A Randomized Trial of Conditioned or Unconditioned Gases for Stabilizing Preterm Infants at Birth.

OBJECTIVE: To determine whether the use of heated-humidified gases for respiratory support during the stabilization of infants <30 weeks of gestational age (GA) in the delivery room reduces rates of hypothermia on admission to the neonatal intensive care unit (NICU). STUDY DESIGN: A multicenter, unblinded, randomized trial was conducted in Melbourne, Australia, between February 2013 and June 2015. Infants <30 weeks of GA were randomly assigned to receive either heated-humidified gases or unconditioned gases during stabilization in the delivery room and during transport to NICU. Infants born to mothers with pyrexia >38°C were excluded. Primary outcome was rate of hypothermia on NICU admission (rectal temperature <36.5°C). RESULTS: A total of 273 infants were enrolled. Fewer infants in the heated-humidified group were hypothermic on admission to NICU (36/132 [27%]) compared with controls (61/141 [43%], P < .01). There was no difference in rates of hyperthermia (>37.5°C); 20% (27/132) in the heated-humidified group compared with 16% (22/141) in the controls (P = .30). There were no differences in mortality or respiratory outcomes. CONCLUSIONS: The use of heated-humidified gases in the delivery room significantly reduces hypothermia on admission to NICU in preterm infants, without increased risk of hyperthermia. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (www.anzctr.org.au) ACTRN12613000093785.

Inflammation, lipids and aortic intima-media thickness in newborns following chorioamnionitis.

AIM: This study investigated whether chorioamnionitis was associated with increased inflammation, dyslipidaemia and adverse cardiovascular phenotypes in the immediate postnatal period. METHODS: This prospective case-control study included preterm infants (30(+0) -35(+6) weeks gestational age, GA) whose mothers did not have pregnancy-related conditions that may influence outcomes. Chorioamnionitis was diagnosed by placental histology, and infants were divided retrospectively into cases (chorioamnionitis-exposed) and controls (unexposed). Serum high-sensitivity C-reactive protein (hsCRP), lipid profile, far-wall abdominal aortic intima-media thickness (aIMT) and blood pressure (BP) were measured in the first week of life. RESULTS: There were 20 (16 male, mean GA 32.4 weeks) cases and 31 (12 male, mean GA 32.6 weeks) controls. Histological chorioamnionitis was associated with a significant increase in hsCRP and a non-significant trend towards an adverse lipid profile. There was no evidence of differences in aIMT or BP. CONCLUSION: Preterm infants exposed to chorioamnionitis have greater postnatal inflammation. There were no early postnatal differences in aIMT or BP. The inflammatory stimulus of chorioamnionitis late in gestation may be of insufficient intensity and duration to result in immediate postnatal alterations to arterial structure. Cardiovascular follow-up of infants exposed to chorioamnionitis may identify differential risk trajectories and subsequent inflammatory responses.

The accuracy of delivery of target pressures using self-inflating bag manometers in a benchtop study.

AIM: We tested whether operators using manometers attached to self-inflating bags could accurately deliver set targeted peak inspiratory pressures (PIPs) compared to the Neopuff(™) T-piece resuscitator (TPR). METHODS: Participants provided positive pressure ventilation to a leak-free neonatal test lung at a rate of 60 inflations/min and a flow of 8 L/min. Participants used three manometers attached to self-inflating bags and a Neopuff(™) TPR to target PIPs of 20, 30 and 40 cmH2 O on each device. Mean PIPs delivered with each manometer were compared to the 'gold standard' Neopuff(™) TPR. RESULTS: In total, 13 991 inflations delivered by 20 participants were analysed. At all target PIPs, the mean PIP delivered using the Mercury Medical manometer attached to a Laerdal self-inflating bag was significantly higher by 5 cmH2 O (p < 0.01) than the Neopuff(™) TPR. The PIP delivered using both the Ambu(™) and Parker Healthcare manometers attached to their respective devices was similar to that delivered by the Neopuff(™) TPR at all targeted PIPs. CONCLUSION: Accurately targeted PIPs can be achieved when a manometer specifically designed for use on a self-inflating bag is used during manual ventilation. This may be useful in settings where access to a Neopuff(™) TPR or a gas flow source is limited.

