Rights, interests and expectations: Indigenous perspectives on unrestricted access to genomic data.

Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.

Is there a way to reduce the inequity in variant interpretation on the basis of ancestry?

The underrepresentation of non-European ancestry groups in current genomic databases complicates interpretation of their genetic test results, yielding a much higher prevalence of variants of uncertain significance (VUSs). Such VUS findings can frustrate the goals of genetic testing, create anxiety in patients, and lead to unnecessary medical interventions. Approaches to addressing underrepresentation of people with genetic ancestries other than European are being undertaken by broad-based recruitment efforts. However, some underrepresented groups have concerns that might preclude participation in such efforts. We describe here two initiatives aimed at meeting the needs of underrepresented ancestry groups in genomic datasets. The two communities, the Sephardi Jewish community in New York and First Peoples of Canada, have very different concerns about contributing to genomic research and datasets. Sephardi concerns focus on the possible negative effects of genetic findings on the marriage prospects of family members. Canadian Indigenous populations seek control over the research uses to which their genetic data would be put. Both cases involve targeted efforts to respond to the groups' concerns; these efforts include governance models aimed at ensuring that the data are used primarily to inform clinical test analyses and at achieving successful engagement and participation of community members. We suggest that these initiatives could provide models for other ancestral groups seeking to improve the accuracy and utility of clinical genetic testing while respecting the underlying preferences and values of community members with regard to the use of their genetic data.

Association of maternal cancer with congenital anomalies in offspring.

BACKGROUND: Congenital anomalies are common, but the possibility that maternal cancer increases the chance of having a child with a birth defect is not fully understood. OBJECTIVES: To examine the association between maternal cancer before or during pregnancy and the risk of birth defects in offspring. METHODS: We conducted a retrospective cohort study of live births in Quebec, Canada, between 1989 and 2022 using hospital data. The main exposure measure was maternal cancer before or during pregnancy. The outcome included birth defects detected in offspring during gestation or at birth. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association of maternal cancer with birth defects using log-binomial regression models adjusted for potential confounders. RESULTS: In this study of 2,568,120 newborns, birth defects were present in 6.0% and 6.7% of infants whose mothers had cancer before or during pregnancy, respectively, compared with 5.7% of infants whose mothers never had cancer. Cancer during pregnancy was associated with heart (RR 1.58, 95% CI 1.03, 2.44), nervous system (RR 4.05, 95% CI 2.20, 7.46) and urinary defects (RR 1.72, 95% CI 1.01, 2.95). Among specific types of malignancies during pregnancy, breast cancer was the most prominent risk factor for birth defects (RR 1.55, 95% CI 1.02, 2.37). Cancer before pregnancy was not associated with any type of birth defect or with defects overall (RR 1.01, 95% CI 0.92, 1.11). Moreover, no specific type of cancer before pregnancy was associated with an increased risk of birth defects. CONCLUSIONS: Maternal cancer during pregnancy is associated with the risk of congenital anomalies in offspring, however, cancer before pregnancy is not associated with this outcome.

Congenital anomalies during Covid-19: artifact of surveillance or a real TORCH?

Infections in the first trimester of pregnancy can be teratogenic, but the possibility that Covid-19 could lead to birth defects is unclear. We examined whether SARS-CoV-2 infection during pregnancy or exposure to pandemic conditions were associated with the risk of congenital anomalies. We carried out a retrospective study of 420,222 neonates born in Quebec, Canada in two time periods: prepandemic (January 1, 2017 to March 12, 2020) vs. pandemic (March 13, 2020 to March 31, 2022). We classified pandemic births as early (first trimester completed before the pandemic) or late (first trimester during the pandemic), and identified patients with SARS-CoV-2 infections during pregnancy. We applied (1) adjusted log-binomial regression models to assess the association between SARS-CoV-2 infection and congenital anomalies, and (2) autoregressive interrupted time series regression to analyze temporal trends in the monthly number of defects in all patients regardless of infection. In total, 29,263 newborns (7.0%) had a congenital anomaly. First trimester SARS-CoV-2 infections were not associated with a greater risk of birth defects compared with no infection (RR 1.07, 95% CI 0.59-1.95). However, births during the late pandemic period were more likely to be diagnosed with congenital microcephaly compared with prepandemic births (RR 1.44, 95% CI 1.21-1.71). Interrupted time series analysis confirmed that the frequency of microcephaly increased during the late pandemic period, whereas other anomalies did not. We conclude that Covid-19 is likely not teratogenic, but enhanced surveillance of anomalies among late pandemic births may have heightened the detection of infants with microcephaly.

