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Women of South Asian background are known to have higher rates of stillbirth than women in other high-income countries, such as Australia or the United Kingdom. To reduce the rate of stillbirth, leading societies recommend antenatal fetal monitoring or induction of labor (IOL) at 41 weeks of gestation regardless of race/ethnicity. However, at 41 weeks' gestation, the risk of stillbirth for South Asian–born women is already up to 5 times higher than for Australian-born women. Initially, the UK National Institution for Health and Care Excellence recommended that all South Asian women undergo IOL earlier, at 39 weeks of gestation. However, this recommendation was criticized as being racist, and perpetuating the myth that race plays a factor in poor outcomes, so it was amended to state that South Asian–born women might benefit from additional monitoring and support. Still, there is no evidence to support this guidance. In July 2017, the State of Victoria in Australia implemented a new clinical guideline to provide South Asian women with biweekly cardiotocography and amniotic fluid measurement at 39 weeks of gestation. The aim of this study was to assess the impact of the new clinical guideline on the rates of stillbirth and select pregnancy outcomes for South Asian women.This was a cohort study that included women with singleton pregnancies who gave birth at term or beyond at a university- affiliated teaching health service located in 3 metropolitan areas in Australia from January 1, 2016, to December 31, 2020. Women were classified as South Asian born if they self-identified as being from Afghanistan, Bangladesh, Bhutan, India, Iran, the Maldives, Nepal, Pakistan, or Sri Lanka. The timeframe between January 1, 2016, and June 30, 2017, represented the period before the change in practice for fetal monitoring for South Asian women; the timeframe between July 1, 2017, and December 31, 2020, represented the period after. Although the new practice was applied to South Asian–born women in the second timeframe, fetal monitoring at 41 weeks was applied to all other women. The primary outcome was stillbirth at the onset of or during labor at 37 weeks and 39 weeks of gestation. The secondary outcomes included neonatal death at <7 days, admission to the special care nursery or neonatal intensive care, Apgar score <7 at 5 minutes, infant birthweight, gestation of birth, IOL, and mode of birth.A total of 3506 South Asian women gave birth before the change in practice, whereas 8532 gave birth postimplementation. The rate of stillbirth at 37 weeks' gestation for South Asian–born women was 2.3 per 1000 births—a 2.6-fold higher rate than for other women (0.9 per 1000 births; P= 0.06). After the change in practice, the rate of stillbirth fell by 64% for South Asian–born women (95% confidence interval, 87%–2%; P= 0.047). The association was stronger when the results were restricted to births after 39 weeks of gestation. Also, after the change in practice, reduced rates for early neonatal death (3.1 per 1000 vs 1.3 per 1000; P= 0.03) and admission to the special care nursery (16.5% vs 11.1%; P< 0.001) were observed. The median gestation of birth for South Asian–born women was 39+3weeks preimplementation compared with 39+2weeks postimplementation, a difference of 1 day. The rate of IOL for South Asian–born women was 4.9% higher than other women (95% confidence interval, 1.3%–8.5%; P= 0.008). However, no significant difference was observed between the 2 groups in the rate of IOL per month after the change in practice, nor across the other secondary outcomes.In conclusion, fetal monitoring starting at 39 weeks' gestation among South Asian–born women reduced the rate of stillbirth, neonatal death, and admission to the special care nursery compared with previous guidelines to begin monitoring at 41 weeks.

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.

