 levels, and its corresponding urinary metabolites E1-3G. Kinder is a portable device designed for quantifying urinary E1-3G, allowing patients to conduct tests in the privacy of their homes, and for many obviating the need to travel substantial distances for monitoring. Study design, size, duration This is a prospective, single-cohort, study of Caucasian patients (28-34 years), conducted at Fertility Specialists of Western Australia in Perth, Australia, where patients may travel vast distances for treatment. Twenty-five patients were enrolled from Aug 2022-Aug 2023, and performed home urine tests utilizing the Kinder device in parallel with clinic scheduled blood (ELISA) and ultrasound tests. The primary end point of the study was the correlation between urinary and blood reproductive hormone concentrations (E1-3G). Participants/materials, setting, methods Spearman and Pearson correlation coefficients (CC) and 95% confidence intervals were calculated for E1-3G and E2, and E1-3G/E2 and follicle development (total volume of ovarian follicles by ultrasound). To assess patient acceptability patient-reported outcomes (PRO) were assessed using the State Trait Anxiety Inventory (STAI) questionnaire. Further, patient-reported experiences (PRE) were evaluated through the System Usability Scale (SUS) questionnaire, along with assessing their likelihood to recommend Kinder to their friends or family undergoing IVF treatment. Main results and the role of chance Upon analysing 100 concurrent urine and blood samples from 25 patients, a robust correlation was found between E1-3G and E2 levels (Spearman CC: 0.818, 95% CI: 0.680-0.904; Pearson CC: 0.847, 95% CI: 0.712-0.939). Additionally, we observed a moderate correlation between E1-3G levels and ovarian volume (Spearman CC: 0.701, 95% CI: 0.556-0.805; Pearson CC: 0.670, 95% CI: 0.519-0.781, n = 72), resembled the correlation between E2 levels and ovarian volume (Spearman CC: 0.874, 95% CI: 0.804-0.920; Pearson CC: 0.849, 95% CI: 0.770-0.902, n = 75). PRE: 22 out of 23 patients who completed the survey confirmed that they would definitely, or probably, recommend Kinder. The mean SUS score (91.4) signified an excellent user experience. PRO: Anxiety levels were not affected by use of Kinder (STAI score below threshold of 42.38) in 18/20 patients who completed three STAI surveys (first one before and second one after the initial Kinder test; third one after the third/fourth Kinder test). Although 2/20 patients reported a STAI score of 49 in the final survey, suggesting increased anxiety, both affirmed in the PRE survey that they “will definitely recommend Kinder”, suggesting that the elevated STAI score can be attributed to the overall IVF treatment rather than the use of Kinder itself. Limitations, reasons for caution The sample size is relatively small, necessitating further multi-centre studies with a larger sample size to validate the findings. Wider implications of the findings The results suggest an acceptable interchangeability between at-home urine E1-3G and at-clinic blood E2 monitoring hormone levels during OS treatment. A digital health approach, combining tele-counselling, remote at-home hormone monitoring, and follicle tracking, could reduce patient burden and save many patients the inconvenience of travelling large distances for cycle monitoring. Trial registration number ACTRN12622000488707

BackgroundUnder‐identification of Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) people can result in inaccurate estimation of health outcomes. Data linkage has improved identification of Aboriginal people in administrative datasets.AimTo compare three methods of ascertainment of Aboriginal status using only pregnancy data from the Western Australian Midwives Notification System (MNS), to the linked Indigenous Status Flag (ISF) derived by the Department of Health.Materials and MethodsThis retrospective population‐based cohort study utilised logistic regression to determine which demographic characteristics were associated with under‐identification, and the effect of ascertainment method on perinatal adverse outcomes.ResultsAll methods identified a core group of 19 017 (83.0%) Aboriginal women and the ISF identified 2298 (10.0%) women who were not identified using any other method. Under‐ascertainment was lowest when a woman's Aboriginal status was determined by ever being recorded as Aboriginal in the MNS data, and highest when taken as it had been recorded for the birth in question. Maternal age <20 years, smoking during pregnancy, pre‐existing diabetes, a history of singleton preterm birth and being in the lowest 20% of Socio‐Economic Indexes for Areas score were all associated with a higher chance of being identified by the methods using only the MNS. These methods were less likely to identify nulliparous women, and those with maternal age ≥35 years. The method of ascertainment of Aboriginality did not make a significant difference to the adjusted predicted marginal probabilities of adverse perinatal outcomes.ConclusionUnlinked pregnancy data can be used for epidemiological research in Aboriginal obstetric populations.