Maternal deaths by suicide and drug overdose in two Canadian provinces; retrospective review.

OBJECTIVE: To identify and review factors associated with maternal deaths by suicide and drug overdose in the Canadian Coroner and Medical Examiners Database (CCMED), from 2017-2019. METHODS: We identified potential maternal deaths in Ontario and British Columbia by searching the CCMED narratives of deaths to females 10 to 60 years old for pregnancy-related terms. Identified narratives were then qualitatively reviewed in quadruplicate to determine if they were maternal deaths by suicide or drug overdose, and to extract information on maternal characteristics, the manner of death, and factors associated with each death. RESULTS: Of the 90 deaths identified in this study, 15 (16.7%) were due to suicide and 20 (22.2%) were due to a drug overdose. These deaths occurred to women of varying ages and across the pregnancy-postpartum period. Among the suicides, 10 were by hanging, and among the overdose-related deaths, 15 had fentanyl detected. Notably, 13 (37.1%) of the 35 deaths to suicide or drug overdose occurred beyond 42 days after pregnancy, 19 (54.3%) followed a miscarriage or induced abortion, and in 23 (65.7%) there was an established history of mental health illness. Substance use disorders were documented in 4 of the 15 suicides (26.7%), and 18 of the 20 overdose-related deaths (90.0%). CONCLUSION: Suicide and drug overdose may contribute more to maternal deaths in Canada than previously realized. Programs are needed to identify women at risk of these outcomes, and to intervene during pregnancy and beyond the conventional postpartum period.

The multigenerational impact of long QT syndrome: A Gitxsan perspective.

Long QT syndrome (LQTS), a rare cardiac condition that can lead to sudden death, is highly prevalent in First Nations communities of northern British Columbia. In the Gitxsan community of 5500, an estimated 1 in 125 individuals are affected, primarily due to the novel pathogenic variant p.V205M in KCNQ1. Over the past decade, more than 800 Gitxsan individuals received genetic testing and counseling for LQTS through a community-based study. Despite the substantial research characterizing the biological underpinnings of LQTS, there are few studies exploring the lived experiences of families with LQTS, especially those of Indigenous peoples. The goal of this study was to gain a greater understanding of the impact of the genetic confirmation of LQTS in this community, and the impact the condition has on individuals, their families, and the community. A qualitative study was developed in consultation with a local research advisory board and a Talking Circle, a traditional Indigenous format for discussion, was held. Four people who belonged to the same kindred group attended the Talking Circle. This article presents the multigenerational impact that LQTS and genetic diagnosis have through the reflections of one Gitxsan family. LQTS affects identity and family relationships, including those between parents and children, siblings, and even extended family members. Laughter and humor played an important part in coping. The role of family relationships for this Gitxsan family was seen to be critical in managing an LQTS diagnosis. This multigenerational perspective provides key insights into family structure and dynamics which can inform genetic counseling and clinical care. As cultural safety is experienced and therefore defined by the person receiving services, listening to the perspectives and preferences of Indigenous peoples is essential to the delivery of culturally informed care.

Extended Risk of Mortality in Children with Inborn Errors of Metabolism: A Longitudinal Cohort Study.