Neonatal resuscitation in resource-limited settings: titrating oxygen delivery without an oxygen blender.

OBJECTIVE: To test whether 4 commonly used self-inflating bags with a reservoir in situ can reliably deliver different oxygen concentrations (21%-100%) using a portable oxygen cylinder with flows of ≤5 L/min. STUDY DESIGN: Four self-inflating bags (from Laerdal, Ambu, Parker Healthcare, and Mayo Healthcare) were tested to provide positive pressure ventilation to a manikin at 60 inflations/min by 4 operators. Oxygen delivery was measured for 2 minutes, combining oxygen flows (0.25, 0.5, 1, 5 L/min) and peak inspiratory pressures (PIPs 20-25, 35-40 cmH2O). RESULTS: Combinations (n=128) were performed twice. Oxygen delivery depended upon device, oxygen flow, and PIP. All self-inflating bags delivered mean oxygen concentrations of <40% with 0.25 L/min, regardless of PIP. Three self-inflating bags delivered ≤40% with flow 0.5 L/min at PIP 35-40 cmH2O, whereas all delivered >40% at PIP 20-25 cmH2O. With 1 L/min, 3 self-inflating bags delivered 40%-60% at PIP 35-40 cmH2O and all delivered >60% at PIP 20-25 cmH2O. With 5 L/min, all self-inflating bags delivered close to or 100%, regardless of PIP. Differences in oxygen delivery between self-inflating bags were statistically significant (P<.001) even when differences were not clinically important. CONCLUSION: Self-inflating bags with a reservoir in situ can deliver a variety of oxygen concentrations without a blender, from <40% with 0.25 L/min oxygen flow to 100% with 5 L/min. The adjustment of oxygen flow may be a useful method of titrating oxygen in settings where air-oxygen blenders are unavailable.

Limited oxygen availability in utero may constrain the evolution of live birth in reptiles.

Although viviparity (live birth) has evolved from oviparity (egg laying) at least 140 times in vertebrates, nearly 120 of these independent events occurred within a single reptile taxon. Surprisingly, only squamate reptiles (lizards and snakes) are capable of facilitating embryonic development to increasingly advanced stages inside the mother during extended periods of oviducal egg retention. Viviparity has never evolved in turtle lineages, presumably because embryos enter and remain in an arrested state until after eggs are laid, regardless of the duration of egg retention. Until now, the limiting factor that initiates and maintains developmental arrest has remained elusive. Here, we show that oviducal hypoxia arrests embryonic development. We demonstrate that hypoxia can maintain developmental arrest after oviposition and that subsequent exposure of arrested embryos to normoxia triggers resumption of their development. We discovered remarkably low oxygen partial pressure in the oviducts of gravid turtles and found that secretions produced by the oviduct retard oxygen diffusion. Our results suggest that an extremely hypoxic environment in the oviduct arrests embryonic development and may constrain the evolution of viviparity in turtles, with the reduced diffusive capacity of oviducal secretions possibly creating or contributing to this hypoxia. We anticipate that these findings will allow us to better understand the mechanisms underlying the evolutionary transition between reproductive modes.

Towards an explainable clinical decision support system for large-for-gestational-age births.

A myriad of maternal and neonatal complications can result from delivery of a large-for-gestational-age (LGA) infant. LGA birth rates have increased in many countries since the late 20th century, partially due to a rise in maternal body mass index, which is associated with LGA risk. The objective of the current study was to develop LGA prediction models for women with overweight and obesity for the purpose of clinical decision support in a clinical setting. Maternal characteristics, serum biomarkers and fetal anatomy scan measurements for 465 pregnant women with overweight and obesity before and at approximately 21 weeks gestation were obtained from the PEARS (Pregnancy Exercise and Nutrition with smart phone application support) study data. Random forest, support vector machine, adaptive boosting and extreme gradient boosting algorithms were applied with synthetic minority over-sampling technique to develop probabilistic prediction models. Two models were developed for use in different settings: a clinical setting for white women (AUC-ROC of 0.75); and a clinical setting for women of all ethnicity and regions (AUC-ROC of 0.57). Maternal age, mid upper arm circumference, white cell count at the first antenatal visit, fetal biometry and gestational age at fetal anatomy scan were found to be important predictors of LGA. Pobal HP deprivation index and fetal biometry centiles, which are population-specific, are also important. Moreover, we explained our models with Local Interpretable Model-agnostic Explanations (LIME) to improve explainability, which was proven effective by case studies. Our explainable models can effectively predict the probability of an LGA birth for women with overweight and obesity, and are anticipated to be useful to support clinical decision-making and for the development of early pregnancy intervention strategies to reduce pregnancy complications related to LGA.

