The influence of birthweight on mortality and severe neonatal morbidity in late preterm and term infants: an Australian cohort study.

Background: The aim of this study was to detail incidence rates and relative risks for severe adverse perinatal outcomes by birthweight centile categories in a large Australian cohort of late preterm and term infants. Methods: This was a retrospective cohort study of singleton infants (≥34+0 weeks gestation) between 2000 and 2018 in Queensland, Australia. Study outcomes were perinatal mortality, severe neurological morbidity, and other severe morbidity. Categorical outcomes were compared using Chi-squared tests. Continuous outcomes were compared using t-tests. Multinomial logistic regression investigated the effect of birthweight centile on study outcomes. Findings: The final cohort comprised 991,042 infants. Perinatal mortality occurred in 1944 infants (0.19%). The incidence and risk of perinatal mortality increased as birthweight decreased, peaking for infants <1st centile (perinatal mortality rate 13.2/1000 births, adjusted Relative Risk Ratio (aRRR) of 12.96 (95% CI 10.14, 16.57) for stillbirth and aRRR 7.55 (95% CI 3.78, 15.08) for neonatal death). Severe neurological morbidity occurred in 7311 infants (0.74%), with the highest rate (19.6/1000 live births) in <1st centile cohort. There were 75,243 cases of severe morbidity (7.59% livebirths), with the peak incidence occurring in the <1st centile category (12.3% livebirths). The majority of adverse outcomes occurred in infants with birthweights between 10 and 90th centile. Almost 2 in 3 stillbirths, and approximately 3 in 4 cases of neonatal death, severe neurological morbidity or other severe morbidity occurred within this birthweight range. Interpretation: Although the incidence and risk of perinatal mortality, severe neurological morbidity and severe morbidity increased at the extremes of birthweight centiles, the majority of these outcomes occurred in infants that were apparently "appropriately grown" (i.e., birthweight 10th-90th centile). Funding: National Health and Medical Research Council, Mater Foundation, Royal Australian College of Obstetricians and Gynaecologists Women's Health Foundation - Norman Beischer Clinical Research Scholarship, Cerebral Palsy Alliance, University of Queensland Research Scholarship.

Prediction of preterm birth in women with fetal growth restriction - Is the weekly change in sFlt-1/PlGF ratio or PlGF levels useful?

INTRODUCTION: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. MATERIAL AND METHODS: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. RESULTS: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68). CONCLUSIONS: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level.

Maternal physical activity and sitting time and its association with placental morphology and blood flow during gestation: Findings from the Queensland Family Cohort study.

OBJECTIVES: Antenatal exercise is associated with placental morphological alterations, however research in this area is limited. Given the emphasis on the beneficial effects of antenatal exercise, it is important to understand its effect on placental function and the relationship to foetal development. The aim of this study was to investigate the association between physical activity, sitting time, and placental outcomes measured during gestation. DESIGN: Prospective cohort study. METHODS: Pregnant women in the Queensland Family Cohort study self-reported physical activity at 24 and 36 weeks of gestation (n = 203) and were categorised into physical activity volume groups of nil-low (0-<500 metabolic equivalent of task·minutes/week), moderate (500-<1000 metabolic equivalent of task·minutes/week), or high-volume activity (≥1000 metabolic equivalent of task·minutes/week). Participants reported average daily sitting time, whereby excessive sitting time was considered as ≥8h/day. Placental stiffness, thickness, and uteroplacental blood flow resistance were measured by ultrasound imaging at each timepoint. RESULTS: Physical activity volume was not associated with changes to placental morphometrics or uteroplacental blood flow resistance at 24 or 36 weeks of gestation. Excessive sitting time at 36 weeks was associated with greater placental stiffness (p = 0.046), and a lower umbilical artery pulsatility index (p = 0.001). CONCLUSIONS: Placental tissue stiffness and umbilical artery resistance were altered in late gestation with higher maternal sitting time but not with physical activity volume. Overall, excessive sitting time may be a risk for suboptimal placental function and could be an important focus for antenatal care.

Five-minute Apgar score and risk of neonatal mortality, severe neurological morbidity and severe non-neurological morbidity in term infants - an Australian population-based cohort study.