OBJECTIVES: To determine the long-term risk of mortality among children with inborn errors of metabolism. STUDY DESIGN: We conducted a retrospective cohort study of 1750 children with inborn errors of metabolism (excluding mitochondrial disorders) and 1 036 668 children without errors of metabolism who were born in Quebec, Canada, between 2006 and 2019. Main outcome measures included all-cause and cause-specific mortality between birth and 14 years of age. We used adjusted survival regression models to estimate HRs and 95% CIs for the association between inborn errors of metabolism and mortality over time. RESULTS: Mortality rates were greater for children with errors of metabolism than for unaffected children (69.1 vs 3.2 deaths per 10 000 person-years). During 7 702 179 person-years of follow-up, inborn errors of metabolism were associated with 21.2 times the risk of mortality compared with no error of metabolism (95% CI 17.23-26.11). Disorders of mineral metabolism were associated with greater mortality the first 28 days of life (HR 60.62, 95% CI 10.04-365.98), and disorders of sphingolipid metabolism were associated with greater mortality by 1 year (HR 284.73, 95% CI 139.20-582.44) and 14 years (HR 1066.00, 95% CI 298.91-3801.63). Errors of metabolism were disproportionately associated with death from hepatic/digestive (HR 208.21, 95% CI 90.28-480.22), respiratory (HR 116.57, 95% CI 71.06-191.23), and infectious causes (HR 119.83, 95% CI 40.56-354.04). CONCLUSIONS: Children with errors of metabolism have a considerably elevated risk of mortality before 14 years, including death from hepatic/digestive, respiratory, and infectious causes. Targeting these causes of death may help improve long-term survival.

Importance of genetic testing in unexplained cardiac arrest.

AIMS: Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). METHODS AND RESULTS: Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of 'explained' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. CONCLUSIONS: Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.

Genomic Research Through an Indigenous Lens: Understanding the Expectations.

Indigenous scholars are leading initiatives to improve access to genetic and genomic research and health care based on their unique cultural contexts and within sovereign-based governance models created and accepted by their peoples. In the past, Indigenous peoples' engagement with genomicresearch was hampered by a lack of standardized guidelines and institutional partnerships, resulting in group harms. This article provides a comparative analysis of research guidelines from Canada, New Zealand, Australia, and the United States that pertain to Indigenous peoples. The goals of the analysis are to identify areas that need attention, support Indigenous-led governance, and promote the development of a model research policy framework for genomic research and health care that has international relevance for Indigenous peoples.

Observational study of birth outcomes in children with inborn errors of metabolism.

BACKGROUND: We examined the birth outcomes of children with inborn errors of metabolism detected at birth or later in life. METHODS: We carried out a retrospective cohort study of 1733 children with inborn errors of metabolism and 1,033,693 unaffected children born in Canada between 2006 and 2019. Primary outcomes included preterm birth, low birth weight, congenital anomalies, and other neonatal complications. We estimated adjusted risk ratios (RR) and 95% confidence intervals (CI) for the association of inborn errors of metabolism with each outcome. RESULTS: Children with inborn errors of metabolism had 2.51 times the risk of preterm birth (95% CI 2.27-2.77) and 3.08 times the risk of low birth weight (95% CI 2.77-3.42) compared with unaffected children. Disorders of mineral and lipoprotein metabolism were more strongly associated with adverse birth outcomes. Inborn errors of metabolism were associated with congenital anomalies (RR 2.62; 95% CI 2.36-2.90), particularly abdominal wall defects (RR 8.35; 95% CI 5.18-13.44). Associations were present for errors of metabolism diagnosed both at birth and later in life. CONCLUSIONS: Children with inborn errors of metabolism, whether detected at birth or later, are at high risk of adverse birth outcomes and congenital anomalies. IMPACT: Inborn errors of metabolism may affect fetal development, but the association with adverse birth outcomes is not well characterized. This study indicates that children with inborn errors of metabolism are at risk of preterm birth, neonatal jaundice, congenital anomalies, and a range of other adverse birth outcomes. Mothers of children with inborn errors of metabolism are at risk of preeclampsia and cesarean delivery. Adverse birth outcomes may be a first sign of inborn errors of metabolism that merit increased screening.

Cascade testing for inherited arrhythmia conditions: Experiences and attitudes of family communication approaches for a Canadian cohort.

