Real-world diagnostic outcomes and cost-effectiveness of genome-wide sequencing for developmental and seizure disorders: Evidence from Canada.

PURPOSE: To determine real-world diagnostic rates, cost trajectories, and cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children with developmental and/or seizure disorders in British Columbia, Canada. METHODS: Based on medical records review, we estimated real-world costs and outcomes for 491 patients who underwent standard of care (SOC) diagnostic testing at British Columbia Children's Hospital. Results informed a state-transition Markov model examining cost-effectiveness of 3 competing diagnostic strategies: (1) SOC with last-tier access to ES, (2) streamlined ES access, and (3) first-tier GS. RESULTS: Through SOC, 49.4% (95% CI: 40.6, 58.2) of patients were diagnosed at an average cost of C$11,683 per patient (95% CI: 9200, 14,166). Compared with SOC, earlier ES or GS access yielded similar or improved diagnostic rates and shorter times to genetic diagnosis, with 94% of simulations demonstrating cost savings for streamlined ES and 60% for first-tier GS. Net benefit from the perspective of the health care system was C$2956 (95% CI: -608, 6519) for streamlined ES compared with SOC. CONCLUSION: Using real-world data, we found earlier access to ES may yield more rapid genetic diagnosis of childhood developmental and seizure disorders and cost savings compared with current practice in a Canadian health care system.

Adherence to direct or vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a long-term observational study.

Our objectives were to measure long-term adherence to oral anticoagulants (OACs) in patients with atrial fibrillation (AF) and to identify patient factors associated with adherence. Using linked, population-based administrative data from British Columbia, Canada, an incident cohort of adults prescribed OACs for AF was identified. We calculated the proportion of days covered (PDC) as a time-dependent covariate for each 90-day window from OAC initiation until the end of follow-up. Associations between patient attributes and adherence were assessed using generalized mixed effect linear regression models. 30,264 patients were included. Mean PDC was 0.69 (SD 0.28) over a median follow-up of 6.7 years. 54% of patients were non-adherent (PDC < 0.8). After controlling for confounders, factors positively associated with adherence were number of drug class switches, history of stroke or transient ischemic attack, history of vascular disease, time since initiation, and age. Age > 75 years at initiation, polypharmacy (among VKA users only), and receiving DOAC (vs. VKA) were negatively associated with adherence. PDC decreased over time for VKA users and increased for DOAC users. Over half of AF patients studied were, on average, nonadherent to OAC therapy and missed 32% of their doses. Several patient factors were associated with higher or lower adherence, and adherence to VKA declined during therapy while DOAC adherence increased slightly over time. To min im ize the risk stroke, adherence-supporting interventions are needed for all patients with AF, particularly those aged > 75 years, those with prior stroke or vascular disease, VKA users with polypharmacy, and DOAC recipients.

Evaluation of out-of-pocket pay genetic testing in a publicly funded healthcare system.

When genetic tests are not funded publicly, out-of-pocket (OOP) pay options may be discussed with patients. We evaluated trends in genetic testing and OOP pay for two publicly funded British Columbia clinical programs serving >12 000 patients/year (The Hereditary Cancer Program [HCP] and Provincial Medical Genetics Program [PMGP]) between 2015-2019. Linear and regression models were used to explore the association of OOP pay with patient demographic variables at HCP. An interrupted time series and linear and logistic regression models were used on PMGP data to examine the effect of a change in the funding body. The total number of tests completed through PMGP, and HCP increased by 260% and 320%, respectively. OOP pay increased at HCP by 730%. The mean annual income of patients who paid OOP at HCP was ≥$3500 higher than in the group with funded testing (p < 0.0001). The likelihood of OOP pay increased at PMGP before the funding body change (OR per month: 1.07; 95% CI: 1.04, 1.10); while this likelihood had an immediate 87% drop when the change occurred (OR: 0.13; 95% CI: 0.06, 0.32). Patients with higher incomes are more likely to pay OOP. Financial barriers can create disparities in clinical outcomes. Funding decisions have a significant impact on rate of OOP pay.