Background: The aim of this study was to ascertain risks of neonatal mortality, severe neurological morbidity and severe non-neurological morbidity related to the 5-min Apgar score in early term (37+0-38+6 weeks), full term (39+0-40+6 weeks), late term (41+0-41+6 weeks), and post term (≥42+0 weeks) infants. Methods: This was a retrospective cohort study of 941,221 term singleton births between 2000 and 2018 in Queensland, Australia. Apgar scores at 5-min were categorized into five groups: Apgar 0 or 1, 2 or 3, 4-6, 7 or 8 and 9 or 10. Gestational age was stratified into 4 groups: Early term, full term, late term and post term. Three specific neonatal study outcomes were considered: 1) Neonatal mortality 2) Severe neurological morbidity and 3) Severe non-neurological morbidity. Poisson multivariable regression models were used to determine relative risk ratios for the effect of gestational age and Apgar scores on these severe neonatal outcomes. We hypothesized that a low Apgar score of <4 was significantly associated with increased risks of neonatal mortality, severe neurological morbidity and severe non-neurological morbidity. Findings: Of the study cohort, 0.04% (345/941,221) were neonatal deaths, 0.70% (6627/941,221) were infants with severe neurological morbidity and 4.3% (40,693/941,221) had severe non-neurological morbidity. Infants with Apgar score <4 were more likely to birth at late term and post term gestations and have birthweights <3rd and <10th percentiles. The adjusted relative risk ratios (aRRR) for neonatal mortality and severe neurological morbidity were highest in the Apgar 0 or 1 cohort. For infants in the Apgar 0 or 1 group, neonatal mortality increased incrementally with advancing term gestation: early term (aRRR 860.16, 95% CI 560.96, 1318.94, p < 0.001); full term (aRRR 1835.77, 95% CI 1279.48, 2633.91, p < 0.001); late term (aRRR 1693.61, 95% CI 859.65, 3336.6, p < 0.001) and post term (aRRR 2231.59, 95% CI 272.23, 18293.07, p < 0.001) whilst severe neurological morbidity decreased as gestation progressed: early term (aRRR 158.48, 95% CI 118.74, 211.51, p < 0.001); full term (aRRR 112.99, 95% CI 90.56, 140.98, p < 0.001); late term (aRRR 87.94, 95% CI 67.09, 115.27, p < 0.001) and post term (aRRR 52.07, 95% CI 15.17, 178.70, p < 0.001). Severe non-neurological morbidity was greatest in the full term, Apgar 2-3 cohort (aRRR 7.36, 95% CI 6.2, 8.74, p < 0.001). Interpretation: A 5-min Apgar score of <4 was prognostic of neonatal mortality, severe neurological morbidity, and severe non-neurological morbidity in infants born >37 weeks' gestation with the risk greatest in the early term cohort. Funding: National Health and Medical Research Council and Mater Foundation.

Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

OBJECTIVE: To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). DESIGN: Prospective, observational cohort study. SETTING: Tertiary maternity hospital in Australia. POPULATION: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). METHODS: Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. MAIN OUTCOME MEASURES: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. RESULTS: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). CONCLUSIONS: Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

Dietary supplements, guideline alignment and biochemical nutrient status in pregnancy: Findings from the Queensland Family Cohort pilot study.

In high-income nations, multiple micronutrient (MMN) supplementation during pregnancy is a common practice. We aimed to describe maternal characteristics associated with supplement use and daily dose of supplemental nutrients consumed in pregnancy, and whether guideline alignment and nutrient status are related to supplement use. The Queensland Family Cohort is a prospective, Australian observational longitudinal study. Maternal characteristics, nutrient intake from food and supplements, and biochemical nutrient status were assessed in the second trimester (n = 127). Supplement use was reported by 89% of participants, of whom 91% reported taking an MMN supplement. Participants who received private obstetric care, had private health insurance and had greater alignment to meat/vegetarian alternatives recommendations were more likely to report MMN supplement use. Private obstetric care and general practitioner shared care were associated with higher daily dose of supplemental nutrients consumed compared with midwifery group practice. There was high reliance on supplements to meet nutrient reference values for folate, iodine and iron, but only plasma folate concentrations were higher in MMN supplement versus nonsupplement users. Exceeding the upper level of intake for folic acid and iron was more likely among combined MMN and individual supplement/s users, and associated with higher plasma concentrations of the respective nutrients. Given the low alignment with food group recommendations and potential risks associated with high MMN supplement use, whole food diets should be emphasized. This study confirms the need to define effective strategies for optimizing nutrient intake in pregnancy, especially among those most vulnerable where MMN supplement use may be appropriate.

