Prenatal alcohol exposure and associations with physical size, dysmorphology and neurodevelopment: a systematic review and meta-analysis.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health concern, yet there is no internationally agreed set of diagnostic criteria or summary of underlying evidence to inform diagnostic decision-making. This systematic review assesses associations of prenatal alcohol exposure (PAE) and outcomes of diagnostic assessments, providing an evidence base for the improvement of FASD diagnostic criteria. METHODS: Six databases were searched (inception-February 2023). Case-controls or cohort studies examining associations between participants with/without PAE or a FASD diagnosis and the domains of physical size, dysmorphology, functional neurodevelopment and/or brain structure/neurology were included. Excluded studies were non-empirical, sample size < 10, PAE determined via biological markers only, or no suitable comparison group. Summary data were extracted and associations between outcomes and standardised levels of PAE or FASD diagnosis determined using random-effects meta-analyses. Certainty of the evidence was assessed using GRADE. RESULTS: Of the 306 included studies, 106 reported physical size, 43 dysmorphology, 195 functional neurodevelopment and 110 structural/neurological outcomes, with 292 different outcomes examined. There was a dose-response relationship between PAE and head circumference, as well as measures of physical size, particularly at birth. There was also an association between higher PAE levels and characteristic sentinel facial dysmorphology, as well as many of the current functional neurodevelopmental outcomes considered during diagnosis. However, data were often lacking across the full range of exposures. There was a lack of evidence from studies examining PAE to support inclusion of non-sentinel dysmorphic features, social cognition, speech-sound impairments, neurological conditions, seizures, sensory processing or structural brain abnormalities (via clinical MRI) in diagnostic criteria. GRADE ratings ranged from very low to moderate certainty of evidence. CONCLUSIONS: This comprehensive review provides guidance on which components are most useful to consider in the diagnostic criteria for FASD. It also highlights numerous gaps in the available evidence. Future well-designed pregnancy cohort studies should specifically focus on dose-response relationships between PAE and dysmorphology, neurodevelopment and brain structure/neurological outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021230522.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Lifestyle and sociodemographic risk factors for stillbirth by region of residence in South Australia: a retrospective cohort study.

BACKGROUND: Stillbirth rates remain a global priority and in Australia, progress has been slow. Risk factors of stillbirth are unique in Australia due to large areas of remoteness, and limited resource availability affecting the ability to identify areas of need and prevalence of factors associated with stillbirth. This retrospective cohort study describes lifestyle and sociodemographic factors associated with stillbirth in South Australia (SA), between 1998 and 2016. METHODS: All restigered births in SA between 1998 ad 2016 are included. The primary outcome was stillbirth (birth with no signs of life ≥ 20 weeks gestation or ≥ 400 g if gestational age was not reported). Associations between stillbirth and lifestyle and sociodemographic factors were evaluated using multivariable logistic regression and described using adjusted odds ratios (aORs). RESULTS: A total of 363,959 births (including 1767 stillbirths) were included. Inadequate antenatal care access (assessed against the Australian Pregnancy Care Guidelines) was associated with the highest odds of stillbirth (aOR 3.93, 95% confidence interval (CI) 3.41-4.52). Other factors with important associations with stillbirth were plant/machine operation (aOR, 1.99; 95% CI, 1.16-2.45), birthing person age ≥ 40 years (aOR, 1.92; 95% CI, 1.50-2.45), partner reported as a pensioner (aOR, 1.83; 95% CI, 1.12-2.99), Asian country of birth (aOR, 1.58; 95% CI, 1.19-2.10) and Aboriginal/Torres Strait Islander status (aOR, 1.50; 95% CI, 1.20-1.88). The odds of stillbirth were increased in regional/remote areas in association with inadequate antenatal care (aOR, 4.64; 95% CI, 2.98-7.23), birthing age 35-40 years (aOR, 1.92; 95% CI, 1.02-3.64), Aboriginal and/or Torres Strait Islander status (aOR, 1.90; 95% CI, 1.12-3.21), paternal occupations: tradesperson (aOR, 1.69; 95% CI, 1.17-6.16) and unemployment (aOR, 4.06; 95% CI, 1.41-11.73). CONCLUSION: Factors identified as independently associated with stillbirth odds include factors that could be addressed through timely access to adequate antenatal care and are likely relevant throughout Australia. The identified factors should be the target of stillbirth prevention strategies/efforts. SThe stillbirth rate in Australia is a national concern. Reducing preventable stillbirths remains a global priority.