Inherited arrhythmia conditions (IAC) can lead to sudden cardiac death at any age, and relatives of an affected person have up to a 50% chance of inheriting the condition and are at risk for developing features. Cascade testing is a stepwise approach for identifying relatives at risk for IACs through clinical screening and genetic testing. Early detection can reduce morbidity and mortality for affected individuals and determine potential risk mitigation strategies for relatives. However, cardiovascular genetic studies have reported an incomplete uptake of cascade testing in at-risk relatives. We explored patient perspectives on cascade testing for IACs and alternative approaches to family communication. Twelve semi-structured phone interviews were conducted with probands of the British Columbia Inherited Arrhythmia Program confirmed to carry a pathogenic or likely pathogenic variant in a gene associated with an IAC. Thematic analysis of transcripts through an iterative coding process revealed five main themes: (a) a stepwise approach is followed in disclosing risk to relatives, (b) relatives' autonomy in cascade testing is supported, (c) lived experience with the condition influences disclosure and uptake of cascade testing, (d) collaborative approach to informing relatives reduces negative impact of disclosure, and (e) direct contact from a healthcare provider is viewed as acceptable. The findings highlight this patient cohort's experiences and opinions with approaches to disclosure and demonstrate their understanding and acceptance of their relatives' approaches to cascade testing. In addition, while the notion of direct contact was generally accepted, a collaborative approach to contacting relatives between the proband and provider may be most effective.

Time trends, geographic variation and risk factors for gastroschisis in Canada: A population-based cohort study 2006-2017.

BACKGROUND: Previous studies showed increases in rates of gastroschisis in Canada in the first decade of the 21st century. OBJECTIVE: We sought to examine the epidemiologic characteristics of gastroschisis in Canada in recent years. METHODS: We conducted a retrospective population-based cohort study of all livebirths and stillbirths delivered in Canada (excluding Quebec) from 2006 to 2017, with information obtained from the Canadian Institute for Health Information. Gastroschisis rates by maternal age, region of residence, and maternal and infant characteristics were quantified using prevalence rate ratios (RR) and 95% confidence intervals (CI). Log-binomial regression was used to quantify the associations between risk factors and gastroschisis. RESULTS: There were 1314 gastroschisis cases among 3 364 116 births. The prevalence rate was 3.7 per 10 000 total births in 2006 and 3.4 per 10 000 total births in 2017, with substantial annual variation in rates. The proportion of mothers aged 20-24 years decreased from 16.5% in 2006 to 11.3% in 2017, while the proportion of mothers aged <20 years halved from 4.8% to 2.3%. The prevalence of gastroschisis at birth remained unchanged among mothers aged <20, 20-24 and 30-49 years but increased among mothers aged 25-29 years. The age-adjusted prevalence rate of gastroschisis increased across the period (for 2016-2017 versus 2006-2007 rate ratio [RR] 1.28, 95% CI 1.05, 1.56), and there was substantial regional variation. Risk factors included problematic use of substances (RR 2.61, 95% CI 2.01, 3.39) and hypothyroidism (RR 2.76, 95% CI 1.56, 4.88). There was a North-to-South difference in gastroschisis prevalence (adjusted RR Far North compared with South 1.54, 95% CI 1.11, 2.15). CONCLUSION: Gastroschisis birth prevalence rates in Canada have stabilised in recent years compared with the increase documented previously. The substantial geographic variation and North-to-South difference in gastroschisis prevalence may indicate variation in socio-economic status, lifestyle and nutritional patterns.

Neonatal hypoglycemia and the CPT1A P479L variant in term newborns: A retrospective cohort study of Inuit newborns from Kivalliq Nunavut.

