The identification of pregnancies within the general practice research database.

BACKGROUND: The United States is moving toward active drug safety surveillance using sources such as administrative claims and electronic medical records, but use of these data for studying teratogenicity has been challenging, as they typically do not allow for the easy identification of pregnancies. Our goal was to develop and validate an algorithm for the identification of pregnancies in the general practice research database (GPRD) that could be used to study pregnancy outcomes. METHODS: The algorithm identified pregnancies in women 15-45-year-old that were pregnant between 1 January 1987 and 31 December 2006. We identified live births, stillbirths, and spontaneous and elective terminations within a woman's record. We validated the algorithm using the additional clinical details maternity (ACDM) file and de-identified free-text records. RESULTS: We analyzed 16,035,394 records from 3,093,927 individuals and identified 383,184 women who had a total of 580,356 pregnancies. There were 415,221 full-term live births, 3080 pre- or post-term births, 1834 multi-fetus deliveries, 86,408 spontaneous abortions or miscarriages, 72 164 elective terminations, and 1649 stillbirths or fetal deaths. A marker of pregnancy care was identifiable for 86.3% of the 580,356 pregnancies. The internal validation steps indicated that the algorithm produced consistent results with the ACDM file. CONCLUSIONS: We were successful in identifying a large number of pregnancies in the GPRD. Our use of a hierarchical approach to identify pregnancy outcomes builds upon the methods suggested in previous work, while implementing additional steps to minimize potential misclassification of pregnancy outcomes.

Validation of neural tube defects in the full featured--general practice research database.

BACKGROUND: The General Practice Research Database (GPRD) has been used to identify associations between pregnancy medication exposures and birth defects, but experts have argued that databases such as this one cannot provide detailed information for the valid identification of complicated congenital anomalies. Our objective was to determine if the GPRD could be used to identify cases of neural tube defects (NTDs). METHODS: First, we created algorithms for anencephaly, encephalocele, meningocele, and spina bifida and used them to identify potential cases. We used the algorithms to identify 217 potential NTD cases in either a child's or a mother's record. We validated cases by querying general practitioners (GPs) via questionnaire. Where cases of NTD were identified in the mother's record, in addition to confirming the diagnosis, we asked the GPs if the diagnosis was for the mother or that of her fetus or offspring. RESULTS: Two hundred seventeen cases were identified, and 165 GP questionnaires were returned. We validated an NTD diagnosis for 117 cases, giving our algorithms a positive predictive value (PPV) of 0.71. The PPVs varied by NTD type: 0.81 for anencephaly, 0.83 for cephalocele, 0.64 for meningocele, and 0.47 for spina bifida. CONCLUSIONS: Our identification algorithm was useful in identifying three of the four types of NTDs studied. Additional information is necessary to accurately identify cases of spina bifida.

Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study.

OBJECTIVE: To compare the risk of suicide in adults using the antidepressant venlafaxine compared with citalopram, fluoxetine, and dothiepin. DESIGN: Retrospective cohort study. SETTING: UK General Practice Research Database. PARTICIPANTS: 219,088 patients, aged 18-89 years, who were prescribed venlafaxine, citalopram, fluoxetine, or dothiepin from 1995 to 2005. MAIN OUTCOME MEASURES: Completed suicide and attempted suicide. RESULTS: Venlafaxine users had a higher burden of risk factors for suicide, including previous suicide attempts and proxies for severe depression or depression that was difficult to treat. In the analysis for completed suicides, unadjusted and adjusted hazard ratios for venlafaxine compared with citalopram were 2.44 (95% confidence interval 1.12 to 5.31) and 1.70 (0.76 to 3.80), for venlafaxine compared with fluoxetine were 2.85 (1.37 to 5.94) and 1.63 (0.74 to 3.59), and for venlafaxine compared with dothiepin were 2.54 (1.07 to 6.02) and 1.31 (0.53 to 3.25). Compared with other study drugs, venlafaxine was also associated with an increased risk of attempted suicide, but adjustment for measured confounders substantially reduced the hazard ratios. CONCLUSIONS: Venlafaxine use was consistently associated with higher risk of suicide compared with citalopram, fluoxetine, and dothiepin. Venlafaxine users had a higher burden of suicide risk factors, however, and adjustment for measured confounders substantially reduced the excess risks. Since the secondary data used in this analysis allowed only indirect and partial measurements of potential confounders, it is possible that residual confounding explains much, if not all, of the observed excess risk.

Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics.

BACKGROUND: Estimates of risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with some antiepileptic drugs (AEDs) have used denominators based on the number of prescriptions or daily doses. Because the risk of SJS is highest in new users of drugs, the use of denominators reflective of all users can lead to low estimates of risk associated with drugs. In this study, risk in new users is assessed. METHODS: Data on all hospitalized patients with SJS and TEN with use of carbamazepine (CBZ), lamotrigine (LTG), phenobarbital (PHB), phenytoin (PHT), or valproic acid (VPA) were obtained from the German Registry for Serious Cutaneous Reactions. For 1998-2001, the numbers of new users were estimated from number of dispensed prescriptions in Germany, the average prescribed doses, and the duration of use in the Mediplus database (IMS Health) Germany, and assumptions that relate new use to growth in national dispensings. To minimize the probability of underestimating risk in new users, conservative estimates of new use that were somewhat lower than predicted from national prescription data were used. RESULTS: More than 90% of SJS and TEN cases occurred in the first 63 days of AED use. Over the 4 years, increases in dispensing were 5% for CBZ, 65% for LTG, 6% for PHB, -16% for PHT, and 26% for VPA. Across a range of assumptions about frequency of incident use, the risk estimates vary between 1 and 10 per 10,000 new users for CBZ, LTG, PHT, and PHY and were consistently lower for VPA. CONCLUSION: Across a range of assumptions used, the risk of hospitalization for Stevens-Johnson syndrome or toxic epidermal necrolysis in new users is low for carbamazepine, lamotrigine, phenytoin, phenobarbital, and valproic acid. Because conservative incidence use fractions were used, it is likely that some risks were overestimated.

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy.

BACKGROUND: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. OBJECTIVE AND METHODS: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years. RESULTS: Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. CONCLUSIONS: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.