The clinical performance and population health impact of birthweight-for-gestational age indices at term gestation.

BACKGROUND: The assessment of birthweight for gestational age and the identification of small- and large-for-gestational age (SGA and LGA) infants remain contentious, despite the recent creation of the Intergrowth 21st Project and World Health Organisation (WHO) birthweight-for-gestational age standards. OBJECTIVE: We carried out a study to identify birthweight-for-gestational age cut-offs, and corresponding population-based, Intergrowth 21st and WHO centiles associated with higher risks of adverse neonatal outcomes, and to evaluate their ability to predict serious neonatal morbidity and neonatal mortality (SNMM) at term gestation. METHODS: The study population was based on non-anomalous, singleton live births between 37 and 41 weeks' gestation in the United States from 2003 to 2017. SNMM included 5-min Apgar score <4, neonatal seizures, need for assisted ventilation, and neonatal death. Birthweight-specific SNMM was modelled by gestational week using penalised B-splines. The birthweights at which SNMM odds were minimised (and higher by 10%, 50% and 100%) were estimated, and the corresponding population, Intergrowth 21st, and WHO centiles were identified. The clinical performance and population impact of these cut-offs for predicting SNMM were evaluated. RESULTS: The study included 40,179,663 live births and 991,486 SNMM cases. Among female singletons at 39 weeks' gestation, SNMM odds was lowest at 3203 g birthweight, and 10% higher at 2835 g and 3685 g (population centiles 11th and 82nd, Intergrowth centiles 17th and 88th and WHO centiles 15th and 85th). Birthweight cut-offs were poor predictors of SNMM, for example, the cut-offs associated with 10% and 50% higher odds of SNMM among female singletons at 39 weeks' gestation resulted in a sensitivity, specificity, and population attributable fraction of 12.5%, 89.4%, and 2.1%, and 2.9%, 98.4% and 1.3%, respectively. CONCLUSIONS: Reference- and standard-based birthweight-for-gestational age indices and centiles perform poorly for predicting adverse neonatal outcomes in individual infants, and their associated population impact is also small.

Consortium for the Study of Pregnancy Treatments (Co-OPT): An international birth cohort to study the effects of antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure. METHODS: The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records. RESULTS AND DISCUSSION: The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS.

Antenatal Corticosteroid Prophylaxis at Late Preterm Gestation: Clinical Guidelines Versus Clinical Practice.

OBJECTIVE: We investigated how the Antenatal Late Preterm Steroids (ALPS) trial findings have been translated into clinical practice in Canada and the United States (U.S.). METHODS: The study included all live births in Nova Scotia, Canada, and the U.S. from 2007 to 2020. Antenatal corticosteroids (ACS) administration within specific categories of gestational age was assessed by calculating rates per 100 live births, and temporal changes were quantified using odds ratio (OR) and 95% confidence intervals (CI). Temporal trends in optimal and suboptimal ACS use were also assessed. RESULTS: In Nova Scotia, the rate of any ACS administration increased significantly among women delivering at 350 to 366 weeks, from 15.2% in 2007-2016 to 19.6% in 2017-2020 (OR 1.36, 95% CI 1.14-1.62). Overall, the U.S. rates were lower than the rates in Nova Scotia. In the U.S., rates of any ACS administration increased significantly across all gestational age categories: among live births at 350 to 366 weeks gestation, any ACS use increased from 4.1% in 2007-2016 to 18.5% in 2017-2020 (OR 5.33, 95% CI 5.28-5.38). Among infants between 240 and 346 weeks gestation in Nova Scotia, 32% received optimally timed ACS, while 47% received ACS with suboptimal timing. Of the women who received ACS in 2020, 34% in Canada and 20% in the U.S. delivered at ≥37 weeks. CONCLUSION: Publication of the ALPS trial resulted in increased ACS administration at late preterm gestation in Nova Scotia, Canada, and the U.S. However, a significant fraction of women receiving ACS prophylaxis delivered at term gestation.

