Impact of the COVID-19 Pandemic on Fecal Immunochemical Testing, Colonoscopy Services, and Colorectal Neoplasia Detection in a Large United States Community-based Population.

BACKGROUND & AIMS: The COVID-19 pandemic has affected clinical services globally, including colorectal cancer (CRC) screening and diagnostic testing. We investigated the pandemic's impact on fecal immunochemical test (FIT) screening, colonoscopy utilization, and colorectal neoplasia detection across 21 medical centers in a large integrated health care organization. METHODS: We performed a retrospective cohort study in Kaiser Permanente Northern California patients ages 18 to 89 years in 2019 and 2020 and measured changes in the numbers of mailed, completed, and positive FITs; colonoscopies; and cases of colorectal neoplasia detected by colonoscopy in 2020 vs 2019. RESULTS: FIT kit mailings ceased in mid-March through April 2020 but then rebounded and there was an 8.7% increase in kits mailed compared with 2019. With the later mailing of FIT kits, there were 9.0% fewer FITs completed and 10.1% fewer positive tests in 2020 vs 2019. Colonoscopy volumes declined 79.4% in April 2020 compared with April 2019 but recovered to near pre-pandemic volumes in September through December, resulting in a 26.9% decline in total colonoscopies performed in 2020. The number of patients diagnosed by colonoscopy with CRC and advanced adenoma declined by 8.7% and 26.9%, respectively, in 2020 vs 2019. CONCLUSIONS: The pandemic led to fewer FIT screenings and colonoscopies in 2020 vs 2019; however, after the lifting of shelter-in-place orders, FIT screenings exceeded, and colonoscopy volumes nearly reached numbers from those same months in 2019. Overall, there was an 8.7% reduction in CRC cases diagnosed by colonoscopy in 2020. These data may help inform the development of strategies for CRC screening and diagnostic testing during future national emergencies.

Index colonoscopy-related risk factors for postcolonoscopy colorectal cancers.

BACKGROUND AND AIMS: Postcolonoscopy colorectal cancers (PCCRCs) are defined as those detected ≤10 years after an index colonoscopy negative for cancer, but modifiable risk factors are not well established in large, community-based populations. METHODS: We evaluated risk factors from the index colonoscopy for PCCRCs diagnosed 1 to 10 years after an index colonoscopy using a case-control design. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for potential confounders. RESULTS: A proximal polyp ≥10 mm (OR, 8.18; 95% CI, 4.59-14.60), distal polyp ≥10 mm (OR, 3.30; 95% CI, 1.65-6.58), adenoma with (OR, 3.23; 95% CI, 1.83-5.68) and without advanced histology (OR, 1.87; 95% CI, 1.37-2.55), and an incomplete colonoscopy (OR, 5.52; 95% CI, 2.98-10.21) were associated with PCCRC. Risk factors for early versus late cancers (12-36 months vs >36 months to 10 years after examination) included incomplete polyp excision in the colonic segment of the subsequent cancer (OR, 4.76; 95% CI, 2.35-9.65); failure to examine the segment (OR, 2.42; 95% CI, 1.27-4.60); and a polyp ≥10 mm in the segment (OR, 2.38; 95% CI, 1.53-3.70). A total of 559 of 1206 patients with PCCRC (46.4%) had 1 or more risk factors that were significant for PCCRC (incomplete examination, large polyp, or any adenoma). CONCLUSIONS: In a large community-based study with comprehensive capture of PCCRCs, almost half of PCCRCs had potentially modifiable factors related to polyp surveillance or removal and examination completeness. These represent potential high-yield targets to further increase the effectiveness of colorectal cancer screening.

Adenoma detection rate and risk of colorectal cancer and death.

