Gestational Age, Infection, and Suboptimal Maternal Prepregnancy BMI Independently Associate with Placental Histopathology in a Cohort of Pregnancies without Major Maternal Comorbidities.

Background: The placenta undergoes morphological and functional adaptations to adverse exposures during pregnancy. The effects ofsuboptimal maternal body mass index (BMI), preterm birth, and infection on placental histopathological phenotypes are not yet well understood, despite the association between these conditions and poor offspring outcomes. We hypothesized that suboptimal maternal prepregnancy BMI and preterm birth (with and without infection) would associate with altered placental maturity and morphometry, and that altered placental maturity would associate with poor birth outcomes. Methods: Clinical data and human placentae were collected from 96 pregnancies where mothers were underweight, normal weight, overweight, or obese, without other major complications. Placental histopathological characteristics were scored by an anatomical pathologist. Associations between maternal BMI, placental pathology (immaturity and hypermaturity), placental morphometry, and infant outcomes were investigated for term and preterm births with and without infection. Results: Fetal capillary volumetric proportion was decreased, whereas the villous stromal volumetric proportion was increased in placentae from preterm pregnancies with chorioamnionitis compared to preterm placentae without chorioamnionitis. At term and preterm, pregnancies with maternal overweight and obesity had a high percentage increase in proportion of immature placentae compared to normal weight. Placental maturity did not associate with infant birth outcomes. We observed placental hypermaturity and altered placental morphometry among preterm pregnancies with chorioamnionitis, suggestive of altered placental development, which may inform about pregnancies susceptible to preterm birth and infection. Conclusions: Our data increase our understanding of how common metabolic exposures and preterm birth, in the absence of other comorbidities or complications, potentially contribute to poor pregnancy outcomes and developmental programming.

Reflex strategy to ensure accurate total testosterone results from consumer initiated, self-collected capillary samples.

BACKGROUND: Self-collected capillary samples are convenient for direct access testing (DAT), but exogenous testosterone use may cause falsely elevated total testosterone (TT) results. We designed a quality assurance workflow to differentiate between accurate or erroneous supraphysiological TT concentrations. METHODS: Clinical samples with TT > 1500 ng/dL were reflexed to luteinizing hormone (LH) and follicle stimulating hormone (FSH) and screened for exogenous testosterone use. Samples (n = 120) with normal TT were reflexed to LH/FSH as a control. RESULTS: A total of 8572 TT samples were evaluated, of which 533 (6.2 %) had TT > 1500 ng/dL and were reflexed. Of these, 441 (82.7 %) had significantly decreased LH/FSH (<0.85/<0.7mIU/mL, respectively), 72 (13.5 %) had normal or borderline normal LH/FSH, and 20 (3.8 %) had insufficient plasma volume. In patients with TT > 1500 ng/dL, injectable exogenous testosterone use was most commonly accompanied by significantly decreased LH/FSH, while topical testosterone use was most commonly accompanied by detectable LH/FSH. Control samples were almost all (99.2 %) within or above the LH/FSH reference intervals. Unique patients ordered 351 TT tests where at least one TT result was > 1500 ng/dL. Based on TT and LH/FSH results, we hypothesized that patients were intermittently or consistently overusing exogenous testosterone, resolved elevated TT with recollection, or repeatedly contaminated their sample. CONCLUSION: Self-collected capillary specimens are acceptable for TT testing. A quality assurance reflex to LH/FSH can determine the validity of supraphysiological TT results in a consumer initiated/DAT population.

Altered placental immune cell composition and gene expression with isolated fetal spina bifida.

