Induction of labor and cesarean birth in lower-risk nulliparous women at term: A retrospective cohort study.

OBJECTIVE: To evaluate whether induction of labor (IOL) is associated with cesarean birth (CB) and perinatal mortality in uncomplicated first births at term compared with expectant management outside the confines of a randomized controlled trial. METHODS: Population-based retrospective cohort study of all births in Victoria, Australia, from 2010 to 2018 (n = 640,191). Preliminary analysis compared IOL at 37 weeks with expectant management at that gestational age and beyond for uncomplicated pregnancies. Similar comparisons were made for IOL at 38, 39, 40, and 41 weeks of gestation and expectant management. The primary analysis repeated these comparisons, limiting the population to nulliparous women with uncomplicated pregnancies and excluding those with a medical indication for IOL. We compared perinatal mortality between groups using Chi-square tests and multivariable logistic regression for all other comparisons. Adjusted odds ratios and 99% confidence intervals were reported. p < 0.01 denoted statistical significance. RESULTS: Among nulliparous, uncomplicated pregnancies at ≥37 weeks of gestation in Victoria, IOL increased from 24.6% in 2010 to 30.0% in 2018 (p < 0.001). In contrast to the preliminary analysis, the primary analysis showed that IOL in lower-risk nulliparous women was associated with increased odds of CB when performed at 38 (aOR 1.23(1.13-1.32)), 39 (aOR 1.31(1.23-1.40)), 40 (aOR 1.42(1.35-1.50)), and 41 weeks of gestation (aOR 1.43(1.35-1.51)). Perinatal mortality was rare in both groups and non-significantly lower in the induced group at most gestations. DISCUSSION: For lower-risk nulliparous women, the odds of CB increased with IOL from 38 weeks of gestation, along with decreased odds of perinatal mortality at 41 weeks only.

Fetal surveillance from 39 weeks' gestation to reduce stillbirth in South Asian-born women.

BACKGROUND: In July 2017, the State of Victoria's largest maternity service implemented a new clinical guideline to reduce the rates of stillbirth at term for South Asian women. OBJECTIVE: This study aimed to evaluate the impact of offering fetal surveillance from 39 weeks to South Asian-born women on rates of stillbirth and neonatal and obstetrical interventions. STUDY DESIGN: This was a cohort study of all women receiving antenatal care at 3 large metropolitan university-affiliated teaching hospitals in Victoria, who gave birth in the term period between January 2016 and December 2020. Differences in rates of stillbirth, neonatal deaths, perinatal morbidities, and interventions after July 2017 were determined. Multigroup interrupted time-series analysis was used to assess changes in rates of stillbirth and induction of labor. RESULTS: A total of 3506 South Asian-born women gave birth before, and 8532 after the change in practice. There was a 64% reduction in term stillbirth (95% confidence interval, 87% to 2%; P=.047) after the change in practice from 2.3 per 1000 births to 0.8 per 1000 births. The rates of early neonatal death (3.1/1000 vs 1.3/1000; P=.03) and special care nursery admission (16.5% vs 11.1%; P<.001) also decreased. There were no significant differences in admission to the neonatal intensive care unit, 5-minute Apgar score <7, or birthweight, or differences in the trends of induction of labor per month. CONCLUSION: Fetal monitoring from 39 weeks may offer an alternative to routine earlier induction of labor to reduce the rates of stillbirth without causing an increase in neonatal morbidity and attenuating trends in obstetrical interventions.

COVID-19 epidemic modelling for policy decision support in Victoria, Australia 2020-2021.

BACKGROUND: Policy responses to COVID-19 in Victoria, Australia over 2020-2021 have been supported by evidence generated through mathematical modelling. This study describes the design, key findings, and process for policy translation of a series of modelling studies conducted for the Victorian Department of Health COVID-19 response team during this period. METHODS: An agent-based model, Covasim, was used to simulate the impact of policy interventions on COVID-19 outbreaks and epidemic waves. The model was continually adapted to enable scenario analysis of settings or policies being considered at the time (e.g. elimination of community transmission versus disease control). Model scenarios were co-designed with government, to fill evidence gaps prior to key decisions. RESULTS: Understanding outbreak risk following incursions was critical to eliminating community COVID-19 transmission. Analyses showed risk depended on whether the first detected case was the index case, a primary contact of the index case, or a 'mystery case'. There were benefits of early lockdown on first case detection and gradual easing of restrictions to minimise resurgence risk from undetected cases. As vaccination coverage increased and the focus shifted to controlling rather than eliminating community transmission, understanding health system demand was critical. Analyses showed that vaccines alone could not protect health systems and need to be complemented with other public health measures. CONCLUSIONS: Model evidence offered the greatest value when decisions needed to be made pre-emptively, or for questions that could not be answered with empiric data and data analysis alone. Co-designing scenarios with policy-makers ensured relevance and increased policy translation.

