Tolerability of MenACWY-TT vaccination in adolescents in the Netherlands; a cross-sectional study.

BACKGROUND: In 2018, meningococcal ACWY-TT vaccine (MenACWY-TT) was offered to adolescents in the Netherlands within the National Immunization Programme at 14 years of age. A questionnaire study assessed the tolerability of this vaccine. METHODS: Five thousand adolescents were invited to participate and to fill in two questionnaires about systemic events in the week before vaccination and local reactions and systemic events in the week after vaccination. Frequencies of local and systemic adverse events in the week after vaccination were calculated. Association between the occurrence of systemic symptoms in the week before and after the vaccination was tested by using generalized mixed models (GLMM). RESULTS: Of all adolescents, 139 returned one or both questionnaires. Any local reaction within 7 days after vaccination was reported by 55.6% of the adolescents. Pain (50%) and reduced use of the injected arm (21.3%) were most often reported. Any systemic event was reported by 67.6% of the participants, with myalgia as the most often reported event (37.0%). Compared with the week before vaccination, there were no increased odds of experiencing systemic symptoms in the week after vaccination (OR 0.95; 95%CI 0.40-2.27). CONCLUSIONS: After vaccination with MenACWY-TT vaccine, most adolescents reported one or more adverse events, which were mostly mild and transient. Systemic symptoms were not reported more often in the week after compared to the week before vaccination. Unfortunately, due to a low response rate we were not able to detect the absolute elevated risks the sample size calculation was based on. However, despite limited data, our results are in line with results from prelicensure data, and indicate that MenACWY-TT vaccination is well tolerated in adolescents.

No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls.

INTRODUCTION: In 2013, the Netherlands Pharmacovigilance Center Lareb published an overview of reports of long-lasting fatigue following bivalent HPV-vaccination (2vHPV). After an update of this overview in 2015, concerns regarding the safety of 2vHPV was picked up by the media, which led to further reports of long-lasting fatigue. Therefore, the Dutch National Institute for Public Health and the Environment (RIVM) investigated a possible association between HPV-vaccination and long-term fatigue. METHODS: In this retrospective cohort study conducted in the Integrated Primary Care Information database, we investigated the occurrence of chronic fatigue syndrome (CFS), fatigue ≥6 months and 3-6 months in all girls born in 1991-2000 during the follow-up period January 1st 2007-December 31st 2014 (2007-2008 pre-vaccination and 2009-2014 post-vaccination). Patients with certain fatigue ≥6 m were asked for consent to link their primary care information with vaccination data. Incidence rates per 10,000 person years (PY) for 12-16-year-old girls were compared between pre- and post-HPV-vaccine era. A self-controlled case series (SCCS) analysis was performed using consenting vaccinated cases. A primary high-risk period of 12 months after each dose was defined. RESULTS: The cohort consisted of 69,429 12-16-year-old girls accounting for 2758 PY pre-vaccination and 57,214 PY post-vaccination. Differences between pre- and post-vaccination incidences (CFS: 3.6 (95% CI 0.5-25.7)/10,000 PY and 0.9 (0.4-2.1); certain fatigue ≥6 m: 7.3 (1.8-29.0) and 19.4 (16.1-23.4); certain fatigue 3-6 m: 0.0 and 16.6 (13.6-20.3), respectively) were not statistically significant. SCCS analyses in 16 consenting vaccinated cases resulted in an age-adjusted RR of 0.62 (95%CI 0.07-5.49). CONCLUSIONS: Fatigue ≥6 m and 3-6 m was frequently found among adolescent girls, but CFS was rarely diagnosed. No statistically significant increased incidence rates were found post-vaccination compared to similar age groups of girls pre-vaccination. The SCCS analysis included a low number of cases but revealed no elevated risk of certain fatigue ≥6 m in the high-risk period.

