[Show abstract][Hide abstract] ABSTRACT: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. Survival to reproductive age and beyond is now the norm. Several manifestations of this syndrome, such as congenital cardiac disease and neuropsychiatric disorders, may increase risk for adverse pregnancy outcomes in the general population. However, there are limited data on reproductive health in 22q11.2DS. We performed a retrospective chart review for 158 adults with 22q11.2DS (75 male, 83 female; mean age 34.3 years) and extracted key variables relevant to pregnancy and reproductive health. We present four illustrative cases as brief vignettes. There were 25 adults (21 > age 35 years; 21 female) with a history of one or more pregnancies. Outcomes for women with 22q11.2DS, compared with expectations for the general population, showed a significantly elevated prevalence of small for gestational age liveborn offspring (p < 0.001), associated mainly with infants with 22q11.2DS. Stillbirths also showed elevated prevalence (p < 0.05). Not all observed adverse events appeared to be attributable to transmission of the 22q11.2 deletion. Recurring issues relevant to reproductive health in 22q11.2DS included the potential impact of maternal morbidities, inadequate social support, unsafe sexual practices, and delayed diagnosis of 22q11.2DS and/or lack of genetic counseling. These preliminary results emphasize the importance of early diagnosis and long term follow-up that could help facilitate genetic counseling for men and women with 22q11.2DS. We propose initial recommendations for pre-conception management, educational strategies, prenatal planning, and preparation for possible high-risk pregnancy and/or delivery.
Journal of Genetic Counseling 01/2015; · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, estimated to affect up to 1 in 2,000 live births. Major features of this multisystem condition include congenital anomalies, developmental delay, and an array of early- and later-onset medical and psychiatric disorders. Advances in pediatric care ensure a growing population of adults with 22q11.2DS. Informed by an international panel of multidisciplinary experts and a comprehensive review of the existing literature concerning adults, we present the first set of guidelines focused on managing the neuropsychiatric, endocrine, cardiovascular, reproductive, psychosocial, genetic counseling, and other issues that are the focus of attention in adults with 22q11.2DS. We propose practical strategies for the recognition, evaluation, surveillance, and management of the associated morbidities.Genet Med advance online publication 08 January 2015Genetics in Medicine (2014); doi:10.1038/gim.2014.175.
Genetics in medicine: official journal of the American College of Medical Genetics 01/2015; · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to determine outcomes in pregnant women with pre-existing coronary artery disease (CAD) or following an acute coronary syndrome (ACS) including myocardial infarction (MI).
The physiological changes of pregnancy can contribute to myocardial ischaemia. The pregnancy risk for women with pre-established CAD or a history of ACS/MI is not well studied.
This was a retrospective multicentre study. Adverse maternal cardiac, obstetric and fetal/neonatal events were examined. The primary outcome was a composite endpoint of cardiac arrest, ACS/MI, ventricular arrhythmia or congestive heart failure. The prevalence of new or progressive angina during pregnancy was also examined.
Fifty pregnancies in 43 women (mean age 35±5 years) were included. Coronary atherosclerosis (40%) and coronary thrombus (36%) were the most common underlying diagnoses. The primary outcome occurred in 10% (5/50) of pregnancies and included one maternal death secondary to cardiac arrest. Other events included ACS/MI (3/50) and heart failure (1/50). New or progressive angina occurred in 18% of pregnancies. Ischaemic complications of any type (new or progressive angina, ACS/MI, ventricular arrhythmia, cardiac arrest) occurred more commonly in women with coronary atherosclerosis compared with those without (50% vs 10%, p=0.003). A high rate of adverse obstetric (16%) and fetal/neonatal (30%) events was observed.
