Anke Rißmann

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies

Objective: To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA). Methods: This was a population-based case–malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995–2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies. Results: There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73–2.33), isolated OC 1.45 (95% CI 0.80–2.63), isolated cleft palate 1.69 (95% CI 0.69–4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01–3.31) and 1.43 (95% CI 0.66–3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy. Conclusions: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study

BackgroundThe use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).MethodsData of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births.ResultsIn total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9–12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2–19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6–12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6–12.7) for singletons and 4.9 (2.4–10.1) for multiple births.ConclusionsThere is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births.

De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations

Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40–50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism‐based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL‐like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL‐like associations. However, we did not identify any disease‐causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non‐coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans.

Heterozygous FGF8 mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies

BACKGROUND The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association. METHODS We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features). RESULTS We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range. CONCLUSION Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.

Congenital bladder exstrophy associated with Duogynon hormonal pregnancy tests—Signal for teratogenicity or consumer report bias?

A combination of ethinylestradiol and 10mg norethisterone under the brand names of Duogynon (Germany) or Primodos (UK) was used as a pregnancy test until the 1970s. Until very recently there was continuing public concern about the safety of these drugs and legal proceedings were instituted against the medicinal authorization holder. Given the lack of epidemiological studies focusing on Duogynon/Primodos, the present study evaluates 296 consumer reports of the German Duogynon database and compares the reported birth defects with data from a population based birth registry. The most striking result is an increase of bladder exstrophy (OR=37.27; 95%-CI 14.56-95.28). Neural tube defects (OR=2.99; 95%-CI 1.85-4.84) and renal agenesis (OR=2.53; 95%-CI 1.17-5.45) were also significantly increased. Bladder exstrophy may be a yet undetected teratogenic effect of Duogynon, but may also represent a reporting bias. The present study highlights the difficulties of evaluating consumer reports which may be influenced by public media.

Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance

BackgroundAnorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM.ResultsWithin our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%).ConclusionsComparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies.

Lamotrigine use in pregnancy and risk of orofacial cleft, an update of eurocat lamotrigine study