Elective induction of labour at full-term gestations and childhood school outcomes.

AIM: To explore the association between induction of labour at full-term gestations in low-risk nulliparous women and childhood school outcomes. METHODS: A retrospective whole-of-population cohort study linking perinatal data to educational test scores at grades 3, 5 and 7 in Victoria, Australia. Low-risk nulliparous women with singleton pregnancies induced at 39 and 40 weeks without a medical indication were compared to those expectantly managed from that week of gestation. Multivariable logistic regressions were used as well as generalised estimating equations on longitudinal data. RESULTS: At 39 weeks, there were 3687 and 103 164 infants in the induction and expectant arms, respectively. At 40 weeks' gestation, there were 7914 and 70 280 infants, respectively. Infants born to nulliparous women induced at 39 weeks' gestation had significantly poorer educational outcomes at grade 3 (adjusted odds ratio (aOR) = 1.39, 95% confidence interval (CI): 1.13-1.70) but not grades 5 (aOR = 1.05, 95% CI: 0.84-1.33) and 7 (aOR = 1.07, 95% CI: 0.81-1.40) compared to those expectantly managed. Infants born to nulliparous women induced at 40 weeks had comparable educational outcomes at grade 3 (aOR = 1.06, 95% CI: 0.90-1.25) but poorer educational outcomes at grades 5 (aOR = 1.23, 95% CI: 1.05-1.43) and 7 (aOR = 1.23, 95% CI: 1.03-1.47) compared to those expectantly managed. CONCLUSIONS: There were inconsistent associations between elective induction of labour at full-term gestations in low-risk nulliparous women and impaired childhood school outcomes.

Widespread implementation of a low-cost telehealth service in the delivery of antenatal care during the COVID-19 pandemic: an interrupted time-series analysis.

BACKGROUND: Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care. METHODS: We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation). FINDINGS: Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (-0·68% change in incidence per week [95% CI -1·37 to -0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care. INTERPRETATION: Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models. FUNDING: None.

Activin A causes endothelial dysfunction of mouse aorta and human aortic cells.

Preeclampsia is a multisystem hypertensive disorder of pregnancy that remains one of the leading causes of maternal and perinatal morbidity and mortality worldwide. The widespread maternal endothelial dysfunction that underlies preeclampsia is thought to arise from excessive placental production of various factors combined with enhanced oxidative stress. While previous studies have reported elevated activin A in women diagnosed with preeclampsia, whether activin A can cause vascular dysfunction has not yet been thoroughly investigated. Here, we demonstrated that different subtypes of activin A receptors were localised to the endothelial and smooth muscle cells of mouse and human aortae. Then, the aorta of healthy female C57Bl6J mice (n = 8) were incubated for 24 h in various concentrations of recombinant activin A to mimic early pregnancy (5 ng/mL), late pregnancy (20 ng/mL) and preeclampsia (50 ng/mL). Vascular reactivity as assessed by wire myography revealed that only the preeclamptic level of activin A impaired agonist-mediated endothelium-dependent relaxation by reducing the vasodilator prostanoid contribution to relaxation. However, agonist-mediated endothelium-independent mechanisms were unaffected. Further investigations carried out on human aortic endothelial cells suggested that the impairment of aorta relaxation could also be driven by increased endothelial cell permeability, and decreased cell viability, adherence and proliferation. This is the first direct evidence to show that activin A can induce endothelial dysfunction in whole blood vessels, suggesting that at high circulating levels it may contribute to the widespread endothelial dysfunction in women with preeclampsia.

The 5-minute Apgar score and childhood school outcomes.