Cannabis use in pregnancy and maternal and infant outcomes: A Canadian cross-jurisdictional population-based cohort study.

BACKGROUND: With the recent legalization of cannabis in Canada, there is an urgent need to understand the effect of cannabis use in pregnancy. Our population-based study investigated the effects of prenatal cannabis use on maternal and newborn outcomes, and modification by infant sex. METHODS: The cohort included 1,280,447 singleton births from the British Columbia Perinatal Data Registry, the Better Outcomes Registry & Network Ontario, and the Perinatal Program Newfoundland Labrador from April 1st, 2012 to March 31st, 2019. Logistic regression determined the associations between prenatal cannabis use and low birth weight, small-for-gestational age, large-for-gestational age, spontaneous and medically indicated preterm birth, very preterm birth, stillbirth, major congenital anomalies, caesarean section, gestational diabetes and gestational hypertension. Models were adjusted for other substance use, socio-demographic and-economic characteristics, co-morbidities. Interaction terms were included to investigate modification by infant sex. RESULTS: The prevalence of cannabis use in our cohort was approximately 2%. Prenatal cannabis use is associated with increased risks of spontaneous and medically indicated preterm birth (1.80[1.68-1.93] and 1.94[1.77-2.12], respectively), very preterm birth (1.73[1.48-2.02]), low birth weight (1.90[1.79-2.03]), small-for-gestational age (1.21[1.16-1.27]) and large-for-gestational age (1.06[1.01-1.12]), any major congenital anomaly (1.71[1.49-1.97]), caesarean section (1.13[1.09-1.17]), and gestational diabetes (1.32[1.23-1.42]). No association was found for stillbirth or gestational hypertension. Only small-for-gestational age (p = 0.03) and spontaneous preterm birth (p = 0.04) showed evidence of modification by infant sex. CONCLUSIONS: Prenatal cannabis use increases the likelihood of preterm birth, low birth weight, small-for-gestational age and major congenital anomalies with prenatally exposed female infants showing evidence of increased susceptibility. Additional measures are needed to inform the public and providers of the inherent risks of cannabis exposure in pregnancy.

Maternal cannabis use during pregnancy and maternal and neonatal outcomes: A retrospective cohort study.

OBJECTIVE: To examine the relationship between reported prenatal cannabis use and neonatal and maternal outcomes and whether the legalisation of cannabis in Canada affected the rates of reported use or the association with maternal and neonatal outcomes. DESIGN: Population-based retrospective cohort study. SETTING: Routinely collected data in a real-world setting. POPULATION: All women in the Canadian province of Nova Scotia with singleton births between 1 January 2004 and 30 June 2021. METHODS: The association between cannabis use and maternal and neonatal outcomes was examined using generalised linear models with inverse probability weighting. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes in the peripartum and postpartum period. RESULTS: Rates of reported cannabis use in pregnancy increased from 1.3% to 7.5% over the study period with no appreciable change in slope after legalisation in 2018. Infants of mothers reporting cannabis use in pregnancy were more likely to have major anomalies and a 5-minute Apgar score ≤7, require neonatal intensive care unit admission, and had lower birthweight, head circumference and birth length than infants of mothers not reporting cannabis use. These associations did not differ before and after legalisation. CONCLUSIONS: Reported cannabis use during pregnancy is associated with early postnatal complications and reduced fetal growth, even after taking into account a range of confounding factors. Rates of reported cannabis use during pregnancy increased over the past 5 years in Nova Scotia with no apparent additional effect of legalisation.

A window into portal hemodynamics in adult fontan patients?

