How I manage pregnant patients who are alloimmunized to RBC antigens.

Hemolytic disease of the fetus and newborn (HDFN) remains an important cause of perinatal morbidity and mortality. HDFN is caused by maternal alloimmunization to red blood cell (RBC) antigens. This article describes and highlights issues in the care of pregnant women with red blood cell (RBC) alloimmunization. This includes monitoring for, and management of fetal anemia caused by maternal red cell alloantibodies, but also considerations for transfusion support for the woman in the event of major bleeding. Many aspects of care for women with RBC alloantibodies are not covered within specific guidelines, particularly with respect to best practice for antenatal management of women with prior significant obstetric morbidity or mortality due to HDFN, and we will outline our approach in these cases. The use of non-invasive monitoring for fetal anemia through measurement of the middle cerebral artery peak systolic velocity has led to a paradigm shift in antenatal care for women with high-risk antibodies, and medical therapies hold promise for women with the most severe disease.

Diagnostic accuracy of small-for-gestational-age status for infant mortality and school-age outcomes of live births <28 weeks' gestation: a cohort study.

OBJECTIVES: To determine the diagnostic accuracy of small-for-gestational-age (SGA; <10th centile) status for infant mortality and adverse school-age outcomes in infants born extremely preterm (EP; <28 weeks' gestation). DESIGN: Geographical cohort studies. SETTING: The state of Victoria, Australia. PATIENTS: For mortality, live births 22-27 weeks' gestation from 2009 to 2017 offered active care after birth. For school-age outcomes, survivors to 8 years' corrected age born in 1991-1992, 1997 or 2005. EXPOSURES: SGA <10th centile on four commonly used growth references: three derived from neonatal data (Fenton, UK-WHO and Intergrowth Newborn Size) and one from fetal data (Intergrowth Estimated Fetal Weight). MAIN OUTCOME MEASURES: (a) Infant mortality; (b) major neurodevelopmental disability, and poor performance on tests of IQ, academic achievement, motor function, and executive function. RESULTS: Infant mortality data were available for 2040 infants, and neurodevelopmental data for 499 children. Diagnostic accuracy of SGA status was low overall and varied with the growth reference. Positive predictive values for infant mortality ranged from 18% to 21%, only marginally higher than its 18% prevalence. Compared with a prevalence of 17%, positive predictive values for major neurodevelopmental disability ranged from 30% to 38% for the neonatal growth references but was only 20% for Intergrowth Estimated Fetal Weight. SGA status was also associated with lower IQ, poor academic achievement and poor motor performance. CONCLUSIONS: Among infants born EP, the diagnostic accuracy of SGA status was low for both infant mortality and adverse neurodevelopmental outcomes at school age, but importantly varied with the growth reference used to identify SGA status.

Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.

Perinatal predictors of clinical instability at birth in late-preterm and term infants.

To identify characteristics associated with delivery room clinical instability in at-risk infants. Prospective cohort study. Two perinatal centres in Melbourne, Australia. Infants born at ≥ 35+0 weeks' gestation with a first-line paediatric doctor requested to attend. Clinical instability defined as any one of heart rate < 100 beats per minute for ≥ 20 s in the first 10 min after birth, maximum fraction of inspired oxygen of ≥ 0.70 in the first 10 min after birth, 5-min Apgar score of < 7, intubated in the delivery room or admitted to the neonatal unit for respiratory support. Four hundred and seventy-three infants were included. The median (IQR) gestational age at birth was 39+4 (38+4-40+4) weeks. Eighty (17%) infants met the criteria for clinical instability. Independent risk factors for clinical instability were labour without oxytocin administration, presence of a medical pregnancy complication, difficult extraction at birth and unplanned caesarean section in labour. Decision tree analysis determined that infants at highest risk were those whose mothers did not receive oxytocin during labour (25% risk). Infants at lowest risk were those whose mothers received oxytocin during labour and did not have a medical pregnancy complication (7% risk). CONCLUSIONS: We identified characteristics associated with clinical instability that may be useful in alerting less experienced clinicians to call for senior assistance early. The decision trees provide intuitive visual aids but require prospective validation. WHAT IS KNOWN: • First-line clinicians attending at-risk births may need to call senior colleagues for assistance depending on the infant's condition. • Delays in effectively supporting a compromised infant at birth is an important cause of neonatal morbidity and infant-mother separation. WHAT IS NEW: • This study identifies risk factors for delivery room clinical instability in at-risk infants born at ≥ 35+0 weeks' gestation. • The decision trees presented provide intuitive visual tools to aid in determining the need for senior paediatric presence.

