Severe Hypoglycemia and Impaired Awareness of Hypoglycemia Persist in People With Type 1 Diabetes Despite Use of Diabetes Technology: Results From a Cross-sectional Survey.

OBJECTIVE: To determine how diabetes technologies, including continuous glucose monitoring (CGM) and automated insulin delivery (AID) systems, impact glycemic metrics, prevalence of severe hypoglycemic events (SHEs), and impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes in a real-world setting within the U.S. RESEARCH DESIGN AND METHODS: In this retrospective, observational study with cross-sectional elements, participants aged ≥18 years were enrolled from the T1D Exchange Registry/online community. Participants completed a one-time online survey describing glycemic metrics, SHEs, and IAH. The primary objective was to determine the proportions of participants who reported achieving glycemic targets (assessed according to self-reported hemoglobin A1c) and had SHEs and/or IAH. We performed additional subgroup analyses focusing on the impact of CGM and insulin delivery modality. RESULTS: A total of 2,074 individuals with type 1 diabetes were enrolled (mean ± SD age 43.0 ± 15.6 years and duration of type 1 diabetes 26.3 ± 15.3 years). The majority of participants (91.7%) were using CGM, with one-half (50.8%) incorporating AID. Despite high use of diabetes technologies, only 57.7% reported achieving glycemic targets (hemoglobin A1c <7%). SHEs and IAH still occurred, with ∼20% of respondents experiencing at least one SHE within the prior 12 months and 30.7% (95% CI 28.7, 32.7) reporting IAH, regardless of CGM or AID use. CONCLUSIONS: Despite use of advanced diabetes technologies, a high proportion of people with type 1 diabetes do not achieve glycemic targets and continue to experience SHEs and IAH, suggesting an ongoing need for improved treatment strategies.

Optimizing therapeutic decision-making for off-label medicines use: A scoping review and consensus recommendations for improving practice and research.

PURPOSE: Off-label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision-makers in applying research evidence to inform off-label medicines use. We aimed to critically evaluate current evidence informing decision-making for off-label use and to develop consensus recommendations to improve future practice and research. METHODS: We conducted a scoping review to summarize the literature on available off-label use guidance, including types, extent and scientific rigor of evidence incorporated. Findings informed the development of consensus recommendations by an international multidisciplinary Expert Panel using a modified Delphi process. Our target audience includes clinicians, patients and caregivers, researchers, regulators, sponsors, health technology assessment bodies, payers and policy makers. RESULTS: We found 31 published guidance documents on therapeutic decision-making for off-label use. Of 20 guidances with general recommendations, only 35% detailed the types and quality of evidence needed and the processes for its evaluation to reach sound, ethical decisions about appropriate use. There was no globally recognized guidance. To optimize future therapeutic decision-making, we recommend: (1) seeking rigorous scientific evidence; (2) utilizing diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking off-label use with timely conduct of clinically meaningful research (including real-world evidence) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision-makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations. CONCLUSIONS: We provide comprehensive consensus recommendations to optimize therapeutic decision-making for off-label medicines use and concurrently drive clinically relevant research. Successful implementation requires appropriate funding and infrastructure support to engage necessary stakeholders and foster relevant partnerships, representing significant challenges that policy makers must urgently address.

Safety and effectiveness of taliglucerase alfa in patients with Gaucher disease: an interim analysis of real-world data from a multinational drug registry (TALIAS).

BACKGROUND: Limited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD). METHODS: Taliglucerase Alfa Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019. RESULTS: A total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients. CONCLUSIONS: The interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.

Incidence Rates of Autoimmune Diseases in European Healthcare Databases: A Contribution of the ADVANCE Project.

INTRODUCTION: The public-private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. METHODS: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell's palsy, Guillain-Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. RESULTS: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell's palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6-24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6-0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. CONCLUSION: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data.

Impact of variable look-back periods on the incidence rates of chronic diseases using real world data.

