Association between routine cell salvage use for lower segment caesarean section and post-operative iron infusion and anemia.

PURPOSE: Intraoperative cell salvage is central to Patient Blood Management including for lower segment caesarean section. Prior to April 2020, we initiated intraoperative cell salvage during caesarean section based on risk assessment for hemorrhage and patient factors. As the pandemic broadened, we mandated intraoperative cell salvage to prevent peri-partum anemia and potentially reduce blood product usage. We examined the association of routine intraoperative cell salvage on maternal outcomes. METHODS: We conducted a single-center non-overlapping before-after study of obstetric patients undergoing lower segment caesarean section in the 2 months prior to a change in practice ('usual care = selective intraoperative cell salvage', n = 203) and the 2 months following ('mandated intraoperative cell salvage', n = 228). Recovered blood was processed when a minimal autologous reinfusion volume of 100 ml was expected. Post-operative iron infusion and length of stay were modelled using logistic or linear regression, using inverse probability weighting to account for confounding. RESULTS: More emergency lower-segment caesarean sections occurred in the Usual Care group. Compared to the Usual Care group, post-operative hemoglobin was higher and anemia cases fewer in the Mandated intraoperative cell salvage group. Rates of post-partum iron infusion were significantly lower in the Mandated intraoperative cell salvage group (OR = 0.31, 95% CI = 0.12 to 0.80, P = 0.016). No difference was found for length of stay. CONCLUSION: Routine cell salvage provision during lower segment caesarean section was associated with a significant reduction in post-partum iron infusions, increased post-operative hemoglobin and reduced anemia prevalence.

Testing equivalence of two doses of intravenous iron to treat iron deficiency in pregnancy: A randomised controlled trial.

OBJECTIVE: To test the equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. DESIGN: Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. SETTING: Single centre in Australia. POPULATION: 278 pregnant women with iron deficiency. METHODS: Participants received either 500 mg (n = 152) or 1000 mg (n = 126) of intravenous ferric carboxymaltose in the second or third trimester. MAIN OUTCOME MEASURES: The proportion of participants requiring additional intravenous iron (500 mg) to achieve and maintain ferritin >30 microg/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth and safety outcomes. RESULTS: The two doses were not equivalent within a 5% margin at any time point. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500-mg group compared with 5/67 (8%) in the 1000-mg group: difference in proportions, 0.283 (95% confidence interval [CI] 0.177-0.389). Overall, participants in the 500-mg arm received twice the repeat infusion rate (0.81 [SD = 0.824] versus 0.40 [SD = 0.69], rate ratio 2.05, 95% CI 1.45-2.91). CONCLUSIONS: Administration of 1000 mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500- mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.

Effect of washed versus unwashed red blood cells on transfusion-related immune responses in preterm newborns.

Objectives: Transfusion with washed packed red blood cells (PRBCs) may be associated with reduced transfusion-related pro-inflammatory cytokine production. This may be because of alterations in recipient immune responses. Methods: This randomised trial evaluated the effect of transfusion with washed compared with unwashed PRBCs on pro-inflammatory cytokines and endothelial activation in 154 preterm newborns born before 29 weeks' gestation. Changes in plasma cytokines and measures of endothelial activation in recipient blood were analysed after each of the first three transfusions. Results: By the third transfusion, infants receiving unwashed blood had an increase in IL-17A (P = 0.04) and TNF (P = 0.007), whereas infants receiving washed blood had reductions in IL-17A (P = 0.013), TNF (P = 0.048), IL-6 (P = 0.001), IL-8 (P = 0.037), IL-12 (P = 0.001) and IFN-γ (P = 0.001). The magnitude of the post-transfusion increase in cytokines did not change between the first and third transfusions in the unwashed group but decreased in the washed group for IL-12 (P = 0.001), IL-17A (P = 0.01) and TNF (P = 0.03), with the difference between the groups reaching significance by the third transfusion (P < 0.001 for each cytokine). Conclusion: The pro-inflammatory immune response to transfusion in preterm infants can be modified when PRBCs are washed prior to transfusion. Further studies are required to determine whether the use of washed PRBCs for neonatal transfusion translates into reduced morbidity and mortality.