Tolerability of 2 doses of pandemic influenza vaccine (Focetria®) and of a prior dose of seasonal 2009-2010 influenza vaccination in the Netherlands.

In the Netherlands, people indicated for seasonal influenza vaccination are divided in 3 risk groups, i.e. those less than 60 y (y) with comorbidity and those 60 y and over with and without comorbidity. Those risk groups were also eligible for pandemic vaccination during the 2009 influenza A(H1N1) pandemic. We assessed tolerability of seasonal influenza vaccination and 2 doses of pandemic influenza A(H1N1) vaccine, adjuvanted with MF-59, administered 2 and 5 weeks after seasonal 2009-2010 vaccination among adults. Vaccinees were asked to return questionnaires on local and systemic adverse events (AEs) after each of 3 consecutive vaccinations given at the office of their General Practitioner. Sex- and risk group-specific AE-frequencies were calculated. Generalized Linear Mixed Model with seasonal vaccination as reference was used to calculate odds ratios (ORs) for AEs of the 2 pandemic doses. 5553 questionnaires (3251 vaccinees) were returned. Vaccinees reported any local AE after seasonal vaccination and both pandemic doses in 34%, 23%, and 18%, respectively. These percentages were 29%, 25%, and 16% for any systemic AE. Men reported fewer local and systemic AEs then women (p<0.0001). The risk of local (OR range 0.34-0.63) and systemic (OR range 0.39-0.99) AEs (overall, stratified by risk group and by sex) was lower after both pandemic doses compared to seasonal vaccination. This decreased risk was more pronounced after the second pandemic dose than after the first. Therefore, we conclude that MF59-adjuvanted pandemic vaccine given after seasonal vaccination was well tolerated.

Safety of vaccination against influenza A (H1N1) during pregnancy in the Netherlands: results on pregnancy outcomes and infant's health: cross-sectional linkage study.

OBJECTIVE: This study aims to assess the safety of Influenza A(H1N1), vaccination administered during the second and third trimester and containing MF59 and thiomersal (Focetria(®) ), measured by pregnancy outcomes and infant's health. DESIGN: Cross-sectional linkage study. SETTING AND SAMPLE: A sample of pregnant women, eligible for prenatal screening, were invited to participate. METHODS: Questionnaire data were linked with the Netherlands Perinatal Registry (n = 1920). Information on infant growth, development (n = 1739) and infection-related contacts with the general practitioner (GP) during the first year of life (n = 1671) was obtained. MAIN OUTCOME MEASURES: Multivariate logistic regression was used to assess the association between H1N1 vaccination and small-for-gestational-age infant, preterm delivery and a composite adverse outcome, i.e. low Apgar-score, neonatal intensive care unit admission, neonatal resuscitation or perinatal death. Influence of maternal vaccination on growth, development and GP infection-related contact rates were assessed using multivariate linear mixed modelling and multivariate negative binomial regression, respectively. RESULTS: Response rate was 21%. Though we found differences in characteristics between unvaccinated and vaccinated women, in the multivariate analyses no association was found between H1N1 vaccination and small-for-gestational-age (odds ratio [OR] 0.84; 95% confidence interval [95% CI] 0.50-1.43), preterm delivery (OR 0.98; 95% CI 0.59-1.62) and the composite adverse outcome (OR 0.84; 95% CI 0.44-1.60). We found no differences in weight-for-age (-0.05; 95% CI -0.13 to 0.04), length-for-age (-0.01; 95% CI -0.09 to 0.06), head-circumference-for-age (-0.05; 95% CI -0.13 to 0.03), developmental scores (-0.06; 95% CI -0.28 to 0.17) and infection-related GP contact rates (incidence rate ratio 1.07; 95% CI 0.91-1.28) between infants of unvaccinated and vaccinated mothers. CONCLUSION: Pregnancy outcomes did not differ between H1N1-vaccinated and unvaccinated women. Furthermore, growth, development and GP infection-related contact rates, assessed after the first year of life, were similar in offspring of vaccinated and unvaccinated mothers. TWEETABLE ABSTRACT: No increased risk for adverse pregnancy outcomes and infant's health following influenza vaccination.