Experiences of antenatal care practices to reduce stillbirth: surveys of women and healthcare professionals pre-post implementation of the Safer Baby Bundle.

BACKGROUND: The Safer Baby Bundle (SBB) aimed to reduce stillbirth rates in Australia through improving pregnancy care across five elements; smoking cessation, fetal growth restriction (FGR), decreased fetal movements (DFM), side sleeping in late pregnancy and decision making around timing of birth. We assessed experiences of women and healthcare professionals (HCPs) with antenatal care practices around the five elements. METHODS: A pre-post study design using online surveys was employed to assess change in HCPs awareness, knowledge, and frequency of performing recommended practices (22 in total) and women's experiences of care received related to reducing their chance of stillbirth. Women who had received antenatal care and HCPs (midwives and doctors) at services participating in the SBB implementation program in two Australian states were invited to participate. Surveys were distributed over January to July 2020 (pre) and August to December 2022 (post). Comparison of pre-post responses was undertaken using Fisher's exact, Pearson's chi-squared or Wilcoxon rank-sum tests. RESULTS: 1,225 women (pre-1096/post-129) and 1,415 HCPs (pre-1148/post-267, ≥ 83% midwives) completed the surveys. The frequency of HCPs performing best practice 'all the time' significantly improved post-SBB implementation across all elements including providing advice to women on side sleeping (20.4-79.4%, p < 0.001) and benefits of smoking cessation (54.5-74.5%, p < 0.001), provision of DFM brochure (43.2-85.1%, p < 0.001), risk assessments for FGR (59.2-84.1%, p < 0.001) and stillbirth (44.5-73.2%, p < 0.001). Practices around smoking cessation in general showed less improvement e.g. using the 'Ask, Advise and Help' brief advice model at each visit (15.6-20.3%, p = 0.088). Post-implementation more women recalled conversations about stillbirth and risk reduction (32.2-50.4%, p < 0.001) and most HCPs reported including these conversations in their routine care (35.1-83.0%, p < 0.001). Most HCPs agreed that the SBB had become part of their routine practice (85.0%). CONCLUSIONS: Implementation of the SBB was associated with improvements in practice across all targeted elements of care in stillbirth prevention including conversations with women around stillbirth risk reduction. Further consideration is needed around strategies to increase uptake of practices that were more resistant to change such as smoking cessation support. TRIAL REGISTRATION: The Safer Baby Bundle Study was retrospectively registered on the Australian New Zealand Clinical Trials Registry database, ACTRN12619001777189, date assigned 16/12/2019.

Breastmilk use in preterm infants <29 weeks' gestational age in Australia, New Zealand and Singapore.

AIMS: To describe the prevalence of use of breastmilk and explore demographic characteristics and clinical outcomes associated with breastmilk provision in infants born <29 weeks' gestational age in Australia, New Zealand and Singapore. METHODS: This is a secondary analysis of data from a randomised controlled trial, which enrolled 1273 infants in 13 neonatal units across Australia, New Zealand and Singapore from 2012 to 2015. Infants were classified as formula-fed, donor milk-fed or mother's milk-fed at their first enteral feed and separately, at hospital discharge. RESULTS: The percentage of infants receiving mother's own milk differed between centres both at first feed (79% to 100%), and at hospital discharge (47.1% to 71.6%). Aboriginal, Torres Strait Islander and Southeast Asian heritage, drug use and smoking were associated with lower rates of fully breastmilk feeding at hospital discharge. There was no significant difference in growth outcomes, length of stay and feeding tolerance between feeding groups. CONCLUSIONS: Achieving high breastmilk feeding rates at hospital discharge for all preterm infants born <29 weeks' gestational age at hospital discharge is possible; however, targeted support for mothers who are Indigenous, Southeast Asian and/or using recreational drugs and/or smoking and/or experiencing social disadvantage may be needed. A better understanding and shared knowledge of practice variations within neonatal units with high breastfeeding rates could improve breastmilk access and equity for preterm infants. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12612000503820.

A systematic review of interventions to increase the use of smoking cessation services for women who smoke during pregnancy.