PROBLEM: Fetal spina bifida (SB) is more common in pregnant people with folate deficiency or anomalies of folate metabolism. It is also known that fetuses with SB have a higher risk of low birthweight, a condition that is typically placental-mediated. We therefore hypothesized that fetal SB would associate with altered expression of key placental folate transporters and an increase in Hofbauer cells (HBCs), which are folate-dependent placental macrophages. METHOD OF STUDY: Folate receptor-α (FRα), proton coupled folate receptor (PCFT), and reduced folate carrier (RFC) protein localization and expression (immunohistochemistry) and HBC phenotypes (HBC abundance and folate receptor-ß [FRß] expression; RNA in situ hybridization) were assessed in placentae from fetuses with SB (cases; n = 12) and in term (n = 10) and gestational age (GA) - and maternal body mass index - matched (n = 12) controls without congenital anomalies. RESULTS: Cases had a higher proportion of placental villous cells that were HBCs (6.9% vs. 2.4%, p = .0001) and higher average HBC FRß expression (3.2 mRNA molecules per HBC vs. 2.3, p = .03) than GA-matched controls. HBCs in cases were largely polarized to a regulatory phenotype (median 92.1% of HBCs). In sex-stratified analyses, only male cases had higher HBC levels and HBC FRß expression than GA-matched controls. There were no differences between groups in the total percent of syncytium and stromal cells that were positive for FRα, PCFT, or RFC protein immunolabeling. CONCLUSIONS: HBC abundance and FRß expression by HBCs are increased in placentae of fetuses with SB, suggesting immune-mediated dysregulation in placental phenotype, and could contribute to SB-associated comorbidities.

Fetal spina bifida associates with dysregulation in nutrient-sensitive placental gene networks: Findings from a matched case-control study.

To improve outcomes in fetuses with spina bifida (SB), better understanding is needed of the molecular drivers of SB and its comorbidities. Pregnant people carrying a fetus with isolated SB (cases; n = 12) or a fetus with no congenital anomalies (controls; n = 21) were recruited at Mount Sinai Hospital, Toronto, Ontario, Canada. Clinical data and placental samples were collected. Placental transcriptome was sequenced (Clariom D microarray) and a nutrient-focused gene expression analysis pipeline was applied to determine whether fetal SB associates with placental dysfunction. Of the 391 differentially expressed genes (DEGs) in cases, 11% (n = 42) had at least one nutrient cofactor, including B vitamins (n = 7 genes), iron/heme (n = 6), and zinc (n = 11). Cases had dysregulation in genes not previously known to associate with SB, and in placental genes that have known links to SB but have not been previously identified in the placenta. Cases also had downregulated nutrient transport and upregulated branching angiogenesis and immune/inflammatory processes. Five nutrient-dependent transcription regulators, collectively predicted to target 46% of DEGs in cases, were identified and were most commonly dependent on B vitamins (n = 3) and zinc (n = 2). Placental gene expression changes were most acute in cases with poor growth. Placentae from fetuses with SB have dysregulation in several gene networks, including those that are sensitive to multiple micronutrients beyond the well-known folic acid. An improved understanding of placental phenotype in fetuses with SB may help identify novel mechanisms associated with comorbidities in fetuses with SB, and reveal new targets to improve fetal outcomes in this population.

Sensory evaluations of a novel iron and zinc-enriched powder for the potential treatment and prevention of iron deficiency in women of reproductive age.

Iron deficiency (ID) and ID with anaemia (IDA) are serious global health problems that disproportionately affect women aged 15-49 years. Although food fortification is one of the most effective and sustainable ways to combat nutritional deficiencies, iron remains one of the most difficult micronutrients to fortify, given its tendency to react strongly with food constituents. Therefore, it is important to assess the sensory properties of foods fortified with iron to determine the acceptability and palatability in target populations. We aimed to determine the palatability and acceptability of a novel iron and zinc-enriched powder fortified in tap water by conducting sensory evaluations in 35 women of reproductive age using a 9-point hedonic scale, where participants rated the sensory properties of six samples containing different amounts of the active or placebo powder. We found significant differences between samples reconstituted at 1, 2, and 3 g/L for sensory properties, including overall taste. Participants were found to be more willing to drink the mineral-enriched powder when prepared at the lowest concentration (1 g/L) compared to higher concentrations. Our results provide important insight into the sensory qualities of a novel formulation of an iron and zinc-enriched powder for at-home fortification and indicate consumer acceptability in reproductive-aged women, a key group at risk for ID/IDA. If found to improve iron status, novel treatments like this product will contribute to global efforts to develop safe, acceptable and sustainable interventions for ID and IDA.

