Women and Infants Research Foundation

Antenatal steroids (ANS) are one of the most widely prescribed medications in pregnancy, being administered to women at risk of preterm delivery. In the setting of preterm delivery at or below 35 weeks' gestation, systematic review data show ANS reduce perinatal morbidity and mortality, primarily by promoting fetal lung maturation. However, with the expanding use of this intervention has come a growing appreciation for the potential off-target, adverse effects of ANS therapy on wider fetal development. We undertook a narrative literature review of the animal and clinical literature to assess current evidence for adverse effects of ANS exposure and fetal development. This review presents a summary of the evidence relating to the potential for wide-ranging, off-target, adverse effects of ANS therapy on fetal development and programming. We highlight an urgent need for further animal and clinical studies investigating the effects of ANS on the fetal immune, cardiovascular, renal and hepatic systems given a current sparsity of evidence. We also strongly suggest an emphasis on open disclosure, discussion and education of clinicians and patients with regard to the potential benefits and risks of ANS therapy, particularly in late preterm and term gestations where infants derive relatively few benefits from these drugs. We also propose further studies on the optimisation of ANS therapy through improved patient selection and improved dosing regimens based on a pharmacokinetic-pharmacodynamic informed understanding of ANS action on the fetal lung.

BackgroundAntenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks’ gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function.MethodsDate-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals (n = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals (n = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals (n = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals (n = 8). Lambs were surgically delivered 48hr after first maternal injection at 122–125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection.ResultsPreterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR < 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration (“Prion Disease”, “Alzheimer’s Disease”, “Arachidonic Acid metabolism”). Adverse changes were independent of respiratory function during ventilation.ConclusionsOur data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens.

IntroductionAround 20–30% of pregnant women experience pregnancy complications and loss (PCL), such as hypertensive disorders in pregnancy, gestational diabetes, miscarriage or stillbirth. A history of PCL can provide an early warning of subsequent increased risk of cardiovascular disease (CVD). Communicating CVD risk with women in the years after PCL depends on transparency around the limitations of current evidence, emphasising the universality of preventive health messages and translating research findings into information that is meaningful to a broad audience. People with lived experience have rarely been involved in the design of interventions to raise awareness of CVD prevention following PCL.MethodsA participatory, qualitative approach that engaged a Lived Experience Expert (n=7) group to codesign a series of virtual workshops with women with a history of PCL (anticipating n=48–80).ResultsThe presentation will describe the process and outcomes of the codesign process, including the design of the resultant workshops to elicit women’s views, preferences and experiences of preventive healthcare in the months and years after PCL. Key ingredients of success as well as challenges will be discussed.DiscussionResearchers and people with lived experience have competing needs and preferences for risk communication. By prioritising women’s preferences, risk communication can avoid unintentionally adding to a stigmatising and victim blaming view of PCL.1 Authentically involving people with lived experience can inform possible future research, intervention design and dissemination strategies. Such involvement is valued by people with lived experience and may lead to the new research priorities, more appropriate patient education resources or preventive health pathways.Conclusion(s)Close collaboration with patient advocates can produce meaningful risk information that is both faithful to research findings and appropriate to people with lived experience of PCL.ReferenceQuigley P. Infertility, recurrent pregnancy loss, and risk of stroke: engage people with lived experience for more sensitive communication. BMJ 2022;379:o2821. DOI: 10.1136/bmj.o2821.

Background and ObjectiveEnvironmental exposure to phthalates and bisphenol A (BPA), chemicals used in the production of plastics, may increase risk for asthma and allergies. However, little is known about the long‐term effects of early life exposure to these compounds. We investigated if prenatal exposure to these compounds was associated with asthma, allergy and lung function outcomes from early childhood into adulthood in a cohort study.MethodsMaternal serum samples collected from 846 pregnant women in the Raine Study were assayed for BPA and phthalate metabolites. The children of these women were followed up at 5, 13 and 22 years where spirometry and respiratory questionnaires were conducted to determine asthma and allergy status. Lung function trajectories were derived from longitudinal spirometry measurements. Multinomial logistic regression and weighted quantile sum regression was used to test associations of individual and chemical mixtures with asthma phenotypes and lung function trajectories.ResultsEffects of prenatal BPA and phthalates on asthma phenotypes were seen in male offspring, where BPA was associated with increased risk for persistent asthma, while mono‐iso‐butyl phthalate and mono‐iso‐decyl phthalate was associated with increased risk for adult asthma. Prenatal BPA had no effect on lung function trajectories, but prenatal phthalate exposure was associated with improved lung function.ConclusionPrenatal BPA exposure was associated with increased likelihood of persistent asthma in males, while prenatal phthalate exposure was associated with increased likelihood of adult asthma in males. Results suggest that prenatal exposure to prenatal BPA and phthalates affect asthma risk, particularly in males, however lung function was not adversely affected.