Examining a possible association between human papilloma virus (HPV) vaccination and migraine: results of a cohort study in the Netherlands.

UNLABELLED: Since the introduction of the bivalent human papilloma virus (HPV) vaccine in the Netherlands, migraine has been reported as a notable event in the passive safety surveillance system. Research on the association between HPV vaccination and migraine is needed. Therefore, potential migraine cases in 2008-2010 were selected from a group of general practitioners and linked to the vaccination registry. Data were analysed in three ways: (i) incidences of migraine postvaccination (2009/2010) were compared to pre-vaccination incidences (2008); (ii) in a cohort, incidence rates of migraine in vaccinated and unvaccinated girls were compared and (iii) in a self-controlled case series analysis, the relative incidence of migraine in potentially high-risk periods was compared to non-high-risk periods. Incidence rates of migraine for 12- to 16-year-old girls and boys postvaccination were slightly higher than pre-vaccination incidence rates. Incidence rate ratios (IRRs) for vaccinated compared to unvaccinated girls were not statistically significantly higher. Furthermore, the RR for migraine in the high-risk period of 6 weeks following each dose versus non-high-risk period was 4.3 (95% confidence interval (CI) 0.69-26.6) for certain migraine. CONCLUSION: Using different methods, no statistically significant association between HPV vaccination and incident migraine was found. However, the number of cases was low; to definitively exclude the risk, an increased sample size is needed.

Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.

BACKGROUND: We estimated the multiple sclerosis (MS) incidence in the Netherlands for better active monitoring of potential vaccine safety signals. METHODS: A retrospective cohort study (1996-2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases. RESULTS: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2-7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3-5) in 1996-2004 to 9/100,000 py in 2007/8 (95% CI, 6-16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005). CONCLUSIONS: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly.

Præventis, the immunisation register of the Netherlands: a tool to evaluate the National Immunisation Programme.

Vaccination coverage is an important performance indicator of any national immunisation programme (NIP). To monitor the vaccination coverage in the Netherlands, an electronic national immunisation register called 'Præventis' was implemented in 2005. Præventis has a link with the population register and can produce letters of invitation for the NIP, register and validate administered vaccinations. The database is used to monitor the vaccination process, produce reminder letters, control the stock of vaccines and provides information used for paying the fees to the different executive organisations involved. Præventis provides a crucial tool for the evaluation of the NIP by producing (sub)national vaccination coverage estimates with high accuracy and allowing additional research: identifying populations at high risk for low coverage based on existing data, conducting specific studies where individuals included in the immunisation register are approached for further research, using vaccination coverage data for the interpretation of (sero)surveillance data, and linking the immunisation register with disease registers to address vaccine safety or vaccine effectiveness. The ability to combine Præventis data with data from other databases or disease registers and the ability to approach individuals with additional research questions offers opportunities to identify areas of priority for improving the Dutch NIP.

Reported adverse events in girls aged 13-16 years after vaccination with the human papillomavirus (HPV)-16/18 vaccine in the Netherlands.

