Marianne Cunnington

Nonadherence to antiepileptic drugs and increased mortality Findings from the RANSOM Study

Objectives: The primary objective was to investigate whether nonadherence to antiepileptic drugs (AEDs) is associated with increased mortality and the secondary objective to examine whether nonadherence increases the risk of serious clinical events, including emergency department (ED) visits, hospitalizations, motor vehicle accident (MVA) injuries, fractures, and head injuries. Methods: A retrospective open-cohort design was employed using Medicaid claims data from Florida, Iowa, and New Jersey from January 1997 through June 2006. Patients aged ≥18 years with ≥1 diagnosis of epilepsy by a neurologist and ≥2 AED pharmacy dispensings were selected. Medication possession ratio (MPR) was used to evaluate AED adherence on a quarterly basis with MPR ≥0.80 considered adherent and <0.80 nonadherent. The association of nonadherence with mortality was assessed using a time-varying Cox regression model adjusting for demographic and clinical confounders. Incidence rates for serious clinical events were compared between adherent and nonadherent quarters using incidence rate ratios (IRRs) with 95% CIs calculated based on the Poisson distribution. Results: The 33,658 study patients contributed 388,564 AED-treated quarters (26% nonadherent). Nonadherence was associated with an over threefold increased risk of mortality compared to adherence (hazard ratio = 3.32, 95% CI = 3.11–3.54) after multivariate adjustments. Time periods of nonadherence were also associated with a significantly higher incidence of ED visits (IRR = 1.50, 95% CI = 1.49–1.52), hospital admissions (IRR = 1.86, 95% CI = 1.84–1.88), MVA injuries (IRR = 2.08, 95% CI = 1.81–2.39), and fractures (IRR = 1.21, 95% CI = 1.18–1.23) than periods of adherence. Conclusion: These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.

Lamotrigine and the risk of malformations in pregnancy.

Objective: To report the frequency of major malformations in lamotrigine-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry. Methods: Health care professionals throughout the world can voluntarily enroll lamotrigine-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects. Results: Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy. Conclusions: The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects.

Impact of nonadherence to antiepileptic drugs on health care utilization and costs: Findings from the RANSOM study

Purpose:  To study the impact of nonadherence to antiepileptic drugs (AEDs) on health care utilization and direct medical costs in a Medicaid population.

Final results from 18 years of the International Lamotrigine Pregnancy Registry

Objective: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure. Methods: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registrys Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates. Results: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%–3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%–17.0%) and was 2.8% (95% CI 1.5%–5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed. Discussion: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

Effect of dose on the frequency of major birth defects following fetal exposure to lamotrigine monotherapy in an international observational study.

Summary:  Data from the International Lamotrigine Pregnancy Registry were analyzed to examine the effect of maximal first‐trimester maternal dose of lamotrigine monotherapy on the risk of major birth defects (MBDs). Among 802 exposures, the frequency of MBDs was 2.7% (95% confidence interval [CI] 1.8–4.2%). The distribution of dose did not differ between infants with and those without MBDs (mean 248.3 milligrams per day [mg/day] and 278.9 mg/day, respectively, median 200 mg/day for both groups). A logistic regression analysis showed no difference in the risk of MBDs as a continuous function of dose (summary odds ratio [OR] per 100 mg increase =0.999, 95% CI 0.996–1.001). There was also no effect of dose, up to 400 mg/day, on the frequency of MBDs.

Data resources for investigating drug exposure during pregnancy and associated outcomes: The General Practice Research Database(GPRD) as an alternative to pregnancy registries

Pregnancy registries are the most commonly used data resource for the post-marketing surveillance of drug teratogenicity. However, the limited sample size and potential selection bias in these registries has led us to investigate the potential of the UK General Practice Research Database (GPRD) as an alternative data source for monitoring drug safety during pregnancy. In addition, a literature review identified further observational data sources that monitor pregnancy outcomes for future evaluation.Initial feasibility studies focused on the ability of the GPRD to capture pregnancy outcomes for a range of drug class exposures, all of which are currently under investigation in pregnancy registries, during pregnancy. The comparator pregnancy registries were identified via a MEDLINE search, whilst eligible pregnancies, in which women received one or more prescriptions for the drug of interest during pregnancy, were identified in the GPRD using the mother-baby link. The number of pregnancy outcomes following exposure to medication for arange of conditions with varying prevalence, including depression, migraine, epilepsy, herpes simplex and HIV, captured by the two data sources were compared. For depression, a relatively prevalent condition, the GPRD recorded the same number of mean annual intrauterine exposures to fluoxetine as the pregnancy registry (118 exposures/year). Ascertainment of intrauterine exposure to drug treatments for less prevalent conditions was found to be higher for the pregnancy registries than the GPRD; for the older antiepileptic drugs (valproate and carbamazepine), the pregnancy registry recorded between four and five times as many mean annual exposures as the GPRD. Virtually no antiretroviral exposures (three) were identified during the time period of interest on the GPRD, compared with 3946 in the Antiretroviral Pregnancy Registry.Data from the GPRD meet established criteria for evaluating outcomes of pregnancy. For prevalent conditions, it has the potential to replace or work alongside standard pregnancy registries and the alternative data sources identified. Further studies are now needed to assess its ability to replicate known teratogenic associations.