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. 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. 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. Term birth was most likely when CL did not decrease across both time periods. The addition of 16-19week 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%. 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.

Polymicrobial sepsis is associated with worse patient outcomes than monomicrobial sepsis. Routinely used culture-dependent microbiological diagnostic techniques have low sensitivity, often leading to missed identification of all causative organisms. To overcome these limitations, culture-independent methods incorporating advanced molecular technologies have recently been explored. However, contamination, assay inhibition and interference from host DNA are issues that must be addressed before these methods can be relied on for routine clinical use. While the host component of the complex sepsis host–pathogen interplay is well described, less is known about the pathogen’s role, including pathogen–pathogen interactions in polymicrobial sepsis. This review highlights the clinical significance of polymicrobial sepsis and addresses how promising alternative molecular microbiology methods can be improved to detect polymicrobial infections. It also discusses how the application of shotgun metagenomics can be used to uncover pathogen/pathogen interactions in polymicrobial sepsis cases and their potential role in the clinical course of this condition.

To test for the association between increasing patient body mass index (BMI) and the cost of total laparoscopic hysterectomy (TLH). Secondary outcomes include the relationship between increasing BMI and both peri- and post-operative morbidity. Retrospective cohort study of patients (N= 510) who underwent TLH between January 2017 and December 2018 at a single public tertiary teaching hospital. Morbid obesity (n= 63) was associated with significantly higher total admission costs ($19 654 vs $17 475 Australian dollars, P= 0.002), operative costs ($9447 vs $8630, P= 0.017) and total costs including readmissions ($20 476 vs $18 399, P= 0.016) when compared to patients with normal BMI (n= 103) and adjusting for age, indication for surgery, additional procedures and conversion to total abdominal hysterectomy. Costs for overweight (n= 134) and obese (n= 210) BMI groups did not differ from costs for the normal BMI group. Increased operative costs observed in the morbidly obese group, were largely driven by the time associated with set-up, transfer and anaesthetic time while surgical and recovery times were not statistically significant. The total cost of TLH is increased in the morbidly obese category of patients. The operative costs appear to be related to pre-operative measures such as theatre set-up and anaesthetic requirements. TLH in the obese and morbidly obese category group is not associated with increased intra-operative or post-operative complications. There may be a role for exploring improvements in managing morbidly obese patients in the pre-operative setting.

Artificial placenta therapy (APT) is an experimental care strategy for extremely preterm infants born at 21-24weeks' gestation. In our previous studies, blood taken from the maternal ewe was used as the basis of priming solutions for the artificial placenta circuit. However, the use of maternal blood as a priming solution is accompanied by several challenges. We explored the use of synthetic red cells (hemoglobin vesicles; HbV) as the basis of a priming solution for APT used to manage extremely early preterm ovine fetuses. Six ewes with singleton pregnancies at 95 d gestation (term = 150 d) were adapted to APT and maintained with constant monitoring of key vital parameters. The target maintenance period was 72 h in duration. A synthetic red cell solution consisting of HbV, sheep albumin and electrolytes was used as priming solutions for the APT circuit. Fetuses were evaluated on gross appearance, physiological parameters and bleeding after euthanasia. Two out of six APT fetuses were successfully maintained for the targeted 72h experimental period with controllable anemia (>10g/dl) and methemoglobinemia (<10%) using an infusion of blood transfusion and nitroglycerin delivered >1 h after APT commencement, a sufficient period of time to cross-match blood products and screen for viral agents of concern. Extremely preterm sheep fetuses were maintained for a period of up to 72 h using APT in combination with circuit priming using a synthetic red cell (HbV) preparation. Although significant further refinements are required, these findings demonstrated the potential clinical utility of synthetic blood products in the eventual clinical translation of artificial placenta technology to support extremely preterm infants.

The primary purpose of this study was to investigate the predictive ability of the Örebro Musculoskeletal Pain Screening Questionnaire (ÖMPSQ) in regard to work productivity (absenteeism and presenteeism) in early adulthood. A prospective study was performed using data from the Raine Study Generation 2 (Gen2) 22-year follow-up. The ÖMPSQ was completed at baseline, and absenteeism and presenteeism assessed at four intervals over the following 12 months. In early adulthood, the full and short versions of the ÖMPSQ showed some predictive ability for work absenteeism but the Receiver Operator Characteristic demonstrated poor discrimination. There was no evidence of predictive ability for presenteeism. Further work is required to increase the fidelity of screening for risk of reduced work productivity at the population level.