AIM: To examine the association between Apgar score at 5 min and childhood developmental and educational outcome. METHODS: A population-based data linkage study of births ≥37 weeks' gestation linked to developmental outcomes at preparatory school and educational outcomes at school grades 3, 5 and 7 in Victoria, Australia. Multivariable logistic regressions and generalised estimating equations were used. RESULTS: There were 167,126 singleton infants with developmental results and 392,933 singleton infants with at least one educational result. There was an inverse relationship between Apgar score at 5 min and poor developmental and educational outcomes, with the worst outcomes among Apgar scores of 0-3. Apgar scores of 7, 8 and 9 were all associated with poorer developmental outcomes (aOR = 1.31, 95% CI: 1.12-1.54; aOR = 1.17, 95% CI: 1.05-1.29; aOR = 1.08, 95% CI: 1.02-1.13 respectively), while Apgar scores of 7 and 8 were associated with poorer educational outcomes at grades 3, 5, and 7. With progression through grades 3, 5, and 7, the extent of the difference in educational outcomes diminished (e.g. for Apgar scores of 0-3: aOR = 3.33, 95% CI: 1.85-6.00 in grade 3 and aOR = 1.49, 95% CI: 0.75-2.96 in grade 7). CONCLUSION: Apgar scores below 10 at 5 min are associated with poorer developmental and educational outcomes in school.

The health and educational costs of preterm birth to 18 years of age in Australia.

BACKGROUND: Preterm birth is the greatest cause of death up to five years of age and an important contributor to lifelong disability. There is increasing evidence that a meaningful proportion of early births may be prevented, but widespread introduction of effective preventive strategies will require financial support. AIMS: This study estimated the economic cost to the Australian government of preterm birth, up to 18 years of age. MATERIALS AND METHODS: A decision-analytic model was developed to estimate the costs of preterm birth in Australia for a hypothetical cohort of 314 814 children, the number of live births in 2016. Costs to Australia's eight jurisdictions included medical expenditures and additional costs to educational services. RESULTS: The total cost of preterm birth to the Australian government associated with the annual cohort was estimated at $1.413 billion (95% CI 1047-1781). Two-thirds of the costs were borne by healthcare services during the newborn period and one-quarter of the costs by educational services providing special assistance. For each child, the costs were highest for those born at the earliest survivable gestational age, but the larger numbers of children born at later gestational ages contributed heavily to the overall economic burden. CONCLUSION: Preterm birth leaves many people with lifelong disabilities and generates a significant economic burden to society. The costs extend beyond those to the healthcare system and include additional educational needs. Assessments of economic costs should inform economic evaluations of interventions aimed at the prevention or treatment of preterm birth.

Impact of chemically defined culture media formulations on extracellular vesicle production by amniotic epithelial cells.

The therapeutic properties of cell derived extracellular vesicles (EVs) make them promising cell-free alternative to regenerative medicine. However, clinical translation of this technology relies on the ability to manufacture EVs in a scalable, reproducible, and cGMP-compliant manner. To generate EVs in sufficient quantity, a critical step is the selection and development of culture media, where differences in formulation may influence the EV manufacturing process. In this study, we used human amniotic epithelial cells (hAECs) as a model system to explore the effect of different formulations of chemically defined, commercially sourced media on EV production. Here, we determined that cell viability and proliferation rate are not reliable quality indicators for EV manufacturing. The levels of tetraspanins and epitope makers of EVs were significantly impacted by culture media formulations. Mass spectrometry-based proteomic profiling revealed proteome composition of hAEC-EVs and the influence of media formulations on composition of EV proteome. This study has revealed critical aspects including cell viability and proliferation rate, EV yield, and tetraspanins, surface epitopes and proteome composition of EVs influenced by media formulations, and further insight into standardised EV production culture media that should be considered in clinical-grade scalable EV manufacture for generation of therapeutic EVs.

Suppression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After a Second Wave in Victoria, Australia.

Countries worldwide are experiencing a second wave of coronavirus disease 2019 (COVID-19), which is proving to be difficult to control. We describe the combination of physical distancing, mandatory mask wearing, movement restrictions, and enhanced test, trace, and isolation efforts that can be used to successfully suppress community transmission to zero.

Potential treatment of keloid pathogenesis with follistatin 288 by blocking the activin molecular pathway.