INTRODUCTION: Neonatal hypoglycemia (NH) in the first days of life can largely be prevented by recognizing those at risk and managing accordingly. The CPT1A P479L variant is prevalent in northern Indigenous populations and is a possible risk factor for hypoglycemia. We report on NH incidence in the Kivalliq region of Nunavut, where all Inuit newborns are screened for NH. METHODS: We reviewed clinical charts of 728 Inuit newborns from Kivalliq (January 1, 2010 to December 31, 2013) for blood glucose (BG) levels and infant/maternal characteristics, linking to CPT1A genotype; 616 newborns had BG data from 2 to 48 hours of life. NH was defined using Canadian Paediatric Society guidelines (≤2.0 mmol/L at 2 hours, <2.6 mmol/L at 2 to 48 hours). RESULTS: NH was documented in 21.4% overall, 24.4% of at-risk newborns and 19.5% of term newborns with no risk factors (≥37 weeks gestation, term-NRF). NH was documented in 22.0% of CPT1A P479L homozygous, 19.8% of P479L heterozygous and 4.8% of noncarrier term-NRF newborns. With multivariable logistic regression, the adjusted ORs for developing NH in term-NRF newborns was 4.97 for CPT1A P479L homozygotes (95% confidence interval [CI]:0.65-38.35, P=0.19) and 4.71 for P479L heterozygotes (95% CI:0.57-37.89, P=0.15). CONCLUSION: Term-NRF newborns had a higher NH incidence than previously reported, similar to that for at-risk newborns, possibly due to the CPT1A P479L variant. Since only Inuit newborns from Kivalliq are screened for NH, further study of long-term outcomes of NH in this population and the role of the P479L variant are warranted to determine if neonatal BG screening is indicated in all Inuit newborns.

Ankyrin-B p.S646F undergoes increased proteasome degradation and reduces cell viability in the H9c2 rat ventricular cardiomyoblast cell line.

Ankyrin-B (AnkB) is scaffolding protein that anchors integral membrane proteins to the cardiomyocyte cytoskeleton. We recently identified an AnkB variant, AnkB p.S646F (ANK2 c.1937 C>T) associated with a phenotype ranging from predisposition for cardiac arrhythmia to cardiomyopathy. AnkB p.S646F exhibited reduced expression levels in the H9c2 rat ventricular-derived cardiomyoblast cell line relative to wildtype AnkB. Here, we demonstrate that AnkB is regulated by proteasomal degradation and proteasome inhibition rescues AnkB p.S646F expression levels in H9c2 cells, although this effect is not conserved with differentiation. We also compared the impact of wildtype AnkB and AnkB p.S646F on cell viability and proliferation. AnkB p.S646F expression resulted in decreased cell viability at 30 h after transfection, whereas we observed a greater proportion of cycling, Ki67-positive cells at 48 h after transfection. Notably, the number of GFP-positive cells was low and was consistent between wildtype AnkB and AnkB p.S646F expressing cells, suggesting that AnkB and AnkB p.S646F affected paracrine communication between H9c2 cells differentially. This work reveals that AnkB levels are regulated by the proteasome and that AnkB p.S646F compromises cell viability. Together, these findings provide key new insights into the putative cellular and molecular mechanisms of AnkB-related cardiac disease.

Severe maternal morbidity surveillance: Monitoring pregnant women at high risk for prolonged hospitalisation and death.

BACKGROUND: There is no international consensus on the definition and components of severe maternal morbidity (SMM). OBJECTIVES: To propose a comprehensive definition of SMM, to create an empirically justified list of SMM types and subtypes, and to use this to examine SMM in Canada. METHODS: Severe maternal morbidity was defined as a set of heterogeneous maternal conditions known to be associated with severe illness and with prolonged hospitalisation or high case fatality. Candidate SMM types/subtypes were evaluated using information on all hospital deliveries in Canada (excluding Quebec), 2006-2015. SMM rates for 2012-2016 were quantified as a composite and as SMM types/subtypes. Rate ratios and population attributable fractions (PAF) associated with overall and specific SMM types/subtypes were estimated in relation to length of hospital stay (LOS > 7 days) and case fatality. RESULTS: There were 22 799 cases of SMM subtypes (among 1 418 545 deliveries) that were associated with a prolonged LOS or high case fatality. Between 2012 and 2016, the composite SMM rate was 16.1 (95% confidence interval [CI] 15.9, 16.3) per 1000 deliveries. Severe pre-eclampsia and HELLP syndrome (514.6 per 100 000 deliveries), and severe postpartum haemorrhage (433.2 per 100 000 deliveries) were the most common SMM types, while case fatality rates among SMM subtypes were highest among women who had cardiac arrest and resuscitation (241.1 per 1000), hepatic failure (147.1 per 1000), dialysis (67.6 per 1000), and cerebrovascular accident/stroke (51.0 per 1000). The PAF for prolonged hospital stay related to SMM was 17.8% (95% CI 17.3, 18.3), while the PAF for maternal death associated with SMM was 88.0% (95% CI 74.6, 94.4). CONCLUSIONS: The proposed definition of SMM and associated list of SMM subtypes could be used for standardised SMM surveillance, with rate ratios and PAFs associated with specific SMM types/subtypes serving to inform clinical practice and public health policy.

