Validity of inpatient electronic health record-based measures of oxygen-related therapy in the United States: Lessons applicable for studying COVID-19 endpoints.

INTRODUCTION: During the COVID-19 pandemic, inpatient electronic health records (EHRs) have been used to conduct public health surveillance and assess treatments and outcomes. Invasive mechanical ventilation (MV) and supplemental oxygen (O2) use are markers of severe illness in hospitalized COVID-19 patients. In a large US system (n = 142 hospitals), we assessed documentation of MV and O2 use during COVID-19 hospitalization in administrative data versus nursing documentation. METHODS: We identified 319 553 adult hospitalizations with a COVID-19 diagnosis, February 2020-October 2022, and extracted coded, administrative data for MV or O2. Separately, we developed classification rules for MV or O2 supplementation from semi-structured nursing documentation. We assessed MV and O2 supplementation in administrative data versus nursing documentation and calculated ordinal endpoints of decreasing COVID-19 disease severity. Nursing documentation was considered the gold standard in sensitivity and positive predictive value (PPV) analyses. RESULTS: In nursing documentation, the prevalence of MV and O2 supplementation among COVID-19 hospitalizations was 14% and 75%, respectively. The sensitivity of administrative data was 83% for MV and 41% for O2, with both PPVs above 91%. Concordance between sources was 97% for MV (κ = 0.85), and 54% for O2 (κ = 0.21). For ordinal endpoints, administrative data accurately identified intensive care and MV but underestimated hospitalizations with O2 requirements (42% vs. 18%). CONCLUSIONS: In comparison to nursing documentation, administrative data under-ascertained O2 supplementation but accurately estimated severe endpoints such as MV. Nursing documentation improved ascertainment of O2 among COVID-19 hospitalizations and can capture oxygen requirements in adults hospitalized with COVID-19 or other respiratory illnesses.

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

PURPOSE: The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. METHODS: We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. RESULTS: There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. CONCLUSIONS: We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015-2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

Reproducing Protocol-Based Studies Using Parameterizable Tools-Comparison of Analytic Approaches Used by Two Medical Product Surveillance Networks.

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol-based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin-based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new-user cohort analyses aligned with those from the CNODES nested case-control studies. The adjusted hazard ratios were 0.95 (0.81-1.12; vs. 1.03 (0.87-1.22) in CNODES) for acute pancreatitis and 0.91 (0.84-1.00; vs. 0.82 (0.67-1.00) in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, whereas the Sentinel's common data model plus pretested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches.