Keloids are benign tumours caused by abnormal wound healing driven by increased expression of cytokines, including activin A. This study compared effects of activins on normal and keloid-derived human dermal fibroblasts and investigated a novel treatment for keloids using follistatin. Normal skin and keloid tissue samples from 11 patients were used to develop primary fibroblast cultures, which were compared in terms of their histology and relevant gene (qRT-PCR and RNAseq) and protein (ELISA) expression. Activin A (INHBA) and connective tissue growth factor (CTGF) gene expression were significantly upregulated in keloid fibroblasts, as was activin A protein expression in cell lysates and culture medium. Activator protein 1 inhibitor (SR11302) significantly decreased INHBA and CTGF expression in keloid fibroblasts and a single treatment of follistatin over 5 days significantly inhibited activin and various matrix-related genes in keloid fibroblasts when compared to controls. Follistatin, by binding activin A, suppressed CTGF expression suggesting a novel therapeutic role in managing keloids and perhaps other fibrotic diseases.

The impact of the definition of preeclampsia on disease diagnosis and outcomes: a retrospective cohort study.

BACKGROUND: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction. OBJECTIVE: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes. STUDY DESIGN: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes. RESULTS: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations. CONCLUSION: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes.

Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia.

Therapeutic hypothermia (TH) is standard care in high-resource birth settings for infants with neonatal encephalopathy. TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55 ± 3 mm Hg in sham controls to 18-20 mm Hg (10.1 ± 1.5 minutes). Lambs were delivered and randomized to control, control + MLT (60 mg iv, from 30 minutes to 24 hours), asphyxia, asphyxia + TH (whole-body cooling to 35.1 ± 0.8°C vs. 38.3 ± 0.17°C in sham controls, from 4-28 hours), asphyxia + MLT, and asphyxia + TH + MLT. At 72 hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (P = .003) and reduced NAA:Choline (P = .005), induced apoptotic and necrotic cell death across gray and white matter brain regions (P < .05), and increased neuroinflammation and oxidative stress (P < .05). TH and MLT were independently associated with region-specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia + TH + MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH + MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy.

Trends in singleton preterm birth in Victoria, 2007 to 2017: A consecutive cross-sectional study.

INTRODUCTION: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries preterm birth rates are increasing, largely as a result of increases in iatrogenic preterm birth, whereas in other countries rates are stable or even declining. The objective of the study is to describe trends in singleton preterm births in Victoria from 2007 to 2017 in relation to trends in perinatal mortality to identify opportunities for improvements in clinical care. MATERIAL AND METHODS: We conducted a consecutive cross-sectional study in all women with a singleton pregnancy giving birth at ≥20 weeks of pregnancy in Victoria, Australia, between 2007 and 2017, inclusive. Rates of preterm birth and perinatal mortality were calculated and trends were analyzed in all pregnancies, in pregnancies complicated by fetal growth problems, hypertension, (pre)eclampsia or prelabor rupture of membranes (PROM), and in (low-risk) pregnancies not complicated by any of these conditions. RESULTS: There were 811 534 singleton births between 2007 and 2017. Preterm birth increased from 5.9% (4074 births) to 6.4% (4893 births; P < .001), due to an increase in iatrogenic preterm birth from 2.5% (1730 births) to 3.6% (2730 births; P < .001). Comparable trends were seen in pregnancies complicated by fetal growth problems and hypertension and in pregnancies not complicated by small for gestational age (SGA), hypertension, (pre)eclampsia or PROM (all P < .001). In pregnancies complicated by SGA, hypertension, (pre)eclampsia or PROM the perinatal mortality rate from 20 weeks of gestation fell (13 to 12 per 1000 births; P < .001). In pregnancies not complicated by SGA, hypertension, (pre)eclampsia or PROM there was no significant change in the perinatal mortality from 28 weeks and no decrease in the preterm weekly prospective stillbirth risk. CONCLUSIONS: The singleton preterm birth rate in Victoria is increasing, driven by an increase in iatrogenic preterm birth, both in pregnancies complicated by SGA and hypertension, and in pregnancies not complicated by SGA, hypertension, (pre)eclampsia or PROM. While perinatal mortality decreased in the pregnancies complicated by SGA, hypertension, (pre)eclampsia or PROM, no significant reduction in perinatal mortality from 28 weeks or in preterm weekly prospective stillbirth risk was noted in the pregnancies not complicated by any of these conditions.

Does detection of fetal growth restriction improve neonatal outcomes?