BACKGROUND: The proportion of screening colonoscopic examinations performed by a physician that detect one or more adenomas (the adenoma detection rate) is a recommended quality measure. However, little is known about the association between this rate and patients' risks of a subsequent colorectal cancer (interval cancer) and death. METHODS: Using data from an integrated health care delivery organization, we evaluated the associations between the adenoma detection rate and the risks of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and of cancer-related death. With the use of Cox regression, our estimates of attributable risk were adjusted for the demographic characteristics of the patients, indications for colonoscopy, and coexisting conditions. RESULTS: We evaluated 314,872 colonoscopies performed by 136 gastroenterologists; the adenoma detection rates ranged from 7.4 to 52.5%. During the follow-up period, we identified 712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer. The unadjusted risks of interval cancer according to quintiles of adenoma detection rates, from lowest to highest, were 9.8, 8.6, 8.0, 7.0, and 4.8 cases per 10,000 person-years of follow-up, respectively. Among patients of physicians with adenoma detection rates in the highest quintile, as compared with patients of physicians with detection rates in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52 (95% confidence interval [CI], 0.39 to 0.69), for advanced-stage interval cancer, 0.43 (95% CI, 0.29 to 0.64), and for fatal interval cancer, 0.38 (95% CI, 0.22 to 0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (hazard ratio, 0.97; 95% CI, 0.96 to 0.98). CONCLUSIONS: The adenoma detection rate was inversely associated with the risks of interval colorectal cancer, advanced-stage interval cancer, and fatal interval cancer. (Funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute.).

Endoscopist fatigue estimates and colonoscopic adenoma detection in a large community-based setting.

BACKGROUND AND AIMS: Endoscopist fatigue may impact colonoscopy quality, but prior studies conflict, and minimal data exist from community-based practices where most colonoscopies are performed. METHODS: Within a large, community-based integrated healthcare system, we evaluated the associations among 4 measures of endoscopist fatigue and colonoscopic adenoma detection from 2010 to 2013. Fatigue measures included afternoon versus morning colonoscopy and the number of GI procedures performed before a given colonoscopy, including consideration of prior procedure complexity. Analyses were adjusted for potential confounders using multivariate logistic regression. RESULTS: We identified 126 gastroenterologists who performed 259,064 total GI procedures (median, 6 per day; range, 1-24), including 76,445 screening and surveillance colonoscopies. Compared with morning examinations, colonoscopies in the afternoon were not associated with lower adenoma detection for screening examinations, surveillance examinations, or their combination (OR for combination, .99; 95% CI, .96-1.03). The number of procedures performed before a given colonoscopy, with or without consideration of prior procedure complexity, was also not inversely associated with adenoma detection (OR for adenoma detection for colonoscopies in the fourth quartile of fatigue based on the number of prior procedures performed vs colonoscopies performed as the first procedure of the day, .99; 95% CI, .94-1.04). CONCLUSIONS: In a large community-based setting, adenoma detection for screening and surveillance colonoscopies were not associated with either time of day or the number of prior procedures performed by the endoscopist, within the range of procedure volumes evaluated. The lack of association persisted after accounting for prior procedure complexity.

Genetic Biomarker Prevalence Is Similar in Fecal Immunochemical Test Positive and Negative Colorectal Cancer Tissue.

BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening. METHODS: FIT-negative and FIT-positive colorectal cancer patients 50-77 years of age were matched on age, sex, and cancer stage. Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients. Quantitative allele-specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers (NDRG4, BMP3, SFMBT2_895, SFMBT2_896, SFMBT2_897, CHST2_7890, PDGFD, VAV3, DTX1, CHST2_7889). RESULTS: One or more biomarkers were found in 414 of 421 CRCs (98.3%). Biomarker expression was not associated with FIT status, with the exception of higher SFMBT2_897 expression in FIT-negative (194 of 210; 92.4%) than in FIT-positive cancers (180 of 211; 85.3%; p = 0.02). There were no consistent differences in biomarker expression by FIT status within age, sex, stage, and cancer location subgroups. CONCLUSIONS: The biomarkers of a currently in-use multi-target stool DNA test (K-ras, NDRG4, and BMP3) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens, independent of FIT result. Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity, specificity, and clinical utility.

Fecal Immunochemical Test Program Performance Over 4 Rounds of Annual Screening: A Retrospective Cohort Study.