In 2009, human papillomavirus (HPV) vaccination was offered to girls born in 1993-1996 in a catch-up campaign, followed in 2010 by the implementation of the vaccination in the National Immunization Programme (NIP) for girls born in 1997. To monitor the tolerability of the 2009 catch-up campaign, we investigated the occurrence of adverse events within 7 days after vaccination with the bivalent HPV vaccine. A total of 6000 girls were asked to participate, including 1500 from each birth cohort from 1993 to 1996. One week after each of the required three successive doses, the participants received by e-mail a Web-based questionnaire focused on local reactions and systemic events. One or more questionnaires were returned by 4248 girls. Any local reaction was reported by 92.1% of the girls after the first dose, 79.4% after the second dose, and 83.3% after the third dose, and 91.7%, 78.7%, and 78.4% reported any systemic event after the three doses, respectively. Pain in the arm was the most frequently reported local reaction, of which 24.0%, 11.7%, and 14.7% was classified as pronounced. Myalgia was the most often reported systemic event. The proportion of local reactions and most systemic events was significantly lower after the second and third dose compared with the first dose (Odds ratio [OR], 0.33-0.76). Older girls reported a higher proportion of adverse events than younger girls. After vaccination with the bivalent HPV vaccine, girls 13-16 years of age reported a high proportion of short-term adverse events. These are maximum estimates and not necessarily caused by the vaccination itself. Although, girls experienced HPV vaccination as painful, no serious or unexpected adverse events were reported. The results of this survey are being communicated to health care workers and the public.

Acute cerebellar ataxia in the Netherlands: a study on the association with vaccinations and varicella zoster infection.

AIM: Acute cerebellar ataxia (ACA, sudden onset of truncal ataxia and gait disturbances) usually follows a benign illness (25% varicella). It is also described after vaccination, like MMR and varicella zoster virus (VZV). We will establish incidence rates of (varicella related) ACA and assess the attributable risk of vaccination to ACA in the Netherlands. METHOD: Data on ACA in children, following infections, like varicella, and vaccinations, obtained from prospective, active pediatric surveillance and passive surveillance on adverse events following immunizations (AEFI) were compared with hospitalization data for ataxia. Capture-recapture (CRC) method was used to estimate the burden of ACA in the Netherlands. RESULTS: 45 children with ACA were included (44 and 1 reported by pediatric and AEFI surveillance respectively, 30 were hospitalized). Chickenpox preceded ACA in 15 cases, one case followed MMR. Of the hospitalization reports, 13 fulfilled the criteria for ACA. Using CRC the estimated number of hospitalized ACA cases was 42. For varicella related ACA, this estimate was 10, resulting in an incidence rate of 0.7:100,000 (95%CI 0.52-0.94, all cases) and 0.17:100,000 (95%CI 0.09-0.31, varicella related cases) for children under 15 years of age. CONCLUSION: The incidence rates were comparable with other studies. We found no association with MMR, but chickenpox was clearly related to ACA. According to age-specific seroprevalence data the incidence rate of ACA was 5:100,000 VZV infections for children up to 5 years, compared to an ACA-reporting rate of 0.15:100,000 doses VZV-vaccine. Therefore, uptake of VZV-vaccine in the immunization programme will diminish the incidence rate of ACA.

Adverse events following booster doses of diphtheria-tetanus-inactivated poliovirus and acellular pertussis vaccines for 4-year-old children in The Netherlands.

The aim of the study was to assess the incidence and severity of local reactions and systemic events among 4-year-old children receiving a fifth dose of diphtheria-tetanus-inactivated poliovirus (dT-IPV) and acellular pertussis (aP) vaccines. Of 810 children, 483 had no adverse events following immunization. Of the reported local reactions of 281 children, pain was the most frequent (n=246). Eighty-one children developed redness, and 54, swelling. Pain, reduced use of the arm, redness, and swelling occurred significantly more often at the dT-IPV injection site than at the aP injection site (p<0.05). Local reactions were mainly mild and transient. Among the 104 reported systemic events, fever was the most frequent (n=42). In general, the vaccinations for the 4-year-olds are well tolerated.

Disease burden of congenital toxoplasmosis.

Although the outcomes of toxoplasmosis have been well documented, an integrated estimate of the impact of this infection on the health status of the population is not available. "Disability-adjusted life years" are the sum of years of life lost and years lived with disability, weighted for the severity of the illness. The estimated disease burden of congenital toxoplasmosis in The Netherlands is 620 (range, 220-1900) disability-adjusted life years per year, which is similar to that for salmonellosis and is mainly caused by fetal loss and chorioretinitis. However, there is considerable uncertainty in this estimate. Scenario analysis indicates that the true burden may be underestimated. In other countries, the disease burden is expected to vary with the incidence of congenital infection, but it may also depend on the health care system. In countries that actively screen for toxoplasmosis, such as France, there may be a lower burden of morbidity but a higher burden of mortality.