Pregnant women with pre-existing CAD or ACS/MI before pregnancy are at increased risk of adverse events during pregnancy. Those with coronary atherosclerosis are at highest risk of adverse maternal cardiac events due to myocardial ischaemia during pregnancy.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Background: Women with preeclampsia may develop pulmonary edema, but the reasons for this are largely unknown. Methods: We performed a case-control study of women with preeclampsia at two major obstetrical centres in Toronto, ON, between 2005 and 2012. Cases (n = 28) were women with preeclampsia who had pulmonary edema on a chest CT or plain X-ray during the index delivery hospitalization. Control subjects (n = 64) were those with preeclampsia but no diagnosis of pulmonary edema or heart failure in the index hospitalization for delivery. Study variables were abstracted from each woman's paper chart and electronic medical record. Multivariable logistic regression with backward elimination was used to select a final set of significant predictors. Results: Approximately one half of the cases of pulmonary edema occurred antepartum. Each 10 × 10(9)/L reduction in platelet count (OR 1.32; 95% CI 1.06 to 1.65) or 10 µmol/ L increase in peak serum uric acid concentration (OR 1.19; 95% CI 1.06 to 1.34) was significantly associated with pulmonary edema, as was receiving magnesium sulphate (OR 10.42; 95% CI 1.39 to 78.22). Multiparity (OR 0.03; 95% CI 0.004 to 0.29) and each 500 mL increase in the volume of intravenous crystalloids received (OR 0.60; 95% CI 0.37 to 0.98) were associated with a lower risk of pulmonary edema. Conclusion: We identified several preliminary risk factors for pulmonary edema in women with preeclampsia. Additional work is needed to better understand the role of these and other factors predicting the development of pulmonary edema in women with preeclampsia.
[Show abstract][Hide abstract] ABSTRACT: Late arrhythmias are common in adults undergoing Rastelli repair with a right ventricle (RV) to pulmonary artery (PA) conduit. The mechanism of arrhythmias has not been described. We sought to describe the prevalence, clinical predictors and mechanisms of supraventricular (SVT) and ventricular tachycardia (VT) in this population.
[Show abstract][Hide abstract] ABSTRACT: Background
Patent foramen ovale (PFO) may be a risk factor for unexplained (“cryptogenic”) stroke or transient ischemic attack (TIA). We sought to determine the efficacy and safety of transcatheter PFO closure compared with antithrombotic therapy for secondary prevention of cerebrovascular events among patients with cryptogenic stroke.
We performed a systematic review and meta-analysis of Medline and Embase (inception – March 2013) for randomized clinical trials (RCTs) comparing transcatheter PFO closure to medical therapy in subjects with cryptogenic stroke. Data were independently extracted on trial conduct quality, baseline characteristics, efficacy, and safety events from published manuscripts and appendices. Risk ratios (RR) and 95% CIs for the composite of stroke or TIA, and adverse cardiovascular events including atrial fibrillation/flutter were constructed.
Three RCTs of 2,303 subjects with prior stroke, TIA, or systemic arterial embolism (mean age 45.7 years, 47.3% women, mean follow-up 2.6 years) were included. PFO closure did not significantly reduce the risk of recurrent stroke/TIA (3.7% vs. 5.2%; RR 0.73, 95% CI, 0.50-1.07; P=0.10); however, an increased risk of incident atrial fibrillation/flutter was detected (3.8% vs. 1.0%; RR 3.67, 95% CI, 1.95-6.89; P<0.0001). No significant heterogeneity was detected for any endpoint among subgroups of patients stratified by age, sex, index cardiovascular event, device type, inter-atrial shunt size, and presence of an atrial septal aneurysm (all P-interactions ≥0.09).
Meta-analysis of RCTs assessing transcatheter PFO closure for secondary prevention of cerebrovascular events in subjects with cryptogenic stroke does not demonstrate benefit compared with antithrombotic therapy, and suggests potential risks.
The Canadian journal of cardiology 10/2014; · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined.Methods:We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions.Results:We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4-BP5) region, including seven novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin (P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases.Conclusion:The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care.Genet Med advance online publication 31 July 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.83.
Genetics in medicine: official journal of the American College of Medical Genetics 07/2014; · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Delayed gas exchange kinetics in the early recovery period after exercise testing has been reported in children and adults with congenital heart disease (ACHD). Our objective was to compare early and late phase recovery kinetics in three groups of ACHD-patients.