Cell therapies for neonatal morbidities are progressing to early phase clinical trials. However, protocols for intravenous (IV) delivery of cell therapies to infants have not been evaluated. It has been assumed the cell dose prescribed is the dose delivered. Early in our clinical trial of human amnion epithelial cells (hAECs), we observed cells settling in the syringe and IV tubing used to deliver the suspension. The effect on dose delivery was unknown. We aimed to quantify this observation and determine an optimal protocol for IV delivery of hAECs to extremely preterm infants. A standard pediatric infusion protocol was modeled in the laboratory. A syringe pump delivered the hAEC suspension over 60 minutes via a pediatric blood transfusion set (200‐μm filter and 2.2 mL IV line). The infusion protocol was varied by agitation methods, IV‐line volumes (0.2‐2.2 mL), albumin concentrations (2% vs 4%), and syringe orientations (horizontal vs vertical) to assess whether these variables influenced the dose delivered. The influence of flow rate (3‐15 mL/h) was assessed after other variables were optimized. The standard infusion protocol delivered 17.6% ± 9% of the intended hAEC dose. Increasing albumin concentration to 4%, positioning the syringe and IV line vertically, and decreasing IV‐line volume to 0.6 mL delivered 99.7% ± 13% of the intended hAEC dose. Flow rate did not affect dose delivery. Cell therapy infusion protocols must be considered. We describe the refinement of a cell infusion protocol that delivers intended cell doses and could form the basis of future neonatal cell delivery protocols. Cell therapy is neonatal medicine's new frontier. While the challenges of translation have been much discussed, we have overlooked a simple yet fundamental hurdle; a protocol that delivers the intended cell dose intravenously to infants. Our existing protocol delivered less than 20% of the intended dose of human amnion epithelial cells. Here, we demonstrate simple measures can optimize cell dose delivery.

There is increasing evidence that administration of many types of stem cells, including human amnion epithelial cells (hAECs), can reduce hypoxic‐ischemic injury, including in the perinatal brain. However, the therapeutic window for single dose treatment is not known. We compared the effects of early and delayed intracerebroventricular administration of hAECs in fetal sheep at 0.7 gestation on brain injury induced by 25 minutes of complete umbilical cord occlusion (UCO) or sham occlusion. Fetuses received either 1 × 106hAECs or vehicle alone, as an infusion over 1 hour, either 2 or 24 hours after UCO. Fetuses were killed for brain histology at 7 days post‐UCO. hAEC infusion at both 2 and 24 hours had dramatic anti‐inflammatory and anti‐gliotic effects, including significantly attenuating the increase in microglia after UCO in the white and gray matter and the number of astrocytes in the white matter. Both protocols partially improved myelination, but had no effect on total or immature/mature numbers of oligodendrocytes. Neuronal survival in the hippocampus was increased by hAEC infusion at either 2 or 24 hours, whereas only hAECs at 24 hours were associated with improved neuronal survival in the striatum and thalamus. Neither protocol improved recovery of electroencephalographic (EEG) power. These data suggest that a single infusion of hAECs is anti‐inflammatory, anti‐gliotic, and neuroprotective in preterm fetal sheep when given up to 24 hours after hypoxia‐ischemia, but was associated with limited white matter protection after 7 days recovery and no improvement in the recovery of EEG power. Human amnion epithelial cells normalize microgliosis and astrogliosis after asphyxia.

To examine changes in the modes of delivery of twins in Victoria over 33 years. Retrospective population‐based study. All twin births in Victoria, 1 January 1983 – 31 December 2015. Mode of birth (vaginal, planned or unplanned caesarean delivery); indications for caesarean delivery. During 1983–2015, 32 187 twin pregnancies ended in live or stillbirths in Victoria. The proportion of twins born by caesarean delivery increased from 24% (156 twin deliveries) in 1983 to 71% (782 deliveries) in 2015. The proportion of twin births by planned caesarean delivery with twin pregnancy as the sole indication for caesarean delivery increased across this period from 1.8% (12 twin deliveries) to 21% (231 deliveries). The proportion of twin births by caesarean delivery and the proportion of caesarean twin deliveries with twin pregnancy as the principal indication each differed between Victorian regions. During 1983–2015, the proportion of twins born in Victoria by caesarean delivery increased almost threefold, mostly because caesarean delivery has become the preferred mode of birth for twin pregnancies. Regional differences in the delivery of twins suggest that the number of caesarean deliveries can be reduced with appropriate system and training support.

(Abstracted from JAMA2021;326:145–153)One of the larger contributors to stillbirth in late pregnancy is fetal growth restriction (FGR). When undetected, the rate of stillbirth between 2000 and 2017 was 16.4 per 1000 births.

(Abstracted from Lancet2021;398:41–52)In response to the COVID-19 pandemic, health care systems around the world had to quickly adapt to protect patients and staff from exposure. In Australia, a government initiative was launched to temporarily change public health funding to support the use of telehealth.