Prevalence of maternal colonisation with group B streptococcus: a systematic review and meta-analysis

BACKGROUND The most important risk factor for early-onset (babies younger than 7 days) invasive group B streptococcal disease is rectovaginal colonisation of the mother at delivery. We aimed to assess whether differences in colonisation drive regional differences in the incidence of early-onset invasive disease. METHODS We did a systematic review of maternal group B streptococcus colonisation studies by searching MEDLINE, Embase, Pascal Biomed, WHOLIS, and African Index Medicus databases for studies published between January, 1997, and March 31, 2015, that reported the prevalence of group B streptococcus colonisation in pregnant women. We also reviewed reference lists of selected studies and contacted experts to identify additional studies. Prospective studies in which swabs were collected from pregnant women according to US Centers for Disease Control and Prevention guidelines that used selective culture methods were included in the analyses. We calculated mean prevalence estimates (with 95% CIs) of maternal colonisation across studies, by WHO region. We assessed heterogeneity using the I(2) statistic and the Cochran Q test. FINDINGS 221 full-text articles were assessed, of which 78 studies that included 73 791 pregnant women across 37 countries met prespecified inclusion criteria. The estimated mean prevalence of rectovaginal group B streptococcus colonisation was 17·9% (95% CI 16·2-19·7) overall and was highest in Africa (22·4, 18·1-26·7) followed by the Americas (19·7, 16·7-22·7) and Europe (19·0, 16·1-22·0). Studies from southeast Asia had the lowest estimated mean prevalence (11·1%, 95% CI 6·8-15·3). Significant heterogeneity was noted across and within regions (all p≤0·005). Differences in the timing of specimen collection in pregnancy, selective culture methods, and study sample size did not explain the heterogeneity. INTERPRETATION The country and regional heterogeneity in maternal group B streptococcus colonisation is unlikely to completely explain geographical variation in early-onset invasive disease incidence. The contribution of sociodemographic, clinical risk factor, and population differences in natural immunity need further investigation to understand these regional differences in group B streptococcus maternal colonisation and early-onset disease. FUNDING None.

Identifying major congenital malformations in the UK general practice research database (GPRD): A study reporting on the sensitivity and added value of photocopied medical records and free text in the GPRD

AbstractBackground: Postmarketing teratogen surveillance is essential and requires a data source that can reliably capture a wide range of congenital malformations. The UK General Practice Research Database (GPRD) may have the potential to be used for this kind of surveillance. Objective: To assess the extent to which this database can be used to accurately identify major congenital malformations. Methods: This study was carried out as part of a broader study to compare data on anticonvulsant use and safety in pregnancy between the GPRD and a pregnancy registry. The study period ran from 1 January 1990 until 31 December 2006. Mother-baby pairs where the mother had a record of epilepsy, seizure or convulsion were identified using the GPRD computerized medical records. Infants of mother-baby pairs who had a record of a major congenital malformation were identified. Full photocopied paper medical records were requested from the infant’s general practitioner and where this was not possible any data entries consisting of uncoded comments, so-called ‘free text’, in the electronic GPRD record were requested from the database provider. This additional information was then reviewed in order to determine the extent to which the congenital malformation diagnoses identified via the computerized records could be confirmed or rejected and then classified as being major or minor. Results: Within the study population of 3869 live mother-baby pairs, 188 potentially major congenital malformations were identified from the GPRD computerized record relating to 161 unique individuals. Using a combination of photocopied medical records and free text it was possible to verify 160 malformations (85.1%) as the malformation indicated by the computerized records; this ranged from 91.7% of those cases verified using photocopied medical records and 77.9% of cases verified using free text. Of the verified congenital malformations, using a combination of computerized data, photocopied medical records and free text, it was possible to classify 78.1% as being major and 15.0% as minor, and this percentage was found to be the same for those cases reviewed by photocopied records and those where free text was used. The proportions of malformations that could be verified and those that could be classified as major or minor were found to vary by malformation class. Conclusions: The GPRD can be used to ascertain a wide range of congenital malformations. In many cases, when a malformation is identified in the GPRD via the computerized medical records, the malformation is likely to exist. However, in this study a small proportion of identified cases had to be excluded because they had been coded incorrectly or diagnostically ruled out. Therefore, depending on the congenital malformation of interest, verification of such malformations using photocopied medical records or free text is generally recommended.