Arrested embryonic development: a review of strategies to delay hatching in egg-laying reptiles.

Arrested embryonic development involves the downregulation or cessation of active cell division and metabolic activity, and the capability of an animal to arrest embryonic development results in temporal plasticity of the duration of embryonic period. Arrested embryonic development is an important reproductive strategy for egg-laying animals that provide no parental care after oviposition. In this review, we discuss each type of embryonic developmental arrest used by oviparous reptiles. Environmental pressures that might have directed the evolution of arrest are addressed and we present previously undiscussed environmentally dependent physiological processes that may occur in the egg to bring about arrest. Areas for future research are proposed to clarify how ecology affects the phenotype of developing embryos. We hypothesize that oviparous reptilian mothers are capable of providing their embryos with a level of phenotypic adaptation to local environmental conditions by incorporating maternal factors into the internal environment of the egg that result in different levels of developmental sensitivity to environmental conditions after they are laid.

An explainable machine learning-based clinical decision support system for prediction of gestational diabetes mellitus.

Gestational Diabetes Mellitus (GDM), a common pregnancy complication associated with many maternal and neonatal consequences, is increased in mothers with overweight and obesity. Interventions initiated early in pregnancy can reduce the rate of GDM in these women, however, untargeted interventions can be costly and time-consuming. We have developed an explainable machine learning-based clinical decision support system (CDSS) to identify at-risk women in need of targeted pregnancy intervention. Maternal characteristics and blood biomarkers at baseline from the PEARS study were used. After appropriate data preparation, synthetic minority oversampling technique and feature selection, five machine learning algorithms were applied with five-fold cross-validated grid search optimising the balanced accuracy. Our models were explained with Shapley additive explanations to increase the trustworthiness and acceptability of the system. We developed multiple models for different use cases: theoretical (AUC-PR 0.485, AUC-ROC 0.792), GDM screening during a normal antenatal visit (AUC-PR 0.208, AUC-ROC 0.659), and remote GDM risk assessment (AUC-PR 0.199, AUC-ROC 0.656). Our models have been implemented as a web server that is publicly available for academic use. Our explainable CDSS demonstrates the potential to assist clinicians in screening at risk patients who may benefit from early pregnancy GDM prevention strategies.

Limited Impact of Fetal Sex and Maternal Body Mass Index on Fetal and Maternal Insulin Resistance and Lipid Metabolism: Findings from the PEARs Study.

The intrauterine environment can have a significant impact on fetal and maternal well-being, both during pregnancy and in later life. We aimed to identify how fetal sex and maternal body mass index (BMI) influence insulin resistance and metabolic function during pregnancy with maternal BMI > 25 kg/m2. This secondary analysis assessed data from the PEARS-randomized controlled trial that recruited pregnant women with body mass indexes 25-39.9 kg/m2. Longitudinal measurements of maternal and fetal insulin resistance and metabolic function were recorded throughout pregnancy. Regression models tested the effects of fetal sex and maternal BMI on markers of metabolic function and insulin regulation. A total of 484 women and their newborns (252 (52%) males vs. 232 (48%) females) were included in the analysis. A total of 333 (69%) women were overweight and 151 (31%) were obese. Male newborns were heavier and larger than females, and had a higher rate of instrumental delivery. Males had a lower LDL, but no other markers of insulin resistance or metabolic function were affected by fetal sex. Women with obesity had elevated markers of insulin resistance and metabolic dysfunction compared with women that were overweight, but maternal BMI did not impact these variables in the fetus. Fetal sex did not impact maternal and fetal metabolic parameters in women with BMI > 25 kg/m2. However, a higher BMI caused increasingly deranged maternal blood lipid concentrations and markers of insulin resistance as pregnancy progressed. Lipid monitoring and interventions to reduce lipids during pregnancy therefore require further evaluation.

