Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes.

Evidence documenting the safety of acid-suppressing drugs in pregnancy is very limited. The authors assessed the prevalence of congenital malformations in first trimester-exposed pregnancies to cimetidine, omeprazole, and ranitidine and compared it with nonexposed pregnancies between 1991 and 1996. Two different sources were used, the United Kingdom General Practice Research Database and the Italian Friuli-Venezia Giulia Health Database. The final study cohort included 1,179 pregnancies from the United Kingdom and 1,057 from Italy. Abortions or ectopic pregnancies were not included. There were 20 stillbirths and 2,261 live-born babies in both cohorts combined, with 100 offspring identified with a malformation. The overall malformation rate was 4.4%. The relative risks for nongenetic congenital malformations associated with the use of cimetidine, omeprazole, and ranitidine were 1.2 (95% confidence interval (CI): 0.6, 2.3), 0.9 (95% CI: 0.3, 2.2), and 1.4 (95% CI: 0.8, 2.4), respectively, compared with the nonexposed. No specific grouping in the distribution of malformations was observed in any of the three exposed groups. Moreover, no relation was found between drug exposure and preterm delivery or growth retardation. These findings suggest that the use of acid-suppressing drugs during the first trimester of pregnancy is not associated with a major teratogenic risk.

Positive predictive value of ICD-9th codes for upper gastrointestinal bleeding and perforation in the Sistema Informativo Sanitario Regionale database.

We identified patients whose records in the Sistema Informativo Sanitario Regionale database in the Italian region of Friuli-Venezia Giulia showed a code of upper gastrointestinal bleeding (UGIB) and perforation according to codes of the International Classification of Diseases (ICD)-9th revision. The validity of site- and lesion-specific codes (531 to 534) and nonspecific codes (5780, 5781, and 5789) was ascertained through manual review of hospital clinical records. The initial group was made of 1779 potential cases of UGIB identified with one of these codes recorded. First, the positive predictive values (PPV) were calculated in a random sample. As a result of the observed high PPV of 531 and 532 codes, additional hospital charts were solely requested for all remaining potential cases with 533, 534, and 578 ICD-9 codes. The overall PPV reached a high of 97% for 531 and 532 site-specific codes, 84% for 534 site-specific codes, and 80% for 533 lesion-specific codes, and a low of 59% for nonspecific codes. These data suggest a considerable research potential for this new computerized health care database in Southern Europe.

Use of amoxicillin and amoxicillin-clavulanic acid and hospitalization for acute liver injury.

Increase of acute liver injury in patients taking amoxicillin-clavulanic acid (co-amoxiclav) as compared to those taking amoxicillin has been suggested. To further investigate the potential hepatotoxicity of the two drugs a historical cohort study was conducted in the Italian region of Friuli-Venezia Giulia. One hundred and eighteen potential cases of acute liver injury were identified through the regional hospital information system and medical records were reviewed for all of them. Overall, 12 cases of acute liver injury were identified: 3 cases occurred in the amoxicillin exposure category, 2 among co-amoxiclav group, and 7 in the non-use category. The adjusted estimate of the rate ratio was 5.7 (CI 95% 1.5-22.1) among users of amoxicillin alone and 6.2 (CI 95% 1.3-29.7) among users of co-amoxiclav.

Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe.

The authors evaluated the risk of venous thromboembolism associated with hormone replacement therapy in a cohort of 265,431 women aged 45-79 years who did not have major risk factors for venous thromboembolism. Through review of hospital charts, 171 cases were confirmed (pulmonary embolism = 77; deep venous thrombosis = 94). Ten thousand controls were randomly sampled. The risk of venous thromboembolism among nonusers of hormone replacement therapy was 1.3 per 10,000 women per year. Current users of hormone replacement therapy had 2.3 times higher risk of venous thromboembolism (95 percent confidence interval 1.0-5.3) compared with nonusers. The increased risk was restricted to the first year of treatment.

Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause substantial morbidity and mortality from upper gastrointestinal tract disease. Ketorolac tromethamine has been singled out as an NSAID with a distinct gastrotoxicity profile. Calcium channel blockers, a class of antihypertensive drugs, have also been found to increase the risk of gastrointestinal tract bleeding. METHODS: We identified 1505 patients hospitalized because of upper gastrointestinal tract bleeding and/or perforation, and we randomly sampled 20,000 controls in the source population. RESULTS: The adjusted relative risk (RR) for upper gastrointestinal tract bleeding and/or perforation in NSAID users compared with nonusers was 4.4 (95% confidence interval [CI], 3.7-5.3). The risk increased with higher daily doses. Ketorolac presented the highest risk (RR, 24.7; 95% CI, 9.6-63.5) and piroxicam ranked second (RR, 9.5; 95% CI, 6.5-13.8). Ketorolac was 5 times more gastrotoxic than all other NSAIDs (RR, 5.5; 95% CI, 2.1-14.4). The excess risk with ketorolac was observed with both oral and intramuscular administration and was already present during the first week of therapy. Among the various antihypertensive drug classes, beta-blockers were associated with the lowest relative risk (RR, 1.0; 95% CI, 0.7-1.4), and current use of calcium channel blockers with the highest (RR, 1.7; 95% CI, 1.3-2.1). The association with calcium channel blockers declined when adjusting for various markers of comorbidity (RR, 1.4; 95% CI, 1.1-1.8). Past use of calcium channel blockers was also associated with an increased risk (RR, 1.5; 95% CI, 1.3-1.8). CONCLUSIONS: The excess risk of major upper gastrointestinal tract complications associated with outpatient use of ketorolac suggests an unfavorable risk-benefit assessment compared with other NSAIDs. More data are required to reduce the uncertainty about the apparent small increased risk of upper gastrointestinal tract bleeding in patients using calcium channel blockers.

Ocular disorders in users of H2 antagonists and of omeprazole.

We have conducted a cohort study of users of omeprazole and H(2) antagonists in Italy to investigate whether the peroral use of these drugs may be associated with an increased incidence of ocular disorders leading to loss of vision. We have used the Sistema Informativo Sanitario Regionale (SISR database) in Friuli-Venezia-Giulia to identify all subjects who received at least one prescription for cimetidine, famotidine, niperotidine, nizatidine, omeprazole, ranitidine or roxatidine between 1 January 1991 and 31 December 1994. We have identified all hospital admissions for serious vascular or inflammatory ocular disorders following any such prescription, reviewed and validated all medical records. There were 71,108 users of any of the study drugs, contributing a total of 101,827 person years of observation. Seven cases of serious eye disorders were identified, giving an annual incidence rate of 7/100,000 persons. By comparison to non-users, the incidence rate ratio for current users of all of the study drugs together was 0, with a 95% confidence interval of 0 to 2.1. By comparison to non-users, the incidence rate ratio for past users was 0.47 (95% CI: 0.06-2.4). Our data are consistent with previous studies and add weight to the general impression of the ocular safety of these drugs.