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Chorioamnionitis remains a major cause of preterm birth and maternal and neonatal morbidity. We reviewed the current evidence for the diagnostic tests of chorioamnionitis and how this relates to clinical practice today. A comprehensive literature search and review was conducted on chorioamnionitis and intra-uterine inflammation. Data from randomized control trials and systematic reviews were prioritized. This review highlights that sterile inflammation plays an important role in chorioamnionitis and that the current tests for chorioamnionitis including clinical criteria, maternal plasma and vaginal biomarkers lack diagnostic accuracy. Concerningly, these tests often rely on detecting an inflammatory response after damage has occurred to the fetus. Care should be taken when interpreting current investigations for the diagnosis of chorioamnionitis and how they guide obstetric/neonatal management. There is an urgent need for further validation of current diagnostic tests and the development of novel, accurate, minimally invasive tests that detect subclinical intra-uterine inflammation.

Background Antenatal 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. Methods Date-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. Results Preterm 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. Conclusions Our 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.

Background Antenatal steroid (ANS) therapy is given to women at risk of preterm delivery to accelerate fetal lung maturation. However, the benefit of ANS therapy is variable and how maternal and fetal factors contribute to this observed variability is unknown. We aimed to test the degree of concordance in preterm lung function, and correlate this with genomic, transcriptomic, and pharmacokinetic variables in preterm dizygotic twin ovine fetuses. Methods Thirty-one date-mated ewes carrying twin fetuses at 123 ± 1 days’ gestation received maternal intramuscular injections of either (i) 1 × 0.25 mg/kg betamethasone phosphate and acetate (CS1, n  = 11 twin pairs) or (ii) 2 × 0.25 mg/kg betamethasone phosphate and acetate, 24 h apart (CS2, n  = 10 twin pairs) or (iii) 2 × saline, 24 h apart (negative control, n  = 10 twin pairs). Fetuses were surgically delivered 24 h after their final treatment and ventilated for 30 min. Results ANS-exposed female fetuses had lower arterial partial pressure of carbon dioxide (PaCO 2 ) values than male fetuses (76.5 ± 38.0 vs. 97.2 ± 42.5 mmHg), although the observed difference was not statistically significant ( p  = 0.1). Only 52% of ANS-treated twins were concordant for lung maturation responses. There was no difference in fetal lung tissue or plasma steroid concentrations within or between twin pairs. Genomic analysis identified 13 single-nucleotide polymorphisms (SNPs) statistically associated with ANS-responsiveness, including in the proto-oncogene MET and the transcription activator STAT1. Conclusions Twin fetal responses and ANS tissue levels were comparable with those from singleton fetuses in earlier studies. Twin ovine fetuses thus benefit from ANS in a similar manner to singleton fetuses, and a larger dose of betamethasone is not required. Assuming no difference in input from the placental or maternal compartments, fetal lung responses to ANS therapy in dizygotic twin preterm lambs are dependent on the fetus itself. These data suggest a potential heritable role in determining ANS responsiveness.