Health Care Resource Utilization and Exacerbation Rates in Patients with COPD Stratified by Disease Severity in a Commercially Insured Population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is associated with substantial economic burden. There is a lack of data regarding COPD outcomes and costs in a real-world setting, particularly by Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity. OBJECTIVES: To (a) characterize a commercially insured U.S. population with COPD and (b) assess prevalence of exacerbations, health care resource utilization (HCRU), costs, and treatment patterns in a cohort of patients with confirmed COPD, overall and stratified by GOLD stage. METHODS: This retrospective observational cohort study used administrative claims data from the HealthCore Integrated Research Database to identify patients with ≥ 1 inpatient, emergency room (ER), or office visit claim for COPD between January 1, 2012, and November 30, 2013, and continuous enrollment for 1 year before and 2 years after the first COPD diagnosis date. Patients with a spirometry claim within 12 months were eligible for medical record abstraction to confirm COPD diagnosis (forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio < 0.7) and GOLD 1-4 classification (based on postbronchodilator FEV1 percent predicted). HCRU, costs, treatment patterns, and rate of moderate/severe exacerbation were identified from diagnosis up to 24 months. Outcomes were analyzed by univariate analysis stratified by GOLD classification. Multivariable analysis was conducted to assess associations between GOLD classification and outcomes of interest. RESULTS: 53,484 patients newly diagnosed with COPD were identified who met initial inclusion criteria: 14,293 (27%) had a qualifying spirometry claim, and 1,505 had confirmed COPD (GOLD 1, 333 [22%]; GOLD 2, 823 [55%]; GOLD 3, 317 [21%]; GOLD 4, 32 [2%]). Patients with greater disease severity had higher rates of moderate/severe COPD exacerbations (GOLD 1 and 2, 40.4 and 48.9 per 100 person-years, respectively; GOLD 3 and 4, 83.6 and 89.1 per 100 person-years, respectively). All-cause and COPD-related inpatient admissions, COPD-related office visits, and COPD-related ER visits were more prevalent with more severe GOLD classification. Mean annual COPD-related medical costs increased with GOLD classification ($5,945 for GOLD 1 patients, $18,070 for GOLD 4). COPD maintenance medication was filled by 42%, 56%, 73%, and 75% of patients in GOLD 1-4 (57% overall), respectively; combination corticosteroid/long-acting beta2-agonist inhalers were the most commonly used medication, regardless of GOLD classification. Patients with more severe disease had greater adherence (range 44%-68% of days covered for GOLD 1-4) and persistence (range 107-209 days for GOLD 1-4). CONCLUSIONS: Trends toward increases in exacerbations, HCRU, and costs were observed as airflow limitation worsened. Adherence and persistence with COPD maintenance therapy was suboptimal even with severe disease. DISCLOSURES: This study was supported by Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT), which was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Willey and Singer are employees of HealthCore (parent company Anthem), which received funding from Boehringer Ingelheim to complete this study. Wallace and Shinde were employed by HealthCore at the time of this study. Wallace and Singer report stock ownership in Anthem. Napier is an employee of Anthem. Kaila, Bayer, and Shaikh are employees of Boehringer Ingelheim Pharmaceuticsls. Portions of this research were presented at the following conferences: (a) A. Wallace, S. Kaila, V. Zubek, A. Shaikh, M. Shinde, V. Willey, M. Napier, and J. Singer, Healthcare resource utilization, costs, and exacerbation rates in patients with COPD stratified by GOLD airflow limitation classification in a US commercially insured population, presented at AMCP Nexus 2017; October 16-19, 2017; Dallas, TX; and (b) A.E. Wallace, V. Zubek, S. Kaila, A. Shaikh, M. Shinde, V. Willey, M.B. Napier, and J.R. Singer, Real-world treatment patterns among newly diagnosed COPD patients according to GOLD airflow limitation severity classification in a U.S. commercially insured/Medicare Advantage population, presented at CHEST 2017 Annual Meeting; October 28-November 1, 2017; Toronto, Ontario, Canada.

Comparison of claims vs patient-reported adherence measures and associated outcomes among patients with nonvalvular atrial fibrillation using oral anticoagulant therapy.

OBJECTIVE: To compare oral anticoagulant (OAC) adherence among patients with nonvalvular atrial fibrillation (NVAF) using patient-reported and claims-based measures, and to evaluate the effect of OAC adherence on health care costs and patient satisfaction with OAC therapy. METHODS: This was a hybrid US observational study consisting of a longitudinal cohort survey followed by linkage and analysis of respondents' administrative claims data. Patients with NVAF receiving warfarin, dabigatran, rivaroxaban, or apixaban completed an initial survey and follow-up surveys at 4, 8, and 12 months. Patient-reported adherence was measured at each survey by Morisky Medication Adherence Scale (MMAS-8) and pharmacy claims-determined adherence by the proportion of days covered (PDC) for the 12-month period following the initial survey date; adherence was defined as MMAS-8 score =8 and PDC ≥80%. Patient satisfaction with OAC therapy was assessed by the Duke Anticoagulation Satisfaction Scale (DASS). RESULTS: Overall, 675 patients completed at least the initial survey (warfarin, n=271; dabigatran, n=266; rivaroxaban, n=128; apixaban, n=10). Fewer than half (47.9%) were PDC adherent, 37.2% were MMAS-8 adherent, and 19.4% were adherent by both measures. Total medical costs of PDC-adherent patients were significantly lower vs PDC-nonadherent patients (US$640 vs $993 per-patient per-month, respectively, p<0.05). MMAS-8-adherent patients reported higher treatment satisfaction; total DASS score was significantly lower among MMAS-8-adherent than MMAS-8-nonadherent patients (37.3 vs 42.9, respectively, p<0.001). CONCLUSION: Using claims-based or patient-reported methods to measure OAC adherence may lead to different results when assessing impact on health care costs and satisfaction with anticoagulation medication. These results underscore the importance of considering both claims-based and patient-reported measures when evaluating treatment adherence in real-world settings.