Are Pregnant Women Who Are Living with Overweight or Obesity at Greater Risk of Developing Iron Deficiency/Anaemia?

Low-grade inflammation is often present in people living with obesity. Inflammation can impact iron uptake and metabolism through elevation of hepcidin levels. Obesity is a major public health issue globally, with pregnant women often affected by the condition. Maternal obesity is associated with increased pregnancy risks including iron deficiency (ID) and iron-deficiency anaemia (IDA)-conditions already highly prevalent in pregnant women and their newborns. This comprehensive review assesses whether the inflammatory state induced by obesity could contribute to an increased incidence of ID/IDA in pregnant women and their children. We discuss the challenges in accurate measurement of iron status in the presence of inflammation, and available iron repletion strategies and their effectiveness in pregnant women living with obesity. We suggest that pre-pregnancy obesity and overweight/obese pregnancies carry a greater risk of ID/IDA for the mother during pregnancy and postpartum period, as well as for the baby. We propose iron status and weight gain during pregnancy should be monitored more closely in women who are living with overweight or obesity.

High binding site occupancy of corticosteroid-binding globulin by progesterone increases fetal free cortisol concentrations.

OBJECTIVE: Corticosteroid-binding globulin (CBG) binds and transports cortisol in the circulation in high cortisol-binding affinity (haCBG) and low affinity (laCBG) forms, the latter resulting from enzyme cleavage to target cortisol delivery at sites of inflammation. CBG also has substantial progesterone binding affinity, 3-fold less than cortisol. Progesterone and cortisol are important in the maintenance of pregnancy and in fetal development, respectively. The interactions of cortisol, progesterone and CBG affinity forms have not been studied together. We examined the interaction between progesterone and cortisol with CBG during fetal development. STUDY DESIGN: A retrospective cohort analysis of 351 neonates born between January and December 2012 at the Women's and Children's Hospital, Adelaide, South Australia. Cord blood serum samples were collected immediately following delivery. Clinical data was provided by hospital records. Total cortisol, free cortisol, total progesterone, total CBG and haCBG were measured by immunoassay. RESULTS: Cord blood total and free cortisol, and progesterone concentrations increased with gestational age. Cord blood progesterone concentrations were 100-fold luteal and 10-fold those in late pregnancy maternal circulation. The proportion of haCBG to total CBG was similar to that in healthy non-pregnant adults. However, free cortisol comprised approximately 15% of total cortisol, 3-fold higher than that in adults. CONCLUSION: In a manner unique to fetal life, very high progesterone concentrations are capable of elevating free cortisol concentrations through competition with cortisol at CBG's hormone binding site, without altered binding affinity through CBG cleavage or altered CBG hormone-binding affinity. High circulating fetal progesterone concentrations compete for CBG binding with cortisol, leading to a 3-fold increase in the free cortisol fraction in cord blood. Higher free-to-bound cortisol may alter fetal cortisol distribution facilitating cortisol's roles such as neurodevelopment in concert with dehydroepiandrosterone (sulfate) and lung maturation, or support cortisol action at times of low ambient cortisol. This mechanism may underlie the known association between cortisol, progesterone and CBG, and be relevant principally in the fetal circulation due to the high progesterone concentrations encountered.

Understanding the preferences of Australian men for accessing health information.

With men currently reporting an increased desire to manage their own health, this mixed-methods study aimed to identify the preferred communication channels to support their access to information. Adult cisgender men (n=410) completed an anonymous survey that assessed current methods, preferences and barriers to accessing health information for general, minor, serious and private health concerns. Seven focus groups, attended by 69 men, further explored health-seeking behaviour. Survey results demonstrated the top methods to access information were through the GP or specialist and online searches, with rates differing by age and the type of health concern. Most men (>85%) reported information-seeking for serious concerns, while ~30% did not seek information for minor or private issues. For all ages, the top preferred methods for accessing information included GP or specialists, online searches and pharmacists, with other preferences varying by age, severity and sensitivity. Analysis of the focus group discussions revealed five key themes that help explain men's decisions and actions about seeking health-information: (i) denial; (ii) delayed information seeking; (iii) social constructs of masculinity; (iv) difficulty initiating discussions about health; and (v) perceived trust and validity of information. This study has provided insight into how information can be tailored to communicate effectively with men of different ages. This will support appropriate health-seeking behaviours in response to minor, serious and private health concerns.

