Risk of congenital anomalies in children who have a sibling with cancer: A matched cohort study.

PURPOSE: We assessed the risk of congenital anomalies in children who have a sibling with cancer. METHODS: We performed a matched cohort study of children born between 2006 and 2022 in Quebec. The exposure was having a sibling with cancer. Exposed children were matched to unexposed children based on sex, number of siblings, birth order, and year. The outcome included heart defects, orofacial clefts, and other anomalies. Using conditional logistic regression, we estimated odds ratios (OR) and 95 % confidence intervals (CI) for the association between having a sibling with cancer and the likelihood of having a congenital anomaly. RESULTS: A total of 2403 children who had a sibling with cancer were matched to 240,257 unexposed children. Congenital anomalies were more frequent in children who had a sibling with cancer compared with unexposed children (10.3 % vs 8.9 %). Overall, having a sibling with cancer was only weakly associated with congenital anomalies (OR 1.18, 95 % CI 1.04-1.35). Exposed children tended to have greater odds of polydactyly/syndactyly (OR 1.89, 95 % CI 1.11-3.21) and urinary defects (OR 1.50, 95 % CI 1.09-2.08) compared with unexposed children. CONCLUSIONS: Children who have a sibling with cancer have an only weakly elevated risk of congenital anomalies.

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.

Association of first trimester anaesthesia with risk of congenital heart defects in offspring.

BACKGROUND: A substantial number of pregnant women require anaesthesia for non-obstetric surgery, but the risk to fetal heart development is unknown. We assessed the relationship between first trimester anaesthesia and risk of congenital heart defects in offspring. METHODS: We conducted a longitudinal cohort study of 2 095 300 pregnancies resulting in live births in hospitals of Quebec, Canada, between 1990 and 2016. We identified women who received general or local/regional anaesthesia in the first trimester, including anaesthesia between 3 and 8 weeks post-conception, the critical weeks of fetal cardiogenesis. The main outcome measures were critical and non-critical heart defects in offspring. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association of first trimester anaesthesia with congenital heart defects, using log-binomial regression models adjusted for maternal characteristics. RESULTS: There were 107.3 congenital heart defects per 10 000 infants exposed to anaesthesia, compared with 87.2 per 10 000 unexposed infants. Anaesthesia between 3 and 8 weeks post-conception was associated with 1.50 times the risk of congenital heart defects (95% CI 1.11-2.03), compared with no anaesthesia. Anaesthesia between 5 and 6 weeks post-conception was associated with 1.84 times the risk (95% CI 1.10-3.08). Associations were driven mostly by general anaesthesia, which was associated with 2.49 times the risk between weeks 5 and 6 post-conception (95% CI 1.40-4.44). CONCLUSIONS: General anaesthesia during critical periods of fetal heart development may increase the risk of congenital heart defects. Further research is needed to confirm that anaesthetic agents are cardiac teratogens.

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.

Objective: Infectious illness, including lower respiratory tract infection (LRTI), is a leading cause of childhood morbidity and infant mortality in Inuit children in Nunavut Canada. The carnitine palmitoyltransferase 1A (CPT1A) p.P479L variant is common in arctic Indigenous populations of Alaska, Canada, and Greenland. CPT1A is a fatty acid oxidation enzyme expressed in the liver, immunocytes and other tissues, and is needed to use fats for energy during fasting. Previous association of the variant with early childhood infectious illness and infant death has been challenged because of sample size and limited adjustment for confounders. We evaluated whether the p.P479L variant is associated with infectious illness in Inuit children of Nunavut, Canada. Methods: We conducted a retrospective clinical chart review of 2,225 Inuit children (0-5 years) for infectious illness (including otitis media, gastroenteritis, and hospital admission for LRTI), prenatal, perinatal, and socioeconomic indicators, subsequently linking to CPT1A genotype. Multivariable logistic regression adjusted for birth characteristics, breastfeeding, maternal smoking, food insecurity, and socioeconomic indicators. Results: Overall, 27% of children were hospitalized for LRTI, 86% had otitis media and 50% had gastroenteritis. The p.P479L allele frequency was 0.82. In multivariable analysis, p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46-5.64), otitis media (aOR:1.83, 95%CI:1.05-3.21), and gastroenteritis (aOR:1.74, 95%CI:1.09-2.77), compared to non-carriers. Conclusion: Children homozygous for the p.P479L variant were more likely to experience infectious illness than non-carriers, including hospitalization for respiratory tract infections. Given the role of CPT1A in immunocytes, our findings indicate that more study is needed to determine if there is a role of the variant in immune response. Continued Inuit involvement is essential when considering next steps.