[Safety surveillance in the National Vaccination Programme; fewer adverse events with the DTP-IPV-Hib vaccine after the transition to an acellular pertussis component in 2005]. / Veiligheidsbewaking van Rijksvaccinatieprogramma; minder bijwerkingen van DKTP-Hib-combinatievaccin sinds overgang in 2005 naar vaccin met acellulaire kinkhoestcomponent.

OBJECTIVE: To determine the adverse reactions to the combined vaccine against diptheria, acellular pertussis, tetanus, poliomyelitis and Haemophilus Infuenzae type B (DTP-IPV-Hib) before and after the introduction of an acellular pertussis component. DESIGN: Descriptive. METHOD: Safety surveillance of the Dutch National Vaccination Programme is performed by the National Institute for Public Health and Environment (RIVM). It is based on an enhanced passive reporting system and complemented by targeted survey-based studies. The data obtained were analysed. RESULTS: The passive surveillance system showed a large increase in reports in 2004, probably linked to increased media attention on the efficacy and safety of the whole-cell DTP-IPV-Hib vaccine. The Health Council recommended transitioning to the use of a DTP-IPV-Hib vaccine with an acellular pertussis component, which was implemented in January 2005. The number of reports dropped sharply in 2005 to a level below that of 2002-2003. Results of a survey study on adverse events following DTP-IPV-Hib vaccination that began in late 2003 and continued in 2005 confirmed the wide coverage ofthe enhanced passive surveillance system and revealed low rates of underreporting of rare adverse events, such as collapse and convulsions. CONCLUSION: This study confirms the data from the passive surveillance system, which show that the newly introduced acellular DTP-IPV-Hib vaccine is associated with fewer adverse events than the whole-cell vaccine that was used previously.

Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke.

BACKGROUND: The role of inherited prothrombotic conditions, including factor V Leiden (FV G1691A), prothrombin G20210A, and the methylenetetrahydrofolate reductase (MTHFR) C677T genotype, in the pathogenesis of ischemic stroke is not well established. The effects of these factors may be potentiated by the use of oral contraceptives, analogous to observations in venous thrombosis. METHODS: Patients (n = 193) were women aged 20-49 years with ischemic stroke. Controls (n = 767) were women without arterial thrombosis stratified for age, calendar year of the index event, and residence. The relative risk of ischemic stroke was estimated with unconditional logistic regression, adjusted for stratification variables. FINDINGS: Factor V Leiden and MTHFR 677TT were more common in patients than in controls [odds ratio (OR): 1.8; 95% confidence interval (CI): 0.9-3.6 respectively OR: 1.5; 95% CI: 0.9-2.6]. The frequency of prothrombin G20210A was similar in cases and controls. Carriers of FV Leiden using oral contraceptives had a 11.2-fold (95% CI: 4.3-29.0) higher risk of ischemic stroke than women without either risk factor. Women with MTHFR 677TT using oral contraceptives had a 5.4-fold (95% CI: 2.4-12.0) higher risk than women without these risk factors. INTERPRETATION: These data suggest that carriers of FV Leiden or MTHFR 677TT who use oral contraceptives have an increased risk of ischemic stroke. When these findings are confirmed, a cost-effectiveness analysis should indicate whether ischemic stroke could be prevented with genetic testing before the start of oral contraceptives.

The RATIO study: oral contraceptives and the risk of peripheral arterial disease in young women.