Intrapartum use of sildenafil citrate to prevent fetal compromise and emergency operative birth in term pregnancies in the United Kingdom and Australia: A preliminary cost-effectiveness analysis.

OBJECTIVE: To compare cost-effectiveness of oral sildenafil citrate, administered after onset of labor, with standard care to health system funders in the UK and Australia. METHODS: We conducted a modeled cost-effectiveness analysis, measuring costs and quality adjusted life years (QALYs), using a decision-analytic model covering onset of labor to 1 month post-birth. The relative risk of emergency cesarean section and operative vaginal birth was taken from a Phase 2 placebo controlled double blinded randomized control trial. RESULTS: Both options of care resulted in the same QALYs gained over the model time period (0.08). Sildenafil citrate was cost-saving compared with standard care, saving £92 per birth in the UK (AU$303 per birth in Australia). Sensitivity analyses did not identify any areas of uncertainty that stopped sildenafil citrate being cost saving compared with standard care. Threshold analysis revealed that sildenafil citrate would be cost saving up to a per birth drug or administration cost of £152.32 in the UK (AU$333.61 in Australia). CONCLUSION: Oral sildenafil citrate may be cost saving compared with standard care; however, the effects on neonatal outcomes still need to be demonstrated in large randomized trials.

The impact of the COVID-19 pandemic on antenatal care provision and associated mental health, obstetric and neonatal outcomes.

OBJECTIVES: The COVID-19 pandemic imposed many challenges on pregnant women, including rapid changes to antenatal care aimed at reducing the societal spread of the virus. This study aimed to assess how the pandemic affected perinatal mental health and other pregnancy and neonatal outcomes in a tertiary unit in Queensland, Australia. METHODS: This was a retrospective cohort study of pregnant women booked for care between March 2019 - June 2019 and March 2020 - June 2020. A total of 1984 women were included with no confirmed cases of COVID-19. The primary outcome of this study was adverse maternal mental health defined as an Edinburgh Postnatal Depression Scale score of ≥13 or an affirmative response to 'EPDS Question 10'. Secondary outcomes were preterm birth <37 weeks and <32 weeks, mode of birth, low birth weight, malpresentation in labour, hypertensive disease, anaemia, iron/vitamin B12 deficiency, stillbirth and a composite of neonatal morbidity and mortality. RESULTS: There were no differences in the primary perinatal mental health outcomes. The rates of composite adverse neonatal outcomes (27 vs. 34 %, p<0.001) during the pandemic were higher; however, there was no difference in perinatal mortality (p=1.0), preterm birth (p=0.44) or mode of delivery (p=0.38). CONCLUSIONS: Although there were no adverse consequences on maternal mental health during the pandemic, there was a concerning increase in neonatal morbidity potentially due to the altered model of maternity care implemented in the early COVID-19 pandemic.

Intimate partner violence is a significant risk factor for adverse pregnancy outcomes.

BACKGROUND: Globally, almost 30% of women report experiencing intimate partner violence. In Australia, intimate partner violence is estimated to affect 2.0% to 4.3% of pregnant women. Those who experience intimate partner violence during pregnancy have poorer perinatal and maternal outcomes, including preterm birth, low birth weight, preterm prelabor rupture of membranes, perinatal death, miscarriage, antepartum hemorrhage, maternal trauma, and death. OBJECTIVE: This study aimed to evaluate the maternal and perinatal outcomes among women who reported intimate partner violence in a tertiary Australian hospital. STUDY DESIGN: This was a retrospective observational study conducted between January 2017 and December 2021 at the Mater Mother's Hospital in Brisbane, Australia. The study cohort included pregnant women who completed a prenatal intimate partner violence questionnaire. Exclusion criteria included infants with known major congenital or chromosomal abnormalities. RESULTS: Of the total study cohort comprising 45,177 births, 3242 births (7.2%) were among women who were exposed to intimate partner violence. Those who identified as Indigenous or had refugee status experienced significantly higher rates of intimate partner violence. Women exposed to intimate partner violence had greater odds of having a small for gestational age infant (adjusted odds ratio, 1.17; 95% confidence interval, 1.04-1.33), preterm birth (adjusted odds ratio, 1.21; 95% confidence interval, 1.07-1.37), preterm prelabor rupture of membranes (adjusted odds ratio, 1.23; 95% confidence interval, 1.05-1.45), and an infant with severe neonatal morbidity (adjusted odds ratio, 1.21; 95% confidence interval, 1.08-1.35). Women who reported intimate partner violence also had higher odds of acute presentation to the obstetrical assessment unit (adjusted odds ratio, 1.71; 95% confidence interval, 1.58-1.85) and admission to hospital (adjusted odds ratio, 1.44; 95% confidence interval, 1.30-1.61). When compared with non-Indigenous women exposed to intimate partner violence, Indigenous women had worse outcomes with significantly higher rates of preterm prelabor rupture of membranes, extreme preterm birth, lower gestational age at birth, low birth weight, and higher rates of infants with birth weight