Recent decades have seen the rapid progress of neonatal intensive care, and the survival rates of the most preterm infants are improving. This improvement is associated with changing patterns of morbidity and new phenotypes of bronchopulmonary dysplasia and preterm brain injury are recognised. Inflammation and immaturity are known contributors to their pathogenesis. However, a new phenomenon, the exhaustion of progenitor cells is emerging as an important factor. Current therapeutic approaches do not adequately address these new mechanisms of injury. Cell therapy, that is the use of stem and stem-like cells, with its potential to both repair and prevent injury, offers a new approach to these challenging conditions. This review will examine the rationale for cell therapy in the extremely preterm infant, the preclinical and early clinical evidence to support its use in bronchopulmonary dysplasia and preterm brain injury. Finally, it will address the challenges in translating cell therapy from the laboratory to early clinical trials.

ObjectiveHigher rates of neonatal morbidity and mortality at term combined with earlier spontaneous delivery have led to the hypothesis that babies born to South Asian born (SA-born) women may mature earlier and/or their placental function decreases earlier than babies born to Australian and New Zealand born (Aus/NZ-born) women. Whether babies born to SA-born women do better in the preterm period, however, has yet to be evaluated. In this study we investigated respiratory outcomes, indicative of functional maturity, of preterm babies born to SA-born women compared with those of Aus/NZ-born women to explore this hypothesis further.Study design and settingThis retrospective cohort study was conducted at Monash Health.PatientsData were collected from neonatal and birth records of moderate-late preterm (32–36 weeks) infants born between 2012 and 2015 to SA-born and Aus/NZ-born women.Outcome measuresRates of nursery admissions and neonatal respiratory outcomes were compared.ResultsBabies born to Aus/NZ-born women were more likely to be admitted to a nursery (80%) compared with SA-born babies (72%, p=0.004). Babies born to SA-born mothers experienced significantly less hyaline membrane disease (7.8%), required less resuscitation at birth (28.6%) and were less likely to require ventilation (20%) than babies born to Aus/NZ-born mothers (18%, 42.2%, 34.6%; p<0.001). There was no difference in the duration of ventilation or length of stay in hospital.ConclusionsModerate-late preterm babies born to SA-born women appear to have earlier functional maturity, as indicated by respiratory outcomes, than Aus/NZ-born babies. Our findings support the hypothesis of earlier fetal maturation in SA-born women.

Background The Healthcare Complaints Analysis Tool (HCAT) is a coding taxonomy developed to interrogate patient complaints for quality and safety improvement lessons. The reliability of the tool has been tested in whole-of-system and whole-of-service settings. We sought to assess whether the taxonomy is functional at the level of a single hospital department.Objectives To demonstrate the feasibility of applying HCAT in the setting of a large maternity department with a view to using it to inform quality and safety improvement opportunities.Methods All 200 de-identified complaints made between 1 April 2011 and 30 April 2016 to a multi-site maternity service were collated. Each complaint entry included a summary of complaint content, complaint report date, complaint closure date and an incident severity rating (ISR). HCAT was applied to the analysis of complaints using a previously validated content analysis framework. A coding flowchart was developed to aid classification.Results The 200 complaints involved 567 issues, an average of 2.8 issues per complaint. The most common issues were rude behaviour (n = 46), poor communication (n = 38), complaints relating to the quality of medical care (n = 36), nursing care (n = 35), surgical/medical complications (n = 28) and complaints relating to the attitude of staff members (n = 23). Complaints in the clinical domain made up the greatest proportion of both severe (ISR 1 – 66.7%) and moderate (ISR 2 – 64.5%) incidents.Conclusions Using a reliable taxonomy, we were able to successfully interrogate patient complaints, identifying quality improvement targets within a single maternity service. The taxonomy appears suitable for adoption and application across health jurisdictions.