With regard to oral contraceptives, much research has concentrated on venous thrombosis and on the coronary and cerebral forms of atherosclerotic disease, while peripheral arterial disease (PAD) has received little attention. In this case-control study, we assessed oral contraceptive use and the risk of PAD in young women using a population-based case-control study. The women were 18-49 years of age, and had been admitted to a collaborating hospital between January 1990 and October 1995, and had a diagnosis of PAD. Participants were patients with PAD (n = 152), and control women (n = 925), identified by random digit dialing. The diagnosis of PAD was based almost exclusively on intra-arterial angiography. Patients and control subjects filled out the same structured questionnaire, which included questions on medical history, cardiovascular risk factors, and contraceptive use. The adjusted odds ratio for PAD in women using any type of oral contraceptives vs. no use, was 3.8 (95% CI 2.4-5.8). When first generation oral contraceptive use was compared with no use, the odds ratio was 8.7 (95% CI 3.6-21.3). For second and third generation oral contraceptives, the adjusted odds ratios (compared with non-users) were 2.6 (95% CI 1.4-4.9) and 3.0 (95% CI 1.4-6.6), respectively. This is the first study on oral contraceptive use and PAD in humans. All types of oral contraceptives were associated with an increased risk of PAD.

The relation between Helicobacter pylori and atherosclerosis cannot be explained by a high homocysteine concentration.

BACKGROUND: Recent studies have suggested that a chronic infection with Helicobacter pylori might be an independent risk factor for atherosclerosis. However, a direct role in atherogenesis is not plausible, since the bacterium has not been isolated from atherosclerotic lesions. An indirect mechanism that could link H. pylori with atherosclerosis might be through an increase in plasma homocysteine concentration caused by deficiencies of vitamin B12 and folate in plasma. MATERIALS AND METHODS: In 150 female patients with peripheral arterial disease (PAD) and in 412 healthy control women from a nation-wide population-based case-control study, blood samples were collected to determine the antibody titre against H. pylori and to measure plasma homocysteine, folate and vitamin B12 levels. First, the odds ratio for PAD in women with a positive antibody titre against H. pylori was calculated and adjusted for homocysteine level. Secondly, mean concentrations of vitamin B12, folate and homocysteine were compared in healthy controls with a positive or negative antibody titre against H. pylori. Thirdly, the relation between H. pylori and PAD in individuals with a normal or high homocysteine level was investigated. RESULTS: A positive immunoglobulin G antibody titre against H. pylori was found in 42% of the PAD patients and in 27% of the controls. The age- and socio-economic-status (SES) adjusted odds ratio for PAD was 1.5 (95%CI; 1.0-2.2). Additional adjustment for homocysteine plasma concentration did not essentially change the odds ratio. Secondly, among the healthy controls, the homocysteine plasma concentration did not depend on the immunoglobulin G titre, neither did the folate plasma concentration. The concentration of vitamin B12 was slightly higher in women with a positive titre. Thirdly, H. pylori infection was a risk factor for PAD in subjects with a normal homocysteine concentration [OR 2.0 (95%CI 1.3-3.1)]. CONCLUSIONS: This study shows a relationship between a positive immunoglobulin G antibody titre against H. pylori and PAD in young women. Moreover, this study does not support the hypothesis that H. pylori infection is related to atherosclerosis via an increase in plasma homocysteine concentration.

Effect of second- and third-generation oral contraceptives on fibrinolysis in the absence or presence of the factor V Leiden mutation.