Background: One previous study of our group reported that acid suppressive drug use during pregnancy is associated with an increased risk for the development of atopic dermatitis in children. However, reported associations could have been confounded by unmeasured risk factors. Objectives: The aim of this study was to assess the association between prenatal exposure to acid-suppressive drugs and the development of atopic dermatitis in children by using a confounding minimizing crossover design. Methods: We conducted a bidirectional case-crossover study within the Clinical Practice Research Database in which 1,445 children with atopic dermatitis were randomly matched to one of their own siblings without atopic dermatitis. Children were defined as having atopic dermatitis if they had a diagnosis of atopic dermatitis and at least 3 prescriptions for ointments containing steroids or calcineurin inhibitors in the year after diagnosis. We applied conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (95%CI). Results: The percentage of exposure to acid suppressive drugs amongst cases was 21.5% compared to 18.8% amongst controls. After adjustments for gender, birth order and maternal age at delivery the exposure to any acid suppressive drug during pregnancy increased the odds for developing atopic dermatitis by 34% (aOR 1.34; 95%CI: 1.05-1.71). Though not significant, exposure to the subgroup proton pump inhibitors conferred an increased risk of 72% (aOR 1.72 95% CI: 0.62-4.79). Conclusions: This study supports previous findings of a small association between gastric acid suppression during pregnancy and the development of atopic dermatitis in children.Background: After extensive media attention on thromboembolic adverse drug reactions (TE-ADRs) and the use of cyproterone/ethinylestradiol (CE), the Netherlands Pharmacovigilance Centre Lareb received a high number of reports about this association, which prompted for detailed analyses. Objectives: To analyse reports of thromboembolic events associated with the use of cyproterone/ ethinylestradiol submitted to Lareb, focusing on the indication of use, presence of risk factors and time between the initial symptoms and the actual diagnosis of the TE. Methods: Reports submitted to Lareb till 11 February 2014 were analysed. The analysis was focussed on reporter type, seriousness of the reaction, age of the patient, BMI, indication, ADRs classified as arterial thrombosis and venous thrombosis, pulmonary embolism, latency period, outcome of the reaction, treatment of the ADR, delay between the first symptoms and diagnosis of the ADR, presence of risk factors. Results: On 11 February 2014, Lareb had received a total of 786 reports about CE, including 41 cases with a fatal outcome. Of all reports, 438 reports considered TE-ADRs which were analysed in more detail. Reported ADRs consisted of arterial thrombosis (N = 74), venous thrombosis (N = 63), pulmonary embolism (N = 219) and thrombosis with an unspecified location (N = 172). Patients mean age was 30.5 years (range 14-57 years). The primary indications for use were acne (N = 193), oral contraceptive (N = 181), hirsutism (N = 13), other (N = 18) or the indication was unknown (N = 33). The median time to onset was 4 years, although many patients reported a longer latency period. There was no distinction between the time of onset in respect to the reported ADR. No differences in risk factors seem to exist between labeled and off-label indications. In 382 out of 438 reports (87%), the reporter was a consumer. Some reports mentioned the fact that thrombosis or embolism were not recognized in an early stage. Conclusions: The reported thromboembolic ADRs are a known risk related to the use of CE, but may be misdiagnosed initially. From the reports that Lareb received it is evident that off-label use is frequent.Background: Recent studies have reported an increased risk of asthma in children after prenatal exposure to antibiotics, notably during third trimester due to altered vaginal bacterial flora. Associations could have been influenced by unmeasured confounders. Objectives: To assess the association between antibiotic use during pregnancy and the development of toddler asthma with a confounding minimizing crossover(casesibling) design. Secondary we wanted to assess the influence of time-invariant confounding by comparing results with a case-control design. Methods: We conducted this study using a linked mother-infant subset of the University Groningen prescription database IADB.nl. We conducted both a crossover study in which 1,228 children with asthma were compared to their own siblings without asthma, and a traditional matched case-control study. Maternal exposure was defined as at least 1 day of supply of systemic antibiotics during pregnancy. Children were considered to have asthma if they received at least 