Building strong health and career trajectories through translational research.

Translational research (TR) is the movement of fundamental scientific discoveries into healthcare settings and population health policy, and parallels the goals of DOHaD research. Unfortunately, there is little guidance on how to become a translational researcher. To understand the opinions of DOHaD trainees towards TR, we conducted a workshop at the DOHaD World Congress 2022. We found that trainees were enthusiastic for their work to have translational impact, and that they feel that holistic, multidisciplinary solutions may lead to more generalisable research. However, there lacks support for TR career pathways, which may stall the execution of the long-term vision of the DOHaD agenda. We put forward recommendations for trainees to clarify their purpose in pursuing TR and for seeking relevant people and patronages to support their training paths. For mentors, training institutions, and scientific societies, we recommend developing TR-specific programmes, and implementing training opportunities, networking events, and funding to support these endeavours.

Oral health-related quality of life among women early postpartum: A cross-sectional study.

BACKGROUND: Periodontal diseases can negatively impact the oral health-related quality of life (OHRQoL) of pregnant women. This study investigates the association between maternal oral inflammatory load (OIL), sociodemographic characteristics, and the OHRQoL in postpartum women. METHODS: In this cross-sectional study, breastfeeding mothers were recruited from St. Michael's Hospital, Toronto within 2-4 weeks postpartum. Mothers were categorized into "Normal/low" and "High" OIL groups based on the absolute counts of oral polymorphonuclear neutrophils (oPMNs). The Oral Health Impact Profile-14 questionnaire was used to assess the impact of the maternal OIL on the OHRQoL. Multiple linear regression analyses were performed to examine the association between maternal sociodemographic factors including age, marital status, education level, employment status, parity, and their OHRQoL. RESULTS: Forty-seven mothers were included in this study. Mothers with high OIL reported higher impact on their OHRQoL (30%) than mothers with normal/low OIL (21%), but these differences were not statistically different. There was a negative relationship between the mother's education level and the extent of impact of OHRQoL on the "physical pain" dimension (p < 0.05), and between the mothers' age and employment status and the "physical disability" dimension (p < 0.05). A positive correlation was noted between multi-parity and the extent of impact of OHRQoL on the "physical disability" dimension (p = 0.009), and between the marital status and the "psychological disability" dimension (p < 0.05). CONCLUSION: This study highlighted the significant impact of sociodemographic characteristics on the OHRQoL of mothers, showcasing the importance of considering these factors when implementing targeted preventive dental care programs for mothers.

Impact of Co-Occurrence of Obesity and SARS-CoV-2 Infection during Pregnancy on Placental Pathologies and Adverse Birth Outcomes: A Systematic Review and Narrative Synthesis.

Obesity is a risk factor for severe COVID-19 disease during pregnancy. We hypothesized that the co-occurrence of high maternal body mass index (BMI) and gestational SARS-CoV-2 infection are detrimental to fetoplacental development. We conducted a systematic review following PRISMA/SWiM guidelines and 13 studies were eligible. In the case series studies (n = 7), the most frequent placental lesions reported in SARS-CoV-2(+) pregnancies with high maternal BMI were chronic inflammation (71.4%, 5/7 studies), fetal vascular malperfusion (FVM) (71.4%, 5/7 studies), maternal vascular malperfusion (MVM) (85.7%, 6/7 studies) and fibrinoids (100%, 7/7 studies). In the cohort studies (n = 4), three studies reported higher rates of chronic inflammation, MVM, FVM and fibrinoids in SARS-CoV-2(+) pregnancies with high maternal BMI (72%, n = 107/149; mean BMI of 30 kg/m2) compared to SARS-CoV-2(-) pregnancies with high BMI (7.4%, n = 10/135). In the fourth cohort study, common lesions observed in placentae from SARS-CoV-2(+) pregnancies with high BMI (n = 187 pregnancies; mean BMI of 30 kg/m2) were chronic inflammation (99%, 186/187), MVM (40%, n = 74/187) and FVM (26%, n = 48/187). BMI and SARS-CoV-2 infection had no effect on birth anthropometry. SARS-CoV-2 infection during pregnancy associates with increased prevalence of placental pathologies, and high BMI in these pregnancies could further affect fetoplacental trajectories.