International Journal of Cardiology 07/2014; · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Progress in management of congenital heart disease has shifted mortality largely to adulthood. However, adult survivors with complex congenital heart disease are not cured and remain at risk of premature death as young adults. Thus, our aim was to describe the evolution and mortality risk of adult patient cohorts with complex congenital heart disease.Methods
Among 12 644 adults with congenital heart disease followed at a single center from 1980 to 2009, 176 had Eisenmenger syndrome, 76 had unrepaired cyanotic defects, 221 had atrial switch operations for transposition of the great arteries, 158 had congenitally corrected transposition of the great arteries, 227 had Fontan palliation, and 789 had repaired tetralogy of Fallot. We depict the 30-year evolution of these 6 patient cohorts, analyze survival probabilities in adulthood, and predict future number of deaths through 2029.ResultsSince 1980, there has been a steady increase in numbers of patients followed, except in cohorts with Eisenmenger syndrome and unrepaired cyanotic defects. Between 1980 and 2009, 308 patients in the study cohorts (19%) died. At the end of 2009, 85% of survivors were younger than 50 years. Survival estimates for all cohorts were markedly lower than for the general population, with important differences between cohorts. Over the upcoming two decades, we predict a substantial increase in numbers of deaths among young adults with subaortic right ventricles, Fontan palliation, and repaired tetralogy of Fallot.Conclusions
Anticipatory action is needed to prepare clinical services for increasing numbers of young adults at risk of dying from complex congenital heart disease.
[Show abstract][Hide abstract] ABSTRACT: Background
Cardiac disease is the leading cause of maternal death. Non-fatal ischemic events may go unnoted during the time of delivery. The aim of this study was to assess the incidence of subclinical myocardial ischemia amongst parturients, as evidenced by a raised troponin assay in the postpartum period.
We undertook a prospective observational pilot study in a tertiary obstetric hospital with over 7000 deliveries a year. Targeted sampling was used to enter subjects in pre-defined high- or low-risk groups for myocardial strain, according to their clinical history and a brief questionnaire. Troponin T levels of 140 women were assessed between 8 and 24 h postpartum.
Ninety-one women considered to be at high risk and 49 at low risk women for myocardial strain were enrolled. The overall mean (± SD) serum troponin T level at 24 h postpartum was 8.7 ± 19.7 ng/L (normal range <14 ng/L). The incidence of a positive troponin result was 4.3% (95% CI 1.6, 9.1). Four patients (8.2%) of the low-risk group and two (2.2%) in the high-risk group had elevated troponin T assays.
This study found that 4% of women had elevated postpartum troponin assays, within levels in the range suggestive of myocardial damage. However, we were unable to ascertain how to identify this group of women prospectively. At this time, we recommend a low threshold for investigation should be maintained.
International Journal of Obstetric Anesthesia 07/2014; 24(1). · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Chronic hemodynamically relevant pulmonary regurgitation (PR) resulting in important right ventricular (RV) dilation and ventricular dysfunction is commonly seen after tetralogy of Fallot (TOF) repair. Late adverse clinical outcomes, including exercise intolerance, arrhythmias, heart failure and/or death, accelerate in the third decade of life and are cause for considerable concern. Timing of pulmonary valve replacement (PVR) to address chronic PR is controversial, particularly in asymptomatic individuals, and impact of PVR on clinical measures has not been determined.
Canadian Outcomes Registry Late After Tetralogy of Fallot Repair (CORRELATE) is a prospective, multi-centre, Canada-wide cohort study. Candidates will be included if they are ≥12 years of age, have had surgically repaired TOF resulting in moderate or severe PR, and are able to undergo cardiovascular magnetic resonance imaging (CMR). Enrollment of >1000 individuals from 15 participating centres (Toronto, Montreal, Quebec City, Sherbrooke, Halifax, Calgary, Edmonton and Vancouver) is anticipated. Clinical data, health-related quality of life metrics and adverse outcomes will be entered into a web-based database. A central core lab will analyze all CMR studies (PR severity, RV volumes and ventricular function). Major adverse outcomes (sustained ventricular tachycardia and cardiovascular cause of death) will be centrally adjudicated.
CORRELATE will be the first prospective pan-Canadian cohort study of congenital heart disease in children and adults. CORRELATE will uniquely link clinical, imaging and functional data in those with repaired TOF and important PR, thereby enabling critical evaluation of clinically relevant outcomes in those managed conservatively as compared with those referred for PVR.
The Canadian journal of cardiology 06/2014; · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In women with valvular heart disease, pregnancy-associated cardiovascular changes can contribute to maternal, fetal, and neonatal complications. Ideally, a woman with valvular heart disease should receive preconception assessment and counselling from a cardiologist with expertise in pregnancy. For women with moderate- and high-risk valve lesions, appropriate risk stratification and management during pregnancy will optimise outcomes. Pregnancy in women with high-risk lesions, such as severe aortic stenosis, severe mitral stenosis, and those with mechanical valves, requires careful planning and coordination of antenatal care by a multidisciplinary team. The purpose of this overview is to describe the expected haemodynamic changes in pregnancy, review pregnancy risks for women with valvular heart disease, and discuss strategies for management.