BACKGROUND: The fecal immunochemical test (FIT) is a common method for colorectal cancer (CRC) screening, yet its acceptability and performance over several rounds of annual testing are largely unknown. OBJECTIVE: To assess FIT performance characteristics over 4 rounds of annual screening. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Northern and Southern California. PATIENTS: 323 349 health plan members aged 50 to 70 years on their FIT mailing date in 2007 or 2008 who completed the first round of FIT and were followed for up to 4 screening rounds. MEASUREMENTS: Screening participation, FIT positivity (≥20 µg of hemoglobin/g), positive predictive values for adenoma and CRC, and FIT sensitivity for detecting CRC obtained from Kaiser Permanente electronic databases and cancer registries. RESULTS: Of the patients invited for screening, 48.2% participated in round 1. Of those who remained eligible, 75.3% to 86.1% participated in subsequent rounds. Median follow-up was 4.0 years, and 32% of round 1 participants crossed over to endoscopy over 4 screening rounds-7.0% due to a positive FIT result. The FIT positivity rate (5.0%) and positive predictive values (adenoma, 51.5%; CRC, 3.4%) were highest in round 1. Overall, programmatic FIT screening detected 80.4% of patients with CRC diagnosed within 1 year of testing, including 84.5% in round 1 and 73.4% to 78.0% in subsequent rounds. LIMITATION: Screening detection, rather than long-term cancer prevention, was evaluated. CONCLUSION: Annual FIT screening was associated with high sensitivity for CRC, with high adherence to annual follow-up screening among initial participants. The findings indicate that annual programmatic FIT screening is feasible and effective for population-level CRC screening. PRIMARY FUNDING SOURCE: National Institutes of Health.

Association Between Time to Colonoscopy After a Positive Fecal Test Result and Risk of Colorectal Cancer and Cancer Stage at Diagnosis.

IMPORTANCE: The fecal immunochemical test (FIT) is commonly used for colorectal cancer screening and positive test results require follow-up colonoscopy. However, follow-up intervals vary, which may result in neoplastic progression. OBJECTIVE: To evaluate time to colonoscopy after a positive FIT result and its association with risk of colorectal cancer and advanced-stage disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study (January 1, 2010-December 31, 2014) within Kaiser Permanente Northern and Southern California. Participants were 70 124 patients aged 50 through 70 years eligible for colorectal cancer screening with a positive FIT result who had a follow-up colonoscopy. EXPOSURES: Time (days) to colonoscopy after a positive FIT result. MAIN OUTCOMES AND MEASURES: Risk of any colorectal cancer and advanced-stage disease (defined as stage III and IV cancer). Odds ratios (ORs) and 95% CIs were adjusted for patient demographics and baseline risk factors. RESULTS: Of the 70 124 patients with positive FIT results (median age, 61 years [IQR, 55-67 years]; men, 52.7%), there were 2191 cases of any colorectal cancer and 601 cases of advanced-stage disease diagnosed. Compared with colonoscopy follow-up within 8 to 30 days (n = 27 176), there were no significant differences between follow-up at 2 months (n = 24 644), 3 months (n = 8666), 4 to 6 months (n = 5251), or 7 to 9 months (n = 1335) for risk of any colorectal cancer (cases per 1000 patients: 8-30 days, 30; 2 months, 28; 3 months, 31; 4-6 months, 31; and 7-9 months, 43) or advanced-stage disease (cases per 1000 patients: 8-30 days, 8; 2 months, 7; 3 months, 7; 4-6 months, 9; and 7-9 months, 13). Risks were significantly higher for examinations at 10 to 12 months (n = 748) for any colorectal cancer (OR, 1.48 [95% CI, 1.05-2.08]; 49 cases per 1000 patients) and advanced-stage disease (OR, 1.97 [95% CI, 1.14-3.42]; 19 cases per 1000 patients) and more than 12 months (n = 747) for any colorectal cancer (OR, 2.25 [95% CI, 1.89-2.68]; 76 cases per 1000 patients) and advanced-stage disease (OR, 3.22 [95% CI, 2.44-4.25]; 31 cases per 1000 patients). CONCLUSIONS AND RELEVANCE: Among patients with a positive fecal immunochemical test result, compared with follow-up colonoscopy at 8 to 30 days, follow-up after 10 months was associated with a higher risk of colorectal cancer and more advanced-stage disease at the time of diagnosis. Further research is needed to assess whether this relationship is causal.

Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.

BACKGROUND & AIMS: Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. METHODS: We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS: Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively. CONCLUSIONS: Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.

Adjusting for patient demographics has minimal effects on rates of adenoma detection in a large, community-based setting.

BACKGROUND & AIMS: Reliable estimates of adenoma detection rates (ADRs) are needed to inform colonoscopy quality standards, yet little is known about the contributions of patient demographics to variation in ADRs. We evaluated the effects of adjusting for patient age, race/ethnicity, and family history of colorectal cancer on variations in ADRs and the relative rank order of physicians. METHODS: In a retrospective cohort study, we collected data from Kaiser Permanente Northern California members who were ≥ 50 years old who received colonoscopies from 2006 through 2008. We evaluated ADRs (before and after adjustment for age, sex, race/ethnicity, and family history of colorectal cancer) for 102 endoscopists who performed 108,662 total colonoscopies and 20,792 screening colonoscopies. Adenomas were identified from the pathology database, and cancers were detected by using the Kaiser Permanente Northern California cancer registry. RESULTS: About two-thirds of examiners had unadjusted ADRs for screening exams that met gastroenterology society guidelines (>25% for men and >15% for women), although rates of detection varied widely (7.7%-61.5% for male patients and 1.7%-45.6% for female patients). Adjusting for case mix reduced the variation in detection rates (from 8-fold to 3-fold for male patients and from 27-fold to 5-fold for female patients), but the median change in physician order by detection rate was just 2 ranks, and few physicians changed quartiles of detection. For example, only 3 of 102 endoscopists moved into and 3 out of the lowest quartile of ADR. CONCLUSIONS: In a community-based setting, most endoscopists met the ADR standards, although there was wide variation in ADRs, which was similar to that reported from academic and referral settings. Case-mix adjustment reduced variability but had only small effects on differences in ADRs between physicians, and only a small percentage of physicians changed quartiles of detection. Adjustments to ADRs are therefore likely only needed in settings in which physicians have very different patient demographics, such as in sex or age. Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection.

Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model.

BACKGROUND & AIMS: Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. METHODS: We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. RESULTS: Hy's Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis. CONCLUSIONS: Hy's Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity.

Validity of diagnostic codes and laboratory tests of liver dysfunction to identify acute liver failure events.

PURPOSE: Identification of acute liver failure (ALF) is important for post-marketing surveillance of medications, but the validity of using ICD-9 diagnoses and laboratory data to identify these events within electronic health records is unknown. We examined positive predictive values (PPVs) of hospital ICD-9 diagnoses and laboratory tests of liver dysfunction for identifying ALF within a large, community-based integrated care organization. METHODS: We identified Kaiser Permanente Northern California health plan members (2004-2010) with a hospital diagnosis suggesting ALF (ICD-9 570, 572.2, 572.4, 572.8, 573.3, 573.8, or V42.7) plus an inpatient international normalized ratio ≥1.5 (off warfarin) and total bilirubin ≥5.0 mg/dL. Hospital records were reviewed by hepatologists to adjudicate ALF events. PPVs for confirmed outcomes were determined for individual ICD-9 diagnoses, diagnoses plus prescriptions for hepatic encephalopathy treatment, and combinations of diagnoses in the setting of coagulopathy and hyperbilirubinemia. RESULTS: Among 669 members with no pre-existing liver disease, chart review confirmed ALF in 62 (9%). Despite the presence of co-existing coagulopathy and hyperbilirubinemia, individual ICD-9 diagnoses had low PPVs (range, 5-15%); requiring prescriptions for encephalopathy treatment did not increase PPVs of these diagnoses (range, 2-23%). Hospital diagnoses of other liver disorders (ICD-9 573.8) plus hepatic coma (ICD-9 572.2) had high PPV (67%; 95%CI, 9-99%) but only identified two (3%) ALF events. CONCLUSIONS: Algorithms comprising relevant hospital diagnoses, laboratory evidence of liver dysfunction, and prescriptions for hepatic encephalopathy treatment had low PPVs for confirmed ALF events. Studies of ALF will need to rely on medical records to confirm this outcome.