ABSTRACTIntroduction: Preeclampsia is a disease specific to pregnancy characterised by new onset hypertension with maternal organ dysfunction and/or fetal growth restriction. It remains a major cause of maternal and perinatal morbidity and mortality. For fifty years, antihypertensives have been the mainstay of treating preeclampsia, reducing maternal morbidity and mortality. With increased knowledge of the mechanisms underlying the disease has come opportunities for novel therapies that complement antihypertensives by protecting the maternal vasculature.Areas covered: In this review, the authors consider, in detail, the antihypertensives commonly used today in the emergency care of women with severe preeclampsia. They also review less common anti-hypertensive agents and discuss the role of magnesium sulphate in the management of preeclampsia and the prevention of eclampsia. Finally, they explore novel therapeutics for the acute management of preeclampsia.Expert opinion: The rapid control of maternal hypertension will, and must, remain the mainstay of emergency treatment for women with severe preeclampsia. The role of magnesium sulphate as a primary prevention for eclampsia is context dependant and should not displace a focus on correcting blood pressure safely. The exploration of novel adjuvant therapies will likely allow us to prolong pregnancy longer and improve perinatal outcomes safely for the mother.

Background Traditionally, managing patient complaints and medicolegal claims has been largely a reactive process. However, attention has recently turned to systematically learning from complaints and litigation to prevent recurrence. Within a high-volume maternity service, we explored whether developing predictive tools for patient complaints and litigation to support proactive management was feasible.Objectives To develop and assess two screening tools to predict the likelihood of (i) patient complaints and/or (ii) medicolegal claims arising from maternity care and to assess practitioner awareness of patient risk factors.Methods Births between 1 April 2011 and 30 April 2016 at a university hospital maternity service in Melbourne, Australia were considered. Univariate binary logistic regression was performed to identify the variables contributing to complaints and claims. Backwards-stepwise logistic regression was applied to develop each screening tool. Clinicians completed a survey to assess awareness of identified risk factors.Results In the study period, there were 41,443 births, 173 complaints and 19 claims. The complaints tool had only fair predictive capacity (receiver operating characteristic 0.72, p < 0.001) and the claims tool failed. Neither approach afforded sufficient discrimination to be useful in routine predictive modelling. One hundred and one practitioners completed the survey (response rate 15.7%). Practitioners were better at recognising risk factors for legal claims than for patient complaints.Conclusion Whilst new risk factors for patient complaints and medicolegal claims were identified, we were unable to develop a screening tool that was sufficiently discriminatory to be useful in routine predictive triaging. However, increasing practitioner awareness of key risk factors may afford opportunities to improve care quality.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that mainly affects premature babies who require ventilator support. The pathogenesis of BPD is complex but includes vascular maldevelopment, alveolarization arrest, and lung inflammation. There is no cure for BPD. Clinical care is limited to supportive respiratory measures. A population of stem‐like cells derived from placental membranes, human amnion epithelial cells (hAECs), has shown therapeutic promise in preclinical models of BPD. With a view to future efficacy trials, we undertook a first‐in‐human clinical trial of hAECs in babies with BPD to assess the safety of these cells. In a single‐center, open‐label phase I trial, we administered allogeneic hAECs (1 × 106per kilogram bodyweight) by intravenous infusion to six premature babies with BPD. The primary outcomes of the study were focused on safety, including local site reaction, anaphylaxis, infection, features of rejection, or tumor formation. Outcomes to discharge from neonatal unit were studied. The hAECs were well tolerated. In the first baby, there was transient cardiorespiratory compromise during cell administration consistent with a pulmonary embolic event. Following changes to cell administration methods, including introduction of an inline filter, and reducing the cell concentration and the rate of cell infusion, no such events were observed in the subsequent five babies. We did not see evidence of any other adverse events related to cell administration. Allogeneic hAECs can be safely infused into babies with established BPD. Future randomized clinical trials to assess efficacy in this patient population are justified. StemCellsTranslationalMedicine2018;7:628–635 Respiratory requirements of 6 babies with established bronchopulmonary dysplasia following intravenous administration of allogeneic amniotic epithelial cells.