Bronchopulmonary dysplasia and carbon dioxide retention.

AIM: The aim of this study was to determine the pre-discharge carbon dioxide (CO2 ) levels of preterm neonates with bronchopulmonary dysplasia (BPD) requiring ongoing nasal cannulae oxygen therapy and who were ready for discharge home. METHODS: We studied a retrospective cohort of infants born <30 weeks gestational age (GA) at ≥36 weeks corrected GA who had established BPD requiring ongoing nasal cannulae oxygen therapy and were ready for discharge home. Neonates were born and admitted between May 2014 and December 2018. Demographic data at the time of birth and at the time of the last blood gas sampled were collected. RESULTS: One hundred five neonates had median GA of 26.1 weeks and birth weight of 775 g. Median (IQR) CO2 level was 54 (49-58) mmHg. Ninety-nine (94%) neonates had CO2 levels exceeding the normal range and 91 (87%) neonates had a CO2 between 45 and 65 mmHg. CONCLUSION: Ninety-four per cent of neonates <30 weeks GA at ≥36 weeks corrected GA requiring ongoing nasal cannulae oxygen therapy for established BPD, who were ready for discharge home, have CO2 levels outside of normocapnia (35-45 mmHg), with 87% having CO2 levels between 45 and 65 mmHg.

Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood.

Introduction: Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring. Methods: Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ad libitum ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (ACTHR), steroidogenic acute regulatory protein (STAR), cytochrome P450 17A1 (CYP17A1), 11beta-hydroxysteroid-dehydrogenase type 2 (11ßHSD2), insulin-like growth factor-2 (IGF2), and in the fetal hippocampus of 11ßHSD1, 11ßHSD2, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 µg/kg) and corticotropin-releasing hormone (CRH, 0.5 µg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of ACTHR, STAR and CYP17A1 were determined in adult adrenals. Results: Fetal adrenal STAR, CYP17A1 and IGF2 mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all p<0.01). PCUN reduced fetal hippocampal MR and GR mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal ACTHR, STAR, and CYP17A1 mRNA expression were not affected by PCUN. Conclusions: We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.

Relationships between maternal body mass index and child cognitive outcomes at 3 years of age are buffered by specific early environments in a prospective Canadian birth cohort.

Fetal and child development are shaped by early life exposures, including maternal health states, nutrition and educational and home environments. We aimed to determine if suboptimal pre-pregnancy maternal body mass index (BMI; underweight, overweight, obese) would associate with poorer cognitive outcomes in children, and whether early life nutritional, educational and home environments modify these relationships. Self-reported data were obtained from mother-infant dyads from the pan-Canadian prospective Maternal-Infant Research on Environmental Chemicals cohort. Relationships between potential risk factors (pre-pregnancy maternal BMI, breastfeeding practices and Home Observation Measurement of the Environment [HOME] score) and child cognitive development at age three (Weschler's Preschool and Primary Scale of Intelligence, Third Edition scale and its subcategories) were each evaluated using analysis of variance, multivariable regression models and moderating analyses. Amongst the 528 mother-child dyads, increasing maternal pre-pregnancy BMI was negatively associated with scores for child full-scale IQ (ß [95% CI]; -2.01 [-3.43, -0.59], p = 0.006), verbal composite (-1.93 [-3.33, -0.53], p = 0.007), and information scale (-0.41 [-0.70, -0.14], p = 0.003) scores. Higher maternal education level or HOME score attenuated the negative association between maternal pre-pregnancy BMI and child cognitive outcome by 30%-41% and 7%-22%, respectively, and accounted for approximately 5%-10% greater variation in male children's cognitive scores compared to females. Maternal education and higher quality home environment buffer the negative effect of elevated maternal pre-pregnancy BMI on child cognitive outcomes. Findings suggest that relationships between maternal, social and environmental factors must be considered to reveal pathways that shape risk for, and resiliency against, suboptimal cognitive outcomes in early life.