Background Antenatal steroids (ANS) are routinely administered to women at risk of preterm birth to accelerate fetal lung maturation. Despite extensive clinical use, dosing and route of ANS administration remain unoptimized beyond intramuscular (IM) injection. We aimed to undertake a proof-of-principle assessment of transdermal ANS administration for accelerated fetal lung maturation. Methods We formulated and tested a transdermal ANS (betamethasone) patch in ex vivo studies. To confirm in vivo transdermal distribution of the ANS patch, we undertook a 24-h pharmacokinetic study in non-pregnant cynomolgus macaques (NHP). To assess the efficacy of transdermal betamethasone on fetal lung maturation, we used a preterm sheep model of pregnancy comparing postnatal ventilation outcomes. Date mated ewes received either of the following: (i) IM normal saline (Saline Control, n  = 13); (ii) IM ANS (betamethasone) delivery 2 or 8 days post-treatment (2-Day IM ANS, n  = 14; 8-day IM ANS Group, n  = 6); (iii) IM saline + 2 × transdermal ANS (Betamethasone) patches delivery 2 days post-treatment (2-Day ANS Patch, n  = 10); or (iv) IM saline + 2 × transdermal ANS (betamethasone) patches replaced with 2 × new patches after 48 h, delivery 8 days post-treatment (8-Day ANS Patch, n  = 11). Lambs were delivered at 123 ± 1 dGA (term 150 days), then ventilated for 30 min to assess lung maturation status. Arterial blood gas, delivery, and ventilation data were analyzed ( p  < 0.05 significant). Results Transdermal administration of ANS in NHPs achieved rapid plasma accumulation, with a plasma half-life of 8.9 h, similar to that achieved with IM dosing in clinical practice. In preterm sheep, all 2- and 8-day IM and transdermal ANS patch groups had clinically important and statistically significant improvements in ventilation parameters (umbilical PaCO 2 , pH, tidal volume) compared to saline control. Conclusions We demonstrate, for the first time, the potential for using transdermal ANS for preterm fetal lung maturation. Transdermal ANS administration eliminates the need for injections, pain, and infection risk. Moreover, transdermal ANS delivery demonstrates advantages in dose control, continuity of exposure, and potential to remove drug exposure should the risk of preterm birth resolve. Further development of this technology may improve preterm outcomes through delivery of a low dose, constant fetal steroid exposure.

Background A lack of tests to assess fetal development impacts decision making around antenatal steroid use in women at risk of preterm birth. We analyzed the expression of 21 cfRNA targets related to human fetal lung maturation. Discovery studies were performed using maternal and fetal sheep plasma, with results compared to fetal lung mRNA expression. These findings were then validated in first, second, and third trimester human maternal plasma samples. Methods Discovery studies utilized a preterm sheep model of pregnancy. Date mated ewes received saline (control n  = 6), or antenatal steroids (dexamethasone n  = 12) (betamethasone n  = 11) prior to delivery and ventilation. We analyzed the expression of 21 human cfRNA targets related to lung maturation in maternal and fetal sheep plasma and compared this to mRNA expression in fetal lung tissue. Findings were first validated in a separate cohort of sheep exposed to betamethasone ( n  = 8), intraamniotic LPS endotoxin for lung maturation ( n  = 6), or untreated term animals ( n  = 6). Findings were further validated in maternal plasma from a human cohort of uncomplicated term pregnancies ( n  = 10). Delivery and ventilation data were analyzed with ANOVA, Tukey HSD, and Dunnett T3 tests. A Random Forest algorithm identified genes that separated mature from immature fetal lung subgroups and determined AUC values for maternal and fetal cell-free RNA (cfRNA) feature sets to predict fetal lung maturation. Results We demonstrate that the analysis of 21 human cfRNA targets in maternal plasma is highly predictive of fetal lung maturation status across antenatal steroid induced (Dexamethasone AUC = 0.93; Betamethasone AUC = 1) and physiological (AUC = 1) lung development models. Maternal plasma cfRNA expression in the dexamethasone antenatal steroid group closely resembled direct fetal lung tissue mRNA expression. These findings were then validated in human maternal plasma samples (1st vs. 3rd trimester AUC = 0.96; 2nd vs. 3rd trimester AUC = 1). Conclusions Further development of this technology may provide a rapid, minimally invasive, and cost-effective clinical tool to optimize patient selection for initial and repeat courses of antenatal steroids, along with insights into the molecular mechanisms underlying fetal lung development. Graphical Abstract Graphical abstract illustrating the potential future application of maternal plasma cell-free RNA analysis. Created in https://BioRender.com .

Contemporary plans to establish human habitation on the Earth’s Moon have increased interest in the ability of humans to establish extraterrestrial pregnancies. There is a lack of data to identify if humans could safely reproduce away from the Earth, and even less guidance with regard to whether we should attempt to do so. This work was developed to stimulate investigation into the likely biological and ethical challenges facing the establishment and maintenance of a healthy human extraterrestrial pregnancy.