ABSTRACTThe role of maternal vaccination in reducing neonatal morbidity and mortality is expanding but uptake remains suboptimal. While the barriers to uptake have been well described, women from minority groups have not been well represented in previous studies. In this study we examine the facilitators and barriers to uptake of antenatal vaccination by women from culturally and linguistically diverse backgrounds in Melbourne, Australia. 537 women attending antenatal care completed a survey; 69% were born overseas. 63% had or intended to receive pertussis vaccine and 57% had or intended to receive influenza vaccine during their pregnancy. On multivariable analysis, predictors of uptake of pertussis vaccine were healthcare provider recommendation (OR 10, 95% CI 5–21, p< 0.001) and belief maternal pertussis vaccination is safe (OR 36, 95% CI 18–70, p < 0.001). For influenza vaccine, predictors of uptake were previous receipt of influenza vaccine (OR 8, 95% CI 5–15, p < 0.001) and healthcare provider recommendation (OR 30, 95% CI 16–56, p < 0.001). Lack of healthcare provider recommendation was the main reason for non-vaccination (17/46, 37%). While most women were aware of and intended to receive recommended vaccinations, recently arrived migrant women (resident in Australia for less than two years) were less likely to be aware of pertussis vaccine (15/22, 68% vs 452/513, 88%, p = 0.01) and less likely to believe it to be safe during pregnancy (4/22, 18% vs 299/514, 58%, p < 0.001). This highlights the important role of healthcare providers in recommending and educating women, particularly newly arrived migrant women, in their decisions about vaccination during pregnancy.

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Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation, severe scarring, and stem cell senescence. Stem cell‐based therapies modulate inflammatory and fibrogenic pathways by release of soluble factors. Stem cell‐derived extracellular vesicles should be explored as a potential therapy for IPF. Human amnion epithelial cell‐derived exosomes (hAEC Exo) were isolated and compared against human lung fibroblasts exosomes. hAEC Exo were assessed as a potential therapy for lung fibrosis. Exosomes were isolated and evaluated for their protein and miRNA cargo. Direct effects of hAEC Exo on immune cell function, including macrophage polarization, phagocytosis, neutrophil myeloperoxidase activity and T cell proliferation and uptake, were measured. Their impact on immune response, histological outcomes, and bronchioalveolar stem cell (BASC) response was assessed in vivo following bleomycin challenge in young and aged mice. hAEC Exo carry protein cargo enriched for MAPK signaling pathways, apoptotic and developmental biology pathways and miRNA enriched for PI3K‐Akt, Ras, Hippo, TGFβ, and focal adhesion pathways. hAEC Exo polarized and increased macrophage phagocytosis, reduced neutrophil myeloperoxidases, and suppressed T cell proliferation directly. Intranasal instillation of 10 μg hAEC Exo 1 day following bleomycin challenge reduced lung inflammation, while treatment at day 7 improved tissue‐to‐airspace ratio and reduced fibrosis. Administration of hAEC Exo coincided with the proliferation of BASC. These effects were reproducible in bleomycin‐challenged aged mice. The paracrine effects of hAECs can be largely attributed to their exosomes and exploitation of hAEC Exo as a therapy for IPF should be explored further. StemCellsTranslationalMedicine2018;7:180–196 Human amnion epithelial cells (hAECs) possess potent reparative and regenerative properties, especially in experimental models of lung fibrosis. It is now evident that these mechanism may be attributed to secretory factors released by hAECs termed exosomes. These hAEC Exo can be isolated with high purity through differential ultracentrifugation. Transmission electron microscopy shows exosomes of typical cup‐shaped morphology, intracellular and outward budding vesicles from hAECs (Scale bar = 100 nm). Administration of 10 μg of hAEC Exo into bleomycin challenged mice ameliorated fibroblast activated αSMA positive cells (Scale bar = 50 μm) and increased lung progenitor cell renewal seen through expression of CC10+/SPC+dual positive staining for bronchioalveolar stem cells (Scale bar = 50 μm).

ABSTRACTFetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDRsiRNA-transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2and TGFB3. TGFB3was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth.

BackgroundFetal growth restriction (FGR) is associated with increased perinatal mortality and long-term cardiovascular and neurodevelopmental sequelae. We hypothesized that FGR impacts on the development of autonomic heart rate and blood pressure control, contributing to unfavorable short- and long-term outcomes following FGR.MethodsWe studied 25 preterm FGR and 22 preterm and 19 term appropriate for gestational age (AGA) infants. Preterm neonates were studied on postnatal day 1, and all infants were studied at 1 and 6 months post-term age. To investigate autonomic cardiovascular control, we examined heart rate variability (HRV) and baroreflex sensitivity using spectral power and transfer-function analyses.ResultsPreterm FGR neonates exhibited higher heart rates and reduced HRV compared with preterm AGA controls on postnatal day 1. No significant differences were found between the three groups at 1 or 6 months post-term age.ConclusionPreterm FGR neonates display compromised HRV on postnatal day 1, which may suggest increased vulnerability to circulatory instability. This may predispose these neonates to systemic and cerebral hypoperfusion and increase the risk of long-term neurodevelopmental sequelae. Differences were no longer found at 1 and 6 months post-term age, suggesting that the maturation of autonomic cardiovascular control may be preserved following FGR.