AIM: Timely delivery of fetal growth restriction (FGR) is a balance between avoiding stillbirth and minimising prematurity. We sought to assess the neonatal outcomes for babies suspected of FGR, both true and false positives. METHODS: This population cohort study examined all singleton births in Victoria, Australia from 2000 to 2017 (n = 1 231 415). Neonatal morbidities associated with neonatal intensive care unit (NICU) admission were assessed for babies born ≥32 weeks' with severe FGR (<3rd centile) and babies with birthweight ≥10th centile who were iatrogenically delivered for suspected FGR. RESULTS: Babies with severe FGR iatrogenically delivered for suspected FGR were more likely to require NICU admission than babies with severe FGR who were not detected (3.0% vs. 1.1%, P < 0.001). After adjusting for potential confounders, the odds of NICU admission were increased (adjusted odds ratio (aOR) = 3.00, 95% confidence interval = 2.45-3.67; P < 0.001). Rates of NICU admission were also higher in ≥10th centile babies iatrogenically delivered for suspected FGR than for ≥10th centile babies who entered labour spontaneously (1.8% vs. 0.5%, P < 0.001). After adjustments, the odds of NICU admission were increased (aOR = 3.91, 95% confidence interval = 3.40-4.49; P < 0.001). NICU admissions were associated with morbidities related to iatrogenic prematurity. CONCLUSIONS: Detection and planned delivery of FGR reduces stillbirth but may be associated with increased neonatal morbidity related to iatrogenic prematurity.

Preventing harm: A balance measure for improving the detection of fetal growth restriction.

BACKGROUND: Increasing the detection of fetal growth restriction (FGR), while reducing stillbirth, also leads to unnecessary early intervention, and associated morbidity, for normally grown babies who are incorrectly suspected of FGR. AIMS: We sought to design a balance measure that addresses the specificity of FGR detection. METHODS: A retrospective cohort study on all singleton births ≥32 weeks gestation in 2016 and 2017 in Victoria. We compared two balance measures for the detection of FGR, defined as the proportion of all babies iatrogenically delivered before 39 weeks gestation for suspected FGR that had a birthweight ≥10th centile (balance measure 1) or ≥25th centile (balance measure 2). Hospital level performance on each balance measure was derived and compared to an existing performance measure for severe FGR detection in Victoria. RESULTS: Of the 38 hospitals analysed, 12 (32%) had a favourable performance on an existing indicator of FGR detection, seven (18%) hospitals had a favourable performance on balance measure 1, and 15 (39%) had a favourable performance on balance measure 2. There was a moderate correlation between hospital performance on the existing indicator and on balance measure 1 (r = 0.447, P = 0.005) but not balance measure 2 (r = -0.063, P = 0.71). There was no difference in perinatal mortality between high performing hospitals and low performing hospitals. CONCLUSION: Introducing a balance measure into routine reporting may bring greater awareness to the unintended harm associated with increased detection of FGR.

Trends in preterm birth in twin pregnancies in Victoria, Australia, 2007-2017.

BACKGROUND: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries, the preterm birth rate in women with a multiple pregnancy is increasing, mostly due to an increase in iatrogenic preterm birth. AIMS: To investigate trends in preterm birth in twin pregnancies in Victoria, Australia, in relation to maternal and perinatal complications. MATERIALS AND METHODS: We conducted a retrospective population-based cohort study in all women with a twin pregnancy who delivered at or after 20 weeks of gestation in the state of Victoria, Australia between 2007 and 2017. Annual spontaneous and iatrogenic preterm birth rates were calculated and trends analysed. Incidence of adverse pregnancy outcomes, maternal complications and risk factors for preterm birth were analysed. RESULTS: We studied 12 757 women with a twin pregnancy. Between 2007 and 2017 the preterm birth rate increased from 641/1231 (52%) to 803/1158 (69%), mainly due to an increase in iatrogenic preterm birth from 342/1231 (28%) to 567/1158 (49%). This was irrespective of the presence of pregnancy complications. Our study showed neither a decrease in perinatal mortality from 28 weeks of gestation nor in preterm average weekly prospective stillbirth risk. CONCLUSION: Preterm birth rates in twins in Victoria are increasing, mainly driven by an increase in iatrogenic preterm birth. This occurred both in complicated and non-complicated twin pregnancies, and has not been accompanied by reduction in perinatal mortality from 28 weeks.

Association Between Iatrogenic Delivery for Suspected Fetal Growth Restriction and Childhood School Outcomes.