Prevention of vertical transmission of hepatitis B: an observational study.

BACKGROUND: For mothers with chronic hepatitis B virus (HBV) infection, the Centers for Disease Control and Prevention recommends immunoprophylaxis to decrease perinatal transmission. However, its effectiveness and risk factors for failure have not been well-studied in community practice. OBJECTIVE: To investigate the effectiveness of a contemporary immunoprophylaxis protocol. DESIGN: Observational study. SETTING: An HBV perinatal immunoprophylaxis program within Kaiser Permanente Northern California. PATIENTS: 4446 infants born to 3253 HBV-positive mothers between 1997 and 2010. MEASUREMENTS: Adherence to immunoprophylaxis, follow-up testing rates, maternal risk factors for HBV transmission, and transmission rates. RESULTS: The infant infection rate was 0.75 per 100 births from 1997 to 2010 (Poisson 95% CI, 0.48 to 1.10). Rates per 100 births were 3.37 (CI, 2.08 to 5.14) for e antigen-positive mothers and 0.04 (CI, 0.001 to 0.24) for e antigen-negative mothers. Among mothers with viral load testing, the lowest level associated with transmission was 6.32 × 107 IU/mL. Infection rates per 100 births were 3.61 (CI, 0.75 to 10.56) among the 83 births to mothers with viral loads of 5 × 107 IU/mL or greater and 0 among the 831 births to mothers with viral loads less than 5 × 107 IU/mL, regardless of e antigen status. LIMITATIONS: Testing for HBV immunity and infection was less complete in earlier years. Viral load testing was only consistently available starting in 2007. CONCLUSION: Prenatal HBV screening followed by postnatal prophylaxis is highly effective in preventing vertical transmission of HBV. A negative e antigen status or a viral load less than 5 × 107 IU/mL (90.9% of women tested) identifies women at extremely low risk for transmission after immunoprophylaxis who are unlikely to benefit from further interventions. PRIMARY FUNDING SOURCE: Kaiser Permanente Community Benefit and National Institutes of Health.

Variation of adenoma prevalence by age, sex, race, and colon location in a large population: implications for screening and quality programs.

BACKGROUND & AIMS: Reliable community-based colorectal adenoma prevalence estimates are needed to inform colonoscopy quality standards and to estimate patient colorectal cancer risks; however, minimal data exist from populations with large numbers of diverse patients and examiners. METHODS: We evaluated the prevalence of adenomas detected by sex, age, race/ethnicity, and colon location among 20,792 Kaiser Permanente Northern California members ≥50 years of age who received a screening colonoscopy examination (102 gastroenterologists, 2006-2008). RESULTS: Prevalence of detected adenomas increased more rapidly with age in the proximal colon (adjusted odds ratio [OR], 2.39; 95% confidence interval [CI], 2.05-2.80; 70-74 vs 50-54 years) than in the distal colon (OR, 1.89; 95% CI, 1.63-2.19). Prevalence was higher among men vs women at all ages (OR, 1.77; 95% CI, 1.66-1.89), increasing in men from 25% to 39% at ≥70 years and in women from 15% at 50-54 years to 26% (P < .001). Proximal adenoma prevalence was higher among blacks than whites (OR, 1.26; 95% CI, 1.04-1.54), although total prevalence was similar, including persons <60 years old (OR, 1.17; 95% CI, 0.91-1.50). CONCLUSIONS: Prevalence of detected adenomas increases substantially with age and is much higher in men; proximal adenomas are more common among blacks than whites, although the total prevalence and the prevalence for ages <60 years were similar by race. These demographic differences are such that current adenoma detection guidelines may not be valid, without adjustment, for comparing providers serving different populations. The variation in prevalence and location may also have implications for the effectiveness of screening methods in different demographic groups.

Serum dioxin concentrations and time to pregnancy.