Third-generation oral contraceptives (OC) have been associated with an increased risk of venous thrombosis compared with second-generation OC. To find an explanation for this increased risk, the effect of a second- and third-generation OC and of the progestagens used in these pills on several fibrinolytic parameters was studied in the absence or presence of the factor V Leiden mutation. In a single-center, double-blind trial, 51 women without and 35 women with the factor V Leiden mutation were randomized to either a second-generation (30 microg ethinylestradiol/150 microg levonorgestrel) or a third-generation (30 microg ethinylestradiol/150 microg desogestrel) oral contraceptive. After two menstrual cycles of use and a wash-out period of two cycles, the participants received the corresponding progestagen-only preparation containing 150 microg levonorgestrel or 150 microg desogestrel. D-Dimers, thrombin-activatable fibrinolysis inhibitor (TAFI) and the clot lysis time in the absence (LYSmin) or the presence (LYSplus) of a blocking anti-factor XI antibody were determined in plasmas of the participating women, and the mean difference in changes between the OC were calculated. Both combined OC induced increased plasma levels of D-dimers and TAFI, and induced a prolongation of LYSplus, whereas LYSmin hardly changed. Virtually no changes in fibrinolytic parameters were observed for the progestagen-only preparations. No differential effects between levonorgestrel- and desogestrel-containing OC were found in women without factor V Leiden. Women with the mutation on levonorgestrel-containing OC showed an increased LYSplus compared with desogestrel containing OC (3.9; 95% confidence interval, 0.1-7.7). When using progestagen-only preparations, no differential effect on the fibrinolytic parameters were found, except for non-carriers on levonorgestrel who showed a reduced LYSmin compared with non-carriers on desogestrel (-4.0; 95% confidence interval, -7.8 to -0.2). In conclusion, the effect of oral contraceptives on fibrinolytic parameters is largely independent of the type of progestagen. The increased fibrinolytic activity during OC use appears to be induced by the estrogen component and may be counteracted by increased TAFI activation. This may result in an enhanced downregulation of fibrinolysis.

Prediction of serious complications in patients admitted to a surgical ward.

BACKGROUND: Prediction of complications is an essential part of risk management in surgery. Knowing which patients are at high risk of developing complications will contribute to the quality and cost reduction of surgery. METHODS: All patients admitted to a general surgical ward during a 1-year interval were followed until 30 days after discharge. Complications and data on potential risk factors were recorded prospectively. Relative risks were calculated for each risk factor and predictive values for the development of a serious or minor complication were computed using logistic regression analysis. The predictive values of different combinations of variables were expressed as receiver operating characteristic curves. RESULTS: Of 3075 patients, 375 suffered one or more serious complications and 319 experienced a minor complication. A model was developed for prediction of serious complications, consisting of 11 variables, with an area under the curve (AUC) of 0.79 (95 per cent confidence interval (c.i.) 0.76 to 0.81). The prognostic value of the model for minor complications (seven variables) was lower (AUC 0.68 (95 per cent c.i. 0.65 to 0.71)). CONCLUSION: Serious complications in patients admitted to a surgical ward can be predicted using a model consisting of 11 variables. The risk score can be used in the decision-making process before surgery.

Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation.

Compared to second generation, the use of third generation oral contraceptives has been associated with an increased risk of venous thrombosis especially in women with the factor V Leiden mutation. To find an explanation for these risk differences we investigated the effects of desogestrel- and levonorgestrel-containing oral contraceptives as well as their progestagens separately on the coagulation system in the absence or presence of the factor V Leiden mutation. In a single center, double blind trial, 51 women without and 35 women with the factor V Leiden mutation were randomized to either a second generation (30 microg ethinylestradiol/150 microg levonorgestrel) or a third generation (30 microg ethinylestradiol/150 microg desogestrel) oral contraceptive. After two cycles of use and a wash-out period of 2 menstrual cycles, the participants received the corresponding progestagen-only preparation containing 150 microg levonorgestrel or 150 microg desogestrel. In plasmas of the participating women fragment 1+2, factor V, VII, VIII, IX, X and XI were determined. Both combined oral contraceptives induced a decrease in factor V, whereas the levels of all other coagulant parameters increased. However, in women without the factor V Leiden mutation the effects of desogestrel-containing preparations were significantly different compared to levonorgestrel-containing oral contraceptives for factor V (-8.0; 95% CI -13.4 to -2.6), factor VII (26.8; 95% CI 15.5 to 38.0) and factor IX (-9.6; 95% CI -16.2 to -3.2). When these women used progestagen-only pills, a differential effect between desogestrel and levonorgestrel was only found for factor IX (-6.5; 95% CI -11.4 to -1.5). In carriers of the factor V Leiden mutation desogestrel-containing oral contraceptives induced more pronounced changes in factor V (-14.2; 95% CI -22.4 to -6.0) and factor VII (36.1; 95% CI 19.7 to 52.6) compared to levonorgestrel-containing oral contraceptives. Comparing desogestrel- and levonorgestrel-only, only for factor V a differential effect was found in these women (-9.5; 95% CI -18.3 to -0.6). It appears that desogestrel-containing oral contraceptives have a more pronounced effect on the coagulation system than levonorgestrel-containing oral contraceptives which may be explained by a less effective compensation of the thrombotic effect of ethinylestradiol by desogestrel.