Employment status, productivity loss, and associated factors among people with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) affects people in their most productive years of life. Consequently, MS can substantially affect employment and work-related outcomes. OBJECTIVES: This study characterizes productivity loss and employment status of people with multiple sclerosis (pwMS) and investigates associated factors. METHODS: We used baseline data collected as part of the Canadian Prospective Cohort Study to Understand Progression in Multiple Sclerosis (CanProCo). Using the Valuation of Lost Productivity questionnaire, we measured MS-related paid work productivity loss for those employed, productivity losses incurred by those unemployed (i.e. lost employment time), and unpaid work productivity losses for all. A set of sociodemographic, disease, and performance-related factors were investigated using a two-part regression model for productivity loss and a multinomial logistic model for employment status. RESULTS: From the cohort of 888 pwMS enrolled at baseline (mostly showing mild to moderate disability), 75% were employed, and of those unemployed, 69% attributed their unemployment to health-related issues. Total productivity loss over a 3-month period averaged 64 and 395 hours for those employed and unemployed, respectively. Some factors that affected productivity loss and employment status included use of disease-modifying therapies, fatigue, and performance indicators such as cognitive processing speed. CONCLUSION: Productivity loss experienced by employed and unemployed pwMS is substantial. Targeting the identified modifiable factors is likely to improve work productivity and permanence of MS patients in the workforce.

Frameworks for Health Technology Assessment at an Early Stage of Product Development: A Review and Roadmap to Guide Applications.

OBJECTIVES: Early health technology assessment (eHTA) can be used to evaluate and optimize a medical product's value proposition and to inform go/no-go decisions by using health economic modeling, literature scanning, and stakeholder preference studies at an early stage of development. eHTA frameworks offer high-level guidance on conducting this complex, iterative, and multidisciplinary process. The objective of this study was to review and summarize existing eHTA frameworks, understood as systematic approaches to guide early evidence generation and decision making. METHODS: Using a rapid review methodology, we identified all relevant studies published in English, French, and Spanish from PubMed/MEDLINE and Embase until February 2022. We only included frameworks relevant to the preclinical and early clinical (phase I) stages of medical product development. RESULTS: From 737 reviewed abstracts, 53 publications describing 46 frameworks were selected for inclusion and classified into categories based on their scope: (1) criteria frameworks, which provide an overview of eHTA; (2) process frameworks, which offer stepwise guidance for conducting eHTA, including preferred methods; and (3) methods frameworks, which provide detailed descriptions of specific eHTA methods. Most of the frameworks did not specify their target users or the specific stage of technology development. CONCLUSIONS: Despite some variability and gaps found across existing frameworks, the structure provided by this review helps inform eHTA applications. Remaining challenges are the frameworks' limited accessibility to users without a background in health economics, poor distinctions being made among early lifecycle stages and technology types, and the inconsistent terminology used to describe eHTA in different contexts.

A Rapid Review on the Value of Biobanks Containing Genetic Information.

OBJECTIVES: Increasing access to health data through biobanks containing genetic information has the potential to expand the knowledge base and thereby improve screening, diagnosis, and treatment options for many diseases. Nevertheless, although privacy concerns and risks surrounding genetic data sharing are well documented, direct evidence in favor of the hypothesized benefits of data integration is scarce, which complicates decision making in this area. Therefore, the objective of this study is to summarize the available evidence on the research and clinical impacts of biobanks containing genetic information, so as to better understand how to quantify the value of expanding genomic data access. METHODS: Using a rapid review methodology, we performed a search of MEDLINE/PubMed and Embase databases; and websites of biobanks and genomic initiatives published from 2010 to 2022. We classified findings into 11 indicators including outputs (a direct product of the biobank activities) and outcomes (changes in scientific and clinical capacity). RESULTS: Of 8479 abstracts and 101 gray literature sources were reviewed, 96 records were included. Although most records did not report key indicators systematically, the available evidence concentrated on research indicators such as publications and gene-disorder association discoveries (63% of studies), followed by research infrastructure (26%), and clinical indicators (11%) such as supporting the diagnosis of individual patients. CONCLUSIONS: Existing evidence on the benefits of biobanks is skewed toward easily quantifiable research outputs. Measuring a comprehensive set of outputs and outcomes inspired by value frameworks is necessary to generate better evidence on the benefits of genomic data sharing.