Translational Comparison of the Human and Mouse Yolk Sac Development and Function.

The yolk sac (YS) is the oldest of the extraembryonic membranes in vertebrates. Considered a transitory structure in the human species, the importance of the YS for a successful pregnancy is often overlooked. Due to the general inaccessibility of healthy human YS tissue for research, the use of experimental animal models is of great value. In order to better understand whether the mouse could be used as a translational model for the study of the human YS under normal and pathological conditions, this review comprehensively describes key developmental aspects of the human and mouse YS, detailing their development and function. YS major similarities in both species comprise the following: (1) histological composition (both being composed of endoderm, mesoderm, and mesothelium layers); (2) endoderm endocytosis, synthesis, secretion, and transport capabilities; and (3) mesoderm onset of haematopoiesis and angiogenesis. Examples of main dissimilarities include (1) persistence across pregnancy (i.e. early pregnancy in humans vs term pregnancy in mice); (2) the existence of a secondary YS in humans; (3) the presence of proliferative primordial germ cells (PGCs) in the human versus their absence in mice; and (4) eversion of histological layers in the mouse. Although these differences should be considered when interpreting data from mouse-based studies, the overall morphofunctional similarities in the YS between these species indicate that the mouse can be potentially used as a translational model for the study of the human YS.

Identification of novel nutrient-sensitive gene regulatory networks in amniocytes from fetuses with spina bifida.

Neural tube defects (NTDs) remain among the most common congenital anomalies. Contributing risk factors include genetics and nutrient deficiencies, however, a comprehensive assessment of nutrient-gene interactions in NTDs is lacking. We applied a nutrient-focused gene expression analysis pipeline to identify nutrient-sensitive gene regulatory networks in amniocyte gene expression data (GSE4182) from fetuses with NTDs (cases; n = 3) and fetuses with no congenital anomalies (controls; n = 5). Differentially expressed genes (DEGs) were screened for having nutrient cofactors. Nutrient-dependent transcriptional regulators (TRs) that regulated DEGs, and nutrient-sensitive miRNAs with a previous link to NTDs, were identified. Of the 880 DEGs in cases, 10% had at least one nutrient cofactor. DEG regulatory network analysis revealed that 39% and 52% of DEGs in cases were regulated by 22 nutrient-sensitive miRNAs and 10 nutrient-dependent TRs, respectively. Zinc- and B vitamin-dependent gene regulatory networks (Zinc: 10 TRs targeting 50.6% of DEGs; B vitamins: 4 TRs targeting 37.7% of DEGs, 9 miRNAs targeting 17.6% of DEGs) were dysregulated in cases. We identified novel, nutrient-sensitive gene regulatory networks not previously linked to NTDs, which may indicate new targets to explore for NTD prevention or to optimise fetal development.

Adaptation of the gut holobiont to malnutrition during mouse pregnancy depends on the type of nutritional adversity.