Mediation analysis quantifying the magnitude of stillbirth risk attributable to small for gestational age infants.

BACKGROUND: Many risk factors for stillbirth are linked to placental dysfunction, which leads to suboptimal intrauterine growth and small for gestational age infants. Such infants also have an increased risk for stillbirth. OBJECTIVE: This study aimed to investigate the effect of known causal risk factors for stillbirth, and to identify those that have a large proportion of their risk mediated through small for gestational age birth. STUDY DESIGN: This retrospective cohort study used data from all births in the state of Queensland, Australia between 2000 and 2018. The total effects of exposures on the odds of stillbirth were determined using multivariable, clustered logistic regression models. Mediation analysis was performed using a counterfactual approach to determine the indirect effect and percentage of effect mediated through small for gestational age. For risk factors significantly mediated through small for gestational age, the relative risks of stillbirth were compared between small for gestational age and appropriate for gestational age infants. We also investigated the proportion of risk mediated via small for gestational age for late stillbirths (≥28 weeks). RESULTS: The initial data set consisted of 1,105,612 births. After exclusions, the final study cohort constituted 925,053 births. Small for gestational age births occurred in 9.9% (91,859/925,053) of the study cohort. Stillbirths occurred in 0.5% of all births (4234/925,053) and 1.5% of small for gestational age births (1414/91,859). Births at ≥28 weeks occurred in 99.4% (919,650/925,053) of the study cohort and in 98.9% (90,804/91,859) of all small for gestational age births. Of the ≥28-week births, stillbirths occurred in 0.2% (2156/919,650) of all births and 0.8% (677/90,804) of the small for gestational age births. Overall, increased odds of stillbirth were significantly mediated through small for gestational age for age <20 years, low socioeconomic status, Indigenous ethnicity, birth in sub-Saharan and North Africa or the Middle East, smoking, nulliparity, multiple pregnancy, assisted conception, previous stillbirth, preeclampsia, and renal disease. Preeclampsia had the largest proportion mediated through small for gestational age (66.7%), followed by nulliparity (61.6%), smoking (29.4%), North-African or Middle Eastern ethnicity (27.6%), multiple pregnancy (26.3%), low socioeconomic status (25.8%), and Indigenous status (18.7%). Sensitivity analysis showed that for late stillbirths, the portions mediated through small for gestational age remained very similar for many of the risk factors. CONCLUSION: Although small for gestational age is an important mediator between many pregnancy risk factors and stillbirth, mitigating the risk of small for gestational age is likely to be of value only when it is a major contributor in the pathway to fetal demise.

SuPreme Study: a protocol to study the neuroprotective potential of sulfate among very/extremely preterm infants.

INTRODUCTION: Antenatal maternal magnesium sulfate (MgSO4) administration is a proven efficacious neuroprotective treatment reducing the risk of cerebral palsy (CP) among infants born preterm. Identification of the neuroprotective component with target plasma concentrations could lead to neonatal treatment with greater efficacy and accessibility. METHODS AND ANALYSIS: This is a prospective observational cohort study, in three tertiary Australian centres. Participants are preterm infants, irrespective of antenatal MgSO4 exposure, born in 2013-2020 at 24+0 to 31+6 weeks gestation, and followed up to 2 years corrected age (CA) (to September 2023). 1595 participants are required (allowing for 17% deaths/loss to follow-up) to detect a clinically significant reduction (30% relative risk reduction) in CP when sulfate concentration at 7 days of age is 1 SD above the mean.A blood sample is collected on day 7 of age for plasma sulfate and magnesium measurement. In a subset of participants multiple blood and urine samples are collected for pharmacokinetic studies, between days 1-28, and in a further subset mother/infant blood is screened for genetic variants of sulfate transporter genes.The primary outcome is CP. Surviving infants are assessed for high risk of CP at 12-14 weeks CA according to Prechtl's Method to assess General Movements. Follow-up at 2 years CA includes assessments for CP, cognitive, language and motor development, and social/behavioural difficulties.Multivariate analyses will examine the association between day 7 plasma sulfate/magnesium concentrations with adverse neurodevelopmental outcomes. A population pharmacokinetic model for sulfate in the preterm infant will be created using non-linear mixed-effects modelling. ETHICS AND DISSEMINATION: The study has been approved by Mater Misericordiae Ltd Human Research Ethics Committee (HREC/14/MHS/188). Results will be disseminated in peer-reviewed journal publications, and provided to the funding bodies. Using consumer input, a summary will be prepared for participants and consumer groups.