Best practice & research. Clinical obstetrics & gynaecology 05/2014; · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background22q11.2 deletion syndrome (22q11.2DS) is a relatively common yet under-recognized genetic syndrome that may present with endocrine features. We aimed to address the factors that contribute to the high prevalence of hypocalcemia.Methods
We investigated hypocalcemia in a well characterized sample of 138 adults with 22q11.2DS (65 M, 73 F; mean age 34.2, SD 11.8, years) using laboratory studies and lifelong medical records. Logistic regression modelling was used to identify features associated with lifetime prevalence of hypocalcemia.ResultsOf the total sample, 111 (80.4%) had a lifetime history of hypocalcemia. Eleven (84.6%) of 13 subjects with neonatal hypocalcemia had documented recurrence of hypocalcemia. Lifetime history of hypocalcemia was associated with lifetime prevalences of hypoparathyroidism (p < 0.0001) and hypothyroidism (p = 0.04), as statistically independent factors. Hypomagnesemia was associated with concurrent hypocalcemic measurements, especially in the presence of concurrent hypoparathyroidism (p = 0.02).Conclusions
The results suggest that, in addition to the major effect of hypoparathyroidism, hypothyroidism may play a role in hypocalcemia in 22q11.2DS, and that there is a high recurrence rate of neonatal hypocalcemia. Hypomagnesemia may contribute to hypocalcemia by further suppressing PTH. Although further studies are needed, the findings support regular lifelong follow-up of calcium, magnesium, PTH, and TSH levels in patients with 22q11.2DS. At any age, hypocalcemia with hypoparathyroidism and/or hypothyroidism may suggest a diagnosis of 22q11.2DS.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: -Individuals with tetralogy of Fallot (TOF) now routinely survive to reproductive age and beyond. Reproductive fitness of adults with TOF and recurrence risks to offspring are of increasing interest in the modern era, especially given recent molecular genetic discoveries.
-After excluding individuals with known genetic syndromes, 543 unrelated adults with TOF underwent a detailed family history assessment and molecular characterization for rare copy number variations (CNVs) using high resolution genome-wide microarrays. Men and women with TOF had significantly fewer offspring compared to an age-matched comparison group without congenital heart disease (CHD) (p=0.0004). No aspect of rare CNV burden was a predictor of decreased reproductive fitness. Corresponding with the advent of modern surgical repairs, reproductive fitness of women began to exceed that of men (p=0.0490) Recurrence risk for CHD in offspring was 4.8%, with no significant differences between men and women with TOF. The risk of severe CHD in offspring (2.3%) far exceeded population expectations (RR=15.6, 95% CI 7.9-31.0). Most cases of vertical transmission of CHD were not explained by the transmission of a large rare CNV. Although conotruncal lesions (31.5%) were the most commonly reported CHD in relatives, the familial spectrum of disease included many anatomically discordant lesions.
-Men and women with TOF have reduced reproductive fitness. Their offspring are at significantly elevated risk for severe CHD. These results support the importance of genetic counseling for both men and women with complex CHD. Many inherited genetic variants remain to be discovered.
[Show abstract][Hide abstract] ABSTRACT: Heart disease, present in 0.5% to 3% of pregnant women, is an important cause of morbidity and the leading cause of death among pregnant women in the developed world. Certain heart conditions are associated with an increased risk of heart failure during pregnancy or the postpartum period; for these conditions, management during pregnancy benefits from multidisciplinary care at a center with expertise in pregnancy and heart disease. This article focuses on cardiac risks and management strategies for women with acquired and congenital heart disease who are at increased risk of heart failure during pregnancy.
[Show abstract][Hide abstract] ABSTRACT: The literature on idiopathic schizophrenia has consistently reported that poor premorbid functioning precedes onset of psychosis. Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at heightened risk of developing schizophrenia. The present study examined the relationship between adult-onset schizophrenia and social and academic functioning across childhood and early adolescent development in 22q11.2DS.
Premorbid adjustment in social and academic domains during childhood (ages 5-11years) and early adolescence (ages 12-15years) of 103 adults with 22q11.2DS was assessed using the Premorbid Adjustment Scale (PAS). Linear mixed-models were used to compare PAS scores between the 43 subjects who later developed schizophrenia and the 60 subjects who did not.