A 20-year investigation of declining leatherback hatching success: implications of climate variation.

Unprecedented increases in air temperature and erratic precipitation patterns are predicted throughout the twenty-first century as a result of climate change. A recent global analysis of leatherback turtle hatchling output predicts that the nesting site at Sandy Point National Wildlife Refuge (SPNWR) will experience the most significant regional climate alterations. We aimed to identify how local air temperatures and precipitation patterns influenced within-nest mortality and overall hatchling output at this site between 1990 and 2010. We show that while the greatest mortality occurred during the latest stages of development (stage three), the rate of embryo mortality was highest during the initial stages (stage zero) of development (approx. 3.8 embryos per day per clutch). Increased mortality at stage three was associated with decreased precipitation and increased temperature during this developmental period, whereas precipitation prior to, and during stage zero had the greatest influence on early mortality. There was a significant decline in overall hatching success (falling from 74% to 55%) and emergence rate (calculated from the number of hatchlings that emerged from the nest as a percentage of hatched eggs) which fell from 96% to 91%. However, there was no trend observed in local temperature or precipitation during this timeframe, and neither variable was related to hatching success or emergence rate. In conclusion, our findings suggest that despite influencing within-nest mortality, climatic variability does not account for the overall decline in hatchling output at SPNWR from 1990 to 2010. Further research is therefore needed to elicit the reasons for this decline.

Histological changes in the umbilical artery following severe chorioamnionitis and funisitis may be indicative of early atherosclerosis.

We investigated whether histological evidence of early atherosclerosis was present in the umbilical artery of 21 pregnancies complicated by severe perinatal inflammation, and 21 controls matched for gestational age, sex and birth weight. Severe chorioamnionitis with funisitis was associated with increased numbers of CD68 and CD45 positive cells (both P < 0.01), indicating accumulation of monocyte-derived macrophages in lesion-susceptible regions. A down-regulation of SMA expression (P = 0.01) was also observed. These preliminary findings suggest that chorioamnionitis with funisitis may promote changes in the intima and media of the umbilical artery similar to that seen in early atherosclerosis.

An increasing citation black hole in ecology and evolution.

Citations published in online supplementary material (OSM) are invisible to search engines used to calculate citation counts, potentially negatively impacting popular performance indices and journal rankings that rely on citation counts for quantification. To quantify the number of citations that are "lost" in OSM, we conducted a systematic survey of supplementary citation practices in four high-ranking, society-run journals from two geographical locations (Europe and North America). In 2012, 6% of all citations were only included in the OSM and were therefore not included in citation counts. We found a significant increase in the number of references invisible to citation counting services over the last two decades. A solution to this problem is urgently required and could include journal indexing of citations in OSM or the inclusion of all references in the main text.

The impact of extended preovipositional arrest on embryonic development and hatchling fitness in the flatback sea turtle.

Turtle embryos pause development before oviposition in a process known as preovipositional arrest. Embryonic development arrests due to hypoxia (low oxygen) in the maternal oviducts and resumes only after exposure to normoxia when eggs are laid. Recently, several studies have hypothesized that the prolonged periods of preovipositional arrest may have a detrimental effect on embryo survival and development after eggs are laid. We tested this hypothesis by comparing embryo survival (determined by white spot formation and hatching success) and hatchling fitness (measured by self-righting, crawling, and swimming ability) of flatback sea turtle (Natator depressus) eggs following incubation in hypoxic (∼ 1%) and normoxic (∼ 21%) treatments for 5 d immediately following oviposition. We also measured embryo survival and hatchling fitness when eggs were incubated in hyperoxic conditions (42% oxygen), to determine whether hyperoxia could improve developmental outcome or whether some consequence of oxidative stress might manifest. Eggs incubated in hypoxia remained arrested during the 5-d treatment, and 97.5% of the eggs successfully recommenced development after exposure to normoxia when the treatment finished. At treatment commencement, 100% and 97.5% of eggs in the hyperoxic and normoxic treatments, respectively, began developing. Although hatching success was significantly lower following hypoxia (15%) compared to normoxia (80%) and hyperoxia (85%), hatchings from the hypoxic treatment were larger (carapace length and width and plastron length) than normoxic hatchlings. Similarly, hypoxic hatchings also swam significantly faster than hyperoxic hatchlings. Considering larger hatchlings may have a greater chance of survival, the production of larger hatchings may offset the high cost (lower hatching success) when preovipositional arrest is prolonged. Hyperoxia does not appear to have deleterious consequences for development.