A well-established association exists between intrauterine bacteria and preterm birth. This study aimed to explore this further through documenting bacterial and cytokine profiles in Australian mid-gestation amniotic fluid samples from preterm and term births. Samples were collected during amniocenteses. DNA was extracted and the full-length 16S rRNA gene was amplified and sequenced. Levels of the cytokines IL-1β, IL-6, IL-10, TNF-α and MCP-1 were determined using the Milliplex MAGPIX system. Bacterial DNA profiles were low in diversity and richness, with no significant differences observed between term and preterm samples. No differences in the relative abundance of individual OTUs between samples were identified. IL-1β and TNF-α levels were significantly higher in samples containing reads mapping to Sphingomonas sp.; however, this result should be interpreted with caution as similar reads were also identified in extraction controls. IL-6 levels were significantly increased in samples with reads that mapped to Pelomonas sp., whilst TNF-α levels were elevated in fluid samples from pregnancies that subsequently delivered preterm. Bacterial DNA unlikely to have originated from extraction controls was identified in 20/31 (64.5%) mid-gestation amniotic fluid samples. Bacterial DNA profiles, however, were not predictive of preterm birth, and although cytokine levels were elevated in the presence of certain genera, the biological relevance of this remains unknown.

Objectives: To assess the frequency of maternal adverse events associated with second trimester medical abortion using sequential mifepristone and misoprostol.Study design: Retrospective analysis of medical abortions 13 to 28 weeks gestation using sequential mifepristone and misoprostol in a single center from January 2008 to December 2018. The main outcomes evaluated were the nature and incidence of adverse procedural events and the impact of gestation upon these outcomes. Results: During the study period, 1393 people underwent a medical abortion with sequential mifepristone and misoprostol. The median maternal age was 31 years (IQR 27-36 years) and 21.8% had at least one prior cesarean delivery. The median gestational age at abortion commencement was 19 weeks (IQR 17-21).The main adverse maternal events were complete or partial placental retention greater than 60 minutes triggering removal in the operating room (19%), maternal hemorrhage > 1000 cc (4.3%), blood transfusion (1.7%), hospital readmission (1.4%), uterine rupture (0.29%) and hysterectomy (0.07%). There were significant reductions in placental retention rates with increasing gestational age (23.3% at 13-16 weeks gestation declining to 10.1% at > 23 weeks gestation, p < 0.001).Conclusions: Serious adverse maternal events associated with second trimester medical abortion with sequential mifepristone-misoprostol are uncommon. Implications: Second trimester medical abortion with mifepristone and misoprostol is generally safe, however, on occasions serious complications may occur. All health care units providing a medical abortion service require the facilities and expertise to deal with these adverse events in a timely manner.(C) 2023 Elsevier Inc. All rights reserved.

Aims: To assess clinical outcomes and complications in women with >= 1 prior caesarean delivery (CS) during mid-pregnancy medical abortion with misoprostol following mifepristone priming. Materials and Methods: Retrospective analysis of abortions at 13-28 weeks gestation using sequential mifepristone and misoprostol at a single centre from 1/2008-12/2018. Procedural outcomes were compared between cases with no prior CS, one prior and >= 2 prior CS. Results: There were 1399 consecutive women who underwent a medical abortion, with 304 (21.7%) having >= 1 prior lower segment CS (241 one, 49 two, 12 three, one four) and one a prior classical CS. Median gestation was 19 weeks (interquartile range (IQR) 17-21) among nulliparas, multiparas with no prior CS and multiparas with prior CS, P = 0.505. Compared with nulliparas (median procedural duration 10.8 h, IQR 7.5-16.5; adjusted hazards ratio (aHR) = 1.20 95%CI 1.04-1.40, P = 0.015), multiparas with prior CS had a shorter procedural duration (9.5 h, IQR 6.5-13.5) while multiparas with no CS had the shortest duration (7.0 h, IQR 5.0-9.8; aHR = 2.28 95%CI 2.01-2.58, P < 0.001). Complications were more frequent with prior CS: estimated blood loss (medians: 100 cc no CS vs 150 cc >= 1 CS, P = 0.002), blood loss >1000 cc (3.6% no CS vs 7.2% >= 1 CS; odds ratio (OR) >= 2.11 95%CI 1.23-3.62, P = 0.007) and placental retention (17.3% no CS vs 25.3% >= 1 CS; adjusted OR = 1.44 95%CI 1.05-1.99, P = 0.024). Uterine rupture occurred in 4/304 women with >= 1 prior CS (1.3%). Conclusions: Mifepristone-misoprostol abortion in women with prior CS is generally safe but associated with an increased risk of procedural complications. Lowering of the misoprostol dosage with prior CS may reduce uterine rupture, although this hypothesis requires ongoing research.

Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large population-based registries or smaller single site registries to provide timely answers at a reduced cost compared with traditional randomised controlled trials. RRCTs can take a number of forms in addition to the traditional individual-level randomised trial, including parallel group trials, platform or adaptive trials, cluster randomised trials and cluster randomised stepped-wedge trials. From an implementation perspective, initially it is advantageous to embed RRCT into well-established registries as these have typically already overcome any issues with end point validation and adjudication. With advances in data linkage and data quality, RRCTs can play an important role in answering clinical questions in a pragmatic, cost-effective way.

Abstract Background Heat-inactivated probiotics may provide an effective alternative to live probiotics by avoiding the risk of probiotic sepsis, altered immune responses and antimicrobial resistance while retaining probiotic benefits. Objective We assessed safety and efficacy of a heat-inactivated probiotic in very preterm (VP: gestation < 32 weeks) infants. Methods VP infants were recruited including a pre-planned subgroup of extremely preterm (EP: gestation < 28 weeks). Mixture of heat-inactivated (HP) or live probiotic (P) strains B. breve M-16V, B. longum subsp. infantis M-63, B. longum subsp. longum BB536 (Total 3 x109 CFU/day) assuring blinding. Primary outcomes included fecal calprotectin (FCP) levels and safety. Secondary outcomes included fecal microbiota assessed by 16S ribosomal RNA and shotgun sequencing and short chain fatty acid (SCFA) levels in samples collected after the 1st (T1) and 3rd (T2) week of supplementation. Results 86 VP (P:43; HP:43) infants were randomized. Median (range) FCP was lower at T2 vs T1 in both HP [75 (8-563) vs 109 (5.1–725) µg/g; p = 0.22] and P [80 (21–277) vs 105 (11–842) µg/g; p = 0.4] groups. Total FCP and SCFA were comparable between HP vs P groups at T1 and T2 (p > 0.05). Propionate was significantly raised in both groups, whilst butyrate was significantly raised in HP group (all p < 0.01). At T2, alpha diversity increased but was comparable and beta diversity showed significantly different community structures in both groups (all p < 0.01). Actinobacteria significantly increased and Bacteroidetes decreased at T2 vs T1 for both groups (p < 0.05). Bifidobacteriacae increased (p < 0.001) whilst Staphylococcaceae decreased (p < 0.05) for both groups. Bifidobacteriacae, B. longum subsp. infantis and B. longum subsp. longum levels were comparable. Clinical outcomes were comparable and there were no adverse events. Conclusions Heat-inactivated probiotic was safe and well tolerated, with an intestinal anti-inflammatory effect comparable to live probiotic. Adequately powered randomised trials are needed to assess its clinically significant effects in preterm infants. Trial Registration ID and URL Australian and New Zealand Clinical Trials Registry (ACTRN12618000489291); ANZCTR - Registration

Preterm birth (PTB) is the greatest cause of mortality and morbidity in children up to five years of age globally. The Western Australian (WA) PTB Prevention Initiative, the world’s first whole-of-population whole-of-state program aimed at PTB prevention, was implemented across WA in 2014. We conducted a prospective population-based cohort study using pregnancy data for singleton births in WA from 2009 to 2019. Logistic regression using the last full year before the Initiative (2013) as the reference, and run charts were used to examine changes in PTB rates compared to pre-Initiative levels, by gestational age group, hospital type, low and high risk of PTB in mid-pregnancy, and onset of labour (spontaneous/medically initiated). Analyses were stratified by Aboriginal and non-Aboriginal maternal ethnicity. Amongst non-Aboriginal women, there was initially a reduction in the PTB rate across the state, and in recent years it returned to pre-Initiative levels. Amongst Aboriginal women there was a small, non- significant reduction in the state-wide PTB rate in the first three years of the Initiative, followed by a rise in recent years. For non-Aboriginal women, the reduction in the rate of PTB at the tertiary centre was sustained and improved further for women of all risk levels and onsets of labour. This reduction was not observed for Aboriginal women giving birth at the tertiary centre, amongst whom there was an increase in the PTB rate overall and in all subgroups, with the exception of medically initiated PTB. Amongst Aboriginal women the PTB rate has also increased across the state. At non-tertiary hospitals there was a large increase in PTB amongst both Aboriginal and non-Aboriginal women, largely driven by medically initiated late PTB. Maternal risk factors cannot account for this increase. The reduction in PTB rates amongst non-Aboriginal women at the state’s tertiary hospital demonstrates that with the right strategies, PTB can be reduced. A sustained collaborative model is required to realise this success in non-tertiary hospitals. The series of interventions was of limited use in Aboriginal women, and future efforts will need to be directed at strategies more likely to be successful, such as midwifery continuity of care models, with Aboriginal representation in the healthcare workforce.