Fetal growth restriction (FGR) is a common complication of pregnancy and, in severe cases, is associated with elevated rates of perinatal mortality, neonatal morbidity, and poor neurodevelopmental outcomes. The leading cause of FGR is placental insufficiency, with the placenta failing to adequately meet the increasing oxygen and nutritional needs of the growing fetus with advancing gestation. The resultant chronic fetal hypoxia induces a decrease in fetal growth, and a redistribution of blood flow preferentially to the brain. However, this adaptation does not ensure normal brain development. Early detection of brain injury in FGR, allowing for the prediction of short- and long-term neurodevelopmental consequences, remains a significant challenge. Furthermore, in FGR infants the detection and diagnosis of neuropathology is complicated by preterm birth, the etiological heterogeneity of FGR, timing of onset of growth restriction, its severity, and coexisting complications. In this review, we examine existing and emerging diagnostic tools from human and preclinical studies for the detection and assessment of brain injury in FGR fetuses and neonates. Increased detection rates, and early detection of brain injury associated with FGR, will offer opportunities for developing and assessing interventions to improve long-term outcomes.

Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC‐derived proresolution lipoxin‐A4(LXA4) on T‐cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin‐induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T‐cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC‐treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T‐cell suppression are LXA4 dependent, whereas the inhibition of neutrophil‐derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid‐based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4‐dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. StemCellsTranslationalMedicine2017;6:1085–1095

Intrauterine inflammation is a significant cause of injury to the developing fetal brain. Using a preterm fetal sheep model of in utero infection, we asked whether human amnion epithelial cells (hAECs) were able to reduce inflammation-induced fetal brain injury. Surgery was undertaken on pregnant sheep at ~105 days gestation (term is 147 days) for implantation of vascular catheters. Lipopolysaccharide (LPS; 150 ng/kg bolus) or saline was administered IV at 109, 110, and 111 days. Sixty million fluorescent-labeled hAECs were administered at 110, 111, and 112 days gestation via the brachial artery catheter. Brains were collected at 114 days for histological assessment. hAECs were observed within the cortex, white matter, and hippocampus. Compared to control lambs, LPS administration was associated with significant and widespread fetal brain inflammation and injury as evidenced by increased number of activated microglia in the periventricular white matter (p= 0.02), increased pyknosis, cell degeneration (p= 0.01), and a nonsignificant trend of fewer oligodendrocytes in the subcortical and periventricular white matter. Administration of hAECs to LPS-treated animals was associated with a significant mitigation in both inflammation and injury as evidenced by fewer activated microglia (p= 0.03) and pyknotic cells (p= 0.03), significantly more oligodendrocytes in the subcortical and periventricular white matter (p= 0.01 and 0.02, respectively), and more myelin basic protein-positive cells within the periventricular white matter (p= 0.02). hAEC administration to fetal sheep exposed to multiple doses of LPS dampens the resultant fetal inflammatory response and mitigates associated brain injury.

ObjectiveWhile delayed umbilical cord clamping (UCC) is thought to facilitate placental to infant blood transfusion, the physiological factors regulating flow in the umbilical arteries and veins during delayed UCC is unknown. We investigated the effects of gravity, by changing fetal height relative to the placenta, and ventilation on umbilical blood flows and the cardiovascular transition during delayed UCC at birth.MethodsCatheters and flow probes were implanted into preterm lambs (128 days) prior to delivery to measure pulmonary, carotid, umbilical artery (UaBF) and umbilical venous (UvBF) blood flows. Lambs were placed either 10 cm below or 10 cm above the ewe. Ventilation commenced 2–3 min before UCC and continued for 30 min after UCC.ResultsGravity reduced umbilical and cerebral flows when lambs were placed below the midline, but the reduction in UaBF and UvBF was similar. Ventilation during delayed UCC reduced UvBF and UaBF by similar amounts, irrespective of the lamb's position, such that flows into and out of the placenta remained balanced. The effects of ventilation on umbilical flows were much greater than the effects of gravity, but no net placental to lamb blood transfusion could be detected under any condition. Cardiovascular parameters, cerebral oxygen kinetics and final blood volumes were similar in both groups 5 min after UCC.ConclusionsGravity caused small transient effects on umbilical and cerebral flow, but given changes were similar in umbilical arteries and veins, no net placental transfusion was detected. Ventilation during delayed UCC has a markedly greater influence on cardiovascular function in the newborn.