Oral contraceptives and the risk of myocardial infarction.

BACKGROUND: An association between the use of oral contraceptives and the risk of myocardial infarction has been found in some, but not all, studies. We investigated this association, according to the type of progestagen included in third-generation (i.e., desogestrel or gestodene) and second-generation (i.e., levonorgestrel) oral contraceptives, the dose of estrogen, and the presence or absence of prothrombotic mutations METHODS: In a nationwide, population-based, case-control study, we identified and enrolled 248 women 18 through 49 years of age who had had a first myocardial infarction between 1990 and 1995 and 925 control women who had not had a myocardial infarction and who were matched for age, calendar year of the index event, and area of residence. Subjects supplied information on oral-contraceptive use and major cardiovascular risk factors. An analysis for factor V Leiden and the G20210A mutation in the prothrombin gene was conducted in 217 patients and 763 controls RESULTS: The odds ratio for myocardial infarction among women who used any type of combined oral contraceptive, as compared with nonusers, was 2.0 (95 percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5 (95 percent confidence interval, 1.5 to 4.1) among women who used second-generation oral contraceptives and 1.3 (95 percent confidence interval, 0.7 to 2.5) among those who used third-generation oral contraceptives. Among women who used oral contraceptives, the odds ratio was 2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5) for those with a mutation CONCLUSIONS: The risk of myocardial infarction was increased among women who used second-generation oral contraceptives. The results with respect to the use of third-generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second-generation oral contraceptives. The risk of myocardial infarction was similar among women who used oral contraceptives whether or not they had a prothrombotic mutation.

Third generation oral contraceptives and risk of venous thrombosis: meta-analysis.

OBJECTIVE: To evaluate quantitatively articles that compared effects of second and third generation oral contraceptives on risk of venous thrombosis. DESIGN: Meta-analysis. STUDIES: Cohort and case-control studies assessing risk of venous thromboembolism among women using oral contraceptives before October 1995. MAIN OUTCOME MEASURES: Pooled adjusted odds ratios calculated by a general variance based random effects method. When possible, two by two tables were extracted and combined by the Mantel-Haenszel method. RESULTS: The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% confidence interval 1.4 to 2.0; seven studies). Similar risks were found when oral contraceptives containing desogestrel or gestodene were compared with those containing levonorgestrel. Among first time users, the odds ratio for third versus second generation preparations was 3.1 (2.0 to 4.6; four studies). The odds ratio was 2.5 (1.6 to 4.1; five studies) for short term users compared with 2.0 (1.4 to 2.7; five studies) for longer term users. The odds ratio was 1.3 (1.0 to 1.7) in studies funded by the pharmaceutical industry and 2.3 (1.7 to 3.2) in other studies. Differences in age and certainty of diagnosis of venous thrombosis did not affect the results. CONCLUSIONS: This meta-analysis supports the view that third generation oral contraceptives are associated with an increased risk of venous thrombosis compared with second generation oral contraceptives. The increase cannot be explained by several potential biases.