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PURPOSE: Pregnancy prevention programmes (PPPs) exist for some medicines known to be highly teratogenic. It is increasingly recognised that the impact of these risk minimisation measures requires periodic evaluation. This study aimed to assess the extent to which some of the data needed to monitor the effectiveness of PPPs may be present in European healthcare databases. METHODS: An inventory was completed for databases contributing to EUROmediCAT capturing pregnancy and prescription data in Denmark, Norway, the Netherlands, Italy (Tuscany/Emilia Romagna), Wales and the rest of the UK, to determine the extent of data collected that could be used to evaluate the impact of PPPs. RESULTS: Data availability varied between databases. All databases could be used to identify the frequency and duration of prescriptions to women of childbearing age from primary care, but there were specific issues with availability of data from secondary care and private care. To estimate the frequency of exposed pregnancies, all databases could be linked to pregnancy data, but the accuracy of timing of the start of pregnancy was variable, and data on pregnancies ending in induced abortions were often not available. Data availability on contraception to estimate compliance with contraception requirements was variable and no data were available on pregnancy tests. CONCLUSION: Current electronic healthcare databases do not contain all the data necessary to fully monitor the effectiveness of PPP implementation, and thus, special data collection measures need to be instituted.

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PURPOSE: Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their ratios during pregnancy. Second, we describe Center for Epidemiologic Studies Depression scale (CES-D) scores during pregnancy. METHODS: During 13 pregnancies, every trimester and 3 months after pregnancy, the clomipramine and desmethylclomipramine concentrations were measured with LC-MSMS and the severity of depression was assessed by taking the CES-D score. All concentrations used in our calculations were in fact the ratio between actual plasma concentration (µg/l) and the actual dose (mg). We compared differences in ratios between trimesters by using the Friedman test. RESULTS: Studying 12 women and 13 pregnancies, we found no changes in mean clomipramine concentrations, a statistically significant decrease in mean desmethylclomipramine concentrations (p = 0.014) and a significant decrease in the ratio of desmethylclomipramine/clomipramine mean concentrations during pregnancy (p = 0.014) compared to the post-partum period. Sub-therapeutic concentrations of clomipramine and desmethylclomipramine were found in three patients during whole pregnancy. CONCLUSIONS: The mean concentrations of the pharmacologically active metabolite of clomipramine and desmethylclomipramine changes during pregnancy, where a decrease in mean concentrations was found during pregnancy. In case of recurrent disease, we recommend to control clomipramine and its metabolite concentrations, while both are active.

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OBJECTIVE: To explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DESIGN: Descriptive drug utilisation study. SETTING: Six electronic healthcare databases in Denmark, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. POPULATION: All women with a pregnancy ending in a live or stillbirth starting and ending between 2004 and 2010. METHODS: A common protocol was implemented across databases to identify SSRI prescriptions issued (UK) or dispensed (non-UK) in the year before, during or in the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries in which the woman received an SSRI prescription in the year before, during or in the year following pregnancy. We also compared the choice of SSRIs and changes in prescribing over the study period. RESULTS: In total, 721 632 women and 862,943 deliveries were identified. In the year preceding pregnancy, the prevalence of SSRI prescribing was highest in Wales [9.6%; 95% confidence interval (CI95 ), 9.4-9.8%] and lowest in Emilia Romagna (3.3%; CI95 , 3.2-3.4%). During pregnancy, SSRI prescribing had dropped to between 1.2% (CI95 , 1.1-1.3%) in Emilia Romagna and 4.5% (CI95 , 4.3-4.6%) in Wales. The higher UK pre-pregnancy prescribing rates resulted in higher first trimester exposures. After pregnancy, SSRI prescribing increased most rapidly in the UK. Paroxetine was more commonly prescribed in the Netherlands and Italian regions than in Denmark and the UK. CONCLUSIONS: The higher SSRI prescribing rates in the UK, compared with other European regions, raise questions about differences in the prevalence and severity of depression and its management in pregnancy across Europe.