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aOR). Sensitivity analyses were performed to estimate the potential influence of unobserved timevarying confounders. Results: The crossover analysis only showed an increase in the toddlers asthma risk if antibiotics were used in the third trimester of pregnancy (aOR 1.37 (95%CI 1.02-1.83)). The matched case-control study yielded a similar increase in the toddlers asthma risk after exposure in the third trimester (aOR 1.40(95%CI 1.15-1.47)). In addition, use of antibiotics, independent of trimester of pregnancy, was associated with an aOR of 1.46 (95%CI 1.33-1.58) in the matched case-control study. Conclusions: Prenatal exposure to antibiotics in the third trimester of pregnancy is associated with a small increased risk of childhood asthma. This association did not appear to be influenced by time-invariant confounders such as genetic predisposition. However the influence of time-variant confounders, such as disease severity, cannot be ruled out.Background: The use of anti-epileptic drugs (AEDs) during pregnancy is associated with an increased risk of birth defects. Since epilepsy itself is also associated with potential risks for mother and child, an optimal AED treatment is needed. Over the past years, the introduction of new AEDs and the amendments of guidelines have changed the use of AEDs in this vulnerable group of patients. The extend of the changes over time in the Netherlands has not been studied before. Objectives: To compare the use of different AEDs in pregnant women over the past 10 years in the Netherlands. Methods: This retrospective cohort study data is based on data from the register that is being used to submit Dutch cases to the EURAP study. Pregnancies were included in which women were exposed to an AED between January 2003 and December 2012 either preconceptionally or during the first trimester. Binary logistic regression analysis was used to compare the proportion of various AEDs annually. Dependent variable was the year in which conception took place; the AED and type of epilepsy were covariates. In addition, the mean number of concomitantly used AEDs were calculated per year and analyzed by ANOVA. Results: A total number of 1,733 pregnancies in were included in the analysis. The proportion of use of levetiracetam and lamotrigine showed an upwards trend from 6.2 and 16.0% in 2003 till 25.0 and 33.5% in 2012, with corresponding adjusted Odds Ratio (OR) of 4.89 (95% CI 2.65-9.06) and 2.77 (95% CI 1.76-4.34) respectively. The proportion of use of valproate and carbamazepine decreased from 28.4 and 28.4% in 2003 till 9.3 and 17.3% in 2013, with an adjusted OR of 0.28 (95% CI 0.16-0.48) and from 0.44 (95%CI 0.28-0.70) respectively. The use of other miscellaneous AEDs decreased from 20.9% to 14.9%, OR 0.61 (95%CI 0.38-0.98). The average number of AEDs being used was 1.30 in 2003 and 1.24 in 2012 (p>0.05). Conclusions: The use of relatively safer AEDs gradually increased over the past 10 years compared to drugs more frequently associated with congenital defects. The mean number of AEDs used remained stable of the years. Our findings are in line with advice provided in the literature on the use of AEDs.Background: This study was part of the Pharmacoepidemiological Research on Outcomes (PROTECT) project which aims at monitoring of the benefit-risk of medicines in Europe. Few epidemiological studies have investigated the association between calcium channel blockers (CCB) and cancer, and have provided contradictory evidence. Objectives: To investigate whether CCB exposure is associated with cancer risk and whether the risk varies according to cancer subtype and duration of exposure. Methods: A population-based matched-cohort study was conducted using data from the Clinical Practice Research Datalink and National Cancer Registration System. Eligible patients (18 to 79 years, over two years primary care and prescription history) with ≥1 CCB prescription between 1996 and 2009 (CCBC) were compared with two CCB unexposed cohorts: 1) patients without CCB exposure (NCCBC), and; 2) patients with no CCB and ≥1 other antihypertensive prescription (AHTC). CCBC was compared with NCCBC and AHTC according to cancer outcomes. Conditional logistic cox-regression models estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI). Results: There were 150,750 patients in the CCBC, 557,931 in the NCCBC, and 156,966 in the AHTC. Cancer rates (crude per 1000 person-years) were 16.51, 15.75 and 10.62 for the CCBC, NCCBC and AHTC respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC and AHTC were 0.88 (0.86-0.89) and 1.01 (0.98-1.04) respectively. Adjusted HRs (CI) of breast, prostate, and colon cancer for the CCBC compared to the AHTC were 0.95 (0.87-1.04), 1.07 (0.98-1.16) and 0.89 (0.81-0.98) respectively. Adjusted HRs (CI) of all cancer for the CCBC compared to the NCCBC were 0.88 (0.85-0.91), 0.98 (0.93-1.04), and 