Sleep health,diseases, and pain syndromes: findings from an electronic health record biobank

Study ObjectivesImplementation of electronic health record biobanks has facilitated linkage between clinical and questionnaire data and enabled assessments of relationships between sleep health and diseases in phenome-wide association studies (PheWAS). In the Mass General Brigham Biobank, a large health system-based study, we aimed to systematically catalog associations between time in bed, sleep timing, and weekly variability with clinical phenotypes derived from ICD-9/10 codes.MethodsSelf-reported habitual bed and wake times were used to derive variables: short (<7 hours) and long (≥9 hours) time in bed, sleep midpoint, social jetlag, and sleep debt. Logistic regression and Cox proportional hazards models were used to test cross-sectional and prospective associations, respectively, adjusted for age, gender, race/ethnicity, and employment status and further adjusted for body mass index.ResultsIn cross-sectional analysis (n = 34,651), sleep variable associations were most notable for circulatory system, mental disorders, and endocrine/metabolic phenotypes. We observed the strongest associations for short time in bed with obesity, for long time in bed and sleep midpoint with major depressive disorder, for social jetlag with hypercholesterolemia, and for sleep debt with acne. In prospective analysis (n = 24,065), we observed short time in bed associations with higher incidence of acute pain and later sleep midpoint and higher sleep debt and social jetlag associations with higher incidence of major depressive disorder.ConclusionsOur analysis reinforced that sleep health is a multidimensional construct, corroborated robust known findings from traditional cohort studies, and supported the application of PheWAS as a promising tool for advancing sleep research. Considering the exploratory nature of PheWAS, careful interrogation of novel findings is imperative.     

Uncovering Outcome Disparities of β2 Adrenergic Agonists in Blacks: A Systematic Review

PurposeOutcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This review assessed systematic variation in β₂ agonist treatment outcomes among Blacks compared to other groups.MethodsWe conducted a systematic review of studies reporting differential response to β₂ agonists among Blacks, including studies identifying pharmacogenetic variants.ResultsOf 3158 papers, 20 compared safety or efficacy of β₂ agonists among Blacks as compared with other subgroups. Six papers evaluating efficacy of short-acting β₂ agonists (SABA) found similar or improved results among Blacks compared with other groups, while one small study found reduced response to SABA therapy among Blacks. Reports of safety and efficacy of long-acting β₂ agonists (LABA) indicated similar results among Blacks in four papers, while four reports found reduced safety among Blacks, as compared with other groups. Four papers assessed genomic variation and relative treatment response in Blacks, with two finding significant effects of the p.Arg16Gly variant in ADRB2 on β₂ agonist response and one finding significant gene-gene IL6/IL6R interaction effects on albuterol response.ConclusionsEvidence suggests the potential for differences in β₂ agonist outcomes among Blacks compared with other groups. This literature, however, remains small and significantly underpowered for substantive conclusions. There are notable opportunities for adequately-powered investigations exploring safety and efficacy of β₂ agonists among Blacks, including pharmacogenomic modifiers of response.     

A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes

Purpose“Genome-first” approaches, in which genetic sequencing is agnostically linked to associated phenotypes, can enhance our understanding of rare variants’ contributions to disease. Loss-of-function variants in LMNA cause a range of rare diseases, including cardiomyopathy.MethodsWe leveraged exome sequencing from 11,451 unselected individuals in the Penn Medicine Biobank to associate rare variants in LMNA with diverse electronic health record (EHR)–derived phenotypes. We used Rare Exome Variant Ensemble Learner (REVEL) to annotate rare missense variants, clustered predicted deleterious and loss-of-function variants into a “gene burden” (N = 72 individuals), and performed a phenome-wide association study (PheWAS). Major findings were replicated in DiscovEHR.ResultsThe LMNA gene burden was significantly associated with primary cardiomyopathy (p = 1.78E-11) and cardiac conduction disorders (p = 5.27E-07). Most patients had not been clinically diagnosed with LMNA cardiomyopathy. We also noted an association with chronic kidney disease (p = 1.13E-06). Regression analyses on echocardiography and serum labs revealed that LMNA variant carriers had dilated cardiomyopathy and primary renal disease.ConclusionPathogenic LMNA variants are an underdiagnosed cause of cardiomyopathy. We also find that LMNA loss of function may be a primary cause of renal disease. Finally, we show the value of aggregating rare, annotated variants into a gene burden and using PheWAS to identify novel ontologies for pleiotropic human genes.     