BACKGROUND: Although many pregnant women accept referrals to stop-smoking support, the uptake of appointments often remains low. AIM: The aim was to review the success of interventions to increase the uptake of external stop-smoking appointments following health professional referrals in pregnancy. MATERIALS AND METHODS: Embase, PubMed, Cochrane Central Register of Controlled Trials, Scopus and CINAHL were searched in February 2023 for studies with interventions to increase the uptake rates of external stop-smoking appointments among pregnant women who smoke. Eligible studies included randomised, controlled, cluster-randomised, quasi-randomised, before-and-after, interrupted time series, case-control and cohort studies. Cochrane tools assessing for bias and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: Two before-and-after studies were included, including a combined total of 1996 women who smoked during pregnancy. Both studies had a serious risk of bias, and meta-analysis was not possible due to heterogeneity. One study testing carbon monoxide monitors and opt-out referrals showed increased uptake of external stop-smoking appointments, health professional referrals and smoking cessation rates compared to self-identified smoking status and opt-in referrals. Results were limited in the second study, which used carbon monoxide monitors, urinary cotinine levels and self-disclosed methods to identify the smoking status with opt-out referrals. Only post-intervention data were available on the uptake of appointments to external stop-smoking services. The number of health professional referrals increased, but change in smoking cessation rates was less clear. CONCLUSIONS: There is insufficient evidence to inform practice regarding strategies to increase the uptake of external stop-smoking appointments by women during pregnancy.

Intrahepatic cholestasis of pregnancy - Diagnosis and management: A consensus statement of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ): Executive summary.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy liver disease, characterised by pruritus and increased total serum bile acids (TSBA), Australian incidence 0.6-0.7%. ICP is diagnosed by non-fasting TSBA ≥19 µmol/L in a pregnant woman with pruritus without rash without a known pre-existing liver disorder. Peak TSBA ≥40 and ≥100 µmol/L identify severe and very severe disease respectively, associated with spontaneous preterm birth when severe, and with stillbirth, when very severe. Benefit-vs-risk for iatrogenic preterm birth in ICP remains uncertain. Ursodeoxycholic acid remains the best pharmacotherapy preterm, improving perinatal outcome and reducing pruritus, although it has not been shown to reduce stillbirth.

My Baby's Movements: An assessment of the effectiveness of the My Baby's Movements phone program in reducing late-gestation stillbirth rates.

BACKGROUND: Delayed reporting of decreased fetal movements (DFM) could represent a missed opportunity to prevent stillbirth. Mobile phone applications (apps) have the potential to improve maternal awareness and reporting of DFM and contribute to stillbirth prevention. AIMS: To evaluate the effectiveness of the My Baby's Movements (MBM) app on late-gestation stillbirth rates. MATERIALS AND METHODS: The MBM trial evaluated a multifaceted fetal movements awareness package across 26 maternity services in Australia and New Zealand between 2016 and 2019. In this secondary analysis, generalised linear mixed models were used to compare rates of late-gestation stillbirth, obstetric interventions, and neonatal outcomes between app users and non-app users including calendar time, cluster, primiparity and other potential confounders as fixed effects, and hospital as a random effect. RESULTS: Of 140 052 women included, app users comprised 9.8% (n = 13 780). The stillbirth rate was not significantly lower among app users (1.67/1000 vs 2.29/1000) (adjusted odds ratio (aOR) 0.79; 95% CI 0.51-1.23). App users were less likely to have a preterm birth (aOR 0.81; 0.75-0.88) or a composite adverse neonatal outcome (aOR 0.87; 0.81-0.93); however, they had higher rates of induction of labour (IOL) (aOR 1.27; 1.22-1.32) and early term birth (aOR 1.08; 1.04-1.12). CONCLUSIONS: The MBM app had low uptake and its use was not associated with stillbirth rates but was associated with some neonatal benefit, and higher rates of IOL and early term birth. Use and acceptability of tools designed to promote fetal movement awareness is an important knowledge gap. The implications of increased IOL and early term births warrant consideration in future studies.

Prenatal Intravenous Magnesium at 30-34 Weeks' Gestation and Neurodevelopmental Outcomes in Offspring: The MAGENTA Randomized Clinical Trial.