This study examines stem cells as a potential intervention for people with cerebral palsy. Results show that stem cells appear to induce short‐term improvements in motor skills. Evidence for stem cells as a potential intervention for cerebral palsy is emerging. Our objective was to determine the efficacy and safety of stem cells for improving motor and cognitive function of people with cerebral palsy. Searches were conducted in October 2015 in CENTRAL, EMBASE, MEDLINE, and Cochrane Libraries. Randomized controlled trials and controlled clinical trials of stem cells for cerebral palsy were included. Two authors independently decided upon included trials, extracted data, quality, and risk of bias. The primary outcome was gross motor function. Secondary outcomes were cognitive function and adverse events (AEs). Effects were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI), using a random‐effects model. Five trials comprising 328 participants met inclusion criteria. Four cell types were studied: olfactory ensheathing, neural, neural progenitors, and allogeneic umbilical cord blood (UCBs). Transplantation procedures differed from central nervous system neurosurgical transplantation to intravenous/arterial infusion. Participants were followed short‐term for only 6 months. Evidence of variable quality indicated a small statistically significant intervention effect from stem cells on gross motor skills (SMD 1.27; 95% CI 0.22, 2.33), with UCBs most effective. There were insufficient and heterogeneous data to compare cognitive effects. Serious AEs were rare (n= 4/135 [3%] stem cells; n= 3/139 [2%] controls). Stem cells appeared to induce short‐term improvements in motor skills. Different types of stem cell interventions were compared, meaning the data were heterogeneous and are a study limitation. Further randomized controlled trials are warranted, using rigorous methodologies. Stem cells are emerging as a scientifically plausible treatment and possible cure for cerebral palsy, but are not yet proven. The lack of valid animal models has significantly hampered the scope of clinical trials. Despite the state of current treatment evidence, parents remain optimistic about the potential improvements from stem cell intervention and feel compelled to exhaust all therapeutic options, including stem cell tourism. Receiving unproven therapies from unvalidated sources is potentially dangerous. Thus it is essential that researchers and clinicians stay up to date. A systematic review and meta‐analysis summarizing and aggregating current research data may provide more conclusive evidence to inform treatment decision making and help direct future research.

Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19 439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20–30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.

Background:Bronchopulmonary dysplasia (BPD) is one of the leading causes of morbidity and mortality in babies born prematurely, yet there is no curative treatment. In recent years, a number of inhibitors against TGFß signaling have been tested for their potential to prevent neonatal injury associated with hyperoxia, which is a contributing factor of BPD. In this study, we assessed the contribution of activin A—a member of the TGFß superfamily—to the development of hyperoxia-induced lung injury in neonatal mice.Methods:We placed newborn C57Bl6 mouse pups in continuous hyperoxia (85% O2) to mimic many aspects of BPD including alveolar simplification and pulmonary inflammation. The pups were administered activin A receptor type IIB-Fc antagonist (ActRIIB-Fc) at 5?mg/kg or follistatin at 0.1?mg/kg on postnatal days 4, 7, 10, and 13.Results:Treatment with ActRIIB-Fc and follistatin protected against hyperoxia-induced growth retardation. ActRIIB-Fc also reduced pulmonary leukocyte infiltration, normalized tissue: airspace ratio and increased septal crest density. These findings were associated with reduced phosphorylation of Smad3 and decreased matrix metalloproteinase (MMP)-9 activity.Conclusion:This study suggests that activin A signaling may contribute to the pathology of bronchopulmonary dysplasia.