Ascertainment of Aboriginal and Torres Strait Islander status for assessment of perinatal health outcomes: Reported versus derived maternal ethnicity in Western Australian pregnancy data.

BACKGROUND: Under-identification of Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) people can result in inaccurate estimation of health outcomes. Data linkage has improved identification of Aboriginal people in administrative datasets. AIM: To compare three methods of ascertainment of Aboriginal status using only pregnancy data from the Western Australian Midwives Notification System (MNS), to the linked Indigenous Status Flag (ISF) derived by the Department of Health. MATERIALS AND METHODS: This retrospective population-based cohort study utilised logistic regression to determine which demographic characteristics were associated with under-identification, and the effect of ascertainment method on perinatal adverse outcomes. RESULTS: All methods identified a core group of 19 017 (83.0%) Aboriginal women and the ISF identified 2298 (10.0%) women who were not identified using any other method. Under-ascertainment was lowest when a woman's Aboriginal status was determined by ever being recorded as Aboriginal in the MNS data, and highest when taken as it had been recorded for the birth in question. Maternal age <20 years, smoking during pregnancy, pre-existing diabetes, a history of singleton preterm birth and being in the lowest 20% of Socio-Economic Indexes for Areas score were all associated with a higher chance of being identified by the methods using only the MNS. These methods were less likely to identify nulliparous women, and those with maternal age ≥35 years. The method of ascertainment of Aboriginality did not make a significant difference to the adjusted predicted marginal probabilities of adverse perinatal outcomes. CONCLUSION: Unlinked pregnancy data can be used for epidemiological research in Aboriginal obstetric populations.

The Relationship Between Early Term Birth and the Risk of Later Childhood Mental Disorders Within a Pregnancy Cohort.

This study examines whether gestational age, birth weight, and early term birth is associated with childhood mental disorders in 342 pregnant women recruited at less than 20 weeks gestation and were then followed up until 4 years postpartum, including 93 children born at early term. Women were assessed at recruitment using the Structured Clinical Interview for DSM. At 4 years of age their children were assessed using the Preschool Age Psychiatric Assessment (PAPA) and the Child Behavior Checklist (CBCL). This study found earlier birth predicted an increased risk for anxiety disorders and demonstrated a significant interaction between gestational age and lower birthweight. The risk for ADHD increased with lower gestational age independent of birthweight. In contrast, gestational age was not associated with Oppositional Defiant Disorder, Conduct Disorder, internalizing or externalizing symptoms. These findings highlight the important differences in the association of early term birth and vulnerability for specific mental disorders.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1) 2 ng/mL (2 ng/mL positive control group, n = 9); 2) 1 ng/mL, (1 ng/mL group, n = 10); 3) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL.NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

Characterisation of Mid-Gestation Amniotic Fluid Cytokine and Bacterial DNA Profiles in Relation to Pregnancy Outcome in a Small Australian Cohort.

A well-established association exists between intrauterine bacteria and preterm birth. This study aimed to explore this further through documenting bacterial and cytokine profiles in Australian mid-gestation amniotic fluid samples from preterm and term births. Samples were collected during amniocenteses. DNA was extracted and the full-length 16S rRNA gene was amplified and sequenced. Levels of the cytokines IL-1ß, IL-6, IL-10, TNF-α and MCP-1 were determined using the Milliplex MAGPIX system. Bacterial DNA profiles were low in diversity and richness, with no significant differences observed between term and preterm samples. No differences in the relative abundance of individual OTUs between samples were identified. IL-1ß and TNF-α levels were significantly higher in samples containing reads mapping to Sphingomonas sp.; however, this result should be interpreted with caution as similar reads were also identified in extraction controls. IL-6 levels were significantly increased in samples with reads that mapped to Pelomonas sp., whilst TNF-α levels were elevated in fluid samples from pregnancies that subsequently delivered preterm. Bacterial DNA unlikely to have originated from extraction controls was identified in 20/31 (64.5%) mid-gestation amniotic fluid samples. Bacterial DNA profiles, however, were not predictive of preterm birth, and although cytokine levels were elevated in the presence of certain genera, the biological relevance of this remains unknown.

Effects of multiple pro-inflammatory stimuli in utero on the ileum of extremely premature ovine fetuses.