Reviewing Accuracy of First Trimester Screening for Preeclampsia Using Maternal Factors and Biomarkers.

Preeclampsia is a common and important complication of pregnancy, one with potentially significant morbidity and even mortality to both mother and baby. Identifying those at high risk of developing the condition is helpful as there is evidence that the incidence of preeclampsia can be reduced with low dose aspirin taken in pregnancy. Accurately predicting the risk of preeclampsia allows for more targeted aspirin prophylaxis and a greater opportunity for early detection of maternal and/or fetal complications associated with impaired placentation through a schedule of enhanced antenatal surveillance. Traditional preeclampsia prediction models use maternal characteristics and risk factors and have been shown to be of low predictive value. Multiparametric screening tests combine patient characteristics with serum biomarkers and ultrasound Doppler indices and have been shown to be more effective at detecting those at high risk of preeclampsia - more specifically, early-onset preeclampsia (onset of preeclampsia <34 weeks' gestation). Multiparametric screening has now been validated in different populations. The true cost effectiveness of a multiparametric screening model for preeclampsia screening is not yet fully known and will vary depending on the clinical setting. Despite the growing body of evidence for its improved detection rates, first trimester preeclampsia screening using multiparametric models is not widely implemented and is not part of the recommendations for antenatal screening from most international bodies. The International Federation of Gynecology and Obstetrics has advised universal preeclampsia screening using maternal risk factors and biomarkers and has strongly encouraged its promotion worldwide. Various barriers to implementation must be considered such as the immediate cost of equipment and training, the need for audit and quality control, and the expected benefit to the population. Low to middle income settings may require a pragmatic approach to the implementation of multiparametric screening given limited resources.

Medical termination of pregnancy for fetal anomaly at or beyond 20 weeks' gestation-What are the maternal risks?

OBJECTIVE: To evaluate the common and severe maternal morbidities associated with medical termination of pregnancy (MTOP) for fetal anomaly ≥20 weeks' gestation. METHODS: A 10-year retrospective cohort study (January 2010-December 2019) analyzing 407 consecutive singleton pregnancies MTOP for fetal anomaly ≥20 weeks' gestation, at a quaternary maternity centre in Australia (Royal Women's Hospital, Melbourne). RESULTS: The cohort comprised of 191 primiparous and 216 multiparous women, of whom 75 (34.7%) had at least one prior Cesarean; 13 women had a low-lying placenta or placenta praevia. The average gestation was 23 weeks (interquartile range 22-26 weeks). A spontaneous unassisted vaginal delivery was achieved by the majority (n = 403, 99.0%). The most common maternal morbidities were transferred to the theater for manual removal of retained placental tissue (n = 65, 16.0%) and postpartum haemorrhage (PPH) (n = 45, 11.1%). Severe maternal morbidity occurred in six cases (1.3%) and included amniotic fluid embolism, cardiac arrest, major obstetric haemorrhage, uterine rupture and intensive care unit admission. There were no maternal deaths. CONCLUSIONS: The most common complications of MTOP for fetal anomaly ≥20 weeks' gestation were manual removal of placenta and PPH. Severe maternal morbidity affected 1 in 81 women.

Placental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction.

Previously, we identified elevated transcripts for the gene Oleoyl-ACP Hydrolase (OLAH) in the maternal circulation of pregnancies complicated by preterm fetal growth restriction. As placental dysfunction is central to the pathogenesis of both fetal growth restriction and preeclampsia, we aimed to investigate OLAH levels and function in the human placenta. We assessed OLAH mRNA expression (qPCR) throughout pregnancy, finding placental expression increased as gestation progressed. OLAH mRNA and protein levels (Western blot) were elevated in placental tissue from cases of preterm preeclampsia, while OLAH protein levels in placenta from growth-restricted pregnancies were comparatively reduced in the preeclamptic cohort. OLAH expression was also elevated in placental explant tissue, but not isolated primary cytotrophoblast cultured under hypoxic conditions (as models of placental dysfunction). Further, we discovered that silencing cytotrophoblast OLAH reduced the expression of pro- and anti-apoptosis genes, BAX and BCL2, placental growth gene, IGF2, and oxidative stress gene, NOX4. Collectively, these findings suggest OLAH could play a role in placental dysfunction and may be a therapeutic target for mitigating diseases associated with this vital organ. Further research is required to establish the role of OLAH in the placenta, and whether these changes may be a maternal adaptation or consequence of disease.