Reproductive investment compromises maternal health in three species of freshwater turtle.

Life-history theory predicts that a trade-off in the allocation of resources between different physiological systems exists because resources are finite. As a result, females investing heavily in reproduction may compromise their future health. We used hematology, serum biochemistry, mass, and morphometric measurements as indicators of physiological health state to investigate whether reproductive investment altered subsequent maternal health in three Australian freshwater turtles: the oblong turtle (Chelodina oblonga; n = 12), the Macquarie turtle (Emydura macquarii; n = 9), and the eastern long-necked turtle (Chelodina longicollis; n = 8). Maternal health was impaired in turtles that produced larger and heavier eggs and clutches. In C. oblonga and E. macquarii, increased reproductive investment generally resulted in negative changes to the hematology and serum biochemistry profile of maternal blood. Generally, increases in heterophil/lymphocyte ratio, aspartate transaminase, creatine kinase, calcium/phosphorus ratio, and albumin/globulin ratio were observed following reproduction, in addition to a decrease in glucose and total protein. These findings agree with the physiological constraint hypothesis and highlight the connection between life-history evolution and animal physiology by documenting, for the first time, how measures of physiological health state relate to reproductive investment in Australian freshwater turtles. Additionally, our findings suggest that body condition, a readily used morphological biomarker, is a poor predictor of health in turtles. Our results emphasize the need to investigate how maternal health is influenced by the reproductive process in different species.

Hematologic and serum biochemical values of gravid freshwater Australian Chelonians.

Hematologic and serum biochemical analyses were performed on 30 wild-caught, gravid, Australian freshwater chelonians. Species sampled were western long-necked turtles (Chelodina oblonga; n = 13), common long-necked turtles (Chelodina longicollis; n = 8), and Murray River turtles (Emydura macquarii; n = 9). Turtles were obtained from Lake Goolellal in Perth, Western Australia (C. oblonga), and Lake Coranderrk in Healesville, Victoria (C. longicollis and E. macquarii). All turtles were considered healthy at the time of sample collection. Blood results were similar to those reported in other freshwater chelonians, with the exception of elevated calcium levels in all species. Hypercalcemia was attributed to egg development and maturation. A hemoparasite morphologically resembling Haemogregarina clelandi was found in all C. oblonga samples and in four C. longicollis samples. Infection with H. clelandi appeared to have no physiological effects on blood parameters or morphometrics of infected turtles. Blood parameters were also considered poor indicators of female chelonian morphometrics and fecundity.

Embryonic death is linked to maternal identity in the leatherback turtle (Dermochelys coriacea).

Leatherback turtles have an average global hatching success rate of ~50%, lower than other marine turtle species. Embryonic death has been linked to environmental factors such as precipitation and temperature, although, there is still a lot of variability that remains to be explained. We examined how nesting season, the time of nesting each season, the relative position of each clutch laid by each female each season, maternal identity and associated factors such as reproductive experience of the female (new nester versus remigrant) and period of egg retention between clutches (interclutch interval) affected hatching success and stage of embryonic death in failed eggs of leatherback turtles nesting at Playa Grande, Costa Rica. Data were collected during five nesting seasons from 2004/05 to 2008/09. Mean hatching success was 50.4%. Nesting season significantly influenced hatching success in addition to early and late stage embryonic death. Neither clutch position nor nesting time during the season had a significant affect on hatching success or the stage of embryonic death. Some leatherback females consistently produced nests with higher hatching success rates than others. Remigrant females arrived earlier to nest, produced more clutches and had higher rates of hatching success than new nesters. Reproductive experience did not affect stage of death or the duration of the interclutch interval. The length of interclutch interval had a significant affect on the proportion of eggs that failed in each clutch and the developmental stage they died at. Intrinsic factors such as maternal identity are playing a role in affecting embryonic death in the leatherback turtle.