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BACKGROUNDS AND AIMS: Infection of sternotomy wound is a rare potentially fatal complication because of the risk for deep sternal infection. Current treatment comprises antibiotics, debridement, negative pressure wound therapy and sometimes transposition of muscle or omental flaps to fill the anterior mediastinal dead space. MATERIAL AND METHODS: The management of 60 consecutive deep sternotomy wound infections is reviewed. The one stage treatment was mostly chosen. In 5 patients after debridement, negative pressure wound therapy was used before flap reconstruction. Fifty-seven patients were rewired and 3 patients had sternectomy. The choice of the flap was based mainly on anatomic location of a sternal wound defect and also on which grafts been used in cardiac operation. RESULTS: The unilateral turnover split pectoralis major flap was the choice for 50 patients. In 8 patients latissimus dorsi flap was used. Rectus abdominis was used as a standalone flap in 4 patients and in combination with pectoralis major in one. All patients survived after deep sternal wound infection. In only 33 patients the recovery was totally uneventful. In the remaining 27 patients there were one or more complications. Not a single flap was lost completely, but due to partial flap necrosis, a redo reconstruction was needed in 3 patients. Negative pressure wound therapy was used after flap reconstruction in eight patients with incomplete post-flap healing to prepare for wound revision and split thickness skin graft. CONCLUSIONS: A structured approach including both cardiac and plastic surgery in case of deep sternal wound infection is recommended. A single stage surgery with the help of muscle flap reconstruction is our standard treatment. With our protocol, we have been able to keep the mortality low.

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PURPOSE: The use of antidepressants during pregnancy is common. Some studies suggest an association between in utero exposure to antidepressants and the occurrence of pulmonary diseases like asthma later in life. Serotonin reuptake inhibitors (SSRIs) as well tricyclic antidepressants (TCAs) are thought to be involved in the development of the respiratory rhythm generator (RRG) and the maturation of the formation of surfactant. In this study the use of drugs for pulmonary diseases in children who were exposed to antidepressants in utero were compared with non-exposed children. METHODS: The pharmacy prescription database IADB.nl was used for a cohort study in which the use of drugs for pulmonary disease in children after in utero exposure to antidepressants (TCAs, SSRIs) was compared with children with no antidepressant exposure in utero. Drugs for pulmonary diseases were applied as a proxy for disturbed development of the respiratory tract. RESULTS: A small though significant increase in the incidence risk ratio (IRR) of the use of drugs for pulmonary disease was found after any-time in utero exposure to SSRIs, adjusted for maternal use of antibiotics, of 1.17 (95 % CI 1.16-1.18). An increase was also seen when we looked specifically for the use of SSRIs in at least the first trimester (IRR = 1.18, 95 % CI 1.17-1.20). An increased IRR in the use of drugs for pulmonary disease was also seen when children were exposed to TCAs, but this was not statistically significant. However, in both groups our sample size was rather small. The effect size is modest and may also be confounded by maternal smoking. CONCLUSIONS: In utero exposure to SSRIs leads to a statistically significant increase in the use of drugs for pulmonary diseases, especially when exposure occurred during the first trimester of pregnancy. The increase in the use of drugs for pulmonary disease may also be related to other factors. Therefore, further study is recommended.

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BACKGROUND: Infertility is a growing problem in western societies. Few studies have examined the drug utilization of common treatments for infertility. Clomiphene citrate (CC) is the first-line treatment for normogonadotropic women with absent or irregular ovulation. We examined CC use among women at reproductive age in the northern Netherlands. METHODS: Drug dispensing data of CC between 1998 and 2007 were retrieved from the IADB.nl database. Two-year prevalences of CC use per 1000 women covered by the database were calculated and stratified by 5-year age group. The duration of CC use was analyzed using Kaplan-Meier survival analysis. RESULTS: From the IADB.nl database, a total of 1854 women aged 20-44 years initiated ovulation induction treatment with CC only in the northern Netherlands during 1998 and 2007. The 2-year prevalence of CC use increased from 6.66 per 1000 women during 1998-1999 to 7.24 per 1000 during 2002-2003, followed by a decrease to 4.82 per 1000 in 2006-2007 (P < 0.05). Median duration of CC use was four cycles for women <30 years of age, three cycles for women aged 30-39 and two cycles for women aged above 40. CONCLUSIONS: There is no increase of CC use during 1998-2007, and indeed a decrease of CC use during recent years, among women at reproductive age in northern Netherlands.