PURPOSE: Estimating disease incidence based on secondary data requires a look-back period to exclude patients with pre-existing disease from the incidence risk set. However, the optimal length of the look-back period and its impact on incidence rates are often unknown. We studied the impact of the length of the look-back period on incidence rates of 24 different chronic diseases. METHODS: Everyone residing in Sweden between January 1, 2005 and December 31, 2013 were identified from national registries and followed up to 2 years (through December 31, 2015). Outcome events were identified from inpatient and outpatient hospital contacts and incidence rates were calculated per 100 000 person-years. The length of the look-back period was varied with 6-month increments, starting at 6 months. The maximum look-back period of 9 years was used as reference period. RESULTS: There were 7 943 807 individuals with a look-back period of at least 9 years (mean age 46.5 years) and a mean follow-up time of 1.97 years. Incidence rates were higher across all diseases when restricting the look-back to 1 year compared to 9 years, with a magnitude of overestimation of the incidence rates between 13% (temporal arteritis) and 174% (type 1 diabetes). However, for most diseases the effect of extending the look-back period beyond 3-5 years appeared comparably small. CONCLUSIONS: This study illustrates how short look-back periods cause overestimation of the incidence rates of chronic diseases, suggesting that sensitivity analyses with respect to look-back period are considered, particularly using data sources with limited information on past medical history.

Age-specific vaccination coverage estimates for influenza, human papillomavirus and measles containing vaccines from seven population-based healthcare databases from four EU countries - The ADVANCE project.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk monitoring of vaccines using existing healthcare databases in Europe. We estimated vaccine coverage from electronic healthcare databases as part of a fit-for-purpose assessment for vaccine benefit-risk studies. METHODS: A retrospective dynamic cohort study was conducted through a distributed network approach. Coverage with measles-vaccine for birth year 2006, human papillomavirus (HPV)-vaccine for birth years 1990-2000 and influenza-vaccine for birth years 1920-1950 was estimated using period-prevalence and inverse probability weighting methods. Seven databases from four countries participated: Italy (Pedianet, Val Padana), Spain (BIFAP, SIDIAP), UK (RCGP-RSC, THIN), Denmark (SSI/AUH). Database access providers extracted the data, transformed it into a common structure and ran an R-script locally. The created output tables were shared and pooled at a central server. RESULTS: The total study population comprised 274,616 persons for measles-vaccine, 2,011,666 persons for HPV-vaccine and 14,904,033 persons for influenza-vaccine. Measles-vaccine coverage varied from 84.3% (Denmark) to 96.5% (Italy, Val Padana) for the first dose and from 82.8% (Italy, Val Padana) to 90.9% (UK) for the second dose at the age of 7 years. The HPV-vaccine coverage, aggregated over birth years 1997-2000, ranged from 60% (UK) to 88.3% (Denmark) at the age of 15 years. The influenza-vaccine coverage for the influenza seasons from 2009 to 2015 for persons aged 65 years and more was roughly stable around 43% in Denmark and around 68% in the UK while a decrease from 58 to 50% was observed in Catalonia (Spain). CONCLUSIONS: We obtained detailed, age-specific coverage estimates though a common procedure. We discussed between database comparability and comparability to published national estimates.

ADVANCE database characterisation and fit for purpose assessment for multi-country studies on the coverage, benefits and risks of pertussis vaccinations.

INTRODUCTION: The public-private ADVANCE consortium (Accelerated development of vaccine benefit-risk collaboration in Europe) aimed to assess if electronic healthcare databases can provide fit-for purpose data for collaborative, distributed studies and monitoring of vaccine coverage, benefits and risks of vaccines. OBJECTIVE: To evaluate if European healthcare databases can be used to estimate vaccine coverage, benefit and/or risk using pertussis-containing vaccines as an example. METHODS: Characterisation was conducted using open-source Java-based (Jerboa) software and R scripts. We obtained: (i) The general characteristics of the database and data source (meta-data) and (ii) a detailed description of the database population (size, representatively of age/sex of national population, rounding of birth dates, delay between birth and database entry), vaccinations (number of vaccine doses, recording of doses, pattern of doses by age and coverage) and events of interest (diagnosis codes, incidence rates). A total of nine databases (primary care, regional/national record linkage) provided data on events (pertussis, pneumonia, death, fever, convulsions, injection site reactions, hypotonic hypo-responsive episode, persistent crying) and vaccines (acellular pertussis and whole cell pertussis) related to the pertussis proof of concept studies. RESULTS: The databases contained data for a total population of 44 million individuals. Seven databases had recorded doses of vaccines. The pertussis coverage estimates were similar to those reported by the World Health Organisation (WHO). Incidence rates of events were comparable in magnitude and age-distribution between databases with the same characteristics. Several conditions (persistent crying and somnolence) were not captured by the databases for which outcomes were restricted to hospital discharge diagnoses. CONCLUSION: The database characterisation programs and workflows allowed for an efficient, transparent and standardised description and verification of electronic healthcare databases which may participate in pertussis vaccine coverage, benefit and risk studies. This approach is ready to be used for other vaccines/events to create readiness for participation in other vaccine related studies.