Importance: Timely delivery of infants suspected of having fetal growth restriction (FGR) is a balance between preventing stillbirth and minimizing prematurity, particularly because many infants with suspected FGR have normal growth. Objective: To explore the association between iatrogenic delivery for suspected FGR and childhood school outcomes. Design, Setting, and Participants: A retrospective whole-population cohort study linking perinatal data from births 32 weeks' or more gestation between January 1, 2003, to December 31, 2013, to developmental and educational test scores at preparatory school, and at school grades 3, 5, and 7 in Victoria, Australia. Follow-up was concluded in 2019. Exposures: Suspicion or nonsuspicion of FGR, presence or absence of iatrogenic delivery (defined as early induction of labor or cesarean delivery prior to labor) for suspected FGR, and presence or absence of small for gestational age (SGA). Main Outcomes and Measures: The coprimary outcomes were being in the bottom 10th percentile on 2 or more of 5 developmental domains at school entry and being below the national minimum standard on 2 or more of 5 educational domains in grades 3, 5, or 7. Results: In the birth population of 705 937 infants, the mean gestation at birth was 39.1 (SD, 1.5) weeks and the mean birth weight was 3426 (SD, 517) grams. The birth population linked to 181 902 children with developmental results and 425 717 children with educational results. Compared with infants with severe SGA (birth weight <3rd percentile) not suspected of having FGR, infants with severe SGA delivered for suspected FGR were born earlier (mean gestation, 37.9 weeks vs 39.4 weeks). They also had a significantly increased risk of poor developmental outcome at school entry (16.2% vs 12.7%; absolute difference, 3.5% [95% CI, 0.5%-6.5%]); adjusted odds ratio [aOR], 1.36 [95% CI, 1.07-1.74]) and poor educational outcomes in grades 3, 5, and 7 (for example, in grade 7: 13.4% vs 10.5%; absolute difference, 2.9% [95% CI, 0.4%-5.5%]); aOR, 1.33 [95% CI, 1.04-1.70]). There was no significant difference between infants with normal growth (birth weight ≥10th percentile) delivered for suspected FGR and those not suspected of having FGR in developmental outcome (8.6% vs 8.1%; absolute difference, 0.5% [95% CI, -1.1% to 2.0%]); aOR, 1.17 [95% CI, 0.95-1.45]) or educational outcome in grade 3, 5 or 7, despite being born earlier (mean gestation, 38.0 weeks vs 39.1 weeks). Conclusions and Relevance: In this exploratory study conducted in Victoria, Australia, iatrogenic delivery of infants with severe SGA due to suspected FGR was associated with poorer school outcomes compared with infants with severe SGA not suspected of having FGR. Iatrogenic delivery of infants with normal growth due to suspected FGR was not associated with poorer school outcomes compared with infants with normal growth not suspected of having FGR.

Delayed versus Immediate Cord Clamping in Preterm Infants.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Prematurity negatively affects regenerative properties of human amniotic epithelial cells in the context of lung repair.

There is a growing appreciation of the role of lung stem/progenitor cells in the development and perpetuation of chronic lung disease including idiopathic pulmonary fibrosis. Human amniotic epithelial cells (hAECs) were previously shown to improve lung architecture in bleomycin-induced lung injury, with the further suggestion that hAECs obtained from term pregnancies possessed superior anti-fibrotic properties compared with their preterm counterparts. In the present study, we aimed to elucidate the differential effects of hAECs from term and preterm pregnancies on lung stem/progenitor cells involved in the repair. Here we showed that term hAECs were better able to activate bronchioalveolar stem cells (BASCs) and type 2 alveolar epithelial cells (AT2s) compared with preterm hAECs following bleomycin challenge. Further, we observed that term hAECs restored TGIF1 and TGFß2 expression levels, while increasing c-MYC expression despite an absence of significant changes to Wnt/ß-catenin signaling. In vitro, term hAECs increased the average size and numbers of BASC and AT2 colonies. The gene expression levels of Wnt ligands were higher in term hAECs, and the expression levels of BMP4, CCND1 and CDC42 were only increased in the BASC and AT2 organoids co-cultured with hAECs from term pregnancies but not preterm pregnancies. In conclusion, term hAECs were more efficient at activating the BASC niche compared with preterm hAECs. The impact of gestational age and/or complications leading to preterm delivery should be considered when applying hAECs and other gestational tissue-derived stem and stem-like cells therapeutically.