Phenome-wide association studies (PheWASs) for functional variants

The genome-wide association study (GWAS) is a powerful approach for studying the genetic complexities of human disease. Unfortunately, GWASs often fail to identify clinically significant associations and describing function can be a challenge. GWAS is a phenotype-to-genotype approach. It is now possible to conduct a converse genotype-to-phenotype approach using extensive electronic medical records to define a phenome. This approach associates a single genetic variant with many phenotypes across the phenome and is called a phenome-wide association study (PheWAS). The majority of PheWASs conducted have focused on variants identified previously by GWASs. This approach has been efficient for rediscovering gene–disease associations while also identifying pleiotropic effects for some single-nucleotide polymorphisms (SNPs). However, the use of SNPs identified by GWAS in a PheWAS is limited by the inherent properties of the GWAS SNPs, including weak effect sizes and difficulty when translating discoveries to function. To address these challenges, we conducted a PheWAS on 105 presumed functional stop-gain and stop-loss variants genotyped on 4235 Marshfield Clinic patients. Associations were validated on an additional 10 640 Marshfield Clinic patients. PheWAS results indicate that a nonsense variant in ARMS2 (rs2736911) is associated with age-related macular degeneration (AMD). These results demonstrate that focusing on functional variants may be an effective approach when conducting a PheWAS.     

The challenges,advantages and future of phenome‐wide association studies

Over the last decade, significant technological breakthroughs have revolutionized human genomic research in the form of genome‐wide association studies (GWASs). GWASs have identified thousands of statistically significant genetic variants associated with hundreds of human conditions including many with immunological aetiologies (e.g. multiple sclerosis, ankylosing spondylitis and rheumatoid arthritis). Unfortunately, most GWASs fail to identify clinically significant associations. Identifying biologically significant variants by GWAS also presents a challenge. The GWAS is a phenotype‐to‐genotype approach. As a complementary/alternative approach to the GWAS, investigators have begun to exploit extensive electronic medical record systems to conduct a genotype‐to‐phenotype approach when studying human disease – specifically, the phenome‐wide association study (PheWAS). Although the PheWAS approach is in its infancy, this method has already demonstrated its capacity to rediscover important genetic associations related to immunological diseases/conditions. Furthermore, PheWAS has the advantage of identifying genetic variants with pleiotropic properties. This is particularly relevant for HLA variants. For example, PheWAS results have demonstrated that the HLA‐DRB1 variant associated with multiple sclerosis may also be associated with erythematous conditions including rosacea. Likewise, PheWAS has demonstrated that the HLA‐B genotype is not only associated with spondylopathies, uveitis, and variability in platelet count, but may also play an important role in other conditions, such as mastoiditis. This review will discuss and compare general PheWAS methodologies, describe both the challenges and advantages of the PheWAS, and provide insight into the potential directions in which PheWAS may lead.     

Obesity Status on associations between cancer-related beliefs and health behaviors in cancer survivors: Implications for patient-clinician communication

ObjectiveAssociations between cancer beliefs and health behavior engagement are largely unexplored in cancer survivors, particularly among those with overweight and obesity. We investigated belief-behavior associations for cancer survivors, and whether obesity altered these associations.MethodsCancer survivors were identified from the National Cancer Institute HINTS Survey 5 data and classified as having had an obesity-related cancer or not. Linear and multiple logistic regression analyses examined whether cancer risk beliefs and self-efficacy predicted dining out behaviors and physical activity (PA). Restricted analyses were conducted in those with overweight or obesity.ResultsLow self-efficacy to take care of one’s health was associated with longer sitting time in the overall sample (p = 0.04). In cancer survivors with overweight or obesity, engagement in healthier behaviors was associated with 1) feeling less overwhelmed by cancer risk recommendations and 2) believing that PA or obesity influences cancer development (both p < 0.05). Among those with overweight and obesity, associations between cancer beliefs and health behaviors were not significantly different by cancer type (obesity-related vs. not).ConclusionsObesity altered associations between cancer risk beliefs and health behavior engagement from the overall sample.Practice ImplicationsWeight status may be a useful tailoring factor when delivering health-promoting interventions for cancer survivors.     