Understanding the personal and community impact of long QT syndrome: A perspective from Gitxsan women.

There is a disproportionately high rate of hereditary long QT syndrome (LQTS) in Northern British Columbia First Nations people, largely due to a novel missense variant in KCNQ1 (p.V205M). The variant has been previously described predisposing those affected to syncope, arrhythmia, and sudden death. Although the biological aspects of LQTS have been explored extensively, less research has been done into the impact of living with a genetic variant that predisposes one to sudden death, and no previous studies have provided cultural insights from a First Nations community. The goal of this study was to explore what facilitates and hinders resiliency and coping for those living with LQTS. Participants were invited to partake in their choice of one-to-one interviews, Photovoice, and Talking Circles. This paper presents the findings from the interview portion of the study. Interviews were recorded, transcribed, and analyzed qualitatively using the systematic text condensation method. Ten women shared their personal experiences of living with LQTS through individual interviews. Half of the women had tested positive for the p.V205M variant, and the other half were awaiting results. In general, learning about a LQTS diagnosis was perceived as traumatic, with gradual acceptance that led to coping. The main factors found to facilitate resiliency and coping were positive family relationships, spirituality, and knowledge about LQTS. The main factors found to hinder resiliency and coping were a poor understanding of the biological or clinical aspects of LQTS, conflicting medical advice (especially regarding physical activity) and LQTS not being taken seriously by social contacts and healthcare providers. It appears that learning to live with LQTS is an ongoing process, requiring balance and interconnectedness between all aspects of well-being.

Maternal proximity to extremely low frequency electromagnetic fields and risk of birth defects.

Causes of birth defects are unclear, and the association with electromagnetic fields is inconclusive. We assessed the relationship between residential proximity to extremely low frequency electromagnetic fields from power grids and risk of birth defects. We analyzed a population-based sample of 2,164,246 infants born in Quebec, Canada between 1989 and 2016. We geocoded the maternal residential postal code at delivery and computed the distance to the nearest high voltage electrical transmission line or transformer station. We used log-binomial regression to estimate risk ratios (RR) and 95% confidence intervals (CI) for the association of residential proximity to transmission lines and transformer stations with birth defects, adjusting for maternal and infant characteristics. The prevalence of birth defects within 200 m of a transmission line (579.4 per 10,000 per live births) was only slightly higher compared with distances further away (568.7 per 10,000). A similar trend was seen for transformer stations. Compared with 200 m, a distance of 50 m was not associated with the risk of birth defects for transmission lines (RR 1.00, 95% CI 1.00-1.01) and transformer stations (RR 1.01, 95% CI 1.00-1.03). There was no consistent association when we examined birth defects in different organ systems. We found no compelling evidence that residential proximity to extremely low frequency electromagnetic fields from electrical power grids increases the risk of birth defects. Women residing near electrical grids can be reassured that an effect on the risk of birth defects is unlikely.

Severe Maternal Morbidity in Canada: Temporal Trends and Regional Variations, 2003-2016.