Social functioning and academic functioning deteriorated from childhood to early adolescence among those who later developed schizophrenia compared to stable functioning, on average, in those who did not later develop a psychotic disorder. Those who developed schizophrenia had significantly higher PAS scores (indicating poorer functioning) in social (β=0.118, 95% CI: 0.046-0.189) and academic (β=0.072, 95% CI: 0.015-0.129) domains between childhood and early adolescence, independent of the presence of intellectual disability. The two groups had similar PAS scores during childhood.
Consistent with the literature on idiopathic schizophrenia, deterioration in social and academic functioning between childhood and early adolescence preceded onset of schizophrenia in this cohort of 22q11.2DS patients, regardless of functioning at baseline. These findings suggest that monitoring for changes in functioning, in addition to emergence of typical symptoms, may help to prevent delays in diagnosis and treatment of major psychotic illness in 22q11.2DS.
Schizophrenia Research 11/2013; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine associations between aortic morphometry evaluated by cardiovascular magnetic resonance (CMR) and pregnancy outcomes in women with aortic coarctation (CoA).
Consecutive women with CoA seen with CMR within 2 years of delivery were reviewed. Aortic dimensions were measured on CMR angiography. Adverse outcomes (cardiovascular, obstetric, and foetal/neonatal) were documented.
We identified 28 women (4 with native and 24 with repaired CoA) who had 30 pregnancies. There were 29 live births (1 stillbirth) at mean gestation 38 ± 2 weeks. Mean maternal ages at first cardiac intervention and pregnancy were 6 ± 8 and 29 ± 6 years, respectively. There were nine cardiovascular events (hypertensive complications in five; stroke in two and arrhythmia in two) occurring in seven pregnancies. Minimum aortic dimensions were smaller in women with cardiovascular events (12.1 vs. 14.3 mm, P = 0.001), specifically in those with hypertensive complications (11.6 vs. 14.4 mm, P < 0.001). From receiver operator curve analysis, optimal discrimination for the development of adverse cardiovascular events occurred at the 12 mm diameter threshold [sensitivity 78%, specificity 91%, area under the curve 0.86 (95% CI: 0.685-1)]. All hypertensive events occurred in conjunction with a minimum aortic diameter of 12 mm (7mm/m(2)) or less. No adverse outcomes occurred if minimum diameter exceeded 15 mm.
Smaller aortic dimensions relate to increased risk of hypertensive events in pregnant women with CoA. CMR can aid in stratification of risk for women with CoA who are considering pregnancy.
European heart journal cardiovascular Imaging. 09/2013;
[Show abstract][Hide abstract] ABSTRACT: To assess the impact of aortic root asymmetry on the relationship between aortic dimensions derived from two-dimensional transthoracic echocardiography (TTE) as compared with cross-sectional cardiovascular magnetic resonance (CMR) imaging in adults with a bicuspid aortic valve (BAV). Maximal CMR cross-sectional aortic measurements at the level of the sinuses of Valsalva, including cusp-commissure, cusp-cusp diameters and aortic root areas, from 68 consecutive patients (65 % male) were retrospectively analyzed. The degree of aortic root asymmetry on CMR was expressed using the coefficient of variance of the root diameters in each dimension for an individual (CoeffVi) as compared with the median of the entire population (CoeffVp) and asymmetry was defined as CoeffVi > CoeffVp. Values obtained from CMR were compared with standard root measurements using TTE from contemporary studies (48 patients, 71 %). Reproducibility of CMR measurements was assessed using the intra-class correlation coefficient (ICC). Echocardiography systematically underestimated aortic root dimensions in comparison with CMR, particularly in asymmetric roots with cusp-cusp measurements in systole (bias: -4.9 mm). Best agreement between modalities existed in symmetric roots with cusp-commissure measurements in diastole (bias: -0.01 mm). CMR measurements showed excellent intra-reader (ICC ≥ 0.98) and moderate inter-reader (ICC range 0.37-0.95) reproducibility, particularly aortic root area (inter/intra-reader ICC ≥ 0.94). In comparison to cross-sectional CMR diameters, standard TTE measurements consistently underestimates maximum aortic root diameter in adults with a BAV and aortic root asymmetry further decreases the agreement between CMR and TTE. CMR-derived aortic root measurements are reproducible and aortic root area showed the best reproducibility.
The international journal of cardiovascular imaging 08/2013; 29(8). · 2.15 Impact Factor