Physiologically based cord clamping for infants ≥32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants ≥35+0 weeks gestation.

BACKGROUND: Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. METHODS AND FINDINGS: Between 4 July 2018 and 18 May 2021, infants born at ≥32+0 weeks' gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference -6 bpm, 95% confidence interval (CI) -17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal-infant bonding and higher iron stores. CONCLUSIONS: In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32+0 weeks' gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213.

Disparities between perceived and true outcomes of infants born at 23-25 weeks' gestation.

BACKGROUND: Decision-making for infants born at 23-25 weeks involves counselling parents about survival and major disability risks. Accurate information is needed for parents to make informed decisions about their baby's care. AIMS: To determine if perinatal clinicians had accurate perceptions of outcomes of infants born at 23-25 weeks' gestation, and if accuracy had changed over a decade. MATERIALS AND METHODS: A web-based survey was sent to midwives, nurses, neonatologists, and obstetricians working in tertiary and non-tertiary hospitals, and the neonatal retrieval service in the state of Victoria in 2020. A similar survey had been completed in 2010. Clinicians' estimates of survival and major neurodevelopmental disability rates were compared with true rates for actively managed infants overall, and by infant birthplace and gestational age, and professional workplace and discipline. Accuracy of outcomes was compared between eras. RESULTS: Overall, 165 surveys were received. Participants underestimated survival (absolute mean difference [%] -14.4%; [95% confidence interval (CI) -16.6 to -12.3]; P < 0.001) and overestimated major disability (absolute mean difference 32.7%; [95% CI 29.7 to 35.8]; P < 0.001) rates overall, and at each week of gestation, and were worse for outborn compared with inborn infants. Perceptions of clinicians in tertiary centres were similar to those of non-tertiary clinicians. Nurses/midwives were more pessimistic, and paediatricians were more optimistic. Clinicians' perceptions of outcome were less accurate in 2020 than in 2010. CONCLUSIONS: Most perinatal clinicians underestimate survival and overestimate major disability of infants born at 23-25 weeks' gestation, which may translate into overly pessimistic counselling of parents.

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast.

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

Parental Preconception Exposures to Outdoor Neighbourhood Environments and Adverse Birth Outcomes: A Protocol for a Scoping Review and Evidence Map.

Parental preconception exposures to built and natural outdoor environments could influence pregnancy and birth outcomes either directly, or via a range of health-related behaviours and conditions. However, there is no existing review summarising the evidence linking natural and built characteristics, such as air and noise pollution, walkability, greenness with pregnancy and birth outcomes. Therefore, the planned scoping review aims to collate and map the published literature on parental preconception exposures to built and natural outdoor environments and adverse pregnancy and birth outcomes. We will search electronic databases (MEDLINE, EMBASE, Scopus) to identify studies for inclusion. Studies will be included if they empirically assess the relationship between maternal and paternal preconception exposures to physical natural and built environment features that occur outdoors in the residential neighbourhood and adverse pregnancy and birth outcomes. Two reviewers will independently screen titles and abstracts, and then the full text. Data extraction and assessment of study quality will be performed by one researcher and checked by a second researcher. Results will be summarised in a narrative synthesis, with additional summaries presented as tables and figures. The scoping review will be disseminated via a peer-reviewed publication, at academic conferences, and published on a website.

Preimplantation Genetic Testing for Monogenic Conditions: Is Cell-Free DNA Testing the Next Step?