Inflammatory Bowel Disease and Risk of Birth Defects in Offspring.

BACKGROUND AND AIMS: The relationship between inflammatory bowel disease in pregnancy and birth defects is not understood. We evaluated whether Crohn's disease and ulcerative colitis in pregnant women were associated with the risk of birth defects in the offspring. METHODS: We undertook a retrospective cohort study of 2 184 888 pregnancies in Quebec, Canada, between 1989 and 2016. We calculated risk ratios [RR] and 95% confidence intervals [CI] for the association between inflammatory bowel disease and the risk of birth defects, using generalised estimating equations adjusted for maternal characteristics. We assessed associations in the period before 2000, when immunosuppressive biologic therapy and folic acid food fortification were not yet available, compared with the period after 2000 when these interventions were more widespread. RESULTS: This study included 13 099 women with Crohn's disease and 7798 with ulcerative colitis. Crohn's disease was associated with 1.90 times [95% CI 1.10-3.28] the risk of abdominal wall defects [gastroschisis, omphalocoele, and diaphragmatic hernia] and ulcerative colitis was associated with 1.53 times [95% CI 1.02-2.30] the risk of central nervous system defects. The association of Crohn's disease with abdominal wall defects was stronger before 2000 [RR 3.62, 95% CI 1.71-7.67] than after 2000 [RR 1.23, 95% CI 0.55-2.75]. Ulcerative colitis was associated with central nervous system defects regardless of time period. CONCLUSIONS: These findings suggest that inflammatory bowel disease is associated with the risk of abdominal wall and central nervous system defects, and that introduction of immunobiologic medications is unlikely to be associated with added risk. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Explaining the variability in cardiovascular risk factors among First Nations communities in Canada: a population-based study.

BACKGROUND: Historical, colonial, and racist policies continue to influence the health of Indigenous people, and they continue to have higher rates of chronic diseases and reduced life expectancy compared with non-Indigenous people. We determined factors accounting for variations in cardiovascular risk factors among First Nations communities in Canada. METHODS: Men and women (n=1302) aged 18 years or older from eight First Nations communities participated in a population-based study. Questionnaires, physical measures, blood samples, MRI of preclinical vascular disease, and community audits were collected. In this cross-sectional analysis, the main outcome was the INTERHEART risk score, a measure of cardiovascular risk factor burden. A multivariable model was developed to explain the variations in INTERHEART risk score among communities. The secondary outcome was MRI-detected carotid wall volume, a measure of subclinical atherosclerosis. FINDINGS: The mean INTERHEART risk score of all communities was 17·2 (SE 0·2), and more than 85% of individuals had a risk score in the moderate to high risk range. Subclinical atherosclerosis increased significantly across risk score categories (p<0·0001). Socioeconomic advantage (-1·4 score, 95% CI -2·5 to -0·3; p=0·01), trust between neighbours (-0·7, -1·2 to -0·3; p=0·003), higher education level (-1·9, -2·9 to -0·8, p<0·001), and higher social support (-1·1, -2·0 to -0·2; p=0·02) were independently associated with a lower INTERHEART risk score; difficulty accessing routine health care (2·2, 0·3 to 4·1, p=0·02), taking prescription medication (3·5, 2·8 to 4·3; p<0·001), and inability to afford prescription medications (1·5, 0·5 to 2·6; p=0·003) were associated with a higher INTERHEART risk score. Collectively, these factors explained 28% variation in the cardiac risk score among communities. Communities with higher socioeconomic advantage and greater trust, and individuals with higher education and social support, had a lower INTERHEART risk score. Communities with difficulty accessing health care, and individuals taking or unable to afford prescription medications, had a higher INTERHEART risk score. INTERPRETATION: Cardiac risk factors are lower in communities with high socioeconomic advantage, greater trust, social support and educational opportunities, and higher where it is difficult to access health care or afford prescription medications. Strategies to optimise the protective factors and reduce barriers to health care in First Nations communities might contribute to improved health and wellbeing. FUNDING: Heart and Stroke Foundation of Canada, Canadian Partnership Against Cancer, Canadian Institutes for Health Research.