BACKGROUND: Fontan circulation alters portal venous hemodynamics, causing chronic passive hepatic congestion and fibrosis. This congestion increases liver stiffness (LS) leading to overestimates of liver fibrosis as measured by ultrasound shear wave elastography (SWE) of the liver. We evaluated whether Fontan circulation has a similar effect on spleen stiffness (SS) and SS/LS ratio as measured by SWE. METHODS: We retrospectively compared the SS of adult Fontan patients to age and gender matched, control patients without congenital heart disease. We correlated SS measurements to LS measurements and also performed a limited subgroup analysis of SS in Fontan patients with various manifestations of Fontan Associated Liver Disease. RESULTS: SS in Fontan patients was similar to healthy controls (1.43 vs. 1.36 m/s, p = 0.26). LS was elevated in 78% of the Fontan patients (mean 1.68 m/s, SD 0.31, 95% CI 1.53-1.85). The correlation between LS and SS was modest (Pearson's correlation coefficient, r = 0.5) but did not reach statistical significance (p = 0.06). The mean SS/LS ratio was 0.85 (95% CI 0.77-0.94). CONCLUSION: Based on our study cohort, SS in Fontan patients is similar to age and gender matched control patients without congenital heart disease. The SS/LS ratio, however, is frequently less than 1, which is lower than that reported in both healthy patients and those with other forms of non-cardiac liver disease. SS and SS/LS ratio may be a useful indicator of portal hemodynamics in Fontan patients.

Neonatal Cardiac Emergencies: A Multidisciplinary Simulation Curriculum for Neonatology and Pediatric Cardiology Fellows.

Introduction: Although care for neonates with cardiac disease is frequently provided by neonatologists and pediatric cardiologists, training in the multidisciplinary management of neonatal cardiac emergencies is not often included in fellowship training. We created a multidisciplinary simulation curriculum to address the skills needed for neonatal cardiac care. Methods: Neonatology and pediatric cardiology fellows participated in 1-hour simulations on 3 different days. They managed a neonate with: (1) cyanosis, (2) cardiogenic shock, and (3) an unstable arrhythmia. Using both remote consultation and bedside evaluation, the participants diagnosed and jointly established a management plan for the infant. During the debrief, facilitators reviewed the clinical decisions and multidisciplinary management skills of the participants. Participants completed pre- and postparticipation surveys to evaluate the curriculum's effect on their confidence in the management of neonatal cardiac disease. Results: Thirty-three paired survey responses from 20 participants (11 neonatology and 9 pediatric cardiology) reported a mean overall satisfaction score of 4.6 (SD = 0.7) based on a 5-point Likert scale. Postparticipation confidence scores improved significantly in: (1) the recognition of the signs of congenital heart disease (pre = 4.1, post = 4.5, p = .01), (2) differentiation of cardiac cyanosis from noncardiac cyanosis (pre = 3.9, post = 4.2, p = .05), and (3) confidence in discussing cardiac concerns with consultants (pre = 3.3, post = 4.1, p = .02). Discussion: This multidisciplinary simulation improved fellows' confidence in the management of neonates with cardiac disease and provided an opportunity to practice team work, remote consultation, and cross-disciplinary communication.

Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations.

Background Patients with hereditary hemorrhagic telangiectasia have liver vascular malformations that can cause high-output cardiac failure (HOCF). Known sequelae include pulmonary hypertension, tricuspid regurgitation, and atrial fibrillation. Methods and Results The objectives of this study were to describe the clinical, echocardiographic, and hemodynamic characteristics and prognosis of hereditary hemorrhagic telangiectasia patients with HOCF who were found to have a subaortic membrane (SAoM). A retrospective observational analysis comparing patients with and without SAoM was performed. Among a cohort of patients with HOCF, 9 were found to have a SAoM in the left ventricular outflow tract by echocardiography (all female, mean age 64.8±4.0 years). The SAoM was discrete and located in the left ventricular outflow tract 1.1±0.1 cm below the aortic annular plane. It caused turbulent flow, mild obstruction (peak velocity 2.8±0.2 m/s, peak gradient 32±4 mm Hg), and no more than mild aortic insufficiency. Patients with SAoM (n=9) had higher cardiac output (12.1±1.3 versus 9.3±0.7 L/min, P=0.04) and mean pulmonary artery pressures (36±3 versus 28±2 mm Hg, P=0.03) compared with those without SAoM (n=19) during right heart catheterization. Genetic analysis revealed activin receptor-like kinase 1 mutations in each of the 8 patients with SAoM who had available test results. The presence of a SAoM was associated with a trend towards higher 5-year mortality during follow-up. Conclusions SAoM with mild obstruction occurs in patients with hereditary hemorrhagic telangiectasia and HOCF. SAoM was associated with features of more advanced HOCF and poor outcomes.