ADVANCE system testing: Can safety studies be conducted using electronic healthcare data? An example using pertussis vaccination.

INTRODUCTION: The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster. METHODS: The study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses. RESULTS: The overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP. CONCLUSIONS: The estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination.

ADVANCE: Towards near real-time monitoring of vaccination coverage, benefits and risks using European electronic health record databases.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private partnership aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European electronic health record (eHR) databases. This proof-of-concept study aimed to test the feasibility of near real-time (NRT) monitoring of vaccination coverage, benefits and risks based on multiple European eHR databases, using acellular pertussis vaccination in children aged <6 years as test case. METHODS: A qualitative feasibility assessment on NRT monitoring was carried out using a survey and face-to-face discussion with ADVANCE data partners. Subsequently, a dynamic cohort study was conducted containing two distinct observation periods: a first period to establish a baseline (Jan 2014 to Mar 2018) and a subsequent 3-month period to test the actual feasibility of weekly NRT monitoring, based on which data latencies were calculated. An interactive web-application was additionally developed to facilitate the visual monitoring of vaccination coverage, the vaccine preventable disease incidence rates (benefits) and the incidence rates of adverse events (risks). RESULTS: Nine databases from four countries (Denmark, Italy, Spain and UK) participated in the qualitative feasibility assessment. Of them, five databases took part in the dynamic cohort study, with 5 databases providing baseline data and 3 databases participating to the NRT monitoring, providing data extractions on an almost weekly basis. The median data latency (time between event date and data release date) was between 1 and 2 weeks except for the benefit and risk events in one of the databases (latency 16 weeks). CONCLUSION: Three European eHR databases successfully demonstrated the feasibility of providing data for weekly NRT monitoring, with short data latencies of 1-2 weeks for most events.

Why we need more collaboration in Europe to enhance post-marketing surveillance of vaccines.

The influenza A/H1N1 pandemic in 2009 taught us that the monitoring of vaccine benefits and risks in Europe had potential for improvement if different public and private stakeholders would collaborate better (public health institutes (PHIs), regulatory authorities, research institutes, vaccine manufacturers). The Innovative Medicines Initiative (IMI) subsequently issued a competitive call to establish a public-private partnership to build and test a novel system for monitoring vaccine benefits and risks in Europe. The ADVANCE project (Accelerated Development of Vaccine benefit-risk Collaboration in Europe) was created as a result. The objective of this paper is to describe the perspectives of key stakeholder groups of the ADVANCE consortium for vaccine benefit-risk monitoring and their views on how to build a European system addressing the needs and challenges of such monitoring. These perspectives and needs were assessed at the start of the ADVANCE project by the European Medicines Agency together with representatives of the main stakeholders in the field of vaccines within and outside the ADVANCE consortium (i.e. research institutes, public health institutes, medicines regulatory authorities, vaccine manufacturers, patient associations). Although all stakeholder representatives stated they conduct vaccine benefit-risk monitoring according to their own remit, needs and obligations, they are faced with similar challenges and needs for improved collaboration. A robust, rapid system yielding high-quality information on the benefits and risks of vaccines would therefore support their decision making. ADVANCE has developed such a system and has tested its performance in a series of proof of concept (POC) studies. The system, how it was used and the results from the POC studies are described in the papers in this supplementary issue.

Incidence rates of cardiovascular outcomes in a community-based population of cancer patients.