Abstract Study question Are adolescents conceived after assisted reproductive technologies (ART) at an increased risk of asthma and allergies, compared to their counterparts conceived without ART? Summary answer No difference in asthma prevalence, better lung-function, and an increase in allergic rhinoconjunctivitis, food allergies and positive skin-prick tests are reported in the ART cohort. What is known already Over 8 million children have been born after conception with ART worldwide. Emerging evidence shows an increased risk of atopic disorders, such as asthma and allergies, in such children, potentially due to epigenetic alterations or underlying parental subfertility and perinatal risk factors. Studies to date are highly heterogeneous, including non-standardized diagnostic tools, non-representative reference populations, and lacking appropriate covariate adjustment. With the increase in atopic disorders worldwide, and the burden they bring to the life of individuals and to society, in combination with the increase in ART, it is important to further investigate the risk of atopy in such offspring. Study design, size, duration The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 offspring conceived after ART (aged 13-21), born 1991-2001 in Western Australia. Their health parameters, including asthma and allergy assessments, were compared with those of counterparts conceived without ART, from the Raine Study Generation 2 (Gen2). The 2,868 Gen2 participants are representative of the local population. At age 14 (2013-2017), 152 GUHS participants replicated atopy assessments previously completed by similarly aged Gen2 participants. Participants/materials, setting, methods Asthma and allergy assessments consisted of a parent-completed modified version of the ‘International Studies of Asthma and Allergies in Childhood’ (ISAAC) questionnaire, spirometry, methacholine challenge- and skin-prick testing (SPT). Chi2, Fisher’s Exact and Mann-Whitney U tests, performed in SPSS V25, examined cohort differences, and generalized estimating equations adjusted for (a subset of) the following covariates: sex, age, height, singleton pregnancy, gestational age, birthweight, mode of delivery, primary caregiver smoking, and being an only child. Main results and the role of chance Current asthma and asthma severity, based on the ISAAC questionnaire, appeared similar between the cohorts. Lung function (mean Forced Expiratory Volume [FEV1], Forced Vital Capacity [FVC] and FEV1/FVC ratio) was better in the ART cohort (3.10 vs. 2.96 L, p = 0.011; 3.72 vs. 3.29 L, p < 0.001; 85.5 vs. 91.8%, p < 0.001, respectively). No difference in mean Forced Expiratory Flow was reported. Bronchial hyperresponsiveness was significantly less prevalent in the ART cohort (8.8% vs.18.6% p = 0.006). Current allergic rhinoconjunctivitis (ARC) rates were significantly higher in the ART cohort (32.4% vs. 25.2%, aOR 1.52 [1.03-2.26], p = 0.036), while prevalence of current atopic dermatitis did not differ. Food allergies were twice as prevalent in the ART cohort (20.7 vs. 10.9%, aOR 1.89 [1.17-3.06], p = 0.010). Significantly more GUHS participants had a positive SPT (68.0% vs. 45.4%, aOR 3.034 [1.989-4.628], p < 0.001). The percentage of polysensitisation (> 1 allergen) did not differ between the cohorts. Sub-analyses comparing offspring conceived after in vitro fertilisation (IVF)[n = 100] and intracytoplasmic sperm injection (ICSI)[n = 40], and fresh and frozen embryo transfers (ETs n = 82, FETs n = 58) within the ART cohort, showed no significant differences, although all allergy outcomes appeared more prevalent in the ET group. Limitations, reasons for caution Despite substantial study size, numbers did not allow for adjustment for all covariates. Sub-analyses (IVF vs. ICSI and ET vs. FET), were conducted with limited power and require replication in larger cohorts. Both cohorts were largely of Caucasian decent (>88.0%), which reduces applicability of findings to other ethnicities. Wider implications of the findings Reassuringly, adolescents conceived after ART had better lung-function than their counterparts and no differences in asthma prevalence. The reported increase in allergies in ART conceived adolescents is of importance to families and healthcare providers, and opens possibilities for targeted screening and treatment. Further studies are required to confirm our findings. Trial registration number Not applicable

To compare mental health and behavior in ART vs. non-ART adolescents.