The 3G Multigenerational Cohort of Nova Scotian women and their mothers and offspring.

BACKGROUND: The negative impact of exposures such as maternal obesity, excessive gestational weight gain, and hypertension in pregnancy on the health of the next generation has been well studied. Evidence from animal studies suggests that the effects of in utero exposures may persist into the second generation, but the epidemiological literature on the influence of pregnancy-related exposures across three generations in humans is sparse. OBJECTIVES: This cohort was established to investigate associations between antenatal and perinatal exposures and health outcomes in women and their offspring. POPULATION: The cohort includes women who were born and subsequently had their own pregnancies in the Canadian province of Nova Scotia from 1980 onward. DESIGN: Intergenerational linkage of data in the Nova Scotia Atlee Perinatal Database was used to establish a population-based dynamic retrospective cohort. METHODS: The cohort has prospectively collected information on sociodemographics, maternal health and health behaviours, pregnancy health and complications, and obstetrical and neonatal outcomes for two generations of women and their offspring. PRELIMINARY RESULTS: As of October 2018, the 3G cohort included 14 978 grandmothers (born 1939-1986), 16 766 mothers or cohort women (born 1981-2003), and 28 638 children (born 1996-2018). The cohort women were generally younger than Nova Scotian women born after 1980, and as a result, characteristics associated with pregnancy at a younger age were more frequently seen in the cohort women; sampling weights will be created to account for this design effect. The cohort will be updated annually to capture future deliveries to women who are already in the cohort and women who become eligible for inclusion when they deliver their first child. CONCLUSIONS: The 3G Multigenerational Cohort is a population-based cohort of women and their mothers and offspring, spanning a time period of 38 years, and provides the opportunity to study inter- and transgenerational associations across the maternal line.

Delayed Diagnosis of Ankylosing Spondylitis: A Missed Opportunity?

Ankylosing spondylitis is an inflammatory condition involving the axial spine, often associated with the human leukocyte antigen (HLA)-B27 genotype and supporting radiographic imaging findings. Patients develop symptomatic low back and/or hip pain beginning in late adolescence or early adulthood. Diagnosis of ankylosing spondylitis is based primarily on clinical presentation and imaging studies. In this article, we are presenting a case of a 40-year-old male patient who presented to the office with chief concerns of chronic mid-thoracic back pain and restricted range of motion of his neck. The imaging study obtained was suggestive of fusion of the sacroiliac joints. This article also highlights the presence of elevated inflammatory markers in the setting of the patients chronic symptomatic complaints which could have guided in early diagnosis.

Reflex Sympathetic Dystrophy of the Right Hand following an Acute Traumatic Injury.

Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy, is a chronic neuropathic pain disorder with significant autonomic features. Recently, it has been recognized that CRPS is not simply a sympathetically mediated peripheral pain condition but rather a disease of the central nervous system as well. Herein, we present a case of a patient who presented with complaints of severe pain following a traumatic event, severing his extensor tendon of his right fifth finger.

Relative effectiveness and cost-effectiveness of the midwifery-led care in Nova Scotia, Canada: A retrospective, cohort study.