Genetic assessment of an embryo via preimplantation genetic testing (PGT) represents an important reproductive option for couples wanting to try and improve success rates from in vitro fertilisation (IVF) cycles, as well as reduce their risk of having a child born with a genetic condition. Currently, biopsy of the developing embryo prior to transfer allows genetic assessment of an embryo for either chromosome copy number (aneuploidy [PGT-A] or segmental rearrangement [PGT-SR]) or to avoid the transmission of a single gene condition (monogenic conditions [PGT-M]). However, this technology is invasive and commands considerable resources. Non-invasive PGT (niPGT) offers a potential alternate mode of embryonic analysis. Whilst the utility of niPGT-A has been recently explored, there has been limited consideration of niPGT-M as an option for couples at risk of passing on a single gene or chromosomal condition. This review examines the historical and current clinical context of preimplantation embryonic analysis for monogenic conditions, in addition to important considerations surrounding the origin and analysis of cell-free deoxyribose nucleic acid (cfDNA), whether it is sourced via blastocentesis or spent embryonic culture medium (SCM). Future capabilities of this testing modality will almost certainly be enhanced by integration of whole genome sequencing into everyday practice. In addition, the increased utilisation of reproductive carrier screening as part of standard reproductive healthcare will likely result in the identification of a larger high-risk population. As a result, stratification of limited and highly specialised reproductive genetic resources will be required. Prospective parents should continue to be made aware of the limitations of this technology, with prenatal confirmatory testing remaining an essential part of antenatal care in these patients. However, niPGT-M poses an important alternate testing modality for high-risk couples, particularly in the setting of embryos that cannot be biopsied for traditional PGT-M and as demand for this treatment continues to grow.

How can obstetricians improve outcomes for infants born extremely preterm?

Prematurity remains a leading cause of perinatal morbidity and mortality, and also has significant implications for long-term health. Obstetricians have a key role to play in improving outcomes for infants born at extremely preterm gestations. This review explores the evidence for interventions available to obstetricians caring for women at risk of birthing at extremely preterm gestations, including antenatal corticosteroids, magnesium sulfate, tocolysis and antibiotics. It also addresses the importance of strategies to facilitate safe in-utero transfer, to maximise the chance of extremely preterm births occurring in tertiary centers, and the clinical value of strategies by which preterm birth can be predicted. The paper concludes with an appraisal of evidence for different modes of birth at extremely preterm gestations, and for delayed cord clamping.

LOX-1 expression is reduced in placenta from pregnancies complicated by preeclampsia and in hypoxic cytotrophoblast.

OBJECTIVES: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is upregulated in the maternal vasculature in preeclampsia, and contributes to oxidative stress and endothelial dysfunction. However, its function in the placenta is unclear. This paper investigated LOX-1 expression in models of placental dysfunction and preeclampsia, and whether candidate therapeutics for preeclampsia could alter its expression. STUDY DESIGN: Placentas were collected from preterm pregnancies and cases of preterm preeclampsia and fetal growth restriction. Blood was collected from participants whose pregnancies were complicated by preterm fetal growth restriction and/or preeclampsia. Primary cytotrophoblast and placental explant tissue were cultured under hypoxic (1% O2) or normoxic (8% O2) conditions. Cytotrophoblast were exposed to 10% preeclamptic or control serum. Cytotrophoblast and preeclamptic explant tissue were treated with 100 µM esomeprazole, lansoprazole or rabeprazole. MAIN OUTCOME MEASURES: LOX-1 expression was assessed in all samples via qPCR. RESULTS: LOX-1 expression was reduced in placentas from cases of preterm preeclampsia, but not fetal growth restriction, compared to controls. LOX-1 expression was reduced in cytotrophoblast under hypoxia, but not in explant tissue. Treatment with preeclamptic serum in vitro did not alter cytotrophoblast LOX-1 expression. Circulating LOX-1 mRNA was unaltered in patients with fetal growth restriction, preeclampsia, and fetal hypoxia, compared to controls. Treatment with esomeprazole or lansoprazole in vitro increased placental LOX-1 expression. CONCLUSIONS: LOX-1 expression is reduced in preeclamptic placentas and hypoxic cytotrophoblast. Esomeprazole and lansoprazole increase placental LOX-1 expression. These findings demonstrate a role for LOX-1 in the placenta, and improve our understanding of maternal adaptations in pregnancy complications.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

BACKGROUND: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 µmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.

The addition of fetal scalp blood lactate measurement as an adjunct to cardiotocography to reduce caesarean sections during labour: The Flamingo randomised controlled trial.