BACKGROUND: Pollution may play a role in population trends of declining semen quality and regional differences in time to pregnancy (TTP) in industrialized societies. Dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been suspected. In 1976, an explosion near Seveso, Italy resulted in the highest TCDD exposure known in residential populations. Twenty years later, we conducted a retrospective cohort study, the Seveso Women's Health Study. METHODS: Of 981 participants, 472 women attempted pregnancy after the explosion, and 278 delivered a livebirth not associated with contraceptive failure. Individual serum TCDD levels were measured from samples collected soon after the explosion and extrapolated to the conception attempt. We examined the relation of TCDD levels to time to pregnancy (parameterized as the monthly probability of conception within the first 12 months of trying) and to infertility (defined as conception after at least 12 months of trying). We modeled fecundability with discrete-time Cox proportional hazards regression, and we modeled fertility with logistic regression. We tested the sensitivity of the conclusions to differing definitions of eligibility and outcome. RESULTS: Median TCDD level was 50 parts per trillion, median time to pregnancy was 2 months, and 17% reported taking 12 or more months to conceive. For every 10-fold increase in serum TCDD, we observed a 25% increase in time to pregnancy (adjusted-fecundability odds ratio = 0.75 [95% confidence interval (CI) = 0.60-0.95]) and about a doubling in odds of infertility (adjusted odds ratio = 1.9 [95% CI = 1.1-3.2]). Results were similar for extrapolated TCDD and sensitivity analyses. CONCLUSIONS: We found dose-related increases in TTP and infertility associated with individual serum TCDD levels in the women from Seveso, Italy. These findings may have implications for fertility in industrialized areas.

Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children.

BACKGROUND: Organophosphate (OP) pesticides are widely used in agriculture and homes. Animal studies suggest that even moderate doses are neurodevelopmental toxicants, but there are few studies in humans. OBJECTIVES: We investigated the relationship of prenatal and child OP urinary metabolite levels with children's neurodevelopment. METHODS: Participating children were from a longitudinal birth cohort of primarily Latino farm-worker families in California. We measured six nonspecific dialkylphosphate (DAP) metabolites in maternal and child urine as well as metabolites specific to malathion (MDA) and chlorpyrifos (TCPy) in maternal urine. We examined their association with children's performance at 6 (n = 396), 12 (n = 395), and 24 (n = 372) months of age on the Bayley Scales of Infant Development [Mental Development (MDI) and Psychomotor Development (PDI) Indices] and mother's report on the Child Behavior Checklist (CBCL) (n = 356). RESULTS: Generally, pregnancy DAP levels were negatively associated with MDI, but child measures were positively associated. At 24 months of age, these associations reached statistical significance [per 10-fold increase in prenatal DAPs: beta = -3.5 points; 95% confidence interval (CI), -6.6 to -0.5; child DAPs: beta = 2.4 points; 95% CI, 0.5 to 4.2]. Neither prenatal nor child DAPs were associated with PDI or CBCL attention problems, but both prenatal and postnatal DAPs were associated with risk of pervasive developmental disorder [per 10-fold increase in prenatal DAPs: odds ratio (OR) = 2.3, p = 0.05; child DAPs OR = 1.7, p = 0.04]. MDA and TCPy were not associated with any outcome. CONCLUSIONS: We report adverse associations of prenatal DAPs with mental development and pervasive developmental problems at 24 months of age. Results should be interpreted with caution given the observed positive relationship with postnatal DAPs.

Risk of Acute Liver Injury With Antiretroviral Therapy by Viral Hepatitis Status.

BACKGROUND: The risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status. METHODS: We followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status. RESULTS: Liver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P < .001). No evidence of differential risk was found between initiators of abacavir/lamivudine versus tenofovir/emtricitabine among coinfected (HR, 0.68; 95% CI, .29-1.57) or HIV-monoinfected (HR, 1.19; 95% CI, .47-2.97) groups. Coinfected patients had a higher risk of aminotransferases >200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36-2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P < .001) but was too uncommon to evaluate in adjusted analyses. CONCLUSIONS: Within the year after ART initiation, aminotransferase elevations were infrequently observed and rarely led to severe ALI. Protease inhibitor use was associated with a higher risk of aminotransferase elevations among viral hepatitis-coinfected patients.