Risks of stillbirth, neonatal mortality, and severe neonatal morbidity by birthweight centiles associated with expectant management at term.

BACKGROUND: Determining the optimal time of birth at term is challenging given the ongoing risks of stillbirth with increasing gestation vs the risks of significant neonatal morbidity at early-term gestations. These risks are more pronounced in small infants. OBJECTIVE: This study aimed to evaluate the risks of stillbirth, neonatal mortality, and severe neonatal morbidity by comparing expectant management with delivery from 37+0 weeks of gestation. STUDY DESIGN: This was a retrospective cohort study evaluating women with singleton, nonanomalous pregnancies at 37+0 to 40+6 weeks' gestation in Queensland, Australia, delivered from 2000 to 2018. Rates of stillbirth, neonatal death, and severe neonatal morbidity were calculated for <3rd, 3rd to <10th, 10th to <25th, 25th to <90th, and ≥90th birthweight centiles. The composite risk of mortality with expectant management for an additional week in utero was compared with rates of neonatal mortality and severe neonatal morbidity. RESULTS: Of 948,895 singleton, term nonanomalous births, 813,077 occurred at 37+0 to 40+6 weeks' gestation. Rates of stillbirth increased with gestational age, with the highest rate observed in infants with birthweight below the third centile: 10.0 per 10,000 (95% confidence interval, 6.2-15.3) at 37+0 to 37+6 weeks, rising to 106.4 per 10,000 (95% confidence interval, 74.6-146.9) at 40+0 to 40+6 weeks' gestation. The rate of neonatal mortality was highest at 37+0 to 37+6 weeks for all birthweight centiles. The composite risk of expectant management rose sharply after 39+0 to 39+6 weeks, and was highest in infants with birthweight below the third centile (125.2/10,000; 95% confidence interval, 118.4-132.3) at 40+0 to 40+6 weeks' gestation. Balancing the risk of expectant management and delivery (neonatal mortality), the optimal timing of delivery for each birthweight centile was evaluated on the basis of relative risk differences. The rate of severe neonatal morbidity sharply decreased in the period between 37+0 to 37+6 and 38+0 to 38+6 weeks, particularly for infants with birthweight below the third centile. CONCLUSION: Our data suggest that the optimal time of birth is 37+0 to 37+6 weeks for infants with birthweight <3rd centile and 38+0 to 38+6 weeks' gestation for those with birthweight between the 3rd and 10th centile and >90th centile. For all other birthweight centiles, birth from 39+0 weeks is associated with the best outcomes. However, large numbers of planned births are required to prevent a single excess death. The healthcare costs and acceptability to women of potential universal policies of planned birth need to be carefully considered.

Cost-effectiveness of closed incision negative pressure wound therapy in preventing surgical site infection among obese women giving birth by caesarean section: An economic evaluation (DRESSING trial).