The contribution of red blood cell transfusion to neonatal morbidity and mortality.

Anaemia of prematurity will affect 90% of all very preterm infants, resulting in at least one red blood cell (RBC) transfusion. A significant proportion of preterm infants require multiple transfusions over the course of hospital admission. Growing evidence supports an association between transfusion exposure and adverse neonatal outcomes. In adults, transfusion-associated sepsis, transfusion-related acute lung injury and haemolytic reactions are the leading causes of transfusion-related morbidity and mortality; however, these are seldom recognised in newborns. The association between transfusion and adverse outcomes remains inconclusive. However, the evidence from preclinical studies demonstrates that RBC products can directly modulate immune cell function, a pathway termed transfusion-related immunomodulation (TRIM), which may provide a mechanism linking transfusion exposure with neonatal morbidities. Finally, we discuss the impact of TRIM on transfusion medicine, how we may address these issues and the emerging areas of research aimed at improving the safety of transfusions in this vulnerable population.

It takes a community to conceive: an analysis of the scope, nature and accuracy of online sources of health information for couples trying to conceive.

This study examined the nature and accuracy of information available across online platforms for couples trying to conceive. A consumer simulation-based investigation of English websites and social media (Facebook, Twitter, Instagram) was undertaken using common search terms identified in a pilot study. Claims about fertility and pregnancy health were then extracted from the results and analysed thematically. The accuracy of each claim was assessed independently by six fertility and conception experts, rated on a scale of 1 (not factual) to 4 (highly factual), with scores collated to produce a median rating. Claims with a median score < 3 were classified as inaccurate. The use of the terms 'trying to conceive' and '#TTC' were common identifiers on online platforms. Claims were extracted predominantly from websites (n = 89) rather than social media, with Twitter and Instagram comprising commercial elements and Facebook focused on community-based support. Thematic analysis revealed three major themes among the claims across all platforms: conception behaviour and monitoring, lifestyle and exposures, and medical. Fact-checking by the experts revealed that 40% of the information assessed was inaccurate, and that inaccuracies were more likely to be present in the conception behaviour and monitoring advice, the topics most amenable to modification. Since online information is a readily accessible and commonly utilized resource, there is opportunity for improved dissemination of evidence-based material to reach interested couples. Further cross-disciplinary and consumer-based research, such as a user survey, is required to understand how best to provide the 'trying to conceive' community with accurate information.

Variability of the cortisol awakening response and morning salivary oxytocin in late adolescence.

Exogenously administered oxytocin interacts with the hypothalamic-pituitary-adrenal (HPA) axis to modulate endogenous cortisol levels, suggesting a synergistic role for these two hormones in the response to stress, cognitive performance and the development of psycho-behavioural disorders. The cortisol awakening response (CAR) is considered a reliable measure of HPA axis function in humans. However, the CAR appears to vary considerably from day to day and may be strongly influenced by the anticipated demands of the day ahead. The level of variation intrinsic to the CAR is unclear because few studies have examined the CAR in the absence of daily environmental variation. It is not known whether oxytocin has a similar or complementary awakening response. Therefore, over three consecutive days, we examined 12 adolescents (aged 15-17 years) in a highly-controlled sleep laboratory. Saliva was collected on days 4-6 of a 9-day laboratory visit. Cortisol and oxytocin levels were determined by an enzyme-linked immunosorbent assay from saliva sampled at 0, 15, 30 and 45 minutes, and 8 and 12 hours post-awakening. CAR magnitude varied between days and was associated with sleep duration and pre-awakening sleep stage. Conversely, oxytocin levels dropped dramatically in the first 15 minutes post-awakening and were highly consistent across participants and days. Older participants had higher awakening oxytocin concentrations. Although cortisol increases and oxytocin rapidly declines upon awakening, their diurnal variation does not appear to be related at basal, peripheral levels, consistent with a previous finding that exogenously administered oxytocin only modulates cortisol under conditions of stress.