Prenatal Exposure to Nitrosatable Drugs, Dietary Intake of Nitrites, and Preterm Birth.

Prenatal exposure to nitrosatable drugs, including secondary or tertiary amines, has been associated with preterm birth. Associations may be accentuated by higher intakes of dietary nitrites because of the increased formation of N-nitroso compounds. Using data from mothers of babies without major birth defects (controls) from the National Birth Defects Prevention Study, we examined the relationship between nitrosatable drug exposure in conjunction with dietary nitrite intake and preterm birth among 496 mothers of preterm infants and 5,398 mothers with full-term deliveries in 1997-2005. A protective association was observed with a high intake of plant nitrites (adjusted hazard ratio (AHR) = 0.72, 95% confidence interval (CI): 0.53, 0.97). Secondary amines in conjunction with high nitrite intake were associated with preterm birth during the first (AHR = 1.84, 95% CI: 1.14, 2.98), second (AHR = 1.89, 95% CI: 1.17, 3.07), and third (AHR = 2.00, 95% CI: 1.22, 3.29) trimesters. The adjusted hazard ratios for tertiary amine use in the third trimester by increasing tertiles of nitrite intake were 0.67 (95% CI: 0.35, 1.31), 1.25 (95% CI: 0.71, 2.19), and 2.02 (95% CI: 1.17, 3.49). Prenatal exposure to nitrosatable drugs, particularly secondary and tertiary amines, in conjunction with higher levels of dietary nitrite intake may increase the risk of preterm birth.

Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births.

BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.

Maternal residential proximity to chlorinated solvent emissions and birth defects in offspring: a case-control study.

BACKGROUND: Some studies have noted an association between maternal occupational exposures to chlorinated solvents and birth defects in offspring, but data are lacking on the potential impact of industrial air emissions of these solvents on birth defects. METHODS: With data from the Texas Birth Defects Registry for births occurring in 1996-2008, we examined the relation between maternal residential proximity to industrial air releases of chlorinated solvents and birth defects in offspring of 60,613 case-mothers and 244,927 control-mothers. Maternal residential exposures to solvent emissions were estimated with metrics that took into account residential distances to industrial sources and annual amounts of chemicals released. Logistic regression was used to generate odds ratios and 95% confidence intervals for the associations between residential proximity to emissions of 14 chlorinated solvents and selected birth defects, including neural tube, oral cleft, limb deficiency, and congenital heart defects. All risk estimates were adjusted for year of delivery and maternal age, education, race/ethnicity, and public health region of residence. RESULTS: Relative to exposure risk values of 0, neural tube defects were associated with maternal residential exposures (exposure risk values >0) to several types of chlorinated solvents, most notably carbon tetrachloride (adjusted odds ratio [aOR] 1.42, 95% confidence interval [CI] 1.09, 1.86); chloroform (aOR 1.40, 95% CI 1.04, 1.87); ethyl chloride (aOR 1.39, 95% CI 1.08, 1.79); 1,1,2-trichloroethane (aOR 1.56, 95% CI 1.11, 2.18); and 1,2,3-trichloropropane (aOR 1.49, 95% CI 1.08, 2.06). Significant associations were also noted between a few chlorinated solvents and oral cleft, limb deficiency, and congenital heart defects. We observed stronger associations between some emissions and neural tube, oral cleft, and heart defects in offspring of mothers 35 years or older, such as spina bifida with carbon tetrachloride (aOR 2.49, 95% CI 1.09, 5.72), cleft palate with 1,2-dichloroethane (aOR 1.93, 95% 1.05, 3.54), cleft lip with or without cleft palate with ethyl chloride (aOR 1.81, 95% CI 1.06, 3.07), and obstructive heart defects with trichloroethylene (aOR 1.43, 95% CI 1.08, 1.88). CONCLUSIONS: These findings suggest that maternal residential proximity to industrial emissions of chlorinated solvents might be associated with selected birth defects in offspring, especially among older mothers.

Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the national birth defects prevention study.

BACKGROUND: Previous studies of prenatal exposure to drinking-water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs. OBJECTIVES: We examined the relation between prenatal exposure to drinking-water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure. METHODS: With data from the National Birth Defects Prevention Study, we linked addresses of 3,300 case mothers and 1,121 control mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work. RESULTS: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. < 0.91 mg) than control mothers. During 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily (vs. < 1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects. CONCLUSIONS: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects.

Prenatal exposure to nitrosatable drugs, vitamin C, and risk of selected birth defects.

UNLABELLED: Nitrosatable drugs, such as secondary or tertiary amines and amides react with nitrite in an acidic environment to form N-nitroso compounds, teratogens in animal models. Vitamin C is a known nitrosation inhibitor. METHODS: Using data from the National Birth Defects Prevention Study, we assessed nitrosatable drug exposure and vitamin C intake during the first trimester among 11,606 case-mothers of infants with oral clefts, limb deficiencies (LDs), or congenital heart defects and 6807 control-mothers of infants without major birth defects during 1997-2005. Daily intake of vitamin C was estimated from maternal interviews that elicited information about supplement use and dietary intake. RESULTS: With no reported use of nitrosatable drugs as the referent group, a lower odds ratio (OR) was observed for transverse LDs among births to mothers exposed to secondary amine drugs and daily vitamin C supplementation (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 0.83-1.8) compared with women taking these drugs and no supplementation (aOR 2.7, 95% CI 1.5-4.6). The OR for longitudinal LDs associated with secondary amine exposure was lower with daily dietary vitamin C intake ≥85 mg (aOR 1.2, 95% CI 0.68-2.0) compared with <85 mg (aOR 1.9, 95% CI 1.2-3.1). Daily vitamin C supplementation in combination with higher dietary vitamin C intake reduced associations between nitrosatable drug exposures and limb deficiencies and atrial septal defects not otherwise specified. CONCLUSION: Prenatal dietary and vitamin C supplement intake may diminish the association between nitrosatable drug exposure during pregnancy and selected birth defects.

Maternal dietary intake of nitrates, nitrites and nitrosamines and selected birth defects in offspring: a case-control study.

BACKGROUND: Dietary intake of nitrates, nitrites, and nitrosamines can increase the endogenous formation of N-nitroso compounds in the stomach. Results from animal studies suggest that these compounds might be teratogenic. We examined the relationship between maternal dietary intake of nitrates, nitrites (including plant and animal sources as separate groups), and nitrosamines and several types of birth defects in offspring. METHODS: For this population-based case-control study, data from a 58-question food frequency questionnaire, adapted from the short Willett Food Frequency Questionnaire and administered as part of the National Birth Defects Prevention Study (NBDPS), were used to estimate daily intake of dietary nitrates, nitrites, and nitrosamines in a sample of 6544 mothers of infants with neural tube defects (NTD)s, oral clefts (OC)s, or limb deficiencies (LD)s and 6807 mothers of unaffected control infants. Total daily intake of these compounds was divided into quartiles based on the control mother distributions. Odds ratios (OR)s and 95% confidence intervals (CI)s were estimated using logistic regression; estimates were adjusted for maternal daily caloric intake, maternal race-ethnicity, education, dietary folate intake, high fat diet (>30% of calories from fat), and state of residence. RESULTS: While some unadjusted ORs for NTDS had 95% (CI)s that excluded the null value, none remained significant after adjustment for covariates, and the effect sizes were small (adjusted odds ratios [aOR]<1.12). Similar results were found for OCs and LDs with the exception of animal nitrites and cleft lip with/without cleft palate (aORs and CIs for quartile 4 compared to quartile 1 =1.24; CI=1.05-1.48), animal nitrites and cleft lip (4th quartile aOR=1.32; CI=1.01-1.72), and total nitrite and intercalary LD (4th quartile aOR=4.70; CI=1.23-17.93). CONCLUSIONS: Overall, odds of NTDs, OCs or LDs did not appear to be significantly associated with estimated dietary intake of nitrate, nitrite, and nitrosamines.