BACKGROUND: Fetal scalp blood sampling for lactate measurement (FBSLM) is sometimes used to assist in identification of the need for expedited birth in the presence of an abnormal cardiotocograph (CTG). However, there is no randomised controlled trial evidence to support this. AIM: To determine whether adding FBSLM reduces the risk of birth by emergency caesarean section in labours complicated by an abnormal CTG, compared with CTG without FBS. MATERIAL AND METHODS: Labouring women at a tertiary maternity hospital in Melbourne, Australia with a singleton, cephalic presentation, at ≥37 weeks gestation with an abnormal CTG pattern were randomised to the intervention (n = 61), with intermittent FBSLM in addition to CTG monitoring, or control (CTG without FBS, n = 62). The primary outcome was rate of birth by caesarean section. Secondary outcomes included overall operative birth and fetal and neonatal safety endpoints. TRIAL REGISTRATION: ACTRN12611000172909. RESULTS: The smaller than anticipated sample was unable to demonstrate an effect from adding FBSLM to CTG monitoring on birth by caesarean section vs monitoring by CTG without FBS (25/61 and 28/62 respectively, P = 0.64, risk ratio 0.91, 95% confidence intervals 0.60-1.36). One newborn infant in the CTG group met the criteria for the composite neonatal outcome of death or serious outcome, neonatal encephalopathy, five-minute Apgar score < 4, neonatal resuscitation, admission to neonatal intensive care unit for 96 h or more. CONCLUSION: We were unable to provide robust evidence of the effectiveness of FBSLM to improve the specificity of the CTG in the assessment of fetal wellbeing.

DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia.

Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78-0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.

Lung ultrasound during newborn resuscitation predicts the need for surfactant therapy in very- and extremely preterm infants.

INTRODUCTION: Early identification of infants requiring surfactant therapy improves outcomes. We evaluated the accuracy of delivery room lung ultrasound (LUS) to predict surfactant therapy in very- and extremely preterm infants. METHODS: Infants born at <320/7 weeks were prospectively enrolled at 2 centres. LUS videos of both sides of the chest were obtained 5-10 min, 11-20 min, and 1-3 h after birth. Clinicians were masked to the results of the LUS assessment and surfactant therapy was provided according to local guidelines. LUS videos were graded blinded to clinical data. Presence of unilateral type 1 ('whiteout') LUS or worse was considered test positive. Receiver Operating Characteristic (ROC) analysis compared the accuracy of LUS and an FiO2 threshold of 0.3 to predict subsequent surfactant therapy. RESULTS: Fifty-two infants with a median age of 276/7 weeks (IQR 260/7-286/7) were studied. Thirty infants (58%) received surfactant. Area under the ROC curve (AUC) for LUS at 5-10 min, 11-20 min and 1-3 h was 0.78 (95% CI, 0.66-0.90), 0.76 (95% CI, 0.65-0.88) and 0.86 (95% CI, 0.75-0.97) respectively, outperforming FiO2 at the 5-10 min timepoint (AUC 0.45, 95% CI 0.29-0.62, p = 0.001). At 11-20 min, LUS had a specificity of 95% (95% CI 77-100%) and sensitivity of 59% (95% CI, 39-77%) to predict surfactant therapy. All infants born at 23-276/7 weeks with LUS test positive received surfactant. Twenty-six infants (50%) had worsening of LUS grades on serial assessment. CONCLUSIONS: LUS in the delivery room and accurately predicts surfactant therapy in infants <320/7 weeks.

Heart Disease and Pregnancy: The Need for a Twenty-First Century Approach to Care .

Pregnancy and childbirth present a specific challenge to the maternal cardiovascular system. Pre-existing cardiac diseases, or cardiac diseases that occur during pregnancy, are associated with a significant risk of morbidity and mortality for both mother and baby. In recent decades, cardiac disease has emerged as a leading cause of maternal death in most high income countries, including Australia and New Zealand. The burden of cardiac disease in pregnancy is likely to be growing due to an increase in adult survivors with congenital heart disease embarking on pregnancy coupled with demographic shifts in the age and cardiovascular risk factors of women giving birth and the persisting high incidence of acute rheumatic fever in First Nations women. There is widespread consensus that the best obstetric and neonatal outcomes in women with cardiac disease are delivered by a strategy of carefully coordinated multidisciplinary care. Australia and New Zealand currently lack nationally agreed strategies for clinical practice and service delivery for women with heart disease in pregnancy. This state-of-the-art review summarises some of the key issues faced in relation to prevention, diagnosis, treatment and health service delivery in this patient group and concludes with suggested priorities for policy and research.