OBJECTIVE: This study sought to quantify temporal trends and provincial and territorial variations in severe maternal morbidity (SMM) in Canada. METHODS: The study used data on all hospital deliveries in Canada (excluding Québec) from 2003 to 2016 to examine temporal trends and from 2012 to 2016 to study regional variations. SMM was identified using diagnosis and intervention codes. Contrasts among periods and regions were quantified using rate ratios (RRs) and 95% confidence intervals (CIs). Temporal changes were also assessed using chi-square tests for trend (Canadian Task Force Classification II-1). RESULTS: The study population included 3 882 790 deliveries between 2003 and 2016 and 1 418 545 deliveries between 2012 and 2016. Severe hemorrhage rates increased from 44.8 in 2003 to 62.4 per 10 000 deliveries in 2012 (P for trend <0.0001) and then declined to 41.8 per 10 000 deliveries in 2016 (P for trend <0.0001). Maternal intensive care unit admission and sepsis rates decreased between 2003 and 2016, whereas rates of stroke, severe uterine rupture, hysterectomy, obstetric embolism, shock, and assisted ventilation increased. Rates of composite SMM in 2012-2016 were higher in Newfoundland and Labrador (RR 1.15; 95% CI 1.04-1.26), Nova Scotia (RR 1.11; 95% CI 1.03-1.19), New Brunswick (RR1.22; 95% CI 1.13-1.32), Manitoba (RR 1.09; 95% CI 1.03-1.15), Saskatchewan (RR 1.15; 95% CI 1.09-1.22), the Yukon (RR 1.74; 95% CI 1.35-2.25), and Nunavut (RR 1.76; 95% CI 1.46-2.11) compared with the rest of Canada, whereas rates were lower in Alberta and British Columbia. CONCLUSION: This surveillance report helps inform clinical practice and public health policy for improving maternal health in Canada.

The p.P479L variant in CPT1A is associated with infectious disease in a BC First Nation.

BACKGROUND: The hepatic carnitine palmitoyltransferase I (CPT1A) p.P479L variant is common in Aboriginal populations across coastal British Columbia, Alaska, the Canadian North, and Greenland. While the high frequency of this variant suggests positive selection, other studies have shown an association with sudden unexpected death in infancy and infection. We utilized administrative health data to evaluate hospitalizations for a single year cohort of children of First Nations descent genotyped for the variant and, matched for location of birth. Seven years of data were reviewed for 150 children split evenly between CPT1A genotypes (homozyous, heterozygous, and noncarrier of the p.P479L variant). RESULTS: Children homozygous for the p.P479L allele had a higher rate of hospital admissions at 2.6 per individual as compared to noncarriers at 0.86. Heterozygous children also showed a significant increase at 1.9 per person. Length of stay per admission was increased for both p.P479L homozygotes and heterozygotes. The odds ratio (OR) for at least one hospitalization for any reason was increased for p.P479L homozygotes relative to noncarriers (OR=10.2, confidence interval [CI] 3.5 to 30.0) as were admissions for dental caries (OR=3.4, CI 1.5 to 7.8), acute lower respiratory tract infections (OR=6.0, CI 1.6 to 22.4), and otitis media (OR=13.5, CI 1.7 to 109.4). CONCLUSIONS: The CPT1A p.P479L variant is associated with an increased rate of hospitalization for those homozygous, primarily for infectious disease causes. Heterozygotes also showed a small but significant increase in hospitalization rates suggesting some dosage effect. Functional studies will be required to identify the underlying pathological mechanism.

Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci.

BACKGROUND & AIMS: Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations. METHODS: In all, 44 individuals with Primary Biliary Cholangitis and 61 unaffected relatives from 32 First Nations families participated. Family history and co-morbidities were documented. Medical records were reviewed and available biopsies were re-reviewed by our team pathologist. Genotyping was performed on DNA from 36 affected persons and 27 unaffected relatives using the Affymetrix Human Mapping 500K Array Set. MERLIN software was used to carry out multipoint parametric and nonparametric linkage analysis. Candidate genes were identified and entered into InnateDB and KEGG software to identify potential pathways affecting pathogenesis. RESULTS: In all, 34% of families were multiplex. Fifty per cent of cases and 33% of unaffected relatives reported other autoimmune disease. Three genomic regions (9q21, 17p13 and 19p13) produced LOD scores of 2.3 or greater suggestive of linkage, but no single linkage peak reached statistical significance. Candidate genes identified in the three regions suggested involvement of IL17, NFκB, IL6, JAK-STAT, IFNγ and TGFß immune signalling pathways. Specifically, four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in these pathways that may influence Primary Biliary Cholangitis pathogenesis. CONCLUSIONS: Our whole genome linkage study results reflect the multifactorial nature of Primary Biliary Cholangitis, support previous studies suggesting signalling pathway involvement and identify new candidate genes for consideration.