1.11 (0.98-1.27) for 0 to 5years, 5 to 10years, and ≥10 years of cumulative drug exposure respectively. Conclusions: This study showed strong evidence that CCB use is not associated with cancer. Shorter periods of CCB exposure showed a small protective effect for cancer, as did CCB exposure for colon cancer. Results will be discussed in relation to other findings from PROTECT work package two.Background: Instrumental variable (IV) analysis with physicians prescribing preference (PPP) as an IV has been used to control for unobserved confounding in pharmacoepidemiology. PPP can be defined in several ways, but it is unclear how different PPPs perform across databases. Objectives: To assess the validity of the IV PPP in two general practice (GP) databases in the study of inhaled long-acting beta2-agonist (LABA) use and the risk of acute myocardial infarction (AMI). Methods: Information on adult patients with a diagnosis of asthma and/or COPD and at least one prescription of an inhaled short-acting beta2-agonist (SABA)/LABA/ muscarinic antagonist (MA) was extracted from the British Clinical Practice Research Datalink (CPRD, n = 490499), and the Dutch Mondriaan (n = 27459) GP databases. Conventional Cox model and two-stage IV analysis were applied to estimate the effect of LABA vs. non-LABA (SABA/MA) on the risk of AMI. PPPs were defined by the proportion of LABA prescriptions per practice (PLP) or previous single (PPP1), or five (PPP5), or ten (PPP10) prescriptions by a physician. Quantitative methods (e.g. correlation (r), odds ratio (OR), standardized difference (SDif)) were used to assess the validity of the IVs. 95% confidence intervals (CI) for IV estimates were estimated using bootstrapping. Results: LABA was not associated with an increased risk of AMI, adjusted hazard ratio 0.96 [95%CI 0.89-1.02] (CPRD) and 1.18 [0.97-1.43] (Mondriaan) in conventional Cox model and 0.95 [0.55-1.63], 1.24 [0.40-3.60], and 1.24 [0.47-3.09] in IV analyses with PPP10 for CPRD, and PPP5 and PPP10 for Mondriaan, respectively. PLP, PPP1 and PPP5 in the CPRD and PPP1 in Mondriaan were weakly associated with LABA (r0.10) across PLP levels in Mondriaan. Conclusions: LABA use was not associated with an increased risk of AMI compared to non-LABA. Validity of IV depends on the definition of IV and the database in which it is applied. We recommend researchers to generate several possible IVs, assess their validity, and report the estimate(s) from the most valid IV.Background: Results from several cohort studies have indicated that long-term low-dose aspirin (acetylsalicylic acid, ASA) use markedly increases the risk for neovascular age-related macular degeneration (nAMD). nAMD is a serious condition that causes rapid decline in central-field vision over the course of days to weeks. The studies currently available obtained data from questionnaires, therefore lacking high-quality information regarding exposure to low-dose ASA, and had few nAMD cases. Objectives: To quantify the risk for nAMD associated with long-term low-dose ASA use. Methods: A case-control study was conducted, including all cases of nAMD in the period 1 January 1987 - 31 December 2012 aged 50 years and older from the UK Clinical Practice Research Datalink (CPRD) database. Cases were matched to up to five controls on age, gender and general practice. Conditional logistic regression was used to estimate odds ratios for the risk of nAMD associated with increasing durations of low-dose ASA use, adjusting for smoking status, obesity, glaucoma, hypercholesterolaemia, and lipid lowering medication, and cardiovascular diseases. Results: 4,125 cases were matched to 20,173 controls. Cases had a median age of 80.1 years and were in majority female (64.7%). Overall, the risk for nAMD associated with low-dose ASA use was a small but significantly increased adjusted risk of 1.12 (95% confidence interval 1.03 - 1.21). We observed a trend for increasing risk with prolonged use: odds ratios were 1.06 (use for less than twoand- a-half years; 95% CI 0.96 - 1.17), 1.07 (twoand- a-half to five years; 95% CI 0.94 - 1.21), 1.17 (five to ten years; 95% CI 1.04 - 1.31), 1.23 (ten to fifteen years; 95% CI 1.05 - 1.45), and 1.33 (more than fifteen years; 95% CI 1.08 - 1.63), compared to no ASA use. Conclusions: Long-term use of low-dose ASA is associated with an increased risk for nAMD. This risk is lower than previously observed and small compared to other risk factors and the benefit-risk balance of low-dose ASA for the prevention of cardiovascular disease will not be impacted.Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.Background: Unmeasured confounding is one of the principal problems in observational pharmacoepidemiologic studies. Prior event rate ratio (PERR) adjustment method has been proposed to control for unmeasured confounding. Objectives: To assess the performance of the PERR method in realistic pharmacoepidemiologic settings. Methods: Simulation studies were performed in several scenarios with varying effects of prior events on the probability of subsequent exposure, incidence rates, strength of confounders in prior and post periods, and rate of mortality/dropout. Exposure effects were estimated using conventional rate ratio (RR) and PERR adjustmentmethods. For the PERR method, the exposure effect is a ratio of two RRs: RR post exposure initiation and RR prior to initiation of exposure. In each simulation, the sample size was 100000 and each scenario was replicated 10000 times. 95% confidence intervals were estimated in a non-parametric way using the 2.5 and 97.5 percentiles of the 10000 estimates. Results: The exposure effects from the PERR adjustment method are highly biased when “prior” events influence the probability of subsequent exposure or when confounding differs considerably between prior and post periods. For example, the RR ranged from 1.52 to 1.10 (true RR= 2.00) when the effect of prior events on the exposure was RR 1.25 to 1.70, respectively. With a strong effect of prior events on the exposure (e.g. RR= 1.70), the bias of the estimates were more pronounced for PERR method than for the conventional method. In such case, even with a null exposure effect (RR = 1.00), the estimates shifted away from the null. In all settings, the confidence intervals of the estimates were wider for the PERR method than for the conventional method. Conclusions: The PERR adjustment method has significant limitations; in particular situations, e.g. when prior events strongly influence the probability of subsequent exposure, it can be more biased than conventional methods. Hence, caution should be exercised when applying this method and theoretical justification should be provided for underlying assumptions of the PERR.Background: At the time of marketing, knowledge on the safety of the use of drugs during pregnancy is still limited, as pregnant women are not included in pre-marketing research. Also after marketing, collecting information on drug use during pregnancy can be bothersome. In 2013 the pREGnant project started in order to develop and implement a national register for medical drug use during pregnancy in the Netherlands. This register will be used for signal detection and conducting epidemiological studies. In February 2014, a pilot study was started to test and validate this register. Objectives: To describe the first results of the pilot phase of the pREGnant register. Methods: In pREGnant, exposure to medical drugs and other potential risk factors are monitored prospectively. Data are collected by means of web-based questionnaires and completed by pregnant women, focusing on medical drug use, the health of the pregnant woman, pregnancy complications and outcomes, and the health of the child. In the pilot phase, different schemes for data collection are introduced in order to choose the best practice for inclusion. During the pilot phase, inclusion takes place at midwiferies and hospitals. Results: The method and approaches applied will be discussed as well as the number and type of inclusions. Based on the initial results of the validation studies and the experiences with implementing data from other data sources, possibilities for the definite system for pREGnant be discussed. Conclusions: The current lack of knowledge on the teratogenic risks of many medical drug use often hampers healthcare professionals in making evidencebased decisions on whether or not the beneficial effects of treatment outweigh the possible risks for the developing foetus and the pregnant woman. The pREGnant register will enable a systematic collection of information and may fill this gap of knowledge.Background: There is no recent data on the epidemiology of type 1 diabetes (T1D) in Dutch children and adolescents. To assess the incidence and prevalence of T1D in children, which is reasonably rare, a large population has to be monitored. Objectives: To assess trends in the incidence and prevalence of T1D in Dutch children and adolescents aged 0-19 years. Methods: A population-based cohort study was conducted in the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions (1998-2010). Insulin prescriptions were used as a proxy to identify cases of T1D. All children and adolescents aged 0-19 years with at least two insulin prescriptions were identified and the numbers of incident and prevalent cases of T1D (numerators) were calculated in each year. The incidence and prevalence of T1D were calculated overall and for different sexes and age categories (age bands: 0-4, 5-9, 10-14, 15-19, and 0-14 years) using the data from the Dutch Central Bureau of Statistics as denominator. Results: In 2010, the incidence and prevalence of T1D was 31.6/100,000 person-years and 195.2/100,000 children, respectively. From 1998 to 2010, the overall incidence