Bariatric surgery and the risk of congenital anomalies in subsequent pregnancies.

BACKGROUND: Data on the relationship between bariatric surgery and risk of birth defects are conflicting. OBJECTIVES: We studied the association of bariatric surgery with birth defects in future pregnancies in a large cohort of women. METHODS: We carried out a retrospective cohort study of 2,194,348 pregnancies that occurred between 1989 and 2016 in Quebec, Canada. We identified women who had bariatric surgery before pregnancy, and included nonobese women with no surgery as a comparison group. We estimated risk ratios (RRs) and 95% CIs for the associations between bariatric surgery and the risk of birth defects, using log-binomial regression models adjusted for maternal age, comorbidities, parity, whether there was a multiple birth, socioeconomic deprivation, and the presence of folic acid food fortification. RESULTS: In this study, 1845 deliveries were among women who had bariatric surgery before pregnancy (0.08%). Having bariatric surgery was associated with 1.20 times the risk of birth defects in later pregnancies (95% CI: 1.01, 1.43), compared with having no surgery or obesity. Obesity without having bariatric surgery was, in contrast, more weakly associated with birth defects (RR: 1.09; 95% CI: 1.07, 1.12). The association with bariatric surgery was greater for heart (RR: 1.47; 95% CI: 1.02, 2.12) and musculoskeletal defects (RR: 1.32; 95% CI: 1.02, 1.71). Associations were primarily present before folic acid food fortification was implemented (RR: 2.03; 95% CI: 1.41, 2.92), but not after (RR: 1.05; 95% CI: 0.86, 1.28). CONCLUSIONS: Having bariatric surgery was a risk factor for birth defects, and particularly heart and musculoskeletal defects. After fortification, however, an association was no longer present. Future studies are needed to determine whether micronutrient supplementation underpins the difference in the changing results pre- and postfortification.

Future risk of cancer in women who have children with birth defects.

PURPOSE: We studied whether having an infant with birth defects was associated with the risk of maternal cancer. METHODS: We carried out a longitudinal cohort study of 1,214,506 women who delivered infants between 1989 and 2016 in Quebec, Canada. We identified women whose infants had birth defects and followed the mothers over time to identify cancers up to 28 years after delivery. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between birth defects and maternal cancer, adjusted for maternal characteristics. RESULTS: A total of 36,050 women developed cancer during 19,251,851 person-years of follow-up. Relative to no birth defects, women whose infants had defects did not have an elevated risk of cancer overall (HR 1.03, 95% CI 0.99-1.06). However, associations were present with placental cancer (HR 2.23, 95% CI 1.04-4.77) and lymphoid leukemia (HR 1.61, 95% CI 1.03-2.51). Among specific birth defects, women whose infants had heart (HR 1.12, 95% CI 1.03-1.21) or sensory (HR 1.16, 95% CI 1.04-1.30) defects had a higher risk of cancer. CONCLUSIONS: We found inconsistent evidence of a clinically meaningful association between having an infant with birth defects and the risk of early maternal cancer.

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.

Prepregnancy asthma and the subsequent risk of central nervous system defects in offspring.