Introduction: Chorioamnionitis is common in preterm birth and associated with a higher risk of intestinal inflammation and necrotizing enterocolitis. The intestinal inflammation influences the enteric nervous system development. We hypothesized that inflammation and innervation in the fetal ileum may be modified by chorioamnionitis induced by repeated challenge with lipopolysaccharide and/or preexisting Ureaplasma parvum infection at very low gestational age equivalent to 60% of term. Materials and methods: Time mated ovine fetuses were exposed by intraamniotic injections to chronic Ureaplasma parvum for 24 days and/or lipopolysaccharide for 7 days, 2 days, or 7 & 2 days before delivery at 94 +/-2 days of gestational age (term at approximately 150 days). Intestinal inflammation as well as structural changes of the enteric nervous system were assessed. Results: Lipopolysaccharide exposure increased CD3 and myeloperoxidase-positive cells (p < 0.05). Repetitive exposure to lipopolysaccharide or combined Ureaplasma parvum & lipopolysaccharide exposure increased intestinal inflammation (p < 0.05). The reduction of nuclei of neurons was most significant with repetitive lipopolysaccharide exposures but could be detected in all other intervention groups compared to the control group. Astrocyte-like glial cells increased if exposure to lipopolysaccharide was only 2 days before delivery or chronic exposure to Ureaplasma parvum existed beforehand (p < 0.05). Discussion: After exposure to chorioamnionitis induced by Ureaplasma parvum and/or lipopolysaccharide, inflammatory responses as well as structural changes of the enteric nervous system were more pronounced the longer and the more frequent the exposure to pro-inflammatory stimuli before birth. These changes may cause functional effects of clinical importance.

A Reduction in Antenatal Steroid Dose Was Associated with Reduced Cardiac Dysfunction in a Sheep Model of Pregnancy.

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart. We tested this hypothesis using low-dose steroid therapy (10 mg delivered to the ewe over 36 h via constant infusion) and compared cardiac effects with those of a higher dose treatment (30 mg delivered to the ewe over 24 h by intramuscular injection; simulating currently employed clinical ACS regimens). Fetal cardiac function was assessed by ultrasound on the day of ACS treatment initiation. Transcriptomic analyses were performed on fetal myocardial tissue. Relative to saline control, fetuses in the higher-dose clinical treatment group had significantly lower ratios between early diastolic ventricular filling and ventricular filling during atrial systole, and showed the differential expression of myocardial hypertrophy-associated transcripts including ßMHC, GADD45γ, and PPARγ. The long-term implications of these changes remain unstudied. Irrespective, optimizing ACS dosing regimens to maximize respiratory benefit while minimizing adverse effects on key organ systems, such as the heart, offers a means of improving the acute and long-term outcomes associated with this important obstetric therapy.

Fetal Growth Trajectories and Measures of Insulin Resistance in Young Adults.

CONTEXT: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life. OBJECTIVE: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. METHODS: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy. RESULTS: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group. CONCLUSION: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders.

The Western Australian preterm birth prevention initiative: a whole of state singleton pregnancy cohort study showing the need to embrace alternative models of care for Aboriginal women.

BACKGROUND: Preterm birth (PTB) is the greatest cause of mortality and morbidity in children up to five years of age globally. The Western Australian (WA) PTB Prevention Initiative, the world's first whole-of-population whole-of-state program aimed at PTB prevention, was implemented across WA in 2014. METHODS: We conducted a prospective population-based cohort study using pregnancy data for singleton births in WA from 2009 to 2019. Logistic regression using the last full year before the Initiative (2013) as the reference, and run charts were used to examine changes in PTB rates compared to pre-Initiative levels, by gestational age group, hospital type, low and high risk of PTB in mid-pregnancy, and onset of labour (spontaneous/medically initiated). Analyses were stratified by Aboriginal and non-Aboriginal maternal ethnicity. RESULTS: Amongst non-Aboriginal women, there was initially a reduction in the PTB rate across the state, and in recent years it returned to pre-Initiative levels. Amongst Aboriginal women there was a small, non- significant reduction in the state-wide PTB rate in the first three years of the Initiative, followed by a rise in recent years. For non-Aboriginal women, the reduction in the rate of PTB at the tertiary centre was sustained and improved further for women of all risk levels and onsets of labour. This reduction was not observed for Aboriginal women giving birth at the tertiary centre, amongst whom there was an increase in the PTB rate overall and in all subgroups, with the exception of medically initiated PTB. Amongst Aboriginal women the PTB rate has also increased across the state. At non-tertiary hospitals there was a large increase in PTB amongst both Aboriginal and non-Aboriginal women, largely driven by medically initiated late PTB. Maternal risk factors cannot account for this increase. CONCLUSIONS: The reduction in PTB rates amongst non-Aboriginal women at the state's tertiary hospital demonstrates that with the right strategies, PTB can be reduced. A sustained collaborative model is required to realise this success in non-tertiary hospitals. The series of interventions was of limited use in Aboriginal women, and future efforts will need to be directed at strategies more likely to be successful, such as midwifery continuity of care models, with Aboriginal representation in the healthcare workforce.