BACKGROUND: There is growing evidence regarding the potential of closed incision negative pressure wound therapy (ci-NPWT) to prevent surgical site infections (SSIs) in healing wounds by primary closure following a caesarean section (CS). AIM: To assess the cost-effectiveness of ci-NPWT compared to standard dressings for prevention of SSI in obese women giving birth by CS. MATERIALS AND METHODS: Cost-effectiveness and cost-utility analyses from a health service perspective were undertaken alongside a multicentre pragmatic randomised controlled trial, which recruited women with a pre-pregnancy body mass index ≥30 kg/m2 giving birth by elective/semi-urgent CS who received ci-NPWT (n = 1017) or standard dressings (n = 1018). Resource use and health-related quality of life (SF-12v2) collected during admission and for four weeks post-discharge were used to derive costs and quality-adjusted life years (QALYs). RESULTS: ci-NPWT was associated with AUD$162 (95%CI -$170 to $494) higher cost per person and an additional $12 849 (95%CI -$62 138 to $133 378) per SSI avoided. There was no detectable difference in QALYs between groups; however, there are high levels of uncertainty around both cost and QALY estimates. There is a 20% likelihood that ci-NPWT would be considered cost-effective at a willingness-to-pay threshold of $50 000 per QALY. Per protocol and complete case analyses gave similar results, suggesting that findings are robust to protocol deviators and adjustments for missing data. CONCLUSIONS: ci-NPWT for the prevention of SSI in obese women undergoing CS is unlikely to be cost-effective in terms of health service resources and is currently unjustified for routine use for this purpose.

Male infants are at higher risk of neonatal mortality and severe morbidity.

BACKGROUND: While a male infant is usually born with a higher birthweight than his female counterpart, he is more at risk of variety of adverse perinatal outcomes. Indeed, throughout life, females exhibit a marked survival advantage compared to males. The aetiology for such pertinent sex disparity remains unclear and is likely multifactorial. AIMS: The aim of this study was to investigate obstetric and perinatal outcomes by infant sex from 28 weeks in a contemporary, large Australian birth cohort. MATERIALS AND METHODS: A 14-year retrospective cohort study of 130 133 births over 28 weeks gestation from a single tertiary centre. RESULTS: Male infants had overall higher rates of neonatal mortality (0.12% vs 0.06%, P < 0.001) and severe neonatal morbidity (12% vs 9.1%, P < 0.001) (adjusted odds ratio (aOR) 1.41, 95% CI 1.35-1.47). The odds of overall perinatal mortality (stillbirth and neonatal death) were higher for male infants (aOR 1.30, 95% CI 1.08-1.56). The difference in severe neonatal morbidity when stratified by gestational age at birth only remained significant from >35 weeks gestation. Regardless of infant sex, rates of neonatal mortality and morbidity were lowest at 39 weeks gestation. Rates of preterm birth and operative birth were also higher for male infants. CONCLUSIONS: Our study demonstrates significant disparities in clinical outcomes by infant sex with males at a disadvantage to female infants.

Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction.

Fetal growth restriction (FGR) leading to low birth weight (LBW) is a major cause of neonatal morbidity and mortality worldwide. Normal placental development involves a series of highly regulated processes involving a multitude of hormones, transcription factors, and cell lineages. Failure to achieve this leads to placental dysfunction and related placental diseases such as pre-clampsia and FGR. Early recognition of at-risk pregnancies is important because careful maternal and fetal surveillance can potentially prevent adverse maternal and perinatal outcomes by judicious pregnancy surveillance and careful timing of birth. Given the association between a variety of circulating maternal biomarkers, adverse pregnancy, and perinatal outcomes, screening tests based on these biomarkers, incorporating maternal characteristics, fetal biophysical or circulatory variables have been developed. However, their clinical utility has yet to be proven. Of the current biomarkers, placental growth factor and soluble fms-like tyrosine kinase 1 appear to have the most promise for placental dysfunction and predictive utility for FGR.

Predictive utility of the fetal cerebroplacental ratio for hypoxic ischaemic encephalopathy, severe neonatal morbidity and perinatal mortality in late-preterm and term infants.

AIMS: The aim of this study was to evaluate the association of a low cerebroplacental ratio (CPR) with hypoxic ischaemic encephalopathy (HIE), severe neonatal morbidity (SNM) and perinatal mortality (PNM). METHODS: This was a retrospective cohort study of late-preterm and term births at Mater Mothers' Hospital, Brisbane, between 2016 and 2020. Study outcomes were HIE, PNM and SNM (a composite of severe acidosis, Apgar score less than four at 5 min, severe respiratory distress or need for significant cardiopulmonary resuscitation at birth). Univariate and multivariable logistic regressions were used to determine if a low CPR was associated with HIE, SNM or PNM. RESULTS: A total of 51 870 births met the inclusion criteria. Of these, 216 (0.42%) were complicated by HIE, 10 224 (19.7%) had SNM and 251 (0.48%) had PNM. Rates of low CPR (<10th and <5th centile) were significantly higher in the SNM cohort (20.1 and 13.2%, respectively) and PNM cohort (21.1 and 15.1%, respectively) compared to the overall cohort. A low CPR was associated with significantly increased adjusted odds for SNM but not for HIE or PNM. The area under the receiver operating characteristic curve for CPR <10th centile was greatest for SNM (0.768) and lowest for HIE (0.595). Predictive margins of a low CPR for HIE, SNM and PNM were significant only for SNM at late-preterm gestations. CONCLUSIONS: A low CPR is associated with increased odds of SNM in infants born >34 weeks' gestation but not for HIE or PNM.