The International Lamotrigine Pregnancy Registry Update for the Epilepsy Foundation

The International Registry, established in 1992, forms part of an epidemiologic safety program monitoring pregnancy outcomes in women exposed to lamotrigine (LTG). This primarily prospective observational study aims to assess the risk of all major malformations associated with first trimester exposure to LTG monotherapy. Data on LTG polytherapy and patterns of specific malformation types also are reviewed. Physicians from around the world (31 countries) report exposure to LTG during pregnancy (therapy type, dose, and treatment duration) and subsequent outcomes to the registry on a voluntary basis. Details of how to enroll patients are available at http://www.inveresk.com/activereg/activereg.asp. Prospective reporting early in pregnancy is encouraged to increase the accuracy of treatment history and to avoid the bias associated with retrospective reporting. Physicians are then approached close to the expected delivery date to confirm treatment and epilepsy history during pregnancy and to ascertain the health of the infant. Major congenital malformations (MCMs) are almost always ascertained at birth or during the hospital stay by the attending physician. Malformations are classified according to the Centers for Disease Control (CDC) criteria, and the reports are reviewed by an independent pediatrician. The percentage of MCMs is calculated for prospective first trimester LTG monotherapy and polytherapy exposures separately. Chromosomal abnormalities are not included in the numerator, as these are unlikely to be related to AED exposure during pregnancy. Retrospective cases are excluded from risk estimates but are reviewed to determine any patterns of malformation types. Conclusions are developed by a scientific advisory committee. Between September 30, 1992, and March 31, 2004, 12 MCMs were observed among 414 monotherapy ex-

Comparing the General Practice Research Database and the UK Epilepsy and Pregnancy Register as tools for postmarketing teratogen surveillance anticonvulsants and the risk of major congenital malformations

AbstractBackground: Use of pregnancy registries is a common method of postmarketing surveillance of pregnancy outcomes to identify potential teratogens. However, with the increase in electronic capture of healthcare data for administrative, audit and research purposes, data generated during routine clinical practice might be used to address questions similar to those explored using pregnancy registries. Objectives: To establish how data from the UK General Practice Research Database (GPRD) compares with data from the UK Epilepsy and Pregnancy Register and to assess how it can contribute to postmarketing surveillance of pregnancy outcomes. Methods: Pregnancy outcomes were identified from the GPRD for women aged 14–49 years with a diagnosis of epilepsy and supporting evidence. Outcomes with a major congenital malformation (MCM) were identified and the relative risks (RRs) of an MCM following a range of first-trimester anti-epileptic drug (AED) exposures were calculated and compared with those reported by the UK Epilepsy and Pregnancy Register. In addition, we also evaluated whether the known association between valproate and spina bifida could be identified using data from the GPRD. The study period ran from 1 January 1990 until 31 December 2006. Results: A total of 1766 live mother-baby pairs were identified, as well as 551 pregnancy terminations, 13 stillbirths and 1 neonatal death. Including those that resulted in a termination, there were 62 unique pregnancy outcomes with an MCM. An increased risk of spina bifida was identified using the GPRD following first-trimester monotherapy exposure to valproate when compared with those with no AED exposure (RR 8.02; 95% CI 1.5, 43.5). More generally, comparing the GPRD with the UK register, the GPRD ascertained a lower number of first-trimester AED exposures: monotherapy 711 versus 2468; polytherapy 156 versus 718. We reproduced the UK register results of an increased MCM risk following first-trimester polytherapy AED exposure compared with no AED exposure (RR 2.89; 95% CI 1.43, 5.84). Using the GPRD, we identified similar point estimates to the UK register following monotherapy and polytherapy exposures (4.1% vs 3.7% and 7.1% vs 6.0%, respectively) but we were unable to reproduce the level of statistical significance. For individual AEDs, the MCM rate following valproate exposure was 4.9% (11/225) in the GPRD compared with 6.2% (44/715) in the UK register. Conclusions: The GPRD has potential for the identification of malformations and of a teratogenic association. For epilepsy, the GPRD does, however, identify fewer exposed pregnancies than a pregnancy registry. Therefore, in many circumstances pregnancy registries are likely to remain preferable as a method of surveillance. The GPRD may be better suited to monitoring medicines used in the treatment of more prevalent conditions, such as depression, or for monitoring medicines that have been on the market for a long time and for which no registry has been set up.