Trends in hospital admissions for chronic obstructive pulmonary disease over 16 years in Canada.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an ambulatory care-sensitive condition, and the rate of hospital admissions for COPD is an indicator of the quality of outpatient care. We sought to determine long-term trends in hospital admissions for COPD in Canada. METHODS: Using a comprehensive national database of hospital admissions in Canada, we identified those with a main discharge diagnosis of COPD for patients aged 40 years and older between 2002 and 2017. We calculated sex-specific, age-standardized trends in annual rates of hospital admissions for COPD separately for younger (40-64 yr) and older adults (≥ 65 yr). We used spline regression to examine changes in the admissions trends for each sex and age group. RESULTS: Over 16 years, 1 134 359 hospital admissions were for COPD. Between 2002 and 2017, the total number of admissions increased by 68.8%, from 52 937 to 89 384. The overall crude admission rate increased by 30.0%, from 368 to 479 per 100 000 population, and the sex-and age-standardized admission rate increased by 9.6%, from 437 to 479 per 100 000 population. Age-standardized rates increased by 12.2% among younger females, by 24.4% among younger males and by 29.8% among older females, but decreased by 9.0% among older males. Over the same period, the all-cause sex-and age-standardized admission rate declined by 23.0%. INTERPRETATION: Hospital admissions for COPD have increased since 2010, even after adjusting for population growth and aging, and despite declining rates of all-cause hospital admissions. The secular increase in COPD admissions indicates that the burden of COPD on Canadian health care systems is increasing.

The Random Effects Warfarin Days' Supply (REWarDS) Model: Development and Validation of a Novel Method for Estimating Exposure to Warfarin Using Administrative Data.

Warfarin's complex dosing is a significant barrier to measurement of its exposure in observational studies using population databases. Using population-based administrative data (1996-2019) from British Columbia, Canada, we developed a method based on statistical modeling (Random Effects Warfarin Days' Supply (REWarDS)) that involves fitting a random-effects linear regression model to patients' cumulative dosage over time for estimation of warfarin exposure. Model parameters included a minimal universally available set of variables from prescription records for estimation of patients' individualized average daily doses of warfarin. REWarDS estimates were validated against a reference standard (manual calculation of the daily dose using the free-text administration instructions entered by the dispensing pharmacist) and compared with alternative methods (fixed window, fixed tablet, defined daily dose, and reverse wait time distribution) using Pearson's correlation coefficient (r), the intraclass correlation coefficient, and the root mean squared error. REWarDS-estimated days' supply showed strong correlation and agreement with the reference standard (r = 0.90 (95% confidence interval (CI): 0.90, 0.90); intraclass correlation coefficient = 0.95 (95% CI: 0.94, 0.95); root mean squared error = 8.24 days) and performed better than all of the alternative methods. REWarDS-estimated days' supply was valid and more accurate than estimates from all other available methods. REWarDS is expected to confer optimal precision in studies measuring warfarin exposure using administrative data.

The effect of rapid exome sequencing on downstream health care utilization for infants with suspected genetic disorders in an intensive care unit.

PURPOSE: This study aimed to compare downstream utilization of medical services among critically ill infants admitted to intensive care units who received rapid exome sequencing (ES) and those who followed alternative diagnostic testing pathways. METHODS: Using propensity score-weighted regression models including sex, age at admission, and severity indicators, we compared a group of 47 infants who underwent rapid ES with a group of 211 infants who did not receive rapid ES. Utilization and cost indicators were compared between cohorts using negative binomial models for utilization and two-part models for costs. RESULTS: After controlling for patients' sociodemographic and clinical characteristics, we found no statistically significant difference in outpatient visits, hospitalizations, intensive care unit or total length of stay, or length of stay-associated costs between the cohorts at 12- or 26-month follow-up. Similarly, there was no evidence of higher utilization or costs by the ES group when infants who died were removed from the analysis. CONCLUSION: When examining utilization during and beyond the diagnostic trajectory, there is no evidence that ES changes frequency of outpatient visits or use of in-hospital resources in critically ill infants with suspected genetic disorders.

Productivity loss among people with early multiple sclerosis: A Canadian study.