OBJECTIVES: To compare neonatal and maternal outcomes, and the relative risk of interventions between mothers attended to by midwives, general practitioners, and obstetricians, and to assess the cost-effectiveness of the employee-model of midwifery-led care in Nova Scotia, Canada, when compared with general practitioners. DESIGN, SETTING, AND PARTICIPANTS: The study was a retrospective cohort study involving routinely collected clinical and administrative data from all low-risk births from January 1st, 2013 to December 31st, 2017. There were 24,662 observations. MEASUREMENTS: Descriptive statistics were used to summarise the mother's socio-demographic characteristics. We used a nearest-neighbour matching estimator in assessing differences in outcomes, and generalized linear models in the estimation of the risks of interventions, adjusting for potential confounders. An analytic decision tree served as the vehicle for the cost-effectiveness analysis, assessed using the net monetary benefit approach. All health care resources utilized were measured and valued. Neonatal intensive care admissions avoided was the measure of outcome. We performed probabilistic sensitivity and subgroup analyses. FINDINGS: Mothers attended to by midwives spent less time at the hospital during birth admissions, were less likely to have interventions, instrumental births, and more likely to have exclusive breastfeeding at discharge from birth admission. There were no differences in Apgar scores and neonatal intensive care unit admissions. The employee-model of midwifery-led care was found to be cost-effective. KEY CONCLUSIONS: The midwifery program is both effective and cost-effective for low-risk pregnancies IMPLICATIONS FOR PRACTICE: Increasing the number of midwives will increase access and represents value for money.

Fetal Echocardiographic Measures to Improve the Prenatal Diagnosis of Coarctation of the Aorta.

The objective of this study is to identify fetal echocardiographic measures that predict postnatal coarctation of the aorta (CoA). A retrospective review of patients from 2013 to 2017 identified 13 cases of prenatal diagnosis of CoA confirmed postnatally and 14 cases of prenatal diagnosis of CoA with normal arches postnatally. There were 30 controls. Measurements were made and indices applied on all available longitudinal fetal echocardiograms for each patient. Linear mixed effects models were used to examine the between-group differences in the trajectories of the measurements. Significant differences were seen in the true CoA group for the following: smaller distal transverse arch diameter to distance between the left common carotid and left subclavian arteries (DT/LCA-LSCA) index (p = 0.04), smaller distal transverse arch diameter (p = 0.005), and longer brachiocephalic to left common carotid artery (LCA) (p = 0.004) and LCA-left subclavian artery (LSCA) distances (p < 0.0001). Additionally, the LCA/DT index trend appears to differentiate false positives from true coarctations (p < 0.03). The fetal echocardiographic DT/LCA-LSCA index, brachiocephalic-LCA distance and LCA-LSCA distance are significant predictors of postnatal coarctation. The LCA/DT index trend over time may differentiate which of those patients with prenatal concern for coarctation are more likely to develop coarctation postnatally. The use of fetal echocardiographic measures may improve prenatal detection and predication of postnatal coarctation.

3-Year Outcomes of the Edwards SAPIEN Transcatheter Heart Valve for Conduit Failure in the Pulmonary Position From the COMPASSION Multicenter Clinical Trial.

OBJECTIVES: This study provides the 3-year follow-up results of the COMPASSION (Congenital Multicenter Trial of Pulmonic Valve Regurgitation Studying the SAPIEN Transcatheter Heart Valve) trial. Patients with moderate to severe pulmonary regurgitation and/or right ventricular outflow tract conduit obstruction were implanted with the SAPIEN transcatheter heart valve (THV). BACKGROUND: Early safety and efficacy of the Edwards SAPIEN THV in the pulmonary position have been established through a multicenter clinical trial. METHODS: Eligible patients were included if body weight was >35 kg and in situ conduit diameter was ≥16 and ≤24 mm. Adverse events were adjudicated by an independent clinical events committee. Three-year clinical and echocardiographic outcomes were evaluated in these patients. RESULTS: Fifty-seven of the 63 eligible patients were accounted for at the 3-year follow-up visit from a total of 69 implantations in 81 enrolled patients. THV implantation was indicated for pulmonary stenosis (7.6%), regurgitation (12.7%), or both (79.7%). Twenty-two patients (27.8%) underwent implantation of 26-mm valves, and 47 patients received 23-mm valves. Functional improvement in New York Heart Association functional class was observed in 93.5% of patients. Mean peak conduit gradient decreased from 37.5 ± 25.4 to 17.8 ± 12.4 mm Hg (p < 0.001), and mean right ventricular systolic pressure decreased from 59.6 ± 17.7 to 42.9 ± 13.4 mm Hg (p < 0.001). Pulmonary regurgitation was mild or less in 91.1% of patients. Freedom from all-cause mortality at 3 years was 98.4%. Freedom from reintervention was 93.7% and from endocarditis was 97.1% at 3 years. There were no observed stent fractures. CONCLUSIONS: Transcatheter pulmonary valve replacement using the Edwards SAPIEN THV demonstrates excellent valve function and clinical outcomes at 3-year follow-up.