and prevalence of T1D in Dutch children increased by 62.9% and 87.9%, respectively. A similar increasing pattern was observed for boys and girls. The largest increase in the incidence and prevalence of T1D was perceived for 15-19 years adolescents (140% and 93%, respectively). A sensitivity analysis restricted to children 0-14 years showed a plateau and even a gradual decrease in the incidence of T1D, mainly driven by a decreasing trend in the 0-4 year old children. Overall, there was an increase in the mean age at the onset of T1D (from 10.9 in 1999 to 13.1 years in 2010). Conclusions: Our study is the most recent populationbased study to investigate the incidence and prevalence of T1D in Dutch children and adolescents. Both incidence and prevalence of T1D nearly doubled from 1998 to 2010. The increase in the number of new cases and older age at the onset of the disease warrants further research to identify environmental triggering factors of T1D.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: ACEI-induced ADRs are the main reason to discontinue ACEI treatment. In prescription databases, information on ADRs is not available; therefore it is necessary to identify proxies for ADRs in such databases to study risk factors for ADRs. Objectives: To study prescription patterns for ACEIs as potential marker for ACEI-induced ADRs. Methods: A cohort of patients starting ACEI from 2000 to 2011 was identified within the Rotterdam Study, (a prospective population-based cohort study of approximately 15,000 individuals aged 45 years and older). Medication dispensing data on daily basis were obtained from the fully computerized linked pharmacies. Participants were followed from the start of ACEI treatment until the end of study period, death or moving out of the area, whichever came first. Patients were classified into 4 mutually exclusive groups: continuous users, discontinued users, switchers to angiotensin receptor blockers (ARBs), and switchers to other antihypertensives. For continuous use or switching, the maximum time interval between two prescription periods was set at 3 or 6months. Patients without a prescription for antihypertensives, 3 or 6months after the end date of the last ACEI prescription were classified as discontinued users. Primary care physician files were searched for reasons of ACEI discontinuation for patients who discontinued or switched ACEIs. Clinical events were classified as definite ADRs (73.5% cough, 3% angioedema, 23.5%others), probable ADRs, possible ADRs and definite non-ADRs. Positive predictive values (PPVs) of the prescription patters of the 3 groups for ADRs were calculated. Results: Totally 1132 patients were included. The PPV for a definite ADR was 56.1% in switchers to ARBs, while the PPVs for switchers to other antihypertensives, and discontinued users were 39.5% and 19.5%. Including probable and possible ADRs, increased the PPVs for switchers to ARBs to 68.3% and 90.5%. A 6-month time interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1% higher). Conclusions: This study showed that switching from ACEI to ARB is the best marker for ACEI-induced ADRs in prescription databases.This journal suppl. entitled: Special Issue: Abstracts of the 30th International Conference on Pharmacoepidemiology and Therapeutic Risk Management ... 2014Background: Results from multiple observational studies on inhaled long-acting beta-2-agonists (LABA) and the risk of acute myocardial infarction (AMI) are conflicting, due to variations in methodological, clinical and health care characteristics. To some extent, the discrepancies in the design might limit the comparability of the results encountered. Objectives: To determine the risk of AMI in inhaled LABA users in two European electronic primary care databases using a common study protocol. Methods: Patients from the Dutch Mondriaan (1.4 Million) and the UK CPRD (5 Million) databases were included if they had a diagnosis of asthma and/or COPD, and were prescribed at least one inhaled LABA, a short-acting beta-2-agonist (SABA), or a short- or long-acting muscarinic antagonist (SAMA, LAMA) during the study period (2002 to 2009). LABA episodes were divided into current, recent (1. Effect of Statin Use on Acute Kidney Injury Following Elective Cardiothoracic Surgery: A Population Cohort Study in Denmark J Bradley Layton, Malene K Hansen, Carl-Johan Jakobsen, Jan J Andreasen, Vibeke E Hjortdal, Bodil S Rasmussen, Abhijit V Kshirsagar, Ross J Simpson, Christian F Christiansen. Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Clinical Epidemiology, Aarhus Univeristy Hosptial, Aarhus, Denmark; Anesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark; Cardiothoracic Surgery, Aalborg University Hospital, Aalborg, Denmark; Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark; Anaesthesia and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark; Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC,Background: Limited quantitative data exist on the burden of chronic comorbidities in children and adolescents with type 1 diabetes (T1D). Such knowledge is necessary for the development of guidelines and prevention programs. Objectives: To determine the incidence of chronic comorbidities in children and adolescents with T1D and to compare the risks with the diabetes-free children. Methods: A population-based cohort study was conducted using the Dutch PHARMO-RLS that comprises community pharmacy dispensing records linked to hospital admissions. Insulin prescriptions were used as a proxy to identify incident cases of T1D. All patients (Background: Pregnancy-induced hypertension (PIH) is possibly caused by an increased activity of the sympatic nervous system. Previous studies have suggested that inhibition of the re-uptake of serotonin and norepinephrine by selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) could contribute to this increased activity. Objectives: To assess the association between the use of antidepressants (ADs) and the development of pregnancyinduced hypertension. Methods: Using the prescription database IADB.nl we conducted a case-control study among pregnant women between 1995 and 2012. Cases were defined as>1 dispensed prescription of an antihypertensive drug (methyldopa, dihydralazine, ketanserin, labetalol, nifidepine) after 20weeks of gestation. Controls were matched for age at time of giving birth. Only first and singleton pregnancies of women not using any antihypertensive drug during 6months before pregnancy till 20weeks of gestation were included. Exposure was defined as>1 dispensed prescription of an antidepressant during pregnancy. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Subanalyses were conducted for class of AD (TCA, SSRI, other) and duration of AD use (1-30, ≥ 31 Defined Daily Doses (DDDs)). As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (36, 38, 40weeks). Results: A total of 312 PIH cases and 12480 controls were included in the analysis (gestational age 36 weeks). The exposure rate among case and control pregnancies was 3.2% and 1.5% respectively. The use of AD increased the risk for developing PIH more than twice (OR [95% CI] 2.24 [1.17-4.27]). Significant associations (OR [95% CI]) were also found for the subgroups TCA (3.39 [1.04-11.08]), SSRI (2.23 [1.03-4.81]) and ≥ 31 DDDs (2.38 [1.16-4.90]). Increasing the theoretical gestational age showed comparable results. Conclusions: Prolonged use of ADs during pregnancy appeared to be associated with an increased risk of developing PIH. When balancing the benefit and risks of using these drugs during pregnancy, this should be taken into account.Background: In observational studies of time-varying treatment, conditioning on time-dependent confounders that are affected by previous treatment using conventional regression methods may adjust-away(indirect) treatment effects.In the presence of unmeasured common causes of confounders and outcome, it can also induce collider-stratification bias. Objectives: To compare time-dependent propensity scores, conventional Cox and marginal structural models (MSM) in a study of selective serotonin reuptake inhibitors (SSRI) and the risk of hip fracture (HF). Methods: A cohort of patients with a first prescription for antidepressants (AD, SSRI or tricyclic antidepressants, TCA) was extracted from the Dutch Mondriaan GP database in the period 2001-2009.Potential confounders were ascertained when antidepressant use changed over time or at six month intervals. Follow-up began with the first day of AD prescription and ended at the occurrence of HF, death, unregistration with the GP, or end of the study.Treatment effects were estimated using time-varying Cox regression, PS stratification, covariate adjustment, and inverse probability weighting (MSM) to control for confounding. In MSMs, censoring was accounted for by including inverse probability of censoring weights (IPCW). Results: The crude HR of HF in current SSRI users versus non-current SSRI users was 1.70 [95%CI 1.09-2.65]. Effects increased after confounder adjustment, PS stratification, and PS adjustment: HR 2.28 [1.45-3.59], 2.47 [1.54-3.95], and 2.51 [1.54-4.09], respectively.When MSMs with stabilized weights were used, the HR was 1.34 [0.65-2.76] and 1.53 [0.81-2.93] with and without accounting for censoring, respectively. After weight truncation, the HR became 2.09 [1.31-3.35] and 2.37 [1.49-3.78] with and without accounting for censoring, respectively. Conclusions: When treatment and confounders are time-varying, accounting for informative censoring can materially influence effect estimates in addition to the potential collider-stratification and confounding bias that arise due conditioning or stratification on time-dependent confounders.Hence, the use of methods such as MSMs is recommended.