Associations between Prenatal Exposure to Phthalates and Features of the Metabolic Syndrome in Males from Childhood into Adulthood.

Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored samples taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model.

Treatment with antenatal steroids (ANS) is standard practice for reducing the risk of respiratory distress in the preterm infant. Despite clear overall benefits when appropriately administered, many fetuses fail to derive benefit from ANS therapies. In standardized experiments using a pregnant sheep model, we have demonstrated that around 40% of ANS-exposed lambs did not have functional lung maturation significantly different from that of saline-treated controls. Surfactant protein A is known to play an important role in lung function. In this genotyping study, we investigated the potential correlation between polymorphisms in SFTPA1, messenger RNA and protein levels, and ventilation outcomes in animals treated with ANS. 45 preterm lambs were delivered 48 h after initial ANS therapy and 44 lambs were delivered 8 days after initial ANS therapy. The lambs were ventilated for 30 min after delivery. SFTPA1 mRNA expression in lung tissue was not correlated with arterial blood PaCO2 values at 30 min of ventilation in lambs delivered 48 h after treatment. SFTPA1 protein in lung tissue was significantly correlated with PaCO2 at 30 min of ventilation in lambs ventilated both 48 h and 8 days after ANS treatment. Six different single nucleotide polymorphisms (SNPs) in the Ovis aries SFTPA1 sequence were detected by Sanger Sequencing. No individual SNPs or SNP haplotypes correlated with alterations in PaCO2 at 30 min of ventilation or SFTPA1 protein levels in the lung. For the subset of animals analyzed in the present study, variable lung maturation responses to ANS therapy were not associated with mutations in SFTPA1.

Relationships between intrauterine fetal growth trajectories and markers of adiposity and inflammation in young adults.

BACKGROUND: There is now good evidence that events during gestation significantly influence the developmental well-being of an individual in later life. This study aimed to investigate the relationships between intrauterine growth trajectories determined by serial ultrasound and subsequent markers of adiposity and inflammation in the 27-year-old adult offspring from the Raine Study, an Australian longitudinal pregnancy cohort. METHODS: Ultrasound fetal biometric measurements including abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs (Gen1-Gen2) in the Raine Study were used to develop fetal growth trajectories using group-based trajectory modeling. Linear mixed modeling investigated the relationship between adult body mass index (BMI), waist circumference (WC), and high-sensitivity C-reactive protein (hs-CRP) of Gen2 at 20 (n = 485), 22 (n = 421) and 27 (n = 437) years and the fetal growth trajectory groups, adjusting for age, sex, adult lifestyle factors, and maternal factors during pregnancy. RESULTS: Seven AC, five FL and five HC growth trajectory groups were identified. Compared to the average-stable (reference) group, a lower adult BMI was observed in two falling AC trajectories: (ß = -1.45 kg/m2, 95% CI: -2.43 to -0.46, P = 0.004) and (ß = -1.01 kg/m2, 95% CI: -1.96 to -0.05, P = 0.038). Conversely, higher adult BMI (2.58 kg/m2, 95% CI: 0.98 to 4.18, P = 0.002) and hs-CRP (37%, 95% CI: 9-73%, P = 0.008) were observed in a rising FL trajectory compared to the reference group. A high-stable HC trajectory associated with 20% lower adult hs-CRP (95% CI: 5-33%, P = 0.011). CONCLUSION: This study highlights the importance of understanding causes of the unique patterns of intrauterine growth. Different fetal growth trajectories from early pregnancy associate with subsequent adult adiposity and inflammation, which predispose to the risk of diabetes and cardiometabolic disease.