BACKGROUND AND OBJECTIVE:Environmental exposure to phthalates and bisphenol A (BPA), chemicals used in the production of plastics, may increase risk for asthma and allergies. However, little is known about the long-term effects of early life exposure to these compounds. We investigated if prenatal exposure to these compounds was associated with asthma, allergy and lung function outcomes from early childhood into adulthood in a cohort study. METHODS:Maternal serum samples collected from 846 pregnant women in the Raine Study were assayed for BPA and phthalate metabolites. The children of these women were followed up at 5, 13 and 22 years where spirometry and respiratory questionnaires were conducted to determine asthma and allergy status. Lung function trajectories were derived from longitudinal spirometry measurements. Multinomial logistic regression and weighted quantile sum regression was used to test associations of individual and chemical mixtures with asthma phenotypes and lung function trajectories. RESULTS:Effects of prenatal BPA and phthalates on asthma phenotypes were seen in male offspring, where BPA was associated with increased risk for persistent asthma, while mono-iso-butyl phthalate and mono-iso-decyl phthalate was associated with increased risk for adult asthma. Prenatal BPA had no effect on lung function trajectories, but prenatal phthalate exposure was associated with improved lung function. CONCLUSION:Prenatal BPA exposure was associated with increased likelihood of persistent asthma in males, while prenatal phthalate exposure was associated with increased likelihood of adult asthma in males. Results suggest that prenatal exposure to prenatal BPA and phthalates affect asthma risk, particularly in males, however lung function was not adversely affected.

STUDY QUESTION Are there differences in thyroid function between adolescents and young adults conceived with and without ART? SUMMARY ANSWER This study demonstrated no evidence of clinically relevant differences in thyroid function between adolescents and young adults conceived with and without ART. WHAT IS KNOWN ALREADY Studies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which makes early detection and correct treatment essential. STUDY DESIGN, SIZE, DURATION The Growing Up Healthy Study (GUHS) is a prospective cohort study, which aimed to recruit all adolescents born after conception with ART between 1991 and 2001 in the study area. The included participants (n = 303, aged 13-20 years) completed various health assessments. Depending on the age at enrolment, participants completed thyroid assessments at the 14- or 20-year follow-up. The outcomes of these replicated thyroid assessments were compared to those of participants conceived without ART from the Raine Study Generation 2 (Gen2). The Gen2 participants (n = 2868) were born between 1989 and 1992 and have been recognized to be representative of the local population. PARTICIPANTS/MATERIALS, SETTING, METHODS Thyroid function assessments were compared between n = 134 GUHS and n = 1359 Gen2 adolescents at age 14 years and between n = 47 GUHS and n = 914 Gen2 young adults at age 20 years. The following mean thyroid hormone concentrations were compared between the cohorts: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and thyroid peroxidase antibodies (TPOAb). The prevalence of the following thyroid hormone profiles, based on individual thyroid hormone concentrations, was compared: euthyroidism, subclinical and overt hypo- and hyperthyroidism and thyroid autoimmunity. Outcomes were compared between the cohorts, and univariately between fresh embryo transfers (ET) and frozen ET (FET) within the GUHS. The correlation between maternal peak E2 concentrations (pE2) and fT4 was assessed within the GUHS. MAIN RESULTS AND THE ROLE OF CHANCE All mean thyroid function outcomes fell within the normal range. At both ages, we report no differences in TSH concentrations. At age 14 years, lower fT3 concentrations (4.80 versus 5.35 pmol/L, P < 0.001) and higher fT4 concentrations (12.76 versus 12.19 pmol/L, P < 0.001) were detected in the GUHS adolescents compared to Gen2 adolescents. At age 20 years, higher fT3 and fT4 concentrations were reported in GUHS adolescents (4.91 versus 4.63 pmol/L, P = 0.012; 13.43 versus 12.45 pmol/L, P < 0.001, respectively) compared to Gen2 participants. No differences in the prevalence of subclinical and overt hypo- and hyperthyroidism or thyroid autoimmunity were demonstrated between the cohorts at age 14 and 20 years. Thyroid function did not differ between ET and FET, and no correlation between pE2 and fT4 was reported. LIMITATIONS, REASONS FOR CAUTION The observational nature of the study limits the ability to prove causation. Furthermore, the comparison of ET and FET offspring at age 20 years may be lacking power. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI) owing to the low number of ICSI cycles at the time of study. As ART laboratory and clinic data were collected contemporaneously with the time of treatment, no other data pertaining to the ART cycles were sought retrospectively; hence, some factors could not be accounted for. WIDER IMPLICATIONS OF THE FINDINGS This study does not support previous findings of clinically relevant differences in thyroid function when comparing a cohort of adolescents conceived after ART to counterparts conceived without ART. The minor differences detected in fT3 and fT4 were considered not biologically relevant. Although these findings appear reassuring, they warrant reinvestigation in adulthood. STUDY FUNDING/COMPETING INTERESTS This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director and a shareholder of PIVET Medical Centre, Perth, Western Australia.