BACKGROUND: There are limited data on the incidence of cardiovascular disease among cancer patients in the pre-tyrosine kinase inhibitor (TKI) era. Such data are important in order to contextualize the incidence of various cardiovascular outcomes among cancer patients enrolled in clinical trials of new agents and for postmarketing surveillance. METHODS: A retrospective cohort study was conducted using data from the Kaiser Permanente Northern California (KPNC) population of cancer patients. The inclusion criterion was a KPNC Cancer Registry diagnosis of any of several selected solid and hematologic tumors between 1997 and 2009 not treated with a TKI. Endpoints were identified using ICD-9 codes and included acute coronary syndrome, heart failure, stroke, cardiac arrest, hypertension, venous thromboembolism, all-cause mortality, and cardiovascular mortality. Event rates were calculated according to type of cancer and number of cardiovascular risk factors. RESULTS: The study included almost 165 000 individuals with a broad variety of tumor types. The parent cohort was 54% female and 35% were ≥70 years old. Cardiovascular risk factors such as diabetes mellitus (14% of patients with solid tumors, 15% of patients with liquid tumors), dyslipidemia (33%, 31%), hypertension (50%, 49%), and smoking (35%, 32%) were common. The most frequent adverse outcomes were incident hypertension (26.8-61.0 cases per 1000 person-years, depending on the type of cancer), heart failure (9.4-78.7), and acute coronary syndrome (2.6-48.1). These event rates are high compared to what has been reported in prior KPNC cohort studies of patients without cancer. The rates of acute coronary syndrome, heart failure, and ischemic stroke increased with increasing numbers of cardiovascular risk factors. CONCLUSIONS: In a population of patients with cancer not exposed to TKIs, cardiovascular risk factors and outcomes are very common, regardless of cancer type. These data can inform the evaluation of potential excess cardiovascular risks from new interventions.

Incidence of outcomes relevant to vaccine safety monitoring in a US commercially-insured population.

BACKGROUND: Background incidence rates (IRs) of potential safety outcomes among vaccine eligible individuals can inform assessment of vaccine safety. Vaccine safety surveillance often uses claims databases, but the impact of outcome definitions on background IR estimates is largely unexplored. Using two definitions for each outcome, we estimated background IRs of 32 cardiac, metabolic, allergic, autoimmune, neurologic, hematologic and nephrologic outcomes among individuals eligible to receive pneumococcal vaccination. METHODS: We defined a cohort of individuals aged 6-100 years in US commercial health plans who had ≥12 months of health plan enrollment between January 2007 and August 2014 and no previous record of conjugate or simple polysaccharide pneumococcal vaccination. We developed a sensitive and a specific definition for each outcome, with the specific definition requiring evidence of additional care consistent with the outcome. IRs per 100,000 person-years for each outcome were presented overall and stratified by age, gender, and invasive pneumococcal disease (IPD) risk category. RESULTS: We followed 19.9 million individuals for a median of 2.5 years. Wide variation was seen in IRs across different definitions of the 32 outcomes, with 19 (59%) outcomes having a specific definition IR less than half of the sensitive definition IR. IRs were particularly variable by definition for outcomes categorized as either hematologic/nephrologic or neurologic (mean ratio of specific IR to sensitive IR = 0.26 and 0.30, respectively). Across definitions, the IRs of the 32 outcomes were often highest in females, adults ≥65, and those at higher IPD risk. CONCLUSIONS: Background IRs of safety outcomes relevant to populations indicated for pneumococcal vaccine varied by outcome definitions and population subgroups in this large US commercially-insured population. Given large differences in estimated IRs using sensitive versus specific case definitions, neurologic, and hematologic/nephrologic safety outcomes as compared to allergic and autoimmune outcomes may warrant more refined definitions and medical record validation.

Benefit-Risk Monitoring of Vaccines Using an Interactive Dashboard: A Methodological Proposal from the ADVANCE Project.