The complex challenge of antenatal steroid therapy nonresponsiveness.

Antenatal steroid therapy is standard care for women at imminent risk of preterm delivery. When deliveries occur within 7 days of treatment, antenatal steroid therapy reduces the risk of neonatal death and improves preterm outcomes by exerting diverse developmental effects on the fetal organs, in particular the preterm lung and cardiovascular system. There is, however, sizable variability in antenatal steroid treatment efficacy, and an important percentage of fetuses exposed to antenatal steroid therapy do not respond sufficiently to derive benefit. Respiratory distress syndrome, for example, is a central metric of clinical trials to assess antenatal steroid outcomes. In the present analysis, we addressed the concept of antenatal steroid nonresponsiveness, and defined a failed or suboptimal response to antenatal steroids as death or a diagnosis of respiratory distress syndrome following treatment. For deliveries at 24 to 35 weeks' gestation, the number needed to treat to prevent 1 case of respiratory distress syndrome was 19 (95% confidence interval, 14-28). Reflecting gestation-dependent risk, for deliveries at >34 weeks' gestation the number needed to treat was 55 (95% confidence interval, 30-304), whereas for elective surgical deliveries at term this number was 106 (95% confidence interval, 61-421). We reviewed data from clinical and animal studies investigating antenatal steroid therapy to highlight the significant incidence of antenatal steroid therapy nonresponsiveness (ie, residual mortality or respiratory distress syndrome after treatment), and the potential mechanisms underpinning this outcome variability. The origins of this variability may be related to both the manner in which the therapy is applied (ie, the treatment regimen itself) and factors specific to the individual (ie, genetic variation, stress, infection). The primary aims of this review were: (1) to emphasize to the obstetrical and neonatal communities the extent of antenatal steroid response variability and its potential impact; (2) to propose approaches by which antenatal steroid therapy may be better applied to improve overall benefit; and (3) to stimulate further research toward the empirical optimization of this important antenatal therapy.

Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the World Health Organization dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy.

BACKGROUND: The intramuscular administration of antenatal steroids to women at risk of preterm delivery achieves high maternal and fetal plasma steroid concentrations, which are associated with adverse effects and may reduce treatment efficacy. We have demonstrated that antenatal steroid efficacy is independent of peak maternofetal steroid levels once exposure is maintained above a low threshold. OBJECTIVE: This study aimed to test, using a sheep model of pregnancy, whether the low-dose antenatal steroid regimen proposed as part of the Antenatal Corticosteroids for Improving Outcomes in Preterm Newborns trial would achieve preterm lung maturation equivalent to that of the existing World Health Organization dexamethasone treatment regimen, but with reduced risk of adverse outcomes. STUDY DESIGN: Following ethical review and approval, date-mated ewes with single fetuses received intramuscular injections of either (1) four 6-mg maternal intramuscular injections of dexamethasone phosphate every 12 hours (n=22), (2) 4 2-mg maternal intramuscular injections of betamethasone phosphate every 12 hours (n=21), or (3) 4 2-mL maternal intramuscular injections of saline every 12 hours (n=16). Of note, 48 hours after first injection, (124±1 day), lambs were delivered, ventilated for 30 minutes, and euthanized for sampling. Arterial blood gas, respiratory, hematological, and biochemical data were analyzed for between-group differences with analysis of variance according to distribution and variance, with P<.05 taken as significant. RESULTS: After 30 minutes of ventilation, lambs from both steroid-treated groups had significant and equivalent improvements in lung function relative to saline control (P<.05). There was no significant difference in arterial blood pH, pO2, pCO2, lung compliance, ventilator efficiency index, or lung volume at necropsy with a static pressure of 40 cmH2O. The messenger RNA expression of surfactant protein (Sp)a, Spb, Spc, Spd, aquaporin (Aqp)1, Aqp5, and sodium channel epithelial 1 subunit beta (Scnn1b) was equivalent between both steroid groups. Maternal and fetal plasma neutrophil, glucose, and fetal plasma C-peptide levels were significantly elevated in the dexamethasone group, relative to the betamethasone group. Fetal plasma insulin-like growth factor 1 was significantly reduced in the dexamethasone group compared with the betamethasone group (P<0.05). Fetal adrenocorticotropic hormone (r=0.53), maternal glucose value (r=-0.52), and fetal glucose values (r=-0.42) were correlated with maternal weight in the betamethasone group (P<.05), whereas fetal pCO2 and pO2 were not correlated. There was no significant difference between male and female lamb outcomes in any groups for any of the items evaluated. CONCLUSION: This study reported that in preterm lambs, a low-dose treatment regimen of 8 mg betamethasone achieves lung maturation equivalent to that of a 24-mg dexamethasone-based regimen, but with smaller perturbations to the maternofetal hypothalamic-pituitary-adrenal axis. These data suggested that given steroid pharmacokinetic differences between sheep and humans, a betamethasone dose of 2 mg may remain above the minimum dose necessary for robust maturation of the preterm lung. Maternal weight-adjusted betamethasone doses might also be a key to reducing perturbations to the maternofetal hypothalamic-pituitary-adrenal axis.