Importance: Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks' gestation reduces the risk of death and cerebral palsy in their children. The effects at later gestational ages are unclear. Objective: To determine whether administration of magnesium sulfate at 30 to 34 weeks' gestation reduces death or cerebral palsy at 2 years. Design, Setting, and Participants: This randomized clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks' gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018. Intervention: Intravenous magnesium sulfate (4 g) was compared with placebo. Main Outcomes and Measures: The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years' corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a pediatrician) at 2 years' corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child. Results: Of the 1433 pregnant individuals enrolled (mean age, 30.6 [SD, 6.6] years; 46 [3.2%] self-identified as Aboriginal or Torres Strait Islander, 237 [16.5%] as Asian, 82 [5.7%] as Maori, 61 [4.3%] as Pacific, and 966 [67.4%] as White) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years' corrected age was not significantly different between the magnesium and placebo groups (3.3% [23 of 691 children] vs 2.7% [18 of 674 children], respectively; risk difference, 0.61% [95% CI, -1.27% to 2.50%]; adjusted relative risk [RR], 1.19 [95% CI, 0.65 to 2.18]). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% [294 of 858] vs 41% [334 of 821], respectively; adjusted RR, 0.85 [95% CI, 0.76 to 0.95]) and chronic lung disease (5.6% [48 of 858] vs 8.2% [67 of 821]; adjusted RR, 0.69 [95% CI, 0.48 to 0.99]) during the birth hospitalization. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% [531 of 690] vs 20% [136 of 667], respectively; adjusted RR, 3.76 [95% CI, 3.22 to 4.39]). Fewer pregnant individuals in the magnesium group had a cesarean delivery vs the placebo group (56% [406 of 729] vs 61% [427 of 704], respectively; adjusted RR, 0.91 [95% CI, 0.84 to 0.99]), although more in the magnesium group had a major postpartum hemorrhage (3.4% [25 of 729] vs 1.7% [12 of 704] in the placebo group; adjusted RR, 1.98 [95% CI, 1.01 to 3.91]). Conclusions and Relevance: Administration of intravenous magnesium sulfate prior to preterm birth at 30 to 34 weeks' gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences. Trial Registration: anzctr.org.au Identifier: ACTRN12611000491965.

Recent advances in policy and practice translation of the evidence for additional omega-3 fatty acids and prematurity.

PURPOSE OF REVIEW: This is a review of the most up-to-date research on the effectiveness of omega-3 fatty acids for reducing the risk of prematurity in well nourished women with access to high-quality obstetric care. It will provide an overview of the translation of the evidence on omega-3 screening into policy, and the latest research on how to implement the policy into practice. RECENT FINDINGS: Findings of the included clinical studies support that omega-3 supplementation for women with a singleton pregnancy who have a low omega-3 status reduces the risk of early preterm birth. SUMMARY: There is evidence that screening and providing appropriate advice to women with a singleton pregnancy who have a low omega-3 status can reduce their risk of early preterm birth, and avoiding supplementation for women who are replete will avoid unnecessary supplementation and potential harm.

The National COVID-19 Clinical Evidence Taskforce: pregnancy and perinatal guidelines.

INTRODUCTION: Pregnant women are at higher risk of severe illness from coronavirus disease 2019 (COVID-19) than non-pregnant women of a similar age. Early in the COVID-19 pandemic, it was clear that evidenced-based guidance was needed, and that it would need to be updated rapidly. The National COVID-19 Clinical Evidence Taskforce provided a resource to guide care for people with COVID-19, including during pregnancy. Care for pregnant and breastfeeding women and their babies was included as a priority when the Taskforce was set up, with a Pregnancy and Perinatal Care Panel convened to guide clinical practice. MAIN RECOMMENDATIONS: As of May 2022, the Taskforce has made seven specific recommendations on care for pregnant women and those who have recently given birth. This includes supporting usual practices for the mode of birth, umbilical cord clamping, skin-to-skin contact, breastfeeding, rooming-in, and using antenatal corticosteroids and magnesium sulfate as clinically indicated. There are 11 recommendations for COVID-19-specific treatments, including conditional recommendations for using remdesivir, tocilizumab and sotrovimab. Finally, there are recommendations not to use several disease-modifying treatments for the treatment of COVID-19, including hydroxychloroquine and ivermectin. The recommendations are continually updated to reflect new evidence, and the most up-to-date guidance is available online (https://covid19evidence.net.au). CHANGES IN MANAGEMENT RESULTING FROM THE GUIDELINES: The National COVID-19 Clinical Evidence Taskforce has been a critical component of the infrastructure to support Australian maternity care providers during the COVID-19 pandemic. The Taskforce has shown that a rapid living guidelines approach is feasible and acceptable.

Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes.