Malnutrition can influence maternal physiology and programme offspring development. Yet, in pregnancy, little is known about how dietary challenges that influence maternal phenotype affect gut structure and function. Emerging evidence suggests that interactions between the environment, multidrug resistance (MDR) transporters and microbes may influence maternal adaptation to pregnancy and regulate fetoplacental development. We hypothesized that the gut holobiont (host and microbes) during pregnancy adapts differently to suboptimal maternal diets, evidenced by changes in the gut microenvironment, morphology, and expression of key protective MDR transporters during pregnancy. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD) 5.5-18.5, or fed 60% high fat diet (HF) for 8 weeks before and during pregnancy. At GD18.5, maternal small intestinal (SI) architecture (H&E), proliferation (Ki67), P-glycoprotein (P-gp - encoded by Abcb1a/b) and breast cancer resistance protein (BCRP/Abcg2) MDR transporter expression and levels of pro-inflammatory biomarkers were assessed. Circulating inflammatory biomarkers and maternal caecal microbiome composition (G3 PhyloChipTM) were measured. MDR transporter expression was also assessed in fetal gut. HF diet increased maternal SI crypt depth and proinflammatory load, and decreased SI expression of Abcb1a mRNA, whilst UN increased SI villi proliferation and Abcb1a, but decreased Abcg2, mRNA expression. There were significant associations between Abcb1a and Abcg2 mRNA levels with relative abundance of specific microbial taxa. Using a systems physiology approach we report that common nutritional adversities provoke adaptations in the pregnancy holobiont in mice, and reveal new mechanisms that could influence reproductive outcomes and fetal development.

The Association between Maternal Oral Inflammation and Neutrophil Phenotypes and Poly-Unsaturated Fatty Acids Composition in Human Milk: A Prospective Cohort Study.

This prospective cohort study aimed to investigate the impact of maternal oral inflammation on human milk composition including neutrophil counts, activation state (based on cluster of differentiation (CD) markers expression), and fatty acid levels. Fifty mothers were recruited from St. Michael's hospital, Toronto, and followed up from 2-4 weeks until 4 months postpartum. Oral rinse and human milk samples were collected at both timepoints. Oral polymorphonuclear neutrophils (oPMNs) within the rinses were quantified using flow cytometry and the participants' oral health state was categorized into three groups (i.e., healthy, moderate, and severe) based on the oPMNs counts. Fatty acids were identified and quantified using a gas chromatography-flame ionization detector (GC-FID). Compared to mothers with a healthy oral health state, mothers with moderate to severe oral inflammation had a statistically significant decrease in the expression of CD64 biomarker, an increase in the expression of CD14 biomarker on human milk neutrophils and a decrease in the levels of eicosapentaenoic acid (C20:5n-3) in their human milk at follow-up compared to baseline. This study demonstrates for the first time that maternal oral inflammation can affect human milk composition. The mechanism by which these alterations can affect infant health outcomes in the long term critically needs to be considered.

Thresholds for blood transfusion in extremely preterm infants: A review of the latest evidence from two large clinical trials.

There are two recently completed large randomized clinical trials of blood transfusions in the preterm infants most at risk of requiring them. Liberal and restrictive strategies were compared with composite primary outcome measures of death and neurodevelopmental impairment. Infants managed under restrictive guidelines fared no worse in regard to mortality and neurodevelopment in early life. The studies had remarkably similar demographics and used similar transfusion guidelines. In both, there were fewer transfusions in the restrictive arm. Nevertheless, there were large differences between the studies in regard to transfusion exposure with almost 3 times the number of transfusions per participant in the transfusion of prematures (TOP) study. Associated with this, there were differences between the studies in various outcomes. For example, the combined primary outcome of death or neurodevelopmental impairment was more likely to occur in the TOP study and the mortality rate itself was considerably higher. Whilst the reasons for these differences are likely multifactorial, it does raise the question as to whether they could be related to the transfusions themselves? Clearly, every effort should be made to reduce exposure to transfusions and this was more successful in the Effects of Transfusion Thresholds on Neurocognitive Outcomes (ETTNO) study. In this review, we look at factors which may explain these transfusion differences and the differences in outcomes, in particular neurodevelopment at age 2 years. In choosing which guidelines to follow, centers using liberal guidelines should be encouraged to adopt more restrictive ones. However, should centers with more restrictive guidelines change to ones similar to those in the studies? The evidence for this is less compelling, particularly given the wide range of transfusion exposure between studies. Individual centers already using restrictive guidelines should assess the validity of the findings in light of their own transfusion experience. In addition, it should be remembered that the study guidelines were pragmatic and acceptable to a large number of centers. The major focus in these guidelines was on hemoglobin levels which do not necessarily reflect tissue oxygenation. Other factors such as the level of erythropoiesis should also be taken into account before deciding whether to transfuse.