The management and prevention of key inflammatory-associated pregnancy complications such as chorioamnionitis and pre-eclampsia is hampered by a lack of early gestation risk screening tools. In a proof-of-principle study we used targeted cell-free RNA analyses of maternal plasma samples from large animal (sheep) and human pregnancy cohorts to develop a minimally invasive screening test for inflammatory markers. This study utilised a preterm sheep model of sterile and bacterial chorioamnionitis. Date-mated ewes received either intraamniotic Saline Control ( n  = 10) or E.Coli LPS (Sterile chorioamnionitis) with 2 days ( n  = 9) or 8 days exposure( n  = 6). Preterm lambs were delivered at 124 ± 1d gestation. Findings were validated in a bacterial model of chorioamnionitis where ewes were exposed to 7 days of intraamniotic M.Hominis with delivery at 98 d gestion( n  = 8) or 128d gestation( n  = 8). Maternal blood was collected prior to intervention and at delivery in each group. Random Forest algorithm was used to analyse 8 cell-free RNA(cfRNA) targets related to inflammation in maternal plasma at baseline and delivery, identifying genes that separated animals with or without intrauterine inflammation. Plasma cfRNA data was compared to mRNA expression in placental tissue. Haematological and placental mRNA comparisons were analysed with ANOVA/Tukey HSD/Dunnett T3 tests. Maternal plasma cfRNA findings of intrauterine inflammation were then validated in human plasma samples from a cohort of patients with late onset pre-eclampsia ( n  = 10) or uncomplicated pregnancies ( n  = 10). We present data showing that targeted maternal cfRNA assays can accurately identify chorioamnionitis of sterile (AUC 1.0) and infectious (AUC 0.84) origin in a sheep model of pregnancy. Findings were then validated in human maternal plasma samples from patients with late-onset pre-eclampsia in the 1st (AUC = 0.85), 2nd (AUC = 0.90) and 3rd (AUC = 0.82) trimesters. In both sheep and human model systems, cfRNA tests offered high levels of sensitivity and specificity in the absence of overt clinical symptoms. We suggest that further development of this technology may serve as a scalable, rapidly deployed and cost-effective means for predicting major inflammatory conditions in pregnancy.

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.

Human Wharton’s jelly stem cells (hWJSCs) are multipotent stem cells that are extensively employed in biotechnology applications. However, the impact of simulated lunar microgravity (sμG) on the growth, differentiation, and viability of this cell population is incompletely characterized. We aimed to determine whether acute (72 h) exposure to sμG elicited changes in growth and lineage differentiation in hWJSCs and if putative changes were maintained once exposure to terrestrial gravity (1.0 G) was restored. hWJSCs were cultured under standard 1.0 G conditions prior to being passaged and cultured under sμG (0.16 G) using a random positioning machine. Relative to control, hWJSCs cultured under sμG exhibited marked reductions in growth but not viability. Cell population expression of characteristic stemness markers (CD 73, 90, 105) was significantly reduced under sμG conditions. hWJSCs had 308 significantly upregulated and 328 significantly downregulated genes when compared to 1.0 G culture conditions. Key markers of cell replication, including MKI67 , were inhibited. Significant upregulation of osteocyte–chondrocyte lineage markers, including SERPINI1, MSX2, TFPI2, BMP6, COMP, TMEM119, LUM, HGF, CHI3L1 and SPP1 , and downregulation of cell fate regulators, including DNMT1 and EZH2 , were detected in sμG-exposed hWJSCs. When returned to 1.0 G for 3 days, sμG-exposed hWJSCs had accelerated growth, and expression of stemness markers increased, approaching normal (i.e. 95%) levels. Our data support earlier findings that acute sμG significantly reduces the cell division potential of hWJSCs and suggest that acute sμG-exposure induces reversible changes in cell growth accompanied by osteocyte–chondrocyte changes in lineage differentiation.