BACKGROUND: Infants born preterm (before 37 weeks' gestation) are at risk of respiratory distress syndrome (RDS) and need for respiratory support due to lung immaturity. One course of prenatal corticosteroids, administered to women at risk of preterm birth, reduces the risk of respiratory morbidity and improves survival of their infants, but these benefits do not extend beyond seven days. Repeat doses of prenatal corticosteroids have been used for women at ongoing risk of preterm birth more than seven days after their first course of corticosteroids, with improvements in respiratory outcomes, but uncertainty remains about any long-term benefits and harms. This is an update of a review last published in 2015. OBJECTIVES: To assess the effectiveness and safety, using the best available evidence, of a repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with the primary aim of reducing fetal and neonatal mortality and morbidity. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials, including cluster-randomised trials, of women who had already received one course of corticosteroids seven or more days previously and were still at risk of preterm birth, randomised to further dose(s) or no repeat doses, with or without placebo. Quasi-randomised trials were excluded. Abstracts were accepted if they met specific criteria. All trials had to meet criteria for trustworthiness, including a search of the Retraction Watch database for retractions or expressions of concern about the trials or their publications. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods. Two review authors independently selected trials, extracted data, and assessed trial quality and scientific integrity. We chose primary outcomes based on clinical importance as measures of effectiveness and safety, including serious outcomes, for the women and their fetuses/infants, infants in early childhood (age two to less than five years), the infant in mid- to late childhood (age five to less than 18 years) and the infant as an adult. We assessed risk of bias at the outcome level using the RoB 2 tool and assessed certainty of evidence using GRADE. MAIN RESULTS: We included 11 trials (4895 women and 5975 babies). High-certainty evidence from these trials indicated that treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s) of corticosteroids, compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary infant outcome of RDS (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.90; 3540 babies; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 11 to 29) and had little or no effect on chronic lung disease (RR 1.00, 95% CI 0.83 to 1.22; 5661 babies). Moderate-certainty evidence indicated that the composite of serious infant outcomes was probably reduced with repeat dose(s) of corticosteroids (RR 0.88, 95% CI 0.80 to 0.97; 9 trials, 5736 babies; NNTB 39, 95% CI 24 to 158), as was severe lung disease (RR 0.83, 95% CI 0.72 to 0.97; NNTB 45, 95% CI 27 to 256; 4955 babies). Moderate-certainty evidence could not exclude benefit or harm for fetal or neonatal or infant death less than one year of age (RR 0.95, 95% CI 0.73 to 1.24; 5849 babies), severe intraventricular haemorrhage (RR 1.13, 95% CI 0.69 to 1.86; 5066 babies) and necrotising enterocolitis (RR 0.84, 95% CI 0.59 to 1.22; 5736 babies).  In women, moderate-certainty evidence found little or no effect on the likelihood of a caesarean birth (RR 1.03, 95% CI 0.98 to 1.09; 4266 mothers). Benefit or harm could not be excluded for maternal death (RR 0.32, 95% 0.01 to 7.81; 437 women) and maternal sepsis (RR 1.13, 95% CI 0.93 to 1.39; 4666 mothers). The evidence was unclear for risk of adverse effects and discontinuation of therapy due to maternal adverse effects. No trials reported breastfeeding status at hospital discharge or risk of admission to the intensive care unit.  At early childhood follow-up, moderate- to high-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids for primary outcomes relating to neurodevelopment (neurodevelopmental impairment: RR 0.97, 95% CI 0.85 to 1.10; 3616 children), survival without neurodevelopmental impairment (RR 1.01, 95% CI 0.98 to 1.04; 3845 children) and survival without major neurodevelopmental impairment (RR 1.02, 95% CI 0.98 to 1.05; 1816 children). An increase or decrease in the risk of death since randomisation could not be excluded (RR 1.06, 95% CI 0.81 to 1.40; 5 trials, 4565 babies randomised). At mid-childhood follow-up, moderate-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids on survival free of neurocognitive impairment (RR 1.01, 95% CI 0.95 to 1.08; 963 children) or survival free of major neurocognitive impairment (RR 1.00, 95% CI 0.97 to 1.04; 2682 children). Benefit or harm could not be excluded for death since randomisation (RR 0.93, 95% CI 0.69 to 1.26; 2874 babies randomised) and any neurocognitive impairment (RR 0.96, 95% CI 0.72 to 1.29; 897 children). No trials reported data for follow-up into adolescence or adulthood.  Risk of bias across outcomes was generally low although there were some concerns of bias. For childhood follow-up, most outcomes had some concerns of risk of bias due to missing data from loss to follow-up. AUTHORS' CONCLUSIONS: The short-term benefits for babies included less respiratory distress and fewer serious health problems in the first few weeks after birth with repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. The current available evidence reassuringly shows no significant harm for the women or child in early and mid-childhood, although no benefit. Further research is needed on the long-term benefits and risks for the baby into adulthood.

Inequitable use of health services for Indigenous mothers who experience stillbirth in Australia.