Large scale clinical exome sequencing uncovers the scope and severity of skin disorders associated with MC1R genetic variants

PurposeGenetic variation in MC1R is a main determinant of red hair color (RHC) phenotype and confers susceptibility to skin disorders.MethodsWe assessed the effects and function of MC1R variants identified in our clinical cohort of 135,947 participants with available exome sequencing using phenome-wide association scan (PheWAS). Expression and function of several variants were evaluated.ResultsWe found 24 nonsense and 215 missense variants in MC1R. Many common missense MC1R variants are strongly associated with skin disorders including skin cancer; however, each variant shows different penetrance and expressivity. Severity of skin phenotype was well correlated with the magnitude of functional defect measured as receptor expression and α-MSH stimulated cAMP production. Remarkably, MC1R deletions and nonsense variants are only weakly associated with milder skin phenotypes.ConclusionOur comprehensive assessment of all MC1R variants in a large cohort clearly establish that individuals with some missense variants are more susceptible to severe skin disorders than those with MC1R deletions or nonsense variants.     

Obstructive sleep apnea treatment and dementia risk in older adults

Study ObjectivesTo examine associations between positive airway pressure (PAP) therapy, adherence and incident diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) in older adults.MethodsThis retrospective study utilized Medicare 5% fee-for-service claims data of 53,321 beneficiaries, aged 65 and older, with an obstructive sleep apnea (OSA) diagnosis prior to 2011. Study participants were evaluated using ICD-9 codes for neurocognitive syndromes (AD [n = 1,057], DNOS [n = 378], and MCI [n = 443]) that were newly identified between 2011 and 2013. PAP treatment was defined as the presence of at least one durable medical equipment (Healthcare Common Procedure Coding System [HCPCS]) code for PAP supplies. PAP adherence was defined as at least two HCPCS codes for PAP equipment, separated by at least 1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses.ResultsIn this sample of Medicare beneficiaries with OSA, 59% were men, 90% were non-Hispanic whites and 62% were younger than 75 years. The majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio [OR] = 0.78, 95% confidence interval [95% CI]: 0.69 to 0.89; and OR = 0.69, 95% CI: 0.55 to 0.85). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (OR = 0.82, 95% CI: 0.66 to 1.02). PAP adherence was associated with lower odds of incident diagnoses of AD (OR = 0.65, 95% CI: 0.56 to 0.76).ConclusionsPAP treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce the risk of subsequent dementia.     

Associations of self-reported obstructive sleep apnea with total and site-specific cancer risk in older women: a prospective study

Background and ObjectivesChronic intermittent hypoxia resulting from obstructive sleep apnea (OSA) may activate multiple carcinogenic pathways and lead to cancer development.MethodsWe prospectively examined the association between OSA and cancer risk among 65,330 women in the Nurses’ Health Study who were free of cancer in 2008 (mean age: 73.3 years). Incident cancer diagnoses were collected until 2016 and confirmed by pathology reports. Clinically diagnosed OSA was self-reported in 2008 and updated in 2012. We used time-dependent Cox regression to estimate hazard ratios (HR) for the associations of OSA with total and site-specific cancer risk.ResultsWe documented 5,257 incident cancer diagnoses during follow-up. In the age-adjusted model, OSA was associated with a 15% (95% CI: 1.03, 1.29) increase in total cancer risk. The association became nonsignificant after adjustment for multiple cancer risk factors (HR: 1.08; 95% CI: 0.96, 1.21). When examining cancer risk by site, OSA was associated with significantly increased risk for lung (fully adjusted HR: 1.52; 95% CI: 1.07, 2.17), bladder (fully adjusted HR: 1.94; 95% CI: 1.12, 3.35), and thyroid cancer (fully adjusted HR: 2.06; 95% CI: 1.01, 4.22) and possibly increased risk for kidney cancer (fully adjusted HR: 1.59; 95% CI: 0.84, 3.01). When grouping cancer sites by risk factor profiles, OSA was positively associated with smoking-related cancers (fully adjusted HR: 1.37; 95% CI: 1.11, 1.67), and this association was stronger in never smokers than ever smokers.ConclusionWhile OSA was not independently associated with overall cancer risk in older women, significant associations were observed for smoking-related cancers, especially in nonsmokers.     