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Most of the publications on isotretinoin, pregnancy and compliance with the pregnancy prevention programme (PPP) originate from North America. Information specific for the European situation is very limited. The aim of this study was to identify publications describing the use of isotretinoin in humans and the compliance with the PPP in Europe, a systematic search in Medline and Embase was conducted using the terms 'isotretinoin, pregnancy (and Europe)'. Furthermore, a manual search in publications was performed. A total of 17 publications were identified. Publications consisted of case reports of exposed pregnancies, surveys among dermatologists or pharmacists and database studies evaluating compliance with the PPP. The studies and surveys dealt with groups of patients exposed to isotretinoin before or during pregnancy and/or compliance with the isotretinoin PPP. Where the information was provided, in 6-26% of cases isotretinoin was prescribed in full accordance with the PPP. Pregnancy incidence was seen in 0·2-1·0 per 1000 women of childbearing age using isotretinoin. Between 65% and 87% of these pregnancies were terminated. This review of studies in Europe performed to date shows failures in the implementation of the PPP. Therefore, the isotretinoin PPP must be scrutinized to identify whether new measures should be taken or whether the failures in the implementation need to be corrected. New measures should take into account the definition of the ultimate goal of a PPP and the acceptable burden. In the meantime, stakeholders could make a start with adjustments in the implementation of the PPP by taking responsibility and enhancing the performance by explicit instructions, monitoring the performance and adjusting, if necessary.

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OBJECTIVE: To evaluate healthcare utilisation by children who were exposed to antidepressant drug use during pregnancy and those whose mothers stopped using antidepressants before pregnancy compared with a control group. DESIGN: Cohort study. Setting Health insurance records in the Netherlands. POPULATION: A total of 38 602 children born between 2000 and 2005. METHODS: Survey of child healthcare utilisation in relation to gestational antidepressant use. MAIN OUTCOME MEASURE: Healthcare utilisation rates during the first year of life, with special emphasis to medical care related to cardiac disease. RESULTS: Children of mothers who used antidepressants during pregnancy showed increased healthcare use during the first year of life, independent of the mother's healthcare use. The relative risk of more than two visits to general practitioners was 1.5 (95% confidence interval, CI: 1.3-1.8) in the continuous antidepressant users group and 1.3 (95% CI: 1.2-1.5) in the group of children whose mothers stopped taking medication. In both study groups there was a trend towards more drug use for infections and inflammation compared with the control group. Children continuously exposed to antidepressants had an increased risk of cardiac interventions such as cardiovascular surgery or heart catheterisation, relative risk of 5.6 (95% CI: 1.8-17.4). The risk of physiotherapy was twice as high in the antidepressant group compared with the control group (relative risk 2.0; 95% CI: 1.5-2.6). CONCLUSION: Antidepressant use during pregnancy is associated with increased child healthcare utilisation and increased risk of major cardiac interventions in early childhood.

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Folic acid supplementation was recommended in the Netherlands after it had been demonstrated that periconceptional use of folic acid protected against foetal neural tube defects; this recommendation led to a slight decrease in prevalence only. According to the Dutch Health Council, fortification of bread should now be considered. Policy-making is complicated by uncertainties regarding potential side effects, such as adverse effects in children, for which scientific evidence is lacking however.

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OBJECTIVE: To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk. METHODS: Population-based case-control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995-2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5,511 nonsyndromic OC registrations, of whom 4,571 were isolated, 1,969 were cleft palate (CP), and 1,532 were isolated CP. Controls were 80,052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use. RESULTS: There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10-2.34) for OC relative to other malformations, 0.80 (95% CI 0.11-2.85) for isolated OC, 0.79 (95% CI 0.03-4.35) for CP, and 1.01 (95% CI 0.03-5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03-1.93) for OC, 1.21 (95% CI 0.82-1.72) for isolated OC, 2.37 (95% CI 1.54-3.43) for CP, and 1.86 (95% CI 1.07-2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed. CONCLUSION: We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.

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OBJECTIVE: To investigate the utilization of antiepileptic drugs (AEDs) in Dutch children and compare this with guidelines on the treatment of epilepsy in children. METHOD: From the Dutch Interaction Database (IADB.nl) we selected children aged 0-19 years who received at least one prescription for an AED (ATC-code beginning with N03A) between 1997 and 2005. We calculated cumulative incidences and prevalences per 1000 children per year, stratified by age-category, sex and type of AED, and the total number of months each patient received at least one prescription of AEDs, and we counted the number of person-months and AEDs prescribed. For each AED, proportions of person-months were calculated for mono- and combination therapy. Kaplan-Meier survival analysis was used to analyse the duration of AED use, stratified by sex. RESULTS: The overall prevalence of the prescription of AEDs to children was constant at approximately 4.0 per 1000 children during the years of the study. The overall cumulative incidence from 1997-2005 was 0.67 per 1000 children. When stratified by age category or sex, there were no relevant differences in incidence or prevalence. Valproic acid was the most frequently prescribed drug, followed by carbamazepine and lamotrigine. In 20.3% of all person-months, patients received combination therapy; of these, 34.2% received combination therapy for 3 person-months or less. The older AEDs were prescribed more often as monotherapy than combination therapy, in contrast with the newer AEDs, for which the opposite was true. The 50% survival probability (= time period when 50% of children had stopped using AEDs) was around 2 years, with a significantly lower discontinuation of treatment for girls than boys (P = 0.04). CONCLUSION: The overall cumulative incidence of AEDs was determined to be 0.67 per 1000 children, and the prevalence 4.0 per 1000 children. The most frequently prescribed drug is valproic acid, followed by carbamazepine and lamotrigine. The prescribing of AEDs seems to be in conformity with the overall recommendations of the guidelines on the treatment of epilepsy in children.