OBJECTIVES: To analyze work productivity loss and costs, including absenteeism (time missed from work), presenteeism (reduced productivity while working), and unpaid work loss, among a sample of employed people with multiple sclerosis (pwMS) in Canada, as well as its association with clinical, sociodemographic, and work-related factors. METHODS: We used cross-sectional data collected as part of the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) and information from the Valuation of Lost Productivity questionnaire. RESULTS: Among 512 pwMS who were employed, 97% showed no or mild disability and 55% experienced productivity loss due to MS in the prior 3 months. Total productivity time loss over a 3-month period averaged 60 hours (SD = 107; 23 from presenteeism, 19 from absenteeism, and 18 from unpaid work), leading to a mean cost of lost productivity of CAD$2480 (SD = 4282) per patient, with an hourly paid productivity loss greater than the wage loss. Fatigue retained significant associations with all productivity loss outcomes. CONCLUSION: Unpaid work loss and productivity losses exceeding those of the employee alone (due to teamwork and associated factors) are key additional contributors of the high economic burden of MS. Workplace accommodations and treatments targeted at fatigue could lessen the economic impact of MS.

16-year trends in asthma hospital admissions in Canada.

BACKGROUND: Asthma hospitalizations declined rapidly in many parts of the world, including Canada, in the 1990s and early 2000s. OBJECTIVE: To examine whether the declining trend of asthma hospitalizations persisted in recent years in Canada. METHODS: Using the Canadian comprehensive nationwide hospitalization data (2002-2017), we identified hospital admissions with the main International Classification of Diseases codes for asthma. We analyzed sex-specific age-standardized trends in annual hospitalization rates among pediatric (&lt; 19 years) and adult (19+ years) patients. We used change-point analysis to evaluate any substantial changes in the trends in the sex-age groups. RESULTS: There were 254,672 asthma-related hospital admissions (59% pediatric, 50% female) during the study period. Among children, age-adjusted annual rates per 100,000 decreased by 55% in females (152-69) and by 60% in males (270-108) from 2002 to 2017. Among adults, the rates decreased by 59% in both sexes (females: 61-25; males: 27-11). Change-point analysis indicated a substantial plateauing of the annual rate in both pediatric (from -15.3 [females] and -25.8 [males] before 2010 to -0.6 [females] and -0.8 [males] after 2010) and adult (from -5.4 [females] and -2.6 [males] before 2008 to -0.6 [females] and -0.2 [males] after 2008) groups. CONCLUSION: After a substantial decline in hospital admissions for acute asthma, there has been minimal further decline since 2010 for children and 2008 for adults. In addition to adhering to the contemporary standards of asthma care, novel, disruptive strategies are likely needed to further reduce the burden of asthma.

Should the number of acute exacerbations in the previous year be used to guide treatments in COPD?

BACKGROUND: In contemporary management of chronic obstructive pulmonary disease (COPD), the frequent exacerbator phenotype, based on a 12-month history of acute exacerbation of COPD (AECOPD), is a major determinant of therapeutic recommendations. However, there is considerable debate as to the stability of this phenotype over time. METHODS: We used fundamental principles in time-to-event analysis to demonstrate that variation in the frequent exacerbator phenotype has two major sources: variability in the underlying AECOPD rate and randomness in the occurrence of individual AECOPDs. We re-analysed data from two large cohorts, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study and the SubPopulations and InteRmediate OutcoMes In COPD Study (SPIROMICS), using a Bayesian model that separated these sources of variability. We then evaluated the stability of the frequent exacerbator phenotype based on these results. RESULTS: In both cohorts, the pattern of AECOPDs strongly supported the presence of an individual-specific underlying AECOPD rate which is stable over time (Bayes Factor less than 0.001). Despite this, the observed AECOPD rate can vary markedly year-to-year within individual patients. For those with an underlying rate of 0.8-3.1 events·year-1, the frequent exacerbator classification, based on the observed rate, changes more than 30% of the time over two consecutive years due to chance alone. This value increases to more than 45% for those with an underlying rate of 1.2-2.2 events·year-1. CONCLUSIONS: While the underlying AECOPD rate is a stable trait, the frequent exacerbator phenotype based on observed AECOPD patterns is unstable, so much so that its suitability for informing treatment decisions should be questioned. Whether evaluating AECOPD history over longer durations or using multivariate prediction models can result in more stable phenotyping needs to be evaluated.