Risk associations for intestinal parasites in symptomatic and asymptomatic schoolchildren in central Mozambique

ObjectivesChronic infections by enteric parasites including protist and helminthic species produce long-term sequelae on the health status of infected children. This study assesses potential associations linked with enteric parasite infections in symptomatic and asymptomatic children in Zambézia province, Mozambique.MethodsIn this prospective cross-sectional study, stool samples and epidemiological questionnaires on demographics and risk associations were collected from symptomatic children (n = 286) from clinical settings and asymptomatic (n = 807) children from 17 schools and creches aged 3?14 years. We detected enteric parasites using PCR-based methods. We calculated prevalence (adjusted for age, sex, house construction, drinking water, and latrine use) and odds ratios (ORs) for risk associations with logistic regression, after adjusting for district, neighbourhood and symptoms.ResultsNumbers and adjusted prevalence (95% confidence intervals in parentheses) for the symptomatic and asymptomatic populations were Giardia duodenalis 120, 52% (22–82), 339, 42% (25–59); followed by Strongyloides stercoralis 52, 14% (9?20), 180, 20% (15–25). Risk associations for G. duodenalis included drinking untreated river/spring water, OR 2.91 (1.80–4.70); contact with ducks, OR 14.96 (2.93?76.31); dogs, OR 1.92 (1.04–3.52); cats, OR 1.73 (1.16–2.59), and a relative with diarrhoea, OR 2.59 (1.54?4.37). Risk associations for S. stercoralis included having no latrine, OR 2.41 (1.44–4.02); drinking well water, OR 1.82 (1.02–3.25), and increasing age, OR 1.11 (1.04–1.20).ConclusionsWe found a high prevalence of intestinal parasites regardless of the children's symptoms. Drinking well or river water, domestic animals, and latrine absence were contributing factors of human infections.     

Molecular diagnostic experience of whole-exome sequencing in adult patients

PurposeWhole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.MethodsWe performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.ResultsMolecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18–30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses.ConclusionEarly WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.     

Nursing process decision support system for urology ward

PurposeWe developed a nursing process decision support system (NPDSS) based on three clinical pathways, including benign prostatic hypertrophy, inguinal hernia, and urinary tract stone. NPDSS included six major nursing diagnoses – acute pain, impaired urinary elimination, impaired skin integrity, anxiety, infection risk, and risk of falling. This paper aims to describe the design, development and validation process of the NPDSS.MethodsWe deployed the Delphi method to reach consensus for decision support rules of NPDSS. A team of nine-member expert nurses from a medical center in Taiwan was involved in Delphi method. The Cronbach's α method was used for examining the reliability of the questionnaire used in the Delphi method. The Visual Basic 6.0 as front-end and Microsoft Access 2003 as back-end was used to develop the system. A team of six nursing experts was asked to evaluate the usability of the developed systems. A 5-point Likert scale questionnaire was used for the evaluation. The sensitivity and specificity of NPDSS were validated using 150 nursing chart.ResultsThe study showed a consistency between the diagnoses of the developed system (NPDSS) and the nursing charts. The sensitivities of the nursing diagnoses including acute pain, impaired urinary elimination, risk of infection, and risk of falling were 96.9%, 98.1%, 94.9%, and 89.9% respectively; and the specificities were 88%, 49.5%, 62%, and 88% respectively. We did not calculate the sensitivity and specificity of impaired skin integrity and anxiety due to non-availability of enough sample size.ConclusionsNPDSS can help nurses in decision making of nursing diagnoses. Besides, it can help them to generate nursing diagnoses based on patient-specific data, individualized care plans, and implementation within their usual nursing workflow.     

User preferences for and engagement with text messages to support antihypertensive medication adherence: Findings from a pilot study evaluating an emergency department-based behavioral intervention

ObjectiveWe examined users’ preferences for and engagement with text messages delivered as part of an emergency department (ED)-based intervention to improve antihypertensive medication adherence.MethodsWe recruited ED patients with elevated blood pressure for a pilot randomized trial evaluating a medication adherence intervention with text messages. Intervention participants chose text content and frequency, received texts for 45 days, and completed a feedback survey. We defined engagement via responses to texts. We examined participant characteristics associated with text preferences, engagement, and feedback.ResultsParticipants (N = 101) were 57% female and 46% non-White. Most participants (71%) chose to receive both reminder and informational texts; 94% chose reminder texts once per day and 97% chose informational texts three times per week. Median text message response rate was 56% (IQR 26–80%). Participants who were Black (p < 0.01), had lower income (p = 0.03), or had lower medication adherence (p < 0.01) rated the program as more helpful and wanted additional functionalities for adherence support.Conclusions and Practice ImplicationsWhile overall engagement was modest, participants at risk of worse health outcomes expressed more value and interest in the program. Findings inform the design of text messaging interventions for antihypertensive medication adherence and support targeting vulnerable patients to reduce health disparities.Clinical trials registrationNCT02672787     

Sleep health and cognitive function among people with and without HIV: the use of different machine learning approaches