A Systematic Review Investigating Maternal Nutrition During Pregnancy After Bariatric Surgery.

The aim of this review was to report on maternal diet, micronutrient supplementation, and gestational weight gain (GWG) during pregnancy following bariatric surgery and explore the impact on maternal micronutrient deficiency, offspring growth, and perinatal outcomes. A search in PubMed, CINAHL, EMBASE, and ProQuest in July 2022 returned 23 eligible studies (n = 30-20, 213). Diet was reported in two studies, supplementation in six and GWG in 19 studies. Although many women did not achieve healthy GWG, no consistent link with adverse outcomes was reported. Studies were grades II and III on the National Health and Medical Research Council evidence hierarchy and received a neutral or negative score on the Academy of Nutrition and Dietetics Quality Criteria Checklist, suggesting that methodological limitations impact the reliability of reported findings.

PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia.

Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, dosing should be initiated at 130 mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen.

Perinatal antecedents of moderate and severe neonatal hypoxic ischaemic encephalopathy: An Australian birth cohort study.

BACKGROUND: Neonatal hypoxic ischaemic encephalopathy (HIE) is the most common cause of encephalopathy in the neonatal period and carries a high risk of mortality and long-term morbidity. AIM: The aim of this study was to investigate key antecedents of moderate and severe HIE in a large contemporary birth cohort. METHODS: A retrospective cohort study of births meeting criteria was conducted between 2016 and 2020 at the Mater Mothers' Hospital, Brisbane, Australia. This is a quaternary perinatal centre and Australia's largest maternity hospital. Univariate and multivariate Firth logistic regression were used to account for imbalanced frequency classes between non-HIE and HIE groups. Maternal variables and intrapartum factors were investigated for associations with neonatal moderate and severe HIE. RESULTS: Overall, 133 of 46 041 (0.29%) infants were diagnosed with HIE: 77 (0.17%) with mild HIE and 56 (0.12%) with moderate/severe HIE. Nulliparity, type 1 diabetes mellitus and maternal intensive care unit admission were associated with increased odds of moderate/severe HIE. Intrapartum risk factors included emergency caesarean birth, emergency caesarean for non-reassuring fetal status or failure to process, intrapartum haemorrhage and an intrapartum sentinel event (shoulder dystocia, cord prolapse, uterine rupture and placental abruption). Neonatal risk factors included male sex, late preterm gestation (35+0 -36+6  weeks), Apgar score less than four at 5 min, severe respiratory distress requiring ventilatory support and severe acidosis at birth. CONCLUSIONS: This cohort study identified a series of potentially modifiable maternal and obstetric risk factors for HIE. Risk factors for HIE do not appear to have changed significantly with evolution in modern obstetric care.

Insufficient Evidence of a Breastmilk Microbiota at Six-Weeks Postpartum: A Pilot Study.

Breastmilk is thought to influence the infant gut by supplying prebiotics in the form of human milk oligosaccharides and potentially seeding the gut with breastmilk microbes. However, the presence of a breastmilk microbiota and origins of these microbes are still debated. As a pilot study, we assessed the microbes present in expressed breastmilk at six-weeks postpartum using shotgun metagenomic sequencing in a heterogenous cohort of women who delivered by vaginal (n = 8) and caesarean delivery (n = 8). In addition, we estimated the microbial load of breastmilk at six-weeks post-partum with quantitative PCR targeting the 16S rRNA gene. Breastmilk at six-weeks postpartum had a low microbial mass, comparable with PCR no-template and extraction controls. Microbes identified through metagenomic sequencing were largely consistent with skin and oral microbes, with four samples returning no identifiable bacterial sequences. Our results do not provide convincing evidence for the existence of a breastmilk microbiota at six-weeks postpartum. It is more likely that microbes present in breastmilk are sourced by ejection from the infant's mouth and from surrounding skin, as well as contamination during sampling and processing.