BACKGROUND: The relationship between childhood asthma and central nervous system defects in offspring is poorly understood. We assessed if childhood asthma was associated with the risk of having an infant with neural tube or other nervous system defects compared with asthma during pregnancy. METHODS: We analyzed a longitudinal cohort of 128,060 women who were 5 years or less at study entry and later delivered an infant in Quebec, Canada (1989-2014). We identified women hospitalized for asthma before pregnancy, including childhood and adolescence, and determined if asthma was present during pregnancy based on obstetric records. Main outcomes were neural tube and non-neural tube defects in pregnancy. We used log-binomial regression models to determine risk ratios (RR) and 95% confidence intervals (CI) for the association between asthma and risk of nervous system defects, adjusting for patient characteristics. RESULTS: Asthma was associated with a greater risk of neural tube defects in offspring (RR 2.39, 95% CI 1.03-5.53) compared with no asthma, but not non-neural tube defects (RR 1.10, 95% CI 0.71-1.71). Women whose asthma resolved before pregnancy had a greater risk of neural tube defects (RR 3.43, 95% CI 1.35-8.69), while women with asthma during pregnancy were at greater risk of non-neural tube defects, especially microcephaly (RR 2.80, 95% CI 1.23-6.40). CONCLUSIONS: Asthma that resolved before pregnancy was associated with an increased risk of neural tube defects in offspring but not non-neural tube defects. Further investigation is needed to determine the pathophysiology connecting childhood asthma with nervous system defects in offspring.

Pregnancy outcomes of women with spina bifida.

PURPOSE: To assess the pregnancy outcomes of women with spina bifida. MATERIALS AND METHODS: We analyzed a population-based cohort of 397 pregnant women with spina bifida and 1,083,211 without spina bifida who delivered infants in hospitals in Quebec, Canada, 1989-2013. Outcomes included maternal and infant morbidity and mortality at delivery. We used log-binomial regression models to estimate prevalence ratios (PR) and 95% confidence intervals (CI) for the association of maternal spina bifida with pregnancy outcomes, accounting for maternal characteristics. RESULTS: Women with spina bifida had a higher prevalence of several adverse outcomes compared with women who had no birth defects. Maternal risks were highest for intensive care unit admission during the delivery hospitalization (PR 3.41, CI 95% 1.56-7.43) and respiratory morbidity (PR 9.46, CI 95% 3.31-26.99). Infant risks were greatest for intracranial hemorrhage (PR 6.85, CI 95% 2.23-21.08), birth hypoxia (PR 1.64, CI 95% 1.21-2.22), and hospital length of stay ≥14 days (PR 2.56, CI 95% 1.58-4.15). After adjustment for confounders, maternal spina bifida was associated with risk of oral clefts and abdominal wall defects in infants. CONCLUSIONS: Women with spina bifida have an increased risk of severe maternal and infant complications at delivery, compared with no spina bifida. Implications for Rehabilitation A growing number of women with spina bifida achieve pregnancy, but pregnancy outcomes are poorly understood. In a large pregnancy cohort, women with spina bifida had a high risk of severe maternal and infant morbidity at delivery. Women with spina bifida may benefit from enhanced periconceptional counseling and obstetric monitoring by health professionals. Guidelines should be developed for rehabilitation care providers to improve the obstetric management of women with spina bifida.

Red blood cell folate levels in Canadian Inuit women of childbearing years: influence of food security, body mass index, smoking, education, and vitamin use.