Treatment of iron deficiency and iron deficiency anemia with intravenous ferric carboxymaltose in pregnancy.

PURPOSE: To evaluate the efficacy and safety of intravenous ferric carboxymaltose administration to pregnant women with varying severities of iron deficiency anemia and iron deficiency without anemia. METHODS: In this prospective observational study of local obstetric practice, we analyzed data from 863 pregnant women with iron deficiency according to anemia status and severity. All women were treated with intravenous ferric carboxymaltose in pregnancy. Treatment efficacy was assessed by repeat hemoglobin measurements at 3 and 6 week post-infusion and ferritin levels, where available. Safety was assessed by analysis of adverse events, fetal heart rate monitoring, and newborn health outcome data. RESULTS: Ferric carboxymaltose significantly increased hemoglobin in women with mild, moderate, and severe iron deficiency anemia and women with iron deficiency alone at 3 and 6 week post-infusion (p < 0.01 for all). No hemoconcentration occurred in iron-deficient women without anemia. No serious adverse events were recorded, with minor temporary side effects (including local skin irritation, nausea, and headache) occurring in 96 (11%) women. No adverse fetal or neonatal outcomes were observed. CONCLUSIONS: Ferric carboxymaltose infusion corrects iron deficiency or various degrees of iron deficiency anemia efficaciously and safely pregnant women, and does not cause hemoconcentration.

Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in 11-13-Year-Old Children Born to Women with Gestational Diabetes Mellitus.

BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. METHODS: Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11-13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. FINDINGS: GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. INTERPRETATION: These results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment.

Determining the venous oxygen reservoir: A novel, hypothetical approach to titration of supplemental oxygen in preterm newborns.

While normal oxygen saturation is commonly thought to be a marker of normal oxygenation, cutaneous saturation does not account for the sufficiency of oxygen within each cell or that of the system overall. Rather, cutaneous oximetry simply defines the saturation of haemoglobin (Hb) with oxygen in a pulsatile vessel. Assessment of sufficiency is best determined by measurement of the amount of oxygen left over following aerobic respiration. This left over oxygen is 'stored' on Hb in the venous compartment and can be calculated as the venous oxygen content. We hypothesize that the development of a venous oxygen content or saturation reference range in a group of well, uninjured very preterm newborns and subsequent application, in a randomised trial, with a structural, functional and molecular outcome will resolve the method for assessment of oxygen sufficiency in preterms by demonstrating both clinical safety and effectiveness. This method could be subsequently used for titration of supplemental oxygen.

Child neurodevelopmental outcomes following preterm and term birth: What can the placenta tell us?

A significant proportion of children born preterm will experience some level of neurodevelopmental impairment. Changes in placental function have been observed with many antenatal conditions that are risk factors for preterm birth and/or poor neurodevelopment including fetal growth restriction and in-utero inflammation. This review will highlight placental factors that have been studied to understand the underlying mechanisms and identify biomarkers that lead to poor child neurodevelopmental outcomes. These include changes in gross morphological and histopathological structure and the placental inflammatory response to prenatal infection. Further, we will describe the placenta's role as both a barrier to maternally-derived bioactive substances critical for normal fetal brain development, such as cortisol, and a source of neuroactive steroids and neurotrophins known to have critical functions in neuronal proliferation, axonal growth, myelination and the regulation of apoptosis. Finally, emerging data supporting the potential utility of novel placental biomarkers in the early prediction of poor neurodevelopmental outcome in infants born both preterm and term will be discussed. These include the assessment of genetic variants (e.g. single nucleotide polymorphisms in placental tissue) and epigenetic biomarkers (e.g. placental microRNAs and placental DNA methylation). With the placenta the key tissue regulating the fetal environment, integration of observed changes in placental function with genetic and epigenetic variations may advance our ability to predict future infant health. Ultimately, this may facilitate targeted allocation of health resources with the aim of improving lifelong neurodevelopmental capability.