OBJECTIVES: The purpose of this study was to identify differences in health service expenditure on Indigenous and non-Indigenous women who experience a stillbirth, women's out-of-pocket costs, and health service use. METHODS: The project used a whole-of-population linked data set called "Maternity1000," which includes all women who gave birth in Queensland, Australia, between July 1, 2012, and June 30, 2018 (n = 396 158). Multivariable analysis was undertaken to assess differences in mean health service expenditure; and number of health care services accessed between Indigenous and non-Indigenous women who had a stillbirth from birth to twelve months postpartum. Costs are presented in 2019/20 Australian dollars. RESULTS: There was a total of 1864 babies stillborn to women in Queensland between July 1, 2012, and June 30, 2018, with 135 being born to Indigenous women and 1729 born to non-Indigenous women. There was significantly lower total expenditure per woman for Indigenous women compared with non-Indigenous women ($16 083 and $18 811, respectively). This was consistent across public hospital inpatient ($12 564 compared with $14 075), outpatient ($1127 compared with $1470), community-based services ($198 compared with $313), pharmaceuticals ($8 compared with $22), private hospital ($434 compared with $1265), and for individual out-of-pocket fees ($21 compared with $86). Mean expenditure on emergency department services per woman was higher for Indigenous women compared with non-Indigenous women ($947 compared with $643). Indigenous women who experienced a stillbirth accessed fewer general practitioners, allied health, specialist, obstetrics, and outpatient services, and fewer pathology and diagnostic test than their non-Indigenous counterparts. CONCLUSIONS: Inequities in access to health services exist between Indigenous and non-Indigenous women who experience a stillbirth.

Early versus delayed introduction of human milk fortification in enterally fed preterm infants: A systematic review and meta-analysis.

AIM: To assess effects of early versus delayed introduction of human milk fortification in preterm infants. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PubMed and CINAHL for randomised controlled trials evaluating start time for human milk fortification in preterm infants (March 2020). Two authors assessed trial eligibility and risk of bias, extracted data and assessed evidence certainty. RESULTS: We identified 1307 publications and included three trials (378 infants). Meta-analysis comparing fortification commencing at an enteral feed volume of ≤40 mL/kg/day versus ≥75 mL/kg/day, showed little to no difference in rates of necrotising enterocolitis (3 trials), sepsis (3 trials), feeding intolerance (2 trials) (low-quality evidence) and infant growth (1 trial, very low-quality evidence). CONCLUSIONS: Whether early introduction of fortification, at an enteral feed volume of ≤40 mL versus delayed at ≥75 mL/kg/day improves growth or influences adverse feeding outcomes is very uncertain.

Perinatal bereavement care during COVID-19 in Australian maternity settings.

OBJECTIVES: Perinatal bereavement care is a complex area of practice. The COVID-19 pandemic led to reconfiguration of maternity and perinatal bereavement care services. This study explores Australian health care providers' perspectives of the impact of COVID-19 on the provision of respectful and supportive care following stillbirth or neonatal death. METHODS: Members of a perinatal bereavement care network were consulted at the commencement of the pandemic in Australia using an online feedback form. Respondents provided ratings and free-text comments on the impact of COVID-19 on implementation of 49 recommendations contained in the Perinatal Society of Australia and New Zealand/Stillbirth Centre of Research Clinical Practice Guideline for Respectful and Supportive Perinatal Bereavement Care. RESULTS: Responses were received from 35 health care providers who provided perinatal bereavement care in clinical settings or through support organisations in Australia. Major impacts of COVID-19 were reported for 8 of 49 guideline recommendations. Impacts included reduced: support for mothers due to visitor restrictions; availability of cultural and spiritual support and interpreters; involvement of support people in decision-making; options for memory-making and commemorative rituals; and staff training and supervision. Adaptations to minimise impacts included virtual consultations, online staff training, use of cold cots, and increased staff support for memory-making. CONCLUSIONS: Health care providers encounter substantial challenges as they strive to implement best practice perinatal bereavement care in pandemic conditions. Some practice adaptations developed during the COVID-19 pandemic could benefit parents; however, evaluation of their effectiveness and acceptability is needed.

Overwhelming and unjust: A qualitative study of fathers' experiences of grief following neonatal death.