BACKGROUND: The benefits of folic acid for prevention of congenital anomalies are well known. For the Inuit of Canada, where vitamin use is low and access to folate-rich foods limited, fortification is likely a major source of intake. We sought to determine whether red blood cell folate (RBCF) levels of Inuit women reached accepted target levels. METHODS: The Inuit Health Survey, 2007-2008, included evaluation of RBCF levels among 249 randomly selected non-pregnant women of reproductive age. Using descriptive statistics and linear regression analyses, RBCF levels were assessed and compared across several socio-demographic variables to evaluate the characteristics associated with RBCF status. RESULTS: Mean (SD) RBCF levels of 935.5 nmol/L (± 192) reached proposed target levels (> 906 nmol/L); however, 47% of women had lower than target levels. In bivariate analysis, non-smoking, higher education, higher income, food security, increased body mass index, and vitamin use were each significantly associated with higher RBCF. Increased levels of smoking had a negative association with RBCF levels (- 5.8 nmol/L per cigarette smoked per day (p = 0.001)). A total of 6.8% of women reported taking vitamin supplements, resulting in a 226 nmol/L higher RBCF level on average compared to non-users (p < 0.001). CONCLUSION: While mean levels of folate reached target levels, this was largely driven by the small number of women taking vitamin supplements. Our results suggest that folate status is often too low in Inuit women of childbearing years. Initiatives to improve food security, culturally relevant education on folate-rich traditional foods, vitamin supplements, and smoking cessation/reduction programs may benefit Inuit women and improve birth outcomes.

Canadian Alliance for Healthy Hearts and Minds: First Nations Cohort Study Rationale and Design.

BACKGROUND: This is the first national indigenous cohort study in which a common, in-depth protocol with a common set of objectives has been adopted by several indigenous communities across Canada. OBJECTIVES: The overarching objective of the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort is to investigate how the community-level environment is associated with individual health behaviors and the presence and progression of chronic disease risk factors and chronic diseases such as cardiovascular disease (CVD) and cancer. METHODS: CAHHM aims to recruit approximately 2,000 First Nations indigenous individuals from up to nine communities across Canada and have participants complete questionnaires, blood collection, physical measurements, cognitive assessments, and magnetic resonance imaging (MRI). RESULTS: Through individual- and community-level data collection, we will develop an understanding of the specific role of the socioenvironmental, biological, and contextual factors have on the development of chronic disease risk factors and chronic diseases. CONCLUSIONS: Information collected in the indigenous cohort will be used to assist communities to develop local management strategies for chronic disease, and can be used collectively to understand the contextual, environmental, socioeconomic, and biological determinants of differences in health status in harmony with First Nations beliefs and reality.

Risk of central nervous system defects in offspring of women with and without mental illness.

We sought to determine the relationship between maternal mental illness and the risk of having an infant with a central nervous system defect. We analyzed a cohort of 654,882 women aged less than 20 years between 1989 and 2013 who later delivered a live born infant in any hospital in Quebec, Canada. The primary exposure was mental illness during pregnancy or hospitalization for mental illness before pregnancy. The outcomes were neural and non-neural tube defects of the central nervous system in any offspring. We computed risk ratios (RR) and 95% confidence intervals (CI) for the association between mental disorders and risk of central nervous system defects in log-binomial regression models adjusted for age at delivery, total parity, comorbidity, socioeconomic deprivation, place of residence, and time period. Maternal mental illness was associated with an increased risk of nervous system defects in offspring (RR 1.76, 95% CI 1.64-1.89). Hospitalization for any mental disorder was more strongly associated with non-neural tube (RR 1.84, 95% CI 1.71-1.99) than neural tube defects (RR 1.31, 95% CI 1.08-1.59). Women at greater risk of nervous system defects in offspring tended to be diagnosed with multiple mental disorders, have more than one hospitalization for mental disease, or be 17 or older at first hospitalization. A history of mental illness is associated with central nervous system defects in offspring. Women hospitalized for mental illness may merit counseling at first symptoms to prevent central nervous system defects at pregnancy.

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.

Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.

BACKGROUND: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. METHODS AND RESULTS: Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant. CONCLUSIONS: We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.

Patient Recall, Interpretation, and Perspective of an Inconclusive Long QT Syndrome Genetic Test Result.