Nitrosatable drug exposure during the first trimester of pregnancy and selected congenital malformations.

BACKGROUND: Nitrosatable drugs can react with nitrite in the stomach to form N-nitroso compounds, and results from animal studies suggest that N-nitroso compounds are teratogens. With data from the National Birth Defects Prevention Study, the relation between prenatal exposure to nitrosatable drugs and limb deficiencies, oral cleft, and heart malformations in offspring was examined. METHODS: Maternal reports of drugs taken during the first trimester of pregnancy were classified with respect to nitrosatability for mothers of 741 babies with limb deficiencies, 2774 with oral cleft malformations, 8091 with congenital heart malformations, and 6807 without major congenital malformations. Nitrite intake was estimated from maternal responses to a food frequency questionnaire. RESULTS: Isolated transverse limb deficiencies and atrioventricular septal defects were associated with secondary amine drug exposures (adjusted odds ratios [aORs], 1.51; 95% confidence limit [CI], 1.11-2.06 and aOR, 1.97; 95% CI, 1.19-3.26, respectively). Tertiary amines were associated with hypoplastic left heart syndrome (aOR, 1.50; 95% CI, 1.10-2.04) and single ventricle (aOR, 1.61; 95% CI, 1.06-2.45). These two malformations were also significantly associated with amide drugs. For several malformations, the strongest associations with nitrosatable drug use occurred among mothers with the highest estimated dietary nitrite intake, especially for secondary amines and atrioventricular septal defects (highest tertile of nitrite, aOR, 3.30; 95% CI, 1.44-7.58). CONCLUSION: Prenatal exposure to nitrosatable drugs may be associated with several congenital malformations, especially with higher nitrite intake. The possible interaction between nitrosatable drugs and dietary nitrite on risk of congenital malformations warrants further attention.

Nitrosatable drug exposure during early pregnancy and neural tube defects in offspring: National Birth Defects Prevention Study.

Nitrosatable drugs, such as secondary or tertiary amines and amides, form N-nitroso compounds in the presence of nitrite. Various N-nitroso compounds have been associated with neural tube defects in animal models. Using data from the National Birth Defects Prevention Study, the authors examined nitrosatable drug exposure 1 month before and 1 month after conception in 1,223 case mothers with neural tube defect-affected pregnancies and 6,807 control mothers who delivered babies without major congenital anomalies from 1997 to 2005. Nitrite intakes were estimated from mothers' responses to a food frequency questionnaire. After adjustment for maternal race/ethnicity, educational level, and folic acid supplementation, case women were more likely than were control women to have taken tertiary amines (odds ratio = 1.60, 95% confidence interval (CI): 1.31, 1.95). This association was strongest with anencephalic births (odds ratio = 1.96, 95% CI: 1.40, 2.73); odds ratios associated with tertiary amines from the lowest tertile of nitrite intake to the highest tertile were 1.16 (95% CI: 0.59, 2.29), 2.19 (95% CI: 1.25, 3.86), and 2.51 (95% CI: 1.45, 4.37), respectively. Odds ratios for anencephaly with nitrosatable drug exposure were reduced among women who also took daily vitamin supplements that contained vitamin C. Prenatal exposure to nitrosatable drugs may increase the risk of neural tube defects, especially in conjunction with a mother's higher dietary intake of nitrites, but vitamin C might modulate this association.