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BACKGROUND: The aim of this study was to explore, among Dutch rheumatologists, aspects such as attitude towards guidelines, pharmacotherapy and information needs in the treatment of pregnant as well as non-pregnant rheumatoid arthritis (RA) patients. METHODS: Fifteen rheumatologists from nine different hospitals were interviewed by means of a semi-structured interview. Questions addressing attitude towards guidelines, pharmacotherapy preferences and information needs with respect to the pregnant and non-pregnant patient were asked. The analysis will be based on descriptive statistics. RESULTS: Guidelines are used by almost half of the hospitals with respect to pregnant RA patients and by all hospitals for RA patients in general. With respect to pregnant women, nine respondents preferred stopping the medication as soon pregnancy is known. When treating RA patients, in general sulfasalazine and methotrexate would be drugs of first choice. Information is found in international and national books and guidelines. CONCLUSION: Dutch rheumatologists are of the view that there is sufficient information on the treatment of RA in pregnant women or women wishing to become pregnant, except for safe use of medication during pregnancy. In the future, pregnancy risk categorization should be updated and discussed regularly. This should be based on more recent literature and experience. A good monitoring system for following all young patients with a rheumatic disease should be set up as a first step to collect more information on the safe use of medication during pregnancy.

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Three spontaneous reports of patients in whom a relationship between hypertrichosis and inhaled corticosteroids (ICS) was suspected, were reported to Lareb, The Netherlands Pharmacovigilance Center. We sought evidence for and against a causal relationship between hypertrichosis and ICS in children. The relationship between hypertrichosis and ICS was studied mathematically by assessing the Reporting Odds Ratio (ROR) and by determining the Naranjo Score (NS). We also studied the reports sent to the Pharmacovigilance Database of the Uppsala Monitoring Centre (UMC) of the WHO and reviewed the literature. In the Dutch children, the ROR between hypertrichosis and ICS was 14.6 (95%CI 3.6-59.5), the NS was 4. In the database of the UMC 20 more reports on hypertrichosis and ICS were found, contributing to the results of the Dutch database. Taken together, 11 boys and 12 girls were involved with a mean age of 7 years (range 1-17). The time between the start of ICS and the occurrence of hypertrichosis varied between 1 month and 3 years. Besides the hypertrichosis, growth retardation was found in 5 children and adrenal suppression in 12. In 12 children the outcome after cessation was reported: in 6 children the hypertrichosis improved, whilst in 6 it did not. We found sufficient evidence to support the suspicion that hypertrichosis might be a true adverse effect of ICS. We found no simple dose-effect relationship but obviously there is an individual susceptibility. After cessation of ICS the exaggerated hair growth will not disappear in all children. Hypertrichosis may be a useful clinical pointer to exogenous steroid excess.

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OBJECTIVE: To evaluate the prevalence of the awareness of and the behaviour towards folic acid in 2003 and the trend of folic acid use among pregnant Dutch women between 1995 and 2003 with regard to socio-economic status (SES). METHOD: We conducted 2-yearly cross-sectional studies among pregnant women who filled in a questionnaire during the first or second antenatal visit. The highest achieved level of education was taken as a proxy for SES. RESULTS: In 2003 the general level of folic acid awareness was high but with significant differences relating to SES; a quarter of the lower educated women did not know about folic acid before pregnancy. Of the subjects with a lower SES 20% knew the correct period of use compared with nearly 50% in the higher SES group. The reported correct use of folic acid among the lower educated women has decreased over the past 3 years (22% in 2003), while it has increased for the higher SES groups (59% in 2003), implying larger differences in health. CONCLUSION: In 2003, 8 years after a mass media campaign, awareness and use of folic acid were increased considerably in comparison with the start of the campaign. However, differences in knowledge and use of folic acid with respect to the level of education had never been so impressive in the Netherlands as in 2003. A once-only campaign has a short-term effect especially for lower educated women. Implementing strategies to promote folic acid use in daily structural health care systems are needed.