Physical activity barriers, preferences, and beliefs in childhood cancer patients.

PURPOSE: Childhood cancer patients report low physical activity levels despite the risk for long-term complications that may benefit from exercise. Research is lacking regarding exercise barriers, preferences, and beliefs among patients (1) on- and off-therapy and (2) across the age spectrum. METHODS: Cross-sectional study in the Yale Pediatric Hematology-Oncology Clinic (October 2013-October 2014). Participants were ≥ 4 years old, > 1 month after cancer diagnosis at < 20 years, not acutely ill, expected to live > 6 months, and received chemotherapy and/or radiation. Participants (or parents if < 13 years) completed a survey. RESULTS: The 162 patients (99% participated) were 34% children (4.0-12.9 years), 31% adolescents (13.0-17.9 years), and 35% adults (≥ 18 years). Most had leukemia/lymphoma (66%); 32% were on-therapy. On-therapy patients were more likely than off-therapy patients (73 vs. 48%; p = 0.003) to report ≥ 1 barrier related to physical complaints, such as "just too tired" (46 vs. 28%; p = 0.021) or "afraid" of injury (22 vs. 9%; p = 0.027). The majority preferred walking (73%), exercising at home (91%), exercising in the afternoon (79%), and a maximum travel time of 10-20 min (54%); preferences did not vary significantly by therapy status or age. Most respondents (94%) recognized the benefits of exercise after cancer, but 50% of on- vs. 12% of off-therapy patients believed "their cancer diagnosis made it unsafe to exercise regularly" (p < 0.001). CONCLUSIONS: Physical activity barriers pertaining to physical complaints and safety concerns were more pronounced in on-therapy childhood cancer patients but persisted off-therapy. Preferences and beliefs were relatively consistent. Our data can inform interventions in different patient subgroups.

Chlamydia trachomatis regulates innate immune barrier integrity and mediates cytokine and antimicrobial responses in human uterine ECC-1 epithelial cells.

PROBLEM: Chlamydia trachomatis infection is the most common sexually transmitted bacterial infection worldwide and known to increase the risk for HIV acquisition. Few studies have investigated how infection of epithelial cells compromises barrier integrity and antimicrobial response. METHOD OF STUDY: ECC-1 cells, a human uterine epithelial cell line, were treated with live and heat-killed C. trachomatis. Epithelial barrier integrity measured as transepithelial resistance (TER), chemokines antimicrobial levels, and antimicrobial mRNA expression was measured by ELISA and Real-time RT-PCR. RESULTS: Epithelial barrier integrity was compromised when cells were infected with live, but not with heat-killed, C. trachomatis. IL-8 secretion by ECC-1 cells increased in response to live and heat-killed C. trachomatis, while MCP-1, HBD2 and trappin2/elafin secretion decreased with live C. trachomatis. CONCLUSION: Live C. trachomatis suppresses ECC-1 innate immune responses by compromising the barrier integrity, inhibiting secretion of MCP-1, HBD2, and trappin-2/elafin. Differential responses between live and heat-killed Chlamydia indicate which immune responses are dependent on ECC-1 infection rather than the extracellular presence of Chlamydia.