Maternal Underweight and Obesity Are Associated with Placental Pathologies in Human Pregnancy.

Maternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies. Data from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro- and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex. Pregnancies complicated by maternal obesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriately mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term. Maternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.

Factors associated with successful extubation following the first course of systemic dexamethasone in ventilator-dependent preterm infants with or at risk of developing bronchopulmonary dysplasia.

OBJECTIVES: We aimed to identify factors present at the start of an initial course of systemic dexamethasone that would be associated with successful extubation in mechanically ventilated neonates <30 weeks gestational age (GA) with or at risk of developing bronchopulmonary dysplasia (BPD). METHODS: We studied a retrospective cohort of neonates (23+0 -29+6 weeks GA), with or at risk of developing BPD, prescribed their first course of systemic dexamethasone to aid in extubation from mechanical ventilation. The data collected only pertained to the first course of dexamethasone. Neonates given dexamethasone for airway edema were not included. The primary outcome of interest was successful extubation (i.e., extubated within 14 days of starting dexamethasone and remaining extubated for at least 7 days). Binary logistic regression was employed. RESULTS: A total of 287 neonates were included. Each additional week of GA at birth led to a 1.53 increase in the odds of successful extubation (95% CI: 1.122-2.096, p < 0.01). Higher average fraction of inspired oxygen (FiO2 ) requirements in the preceding 24 h resulted in a 0.94 decrease in the odds of successful extubation (p < 0.05) and higher mean airway pressure (MAP) resulted in 0.76 decrease in odds of successful extubation (p < 0.01). CONCLUSIONS: Mechanically ventilated neonates with or at risk of developing BPD, born at <30 week GA and initiated on dexamethasone to facilitate extubation, had a lower likelihood of successful extubation by Day 14 if they had younger GA at birth, and at the time of commencing steroids had higher MAPs and had higher oxygen requirements.

Efficacy of standard- vs reduced-dose insulin for treatment of hyperkalemia: A quasi-experiment.

PURPOSE: Hyperkalemia more commonly affects patients with a glomerular filtration rate of less than 60 mL/min. Using intravenous (IV) insulin to shift potassium intracellularly may cause hypoglycemia, requiring additional treatment or longer hospitalization. Literature on insulin dosing in this context is limited, with one previous study indicating that 5 units of IV insulin might be as effective and result in less hypoglycemia than the standard dose of 10 units of IV insulin. The hyperkalemia treatment pathway at our institution was revised in May 2018 to include a reduced-dose option (5 units of insulin) for patients with end-stage renal disease. This study aimed to compare the prevalence of hypoglycemia between patients who received standard-dose vs reduced-dose IV insulin. METHODS: This single-center, retrospective, quasi-experimental study evaluated the impact of revision of the hyperkalemia treatment pathway by assessing rates of hypoglycemia during the 6 months before and after implementation of the revised pathway. The primary endpoint was prevalence of hypoglycemia, defined as a blood glucose level of less than or equal to 70 mg/dL. RESULTS: There was no statistically significant difference in the occurrence of hypoglycemia when comparing the pre- and postimplementation groups (36 [17.7%] patients vs 34 [18.7%] patients; P = 0.7924). The postimplementation group had a statistically significant lower reduction in potassium levels after treatment than the preimplementation group (mean [interquartile range], -0.9 [-1.3, -0.5] mEq/L vs -0.6 [-1.2, -0.2] mEq/L; P = 0.0095). Baseline potassium levels were similar between the groups. CONCLUSION: Administration of reduced-dose IV insulin for treatment of hyperkalemia was significantly less effective in lowering serum potassium levels and did not decrease prevalence of hypoglycemia. When accounting for potential confounders, the only variable that was associated with hypoglycemia was pretreatment glucose level.