Limited research has examined the grief experiences of fathers following neonatal death. Using a qualitative research design, ten fathers were interviewed, and thematic analysis resulted in three overarching themes: 'A complicated grief experience: Neonatal death is highly emotional', 'Grief is multidimensional' and 'Sense of injustice'. Overall, results showed that grief was a multidimensional experience for fathers, with expressions of grief including strong feelings of anger and guilt and the manifestation of grief in physical symptoms. In addition, the findings also indicated a sense of injustice that contributed to the disenfranchisement of grief for fathers. The results of this study contribute to developing a better understanding of the grief that fathers experience following neonatal death, and can inform improvements in healthcare practices after the death of a baby in the neonatal period, including father-specific programs and adequate provision of information.

Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period.

BACKGROUND: Venous thromboembolism (VTE), although rare, is a major cause of maternal mortality and morbidity. Some women are at increased risk of VTE during pregnancy and the early postnatal period (e.g. caesarean section, family history of VTE, or thrombophilia), and so prophylaxis may be considered. As some methods of prophylaxis carry risks of adverse effects, and risk of VTE is often low, benefits of thromboprophylaxis may be outweighed by harms. OBJECTIVES: To assess the effects of thromboprophylaxis during pregnancy and the early postnatal period on the risk of venous thromboembolic disease and adverse effects in women at increased risk of VTE. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 October 2019). In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (18 October 2019). SELECTION CRITERIA: Randomised trials comparing one method of thromboprophylaxis with placebo or no treatment, or two (or more) methods of thromboprophylaxis. DATA COLLECTION AND ANALYSIS: At least two review authors assessed trial eligibility, extracted data, assessed risk of bias, and judged certainty of evidence for selected critical outcomes (using GRADE). We conducted fixed-effect meta-analysis and reported data (all dichotomous) as summary risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: Twenty-nine trials (involving 3839 women), overall at moderate to high risk of bias were included. Trials were conducted across the antenatal, peripartum and postnatal periods, with most in high-income countries. Interventions included types and regimens of heparin (low molecular weight heparin (LMWH) and unfractionated heparin (UFH)), hydroxyethyl starch (HES), and compression stockings or devices. Data were limited due to a small number of trials in comparisons and/or few or no events reported. All critical outcomes (assessed for comparisons of heparin versus no treatment/placebo, and LMWH versus UFH) were considered to have very low-certainty evidence, downgraded mainly for study limitations and imprecise effect estimates.  Maternal death was not reported in most studies. Antenatal (± postnatal) prophylaxis For the primary outcomes symptomatic thromboembolic events pulmonary embolism (PE) and/or deep vein thrombosis (DVT), and the critical outcome of adverse effects sufficient to stop treatment, the evidence was very uncertain.  Symptomatic thromboembolic events: - heparin versus no treatment/placebo (RR 0.39; 95% CI 0.08 to 1.98; 4 trials, 476 women; very low-certainty evidence); - LMWH versus UFH (RR 0.47; 95% CI 0.09 to 2.49; 4 trials, 404 women; very low-certainty evidence); Symptomatic PE: - heparin versus no treatment/placebo (RR 0.33; 95% CI 0.02 to 7.14; 3 trials, 187 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 287 women); Symptomatic DVT: - heparin versus no treatment/placebo (RR 0.33; 95% CI 0.04 to 3.10; 4 trials, 227 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 287 women); Adverse effects sufficient to stop treatment: - heparin versus no treatment/placebo (RR 0.49; 95% CI 0.05 to 5.31; 1 trial, 139 women; very low-certainty evidence); - LMWH versus UFH (RR 0.07; 95% CI 0.01 to 0.54; 2 trials, 226 women; very low-certainty evidence). Peripartum/postnatal prophylaxis Vaginal or caesarean birth When UFH and no treatment were compared, the effects on symptomatic thromboembolic events (RR 0.16; 95% CI 0.02 to 1.36; 1 trial, 210 women; very low-certainty evidence), symptomatic PE (RR 0.16; 95% CI 0.01 to 3.34; 1 trial, 210 women; very low-certainty evidence), and symptomatic DVT  (RR 0.27; 95% CI 0.03 to 2.55; 1 trial, 210 women; very low-certainty evidence) were very uncertain.  Maternal death and adverse effects sufficient to stop treatment were not reported. Caesarean birth Symptomatic thromboembolic events: - heparin versus no treatment/placebo (RR 1.30; 95% CI 0.39 to 4.27; 4 trials, 840 women; very low-certainty evidence); - LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low-certainty evidence); Symptomatic PE: - heparin versus no treatment/placebo (RR 1.10; 95% CI 0.25 to 4.87; 4 trials, 840 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 217 women);  Symptomatic DVT: - heparin versus no treatment/placebo (RR 1.30; 95% CI 0.24 to 6.94; 5 trials, 1140 women; very low-certainty evidence); LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low-certainty evidence); Maternal death: - heparin versus placebo (no events, 1 trial, 300 women); Adverse effects sufficient to stop treatment: - heparin versus placebo (no events;  1 trial, 140 women). Postnatal prophylaxis No events were reported for LMWH versus no treatment/placebo for: symptomatic thromboembolic events, symptomatic PE and symptomatic DVT (all 2 trials, 58 women), or maternal death (1 trial, 24 women). Adverse effects sufficient to stop treatment were not reported. We were unable to conduct subgroup analyses due to lack of data. Sensitivity analysis including the nine studies at low risk of bias did not impact overall findings. AUTHORS' CONCLUSIONS: The evidence is very uncertain about benefits and harms of VTE thromboprophylaxis in women during pregnancy and the early postnatal period at increased risk of VTE. Further high-quality very large-scale randomised trials are needed to determine effects of currently used treatments in women with different VTE risk factors. As sufficiently large definitive trials are unlikely to be funded, secondary data analyses based on high-quality registry data are important.