Patients' perceptions of inconclusive results have been previously investigated in cancer genetics. The differences in how patients recall and interpret an uninformative test result compared to a known pathogenic result can affect medical decisions post disclosure. However, there is little to no data available on patients' interpretation and perception of uninformative genetic results in inherited heart disease. We report the results of a qualitative analysis of 16 telephone interviews with participants who received a negative or a variant of unknown significance (VUS) result from Long QT syndrome (LQTS) genetic testing. Our results suggest that the type of result (negative versus VUS) does not affect recall, regardless of the reason for testing. When receiving a negative result, a majority of participants appropriately perceived no change in their diagnosis, while the perception of risk for family members varied. The majority of participants felt they maintained an awareness of their condition after the result disclosure, and that clinical follow-up was similar to that planned prior to the genetic test result. Further work is needed to determine if there are any differences between obtaining a VUS result versus a negative result in this population.

Elevated ambient temperatures and risk of neural tube defects.

OBJECTIVES: The association between ambient heat and neural tube defects has received limited attention, despite imminent climate warming this century. We sought to determine the relationship between elevated outdoor temperatures during neurogenesis and risk of neural tube defects. METHODS: We carried out a retrospective cohort study of 887 710 fetuses between 3 and 4 weeks postconception from the months of April through September for 1988-2012 in Quebec, Canada. The exposure was maximum daily temperature and the outcome presence of neural tube defects at delivery. We estimated prevalence ratios (PR) and 95% CIs for the association between maximum temperature and neural tube defects in log-binomial regression models adjusted for maternal characteristics. RESULTS: Relative to 20°C, exposure to temperatures of 30°C was associated with risk of neural tube defects on day 5 (PR 1.56, 95% CI 1.04 to 2.35) and day 6 (PR 1.49, 95% CI 1.00 to 2.21) of the 4th week postconception, during the time of neural tube closure. The trend was apparent for spina bifida and anencephalus/encephalocoele, the main subtypes of neural tube defects. Temperature during the 3rd week postconception was not associated with neural tube defects. CONCLUSIONS: Elevated ambient temperatures may be weakly associated with risk of neural tube defects during tube closure.

Air pollution, neighbourhood and maternal-level factors modify the effect of smoking on birth weight: a multilevel analysis in British Columbia, Canada.

BACKGROUND: Maternal smoking during pregnancy negatively impacts fetal growth, but the effect is not homogenous across the population. We sought to determine how the relationship between cigarette use and fetal growth is modified by the social and physical environment. METHODS: Birth records with covariates were obtained from the BC Perinatal Database Registry (N = 232,291). Maternal smoking status was self-reported as the number of cigarettes smoked per day usually at the first prenatal care visit. Census dissemination areas (DAs) were used as neighbourhood-level units and linked to individual births using residential postal codes to assign exposure to particulate air pollution (PM2.5) and neighbourhood-level attributes such as socioeconomic status (SES), proportion of post-secondary education, immigrant density and living in a rural place. Random coefficient models were used with cigarettes/day modeled with a random slope to estimate its between-DA variability and test cross-level interactions with the neighbourhood-level variables on continuous birth weight. RESULTS: A significant negative and non-linear association was found between maternal smoking and birth weight. There was significant between-DA intercept variability in birth weight as well as between-DA slope variability of maternal smoking on birth weight of which 68 and 30 % respectively was explained with the inclusion of DA-level variables and their cross-level interactions. High DA-level SES had a strong positive association with birth weight but the effect was moderated with increased cigarettes/day. Conversely, heavy smokers showed the largest increases in birth weight with rising neighbourhood education levels. Increased levels of PM2.5 and immigrant density were negatively associated with birth weight, but showed positive interactions with increased levels of smoking. Older maternal age and suspected drug or alcohol use both had negative interactions with increased levels of maternal smoking. CONCLUSION: Maternal smoking had a negative and non-linear dose-response association with birth weight which was highly variable between neighbourhoods and evidence of effect modification with neighbourhood-level factors. These results suggest that focusing exclusively on individual behaviours may have limited success in improving outcomes without addressing the contextual influences at the neighbourhood-level. Further studies are needed to corroborate our findings and to understand how neighbourhood-level attributes interact with smoking to affect birth outcomes.