The Relationship Between Fetal Growth and Retinal Nerve Fiber Layer Thickness in a Cohort of Young Adults.

Purpose: To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood. Methods: Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW). Results: Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW. Conclusions: FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth. Translational Relevance: This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning.

The clinical utility of ongoing sonographic cervix length surveillance in pregnancies prescribed vaginal progesterone therapy.

BACKGROUND: Vaginal progesterone therapy significantly reduces preterm birth (PTB) rates in those high-risk pregnancies with a sonographic short cervix (≤25 mm) and/or a history of spontaneous PTB. Cervical length (CL) is routinely measured at the midtrimester morphology scan; however, CL surveillance thereafter is not currently recommended. Progesterone's precise mechanism of action remains unknown, though if it indeed influences CL, shortening after treatment initiation could indicate therapeutic failure and risk of PTB. AIMS: The aim was to explore the utility of serial transvaginal ultrasound (TVU) measurement of CL at 16, 19 and 22 weeks for predicting PTB in high-risk pregnancies prescribed progesterone therapy. METHODS: A retrospective cohort study was conducted involving women who attended the King Edward Memorial Hospital PTB Prevention Clinic from 2015 to 2019 and were prescribed progesterone therapy. CL was measured at 16, 19 and 22 weeks by TVU. CL change across three time points was assessed using linear mixed models; then relationships between CL change between 16-19 and 19-22 weeks and PTB were analysed using logistic regression models. RESULTS: Term birth was most likely when CL did not decrease across both time periods. The addition of 16-19 week decrease in CL to a model, including CL at 19 weeks alone, for predicting PTB increased sensitivity from 43.2 to 56.3%, specificity from 73.2 to 77.4%, and overall accuracy from 61.7 to 70.2%. CONCLUSION: For high-risk women prescribed vaginal progesterone therapy, serial measurement of the cervix at 16 and 19 weeks improves clinical ability to predict PTB from current recommendations of 19-week measurement alone.

Perinatal care for the extremely preterm infant.

Being born preterm (prior to 37 weeks of completed gestation) is a leading cause of childhood death up to five years of age, and is responsible for the demise of around one million preterm infants each year. Rates of prematurity, which range from approximately 5 to 18% of births, are increasing in most countries. Babies born extremely preterm (less than 28 weeks' gestation) and in particular, in the periviable (200/7-256/7 weeks) period, are at the highest risk of death, or the development of long-term disabilities. The perinatal care of extremely preterm infants and their mothers raises a number of clinical, technical, and ethical challenges. Focusing on 'micropremmies', or those born in the periviable period, this paper provides an update regarding the aetiology and impacts of periviable preterm birth, advances in the antenatal, intrapartum, and acute post-natal management of these infants, and a review of counselling/support approaches for engaging with the infant's family. It concludes with an overview of emerging technology that may assist in improving outcomes for this at-risk population.

One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus.

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly (P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

Continuous but not pulsed low-dose fetal betamethasone exposures extend the durability of antenatal steroid therapy.