Factors contributing to men's grief following pregnancy loss and neonatal death: further development of an emerging model in an Australian sample.

BACKGROUND: Historically, men's experiences of grief following pregnancy loss and neonatal death have been under-explored in comparison to women. However, investigating men's perspectives is important, given potential gendered differences concerning grief styles, help-seeking and service access. Few studies have comprehensively examined the various individual, interpersonal, community and system/policy-level factors which may contribute to the intensity of grief in bereaved parents, particularly for men. METHODS: Men (N = 228) aged at least 18 years whose partner had experienced an ectopic pregnancy, miscarriage, stillbirth, termination of pregnancy for foetal anomaly, or neonatal death within the last 20 years responded to an online survey exploring their experiences of grief. Multiple linear regression analyses were used to examine the factors associated with men's grief intensity and style. RESULTS: Men experienced significant grief across all loss types, with the average score sitting above the minimum cut-off considered to be a high degree of grief. Men's total grief scores were associated with loss history, marital satisfaction, availability of social support, acknowledgement of their grief from family/friends, time spent bonding with the baby during pregnancy, and feeling as though their role of 'supporter' conflicted with their ability to process grief. Factors contributing to grief also differed depending on grief style. Intuitive (emotion-focused) grief was associated with support received from healthcare professionals. Instrumental (activity-focused) grief was associated with time and quality of attachment to the baby during pregnancy, availability of social support, acknowledgement of men's grief from their female partner, supporter role interfering with their grief, and tendencies toward self-reliance. CONCLUSIONS: Following pregnancy loss and neonatal death, men can experience high levels of grief, requiring acknowledgement and validation from all healthcare professionals, family/friends, community networks and workplaces. Addressing male-specific needs, such as balancing a desire to both support and be supported, requires tailored information and support. Strategies to support men should consider grief styles and draw upon father-inclusive practice recommendations. Further research is required to explore the underlying causal mechanisms of associations found.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Evaluation of an online education module designed to reduce stillbirth.

BACKGROUND: The Safer Baby Bundle (SBB) eLearning is an online education module that addresses practice gaps in stillbirth prevention in Australia. It provides healthcare professionals with evidence-based resources for: smoking cessation; fetal growth restriction; decreased fetal movements; maternal safe going-to-sleep position; and timing of birth for women with risk factors for stillbirth. AIMS: To determine whether participants' reported knowledge and confidence in providing care designed to reduce stillbirth changed following completion of the module. To assess the module's suitability and acceptability, and participants' reported likelihood to change practice. MATERIALS AND METHODS: In-built surveys undertaken pre- and post-eLearning module assessed participant knowledge and confidence, module suitability and acceptability, and likelihood of practice change using Likert items. Responses were dichotomised. Differences pre- and post-module were tested using McNemar's test and differences by profession were examined using descriptive statistics and Pearson's χ2 test. RESULTS: Between 15 October 2019 and 2 November 2020, 5223 participants across Australia were included. Most were midwives (82.0%), followed by student midwives (4.6%) and obstetricians (3.3%). Reported knowledge and confidence improved in all areas (P < 0.001). Post-module 96.7-98.9% 'agreed' they had a sound level of knowledge and confidence across all elements of the SBB. Over 95% of participants agreed that the module was helpful and relevant, well organised, and easy to access and use. Eighty-eight percent reported they were likely to change some aspect of their clinical practice. CONCLUSIONS: The SBB eLearning module is a valuable education program that is well-received and likely to result in improvements in practice.