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status.

BACKGROUND: Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals. METHODS: We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. RESULTS: Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4-14.6]), ketoconazole (19.3 [13.8-26.3]), and itraconazole (24.5 [10.6-48.2]). Rates were higher with voriconazole (181.9 [112.6-278.0]) and posaconazole (191.1 [23.1-690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4-2.7]), ketoconazole (2.9 [1.1-6.3]), and itraconazole (0.0 [0.0-11.2]), but more frequent with voriconazole (16.7 [2.0-60.2]) and posaconazole (93.4 [2.4-520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68-5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56-12.35]). CONCLUSIONS: Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury.

Serum dioxin concentrations and age at menopause.

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD), a halogenated compound that binds the aryl hydrocarbon receptor, is a by-product of numerous industrial processes including waste incineration. Studies in rats and monkeys suggest that TCDD may affect ovarian function. We examined the relationship of TCDD and age at menopause in a population of women residing near Seveso, Italy, in 1976, at the time of a chemical plant explosion. We included 616 of the women who participated 20 years later in the Seveso Women's Health Study. All women were premenopausal at the time of the explosion, had TCDD levels measured in serum collected soon after the explosion, and were > or = 35 years of age at interview. Using proportional hazards modeling, we found a 6% nonsignificant increase in risk of early menopause with a 10-fold increase in serum TCDD. When TCDD levels were categorized, compared with women in the lowest quintile (< 20.4 ppt), women in quintile 2 (20.4-34.2 ppt) had a hazard ratio (HR) of 1.1 (p = 0.77), quintile 3 (34.3-54.1 ppt) had an HR of 1.4 (p = 0.14), quintile 4 (54.2-118 ppt) had an HR of 1.6 (p = 0.10), and quintile 5 (> 118 ppt) had an HR of 1.1 (p = 0.82) for risk of earlier menopause. The trend toward earlier menopause across the first four quintiles is statistically significant (p = 0.04). These results suggest a nonmonotonic dose-related association with increasing risk of earlier menopause up to about 100 ppt TCDD, but not above.

Metformin use and risk of colorectal adenoma after polypectomy in patients with type 2 diabetes mellitus.

BACKGROUND: Existing literature suggests that metformin, the most commonly used biguanide, may lower colorectal cancer risk. Because most colorectal cancers originate in precancerous adenomas, we examined whether metformin use lowered colorectal adenoma risk after polypectomy in patients with type-2 diabetes. METHODS: Retrospective cohort study of 40- to 89-year-old Kaiser Permanente Northern California patients who had type 2 diabetes, and ≥1 adenoma detected at baseline colonoscopy during 2000 to 2009 and a repeat colonoscopy 1 to 10 years from baseline adenoma diagnosis through 2012. Cox models evaluated the association between metformin use during follow-up and subsequent adenoma diagnoses, controlling for age, race/ethnicity, sex, body mass index, and repeat examination indication. RESULTS: Study included 2,412 patients followed for a median of 4.5 years; cumulatively, 1,117 (46%) patients had ≥1 adenoma at repeat colonoscopy. Compared with patients not receiving diabetes medications (n = 1,578), metformin-only use (n = 457) was associated with lower adenoma recurrence risk [adjusted HR, 0.76; 95% confidence interval (CI), 0.65-0.89], and the association was stronger with increasing total metformin dose [quartile (Q) 1: HR, 0.90; 95% CI, 0.72-1.12; Q2: HR, 0.89; 95% CI, 0.70-1.12; Q3: HR, 0.80; 95% CI, 0.63-1.01; Q4: HR, 0.50; 95% CI, 0.42-0.60, Ptrend < 0.001]. Findings were unchanged in sensitivity analyses, including evaluating only outcomes during the 3- to 10-year period from baseline. CONCLUSION: Our study suggests a potential benefit of metformin use in lowering the risk of subsequent adenomas after polypectomy in patients with type 2 diabetes. IMPACT: Metformin may lower colorectal cancer risk by reducing the formation of precancerous lesions, reinforcing the potential additional benefits of its use.