Antenatal steroid (ANS) therapy is the standard care for women at imminent risk of preterm labor. Despite extensive and long-standing use, 40%-50% of babies exposed antenatally to steroids do not derive benefit; remaining undelivered 7 days or more after ANS treatment is associated with a lack of treatment benefit and increased risk of harm. We used a pregnant sheep model to evaluate the impact of continuous versus pulsed ANS treatments on fetal lung maturation at an extended, 8-day treatment to delivery interval. Continuous low-dose ANS treatments for more than 72 h in duration improved fetal lung maturation at 8 days after treatment initiation. If fetal ANS exposure was interrupted, the beneficial ANS effect was lost. Truncated treatments, including that simulating the current clinical treatment regimen, did not improve lung function. Variable fetal lung maturation was correlated to the amount of saturated phosphatidylcholine present in the lung fluid. These data demonstrate that 1) the durability of ANS therapy may be enhanced by employing an extended, low-dose treatment regimen by reducing total dose and 2) interrupting the continuity of fetal exposure by allowing it to fall below a minimal threshold was associated with comparably poor functional maturation of the preterm ovine lung.

Prenatal tobacco and alcohol exposures and the risk of anxiety symptoms in young adulthood: A population-based cohort study.

BACKGROUND: Epidemiological studies have linked prenatal tobacco and alcohol exposures to internalizing behaviours in children and adolescents with inconsistent findings. Dearth of epidemiological studies have investigated the associations with the risk of experiencing symptoms of anxiety in young adulthood. METHODS: Study participants (N = 1190) were from the Raine Study, a population-based prospective birth cohort based in Perth, Western Australia. Data on prenatal tobacco and alcohol exposures were available for the first and third trimesters of pregnancy. Experiencing symptoms of anxiety in young adulthood at age 20 years was measured by a short form of the Depression Anxiety Stress Scale (DASS 21). Relative risk (RR) of experiencing symptoms of anxiety in young adulthood for prenatal tobacco and alcohol exposures were estimated with log binomial regression. RESULTS: After adjusting for potential confounders, we observed increased risks of experiencing symptoms of anxiety in young adults exposed to prenatal tobacco in the first trimester [RR = 1.52, 95% CI: 1.12-2.06, p-value < 0.01] and third trimester [RR = 1.53, 95% CI: 1.10-2.13, p-value  = 0.02]. However, we found insufficient statistical evidence for an association between first trimester [RR = 1.01, 95% CI: 0.76-1.22, p-value = 0.90] and third trimester [RR = 1.03, 95% CI: 0.80-1.34, p-value = 0.91] prenatal exposure to alcohol and the risk of experiencing symptoms of anxiety in young adults. There was a dose response association between prenatal tobacco exposure and increasing anxiety symptoms in offspring. CONCLUSION: The findings of this study suggest that an association between prenatal tobacco exposure and risk of anxiety symptoms remains apparent into young adulthood.

Prenatal alcohol and tobacco exposures and the risk of cannabis use in offspring: Findings from a population-based cohort study.

BACKGROUND: There is a paucity of prospective longitudinal studies examining the associations between maternal use of alcohol and tobacco during pregnancy and the risk of cannabis use in offspring. The aim of this study was to examine the association between prenatal alcohol and tobacco exposures and offspring cannabis use. METHODS: Data were from the Raine Study, a longitudinal prospective birth cohort based in Western Australia. Cannabis use at 17 years of age was measured with a self-reported questionnaire developed to capture risky behaviors in adolescents. Associations between prenatal alcohol and tobacco exposures and the risk of cannabis use in offspring were examined using log-binomial regression models, computing relative risk (RR). We also computed the E-values (E) to estimate the extent of unmeasured confounding. RESULTS: After adjusting for potential confounders, we observed increased risks of cannabis use in offspring exposed to first trimester prenatal alcohol use (RR = 1.38, 95% CI: 1.09-1.75; E = 2.10, CI:1.40) and tobacco use (RR = 1.42, 95% CI: 1.08-1.86; E = 2.19, CI:1.37) as well as third trimester prenatal alcohol use (RR = 1.39, 95% CI: 1.09-1.79; E = 2.13, CI:1.40) and tobacco use (RR = 1.39, 95% CI: 1.09-1.79; E = 2.21, CI:1.34]. We also noted dose-response associations in which risk estimates in offspring increased with the level of exposures to prenatal alcohol and tobacco use. CONCLUSION: These findings provide epidemiological evidence for effects of prenatal alcohol and tobacco exposures on offspring cannabis use. Although these results should be confirmed by other studies, the present study adds to the mounting evidence suggesting that women should be encouraged to abstain from alcohol and tobacco during pregnancy.