Study ObjectivesWe investigated associations between actigraphy-assessed sleep measures and cognitive function in people with and without HIV using different analytical approaches to better understand these associations and highlight differences in results obtained by these approaches.MethodsCognitive and 7-day/night actigraphy data were collected from people with HIV (PWH) and lifestyle-similar HIV-negative individuals from HIV and sexual health clinics in the United Kingdom/Ireland. A global cognitive T-score was obtained averaging the standardized individual cognitive test scores accounting for sociodemographics. Average and SD of 11 sleep measures over 7 days/nights were obtained. Rank regression, partial least-squares (PLS) regression, random forest, sleep dimension construct, and latent class analysis (LCA) were applied to evaluate associations between global T-scores and sleep measures.ResultsIn 344 PWH (median age 57 years, 86% males), average sleep duration, efficiency, and wake after sleep onset were not associated with global T-scores according to rank regression (p = 0.51, p = 0.09, p = 0.16, respectively). In contrast, global T-scores were associated with average and SD of length of nocturnal awakenings, SD of maintenance efficiency, and average out-of-bed time when analyzed by PLS regression and random forest. No associations were found when using sleep dimensions or LCA. Overall, findings observed in PWH were similar to those seen in HIV-negative individuals (median age 61 years, 67% males).ConclusionsUsing multivariable analytical approaches, measures of sleep continuity, timing, and regularity were associated with cognitive performance in PWH, supporting the utility of newer methods of incorporating multiple standard and novel measures of sleep-wake patterns in the assessment of health and functioning.     

Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants

PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient–participants and their clinicians. We queried patient–participants’ electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient–participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient–participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer—including a stage 1C fallopian tube cancer—via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.     

Artificial intelligence–assisted phenotype discovery of fragile X syndrome in a population-based sample

PurposeFragile X syndrome (FXS), the most prevalent inherited cause of intellectual disability, remains underdiagnosed in the general population. Clinical studies have shown that individuals with FXS have a complex health profile leading to unique clinical needs. However, the full impact of this X-linked disorder on the health of affected individuals is unclear and the prevalence of co-occurring conditions is unknown.MethodsWe mined the longitudinal electronic health records from more than one million individuals to investigate the health characteristics of patients who have been clinically diagnosed with FXS. Additionally, using machine-learning approaches, we created predictive models to identify individuals with FXS in the general population.ResultsOur discovery-oriented approach identified the associations of FXS with a wide range of medical conditions including circulatory, endocrine, digestive, and genitourinary, in addition to mental and neurological disorders. We successfully created predictive models to identify cases five years prior to clinical diagnosis of FXS without relying on any genetic or familial data.ConclusionAlthough FXS is often thought of primarily as a neurological disorder, it is in fact a multisystem syndrome involving many co-occurring conditions, some primary and some secondary, and they are associated with a considerable burden on patients and their families.     

Better maternal quality of life in pregnancy yields better offspring respiratory outcomes: A birth cohort

BackgroundIt is suggested that maternal mental health during pregnancy may affect offspring immune and respiratory features, based on the developmental origins of health and disease hypothesis.ObjectiveTo evaluate whether maternal quality of life (QoL) and depression during pregnancy leads to wheezing, asthma, and food allergy of the offspring at 3 years of age.MethodsWe conducted a nationwide, multicenter, prospective birth cohort study, Japan Environment and Children’s Study. All variables were collected from questionnaires. Health-related QoL was measured using the Medical Outcomes Survey Short Form–8 questionnaire with a physical component summary and a mental component summary score. We conducted logistic regression analyses to evaluate the associations of offspring’s wheezing, asthma, and food allergy with maternal QoL and depression.ResultsThere were 72,685 participants with no missing variables. Maternal physical component summary scores of the Medical Outcomes Survey Short Form–8 questionnaire were negatively associated with offspring’s asthma (adjusted odds ratio [aOR], 0.99; 95% confidence interval [CI], 0.99-1.00), current wheezing (aOR, 0.99; 95% CI, 0.99-0.99), and food allergy diagnoses (aOR, 0.99; 95% CI, 0.98-0.99) in children. Offspring’s wheezing and asthma were also associated with maternal depression and anxiety during pregnancy.ConclusionPoor maternal prenatal QoL increased the risk of wheezing, asthma, and food allergy in offspring. In addition, maternal depression and anxiety increased the risk of offspring’s wheezing, asthma, and food allergy.     

Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

BackgroundThe prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking.MethodsWe searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study.ResultsWe reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR, MTRR and MTR, GATA4, NKX2-5, SRD5A2, CFTR, and 1p22 and 20q12 anomalies.ConclusionThis study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.