INTRODUCTION: New vaccines are launched based on their benefit-risk (B/R) profile anticipated from clinical development. Proactive post-marketing surveillance is necessary to assess whether the vaccination uptake and the B/R profile are as expected and, ultimately, whether further public health or regulatory actions are needed. There are several, typically not integrated, facets of post-marketing vaccine surveillance: the surveillance of vaccination coverage, vaccine safety, effectiveness and impact. OBJECTIVE: With this work, we aim to assess the feasibility and added value of using an interactive dashboard as a potential methodology for near real-time monitoring of vaccine coverage and pre-specified health benefits and risks of vaccines. METHODS: We developed a web application with an interactive dashboard for B/R monitoring. The dashboard is demonstrated using simulated electronic healthcare record data mimicking the introduction of rotavirus vaccination in the UK. The interactive dashboard allows end users to select certain parameters, including expected vaccine effectiveness, age groups, and time periods and allows calculation of the incremental net health benefit (INHB) as well as the incremental benefit-risk ratio (IBRR) for different sets of preference weights. We assessed the potential added value of the dashboard by user testing amongst a range of stakeholders experienced in the post-marketing monitoring of vaccines. RESULTS: The dashboard was successfully implemented and demonstrated. The feedback from the potential end users was generally positive, although reluctance to using composite B/R measures was expressed. CONCLUSION: The use of interactive dashboards for B/R monitoring is promising and received support from various stakeholders. In future research, the use of such an interactive dashboard will be further tested with real-life data as opposed to simulated data.

The impact of socioeconomic status across early life on age at menarche among a racially diverse population of girls.

PURPOSE: We sought to evaluate the association between childhood socioeconomic status (SES) at two time points and age at menarche in a multiracial sample of U.S. girls. METHODS: Our study population consisted of a cohort of female participants enrolled at birth at the New York site of the Collaborative Perinatal Project, who were born during the period 1959-1963 (n = 262). SES at birth, at age 7, and change between birth and age 7 were measured prospectively through an index score of family income, paternal occupation, and education. Data on age at menarche were collected retrospectively through adult self-report. We used multivariable linear regression to examine the association between SES and age at menarche after adjusting for childhood body mass index (BMI) and other covariates associated with age at menarche. RESULTS: After adjustment, SES at age 7 was positively associated with age at menarche (beta: 0.015, 95% confidence interval [CI]: 0.003-0.024 per unit of SES index). Change in SES was significantly associated with age at menarche; a 20-unit decrease in SES was associated with a 4-month decrease in age at menarche. CONCLUSIONS: Our results suggest that lower SES at 7 years and reductions in SES in early childhood are both associated with an earlier age at menarche.

Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma.

OBJECTIVE: Little is known about the causes of sporadic (noninherited) retinoblastoma. Rates seem to be somewhat higher among poorer populations in Mexico. Fruits and vegetables are important sources of carotenoids and folate. We examined whether decreased gestational maternal intake of fruits and vegetables may contribute to development of sporadic retinoblastoma. METHODS: At the Instituto Nacional de Pediatria in Mexico City, we conducted a hospital-based case-control study to evaluate prenatal maternal diet. We examined dietary intake of fruits and vegetables of mothers of 101 children with retinoblastoma and 172 control children using a dietary recall questionnaire and published food nutrient content tables. RESULTS: The reported number of mean daily servings of fruits and vegetables was lower among case mothers when compared with control mothers [vegetables: 2.28 in controls, 1.75 in cases (P < 0.01); fruits: 2.13 in controls, 1.59 in cases (P = 0.07)]. Mean daily maternal folate intake from both vegetables and fruits was higher in controls (103 microg) than in cases (48 microg; P < 0.05). Risk for having a child with retinoblastoma was increased for mothers consuming fewer than 2 daily servings of vegetables [odds ratios (OR), 3.4; 95% confidence interval (95% CI), 2.0-6.0] or with a low intake of folate (OR, 3.9; 95% CI, 2.1, 7.3), or lutein/zeaxanthin (OR, 2.6; 95% CI, 1.5-4.6) derived from fruits and vegetables. CONCLUSIONS: Decreased intake of vegetables and fruits during pregnancy and the consequent decreased intake of nutrients such as folate and lutein/zeaxanthin, necessary for DNA methylation, synthesis, and retinal function, may increase risk for having a child with sporadic retinoblastoma.