A Theoretical and Practical Approach to Defining "Adequate Oxygenation" in the Preterm Newborn.

John Scott Haldane recognized that the administration of supplemental oxygen required titration in the individual. Although he made this observation in adults, it is equally applicable to the preterm newborn. But how, in practice, can the oxygen requirements in the preterm newborn be determined to avoid the consequences of too little and too much oxygen? Unfortunately, the current generation of oxygen saturation trials in preterm newborns guides saturation thresholds rather than individual oxygen requirements. For this reason, we propose an alternate model for the description of oxygen sufficiency. This model considers the adequacy of oxygen delivery relative to simultaneous consumption. We describe how measuring oxygen extraction or the venous oxygen reservoir could define a physiologically based definition of adequate oxygen. This definition would provide a clinically useful reference value while making irrelevant the absolute values of both oxygen delivery and consumption. Additional trials to test adjunctive, noninvasive measurements of oxygen status in high-risk preterm newborns are needed to minimize the effects of both insufficient and excessive oxygen exposure.

Cord Blood DNA Methylation Biomarkers for Predicting Neurodevelopmental Outcomes.

Adverse environmental exposures in pregnancy can significantly alter the development of the fetus resulting in impaired child neurodevelopment. Such exposures can lead to epigenetic alterations like DNA methylation, which may be a marker of poor cognitive, motor and behavioral outcomes in the infant. Here we review studies that have assessed DNA methylation in cord blood following maternal exposures that may impact neurodevelopment of the child. We also highlight some key studies to illustrate the potential for DNA methylation to successfully identify infants at risk for poor outcomes. While the current evidence is limited, in that observations to date are largely correlational, in time and with larger cohorts analyzed and longer term follow-up completed, we may be able to develop epigenetic biomarkers that not only indicate adverse early life exposures but can also be used to identify individuals likely to be at an increased risk of impaired neurodevelopment even in the absence of detailed information regarding prenatal environment.

Antenatal steroid exposure in the late preterm period is associated with reduced cord blood neurotrophin-3.

BACKGROUND: Neurotrophins are proteins critically involved in neural growth, survival and differentiation, and therefore important for fetal brain development. Reduced cord blood neurotrophins have been observed in very preterm infants (<32weeks gestation) who subsequently develop brain injury. Antenatal steroid exposure can alter neurotrophin concentrations, yet studies to date have not examined whether this occurs in the late preterm infant (33-36weeks gestation), despite increasing recognition of subtle neurodevelopmental deficits in this population. AIM: To assess the impact of antenatal steroids on cord blood neurotrophins in late preterm infants following antenatal steroid exposure. STUDY DESIGN: Retrospective analysis. SUBJECTS: Late preterm infants (33-36weeks; n=119) and term infants (37-41weeks; n=129) born at the Women's and Children's Hospital, Adelaide. OUTCOME MEASURES: Cord blood neurotrophin-3 (NT-3), NT-4, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) concentrations measured by ELISA. RESULTS: Cord blood NT-4 and NGF were increased at term compared to the late preterm period (p<0.001), while BDNF and NT-3 were not different. In the late preterm period, cord blood NT-3 was reduced when antenatal steroids were administered >24h prior to delivery (p<0.01). CONCLUSION: This study identified an association between reduced cord blood NT-3 and antenatal steroid exposure in the late preterm period. The reduced NT-3 may be a consequence of steroids inducing neuronal apoptosis, thereby reducing endogenous neuronal NT3 production, or be an action of steroids on other maternal or fetal NT-3 producing cells, which may then affect neuronal growth, differentiation and survival. Regardless of the specific mechanism, a reduction in NT-3 may have long term implications for child neurodevelopment, and emphasizes the ongoing vulnerability of the fetal brain across the full preterm period.