Out-of-pocket and private pay in clinical genetic testing: A scoping review.

Full coverage of the cost of clinical genetic testing is not always available through public or private insurance programs, or a public healthcare system. Consequently, some patients may be faced with the decision of whether to finance testing out-of-pocket (OOP), meet OOP expenses required by their insurer, or not proceed with testing. A scoping review was conducted to identify literature associated with patient OOP and private pay in clinical genetic testing. Seven databases (EMBASE, MEDLINE, CINAHL, PsychINFO, PAIS, the Cochrane Database of Systematic Reviews, and the JBI Evidence-Based Practice database) were searched, resulting in 83 unique publications included in the review. The presented evidence includes a descriptive analysis, followed by a narrative account of the extracted data. Results were divided into four groups according to clinical indication: (1) hereditary breast and ovarian cancer, (2) other hereditary cancers, (3) prenatal testing, (4) other clinical indications. The majority of studies focused on hereditary cancer and prenatal genetic testing. Overall trends indicated that OOP costs have fallen and payer coverage has improved, but OOP expenses continue to present a barrier to patients who do not qualify for full coverage.

Gender modifies the effect of body mass index on lung function decline in mild-to-moderate COPD patients: a pooled analysis.

BACKGROUND: Low body weight is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, it is not known whether gender modifies this relationship. METHODS: We pooled data of 8686 COPD patients from 7 studies with a median length of 36-months of follow up. Using a longitudinal natural cubic spline regression model, we examined the dose-response relationship between body mass index (BMI) and the rate of decline in forced expiratory volume in one second (FEV1) in patients with GOLD 1 and 2 disease, stratified by gender and adjusted for age, smoking status, and cohort effects. RESULTS: There was an inverse linear relationship between BMI and the rate of FEV1 decline in GOLD Grades 1 and 2, which was modified by gender (p < 0.001). In male patients, an increase of BMI by 1 kg/m2 reduced FEV1 decline by 1.05 mL/year (95% CI 0.96, 1.14). However, in female patients, BMI status did not have a clinically meaningful impact on FEV1 decline: an increase of baseline BMI by 1 kg/m2 reduced FEV1 decline by 0.16 ml/year (95% CI 0.11, 0.21). These gender-modified relationships were similar between GOLD 1 and 2 patients, and between current and former smokers. CONCLUSION: In mild to moderate COPD, higher BMI was associated with a less rapid decline of FEV1 in male patients whereas this association was minimal in females patients. This gender-specific BMI effect was independent of COPD severity and smoking status.

Trends in oral corticosteroids use in severe asthma: a 14-year population-based study.

BACKGROUND: Oral corticosteroids are important components of pharmacotherapy in severe asthma. Our objective was to describe the extent, trends, and factors associated with exposure to oral corticosteroids (OCS) in a severe asthma cohort. METHODS: We used administrative health databases of British Columbia, Canada (2000-2014) and validated algorithms to retrospectively create a cohort of severe asthma patients. Exposure to OCS within each year of follow-up was measured in two ways: maintenance use as receiving on average ≥ 2.5 mg/day (prednisone-equivalent) OCS, and episodic use as the number of distinct episodes of OCS exposure for up to 14 days. Trends and factors associated with exposure on three time axes (calendar year, age, and time since diagnosis) were evaluated using Poisson regression. RESULTS: 21,144 patients (55.4% female; mean entry age 28.7) contributed 40,803 follow-up years, in 8.2% of which OCS was used as maintenance therapy. Maintenance OCS use declined by 3.8%/calendar year (p < 0.001). The average number of episodes of OCS use was 0.89/year, which increased by 1.1%/calendar year (p < 0.001). Trends remained significant for both exposure types in adjusted analyses. Both maintenance and episodic use increased by age and time since diagnosis. CONCLUSIONS: This population-based study documented a secular downward trend in maintenance OCS use in a period before widespread use of biologics. This might have been responsible for a higher rate of exacerbations that required episodic OCS therapy. Such trends in OCS use might be due to changes in the epidemiology of severe asthma, or changes in patient and provider preferences over time.

Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

OBJECTIVES: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs. METHODS: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs. RESULTS: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients. CONCLUSIONS: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.

Correction: The composition and capacity of the clinical genetics workforce in high-income countries: a scoping review.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The composition and capacity of the clinical genetics workforce in high-income countries: a scoping review.

As genetics becomes increasingly integrated into all areas of health care and the use of complex genetic tests continues to grow, the clinical genetics workforce will likely face greatly increased demand for its services. To inform strategic planning by health-care systems to prepare to meet this future demand, we performed a scoping review of the genetics workforce in high-income countries, summarizing all available evidence on its composition and capacity published between 2010 and 2019. Five databases (MEDLINE, Embase, PAIS, CINAHL, and Web of Science) and gray literature sources were searched, resulting in 162 unique studies being included in the review. The evidence presented includes the composition and size of the workforce, the scope of practice for genetics and nongenetics specialists, the time required to perform genetics-related tasks, case loads of genetics providers, and opportunities to increase efficiency and capacity. Our results indicate that there is currently a shortage of genetics providers and that there is a lack of consensus about the appropriate boundaries between the scopes of practice for genetics and nongenetics providers. Moreover, the results point to strategies that may be used to increase productivity and efficiency, including alternative service delivery models, streamlining processes, and the automation of tasks.

The cost trajectory of the diagnostic care pathway for children with suspected genetic disorders.

PURPOSE: This study describes the cost trajectory of the standard diagnostic care pathway for children with suspected genetic disorders in British Columbia, Canada. METHODS: Average annual per-patient costs were estimated using medical records review and a caregiver survey for a cohort of 498 children referred to BC Children's and Women's Hospitals (C&W) with unexplained intellectual disability (the TIDE-BC study) and families enrolled in the CAUSES study, which offered diagnostic genome-wide sequencing (GWS; exome and genome sequencing) to 500 families of children with suspected genetic disorders. RESULTS: Direct costs peaked in the first year of patients' diagnostic odyssey, with an average of C$2257 per patient (95% confidence interval [CI] C$2074, C$2441) for diagnostic testing and C$631 (95% CI C$543, C$727) for specialist consultations at C&W. In subsequent years, direct costs accrued at a constant rate, with an estimated annual per-patient cost of C$511 (95% CI C$473, C$551) for diagnostic testing and C$334 (95% CI C$295, C$369) for consultations at C&W. Travel costs and caregiver productivity loss associated with attending diagnosis-related physician appointments averaged C$1907/family/year. CONCLUSIONS: The continuing long-term accrual of costs by undiagnosed patients suggests that economic evaluations of diagnostic GWS services should use longer time horizons than have typically been used.

Maternal and neonatal outcomes associated with biologic exposure before and during pregnancy in women with inflammatory systemic diseases: a systematic review and meta-analysis of observational studies.

OBJECTIVE: To determine the association between exposure to biologics in pregnant women with inflammatory systemic diseases and maternal and neonatal outcomes through a meta-analysis of findings from studies identified in a systematic review. METHODS: We conducted a systematic review of Medline, Embase, and Cochrane Database of Systematic Reviews to identify observational studies assessing the perinatal impacts of biologic in women with inflammatory systemic disease. Findings were meta-analysed across included studies with random-effects models. Crude risk estimates and, where possible, adjusted risk estimates were pooled to determine the impact on results when confounding is addressed. RESULTS: Overall, 24 studies were included in the meta-analysis. Meta-analyses of crude risk estimates resulted in pooled odds ratios (OR) for the association of biologic use during pregnancy and the following respective outcomes: congenital anomalies (1.30, 95% CI: 1.02, 1.67), preterm birth (OR 1.61, 95% CI: 1.37, 1.89), and low birth weight (OR 1.68, 95% CI: 1.21, 2.31). However, in pooled analyses of adjusted risk estimates we observed that the association between biologics use during pregnancy in disease-matched exposed and unexposed pregnant women was no longer statistically significant for congenital anomalies (adjusted OR 1.18, 95% CI: 0.88, 1.57). CONCLUSION: Pooled results from studies reporting adjusted risk estimates showed no increased risk of congenital anomalies associated with biologics use, suggesting that increased rates of adverse outcomes may be due to disease activity itself or other confounders.