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BACKGROUND: An increase of therapeutic substitution after patent expiry might have a negative effect on cost-savings generated with newly introduced generic drugs. To evaluate influences of patent expiry on therapeutic substitution, switch behaviour before and after patent expiry was investigated. AIM: To describe proton pump inhibitor use and investigate substitution patterns from omeprazole before and after patent expiry. METHODS: Data were obtained from the InterAction DataBase. Proportional proton-pump inhibitor use was identified per quarter during the study period 2000-2003. For the second part two cohorts--one before and one after patent expiry--were defined. The number of switchers was quarterly identified during 2-year follow-up period. For statistical analyses the chi-square test and hazard ratio were used. RESULTS: In proportional use, a downward trend for omeprazole was found. After patent expiry, significantly more patients switched to other proton pump inhibitors (P < 0.001). The hazard ratio of 0.62 (95% CI: 0.57-0.69), indicates that for every six patients switching before patent expiry, 10 patients switch after patent expiry. CONCLUSION: After patent expiry more patients switch to another proton pump inhibitor. In light of the total savings achieved with generic omeprazole, the importance of this negative impact on total cost-savings on proton pump inhibitors is unclear.

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OBJECTIVE: To compare the prescription of drugs in women over a period from 2 years before until 3 months after pregnancy, regarding the type of drugs used and the fetal risk. DESIGN: A cohort study based on pharmacy records of women giving birth to a child between 1994 and 2003. SETTING: The study was performed with data from the InterAction database, containing prescription-drug-dispensing data from community pharmacies. POPULATION: The study population included 5412 women for whom complete pharmacy records were available. METHODS: Drugs were classified into three categories: (1) drugs for chronic conditions, (2) drugs for occasional use and (3) drugs for pregnancy-related symptoms and also classified according to the Australian classification system. MAIN OUTCOME MEASURES: The prescription rate was calculated as the number of women per 100 women who received one or more prescriptions for a given drug within a specified time period. RESULTS: About 79.1% of the women received at least one prescription during pregnancy. The prescription rate for most drugs for chronic diseases and for occasional use decreased during pregnancy, whereas, as expected, the prescription rate for pregnancy-related drugs increased. During the first trimester of pregnancy, 1.7% of all drugs prescribed for chronic conditions and 2.3% of the occasional drugs were classified as harmful. CONCLUSIONS: The increase in prescription rate during pregnancy is caused by an increase in prescription rate of drugs for pregnancy-related symptoms. The prescription of harmful drugs is more commonly associated with drugs for occasional use rather than with drugs for chronic conditions. Therefore, a more cautious prescribing of drugs to healthy women in the fertile age is necessary.

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OBJECTIVES: Inhaled corticosteroids (ICS) are widely used in the treatment of asthma. We studied the suspected adverse drug reactions (sADRs) reported during the use of ICS in the Netherlands. METHODS: In the Netherlands, health professionals and patients can report suspected ADRs to the Pharmacovigilance Centre Lareb. All reported sADRs on ICS were categorised and assessed as to whether these were likely to be associated with use of the steroid. Age and gender adjusted Reported Odds Ratios (RORs) and Naranjo Scores (NS) were computed for sADRs reported more than 3 times. RESULTS: Since 1984, sADRs of ICS were reported in 89 children (mean age 6 years), 48 (54%) were boys. Suspected drugs were fluticasone in 46 children (52%), budesonide in 21 (24%), and beclomethasone in 22 cases (24%). Psychiatric symptoms were reported in 19 children (21%; ROR 3.8, NS 3.6), growth retardation in 6 children (7%; ROR 47.8, NS 3.0) and rashes in 6 cases (7%; ROR 0.7, NS 2.4). There were 7 reports (8%; ROR 2.1, NS 3.4) concerning abnormalities of the teeth, 4 reports of alopecia (4%; ROR 3.3, NS 3.5), and 3 reports of hirsutism and hypertrichosis (NS 4.0). Non-fatal adrenal insufficiency was reported once. CONCLUSIONS: Alteration of behaviour was the most frequently reported sADR. There are more indications that alterations of behaviour could be a real sADR of ICS. Non-fatal adrenal insufficiency was the only reported possible life threatening sADR. The association of hypertrichosis and teeth abnormalities after ICS in children has not been reported in the literature before.

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Randomized controlled trials have proven that periconceptional folic acid intake reduces the risk of neural tube defects (NTDs). This lead to different public health policies: fortification of foods in many countries and supplementation in some others. We concentrate here on pro's and con's of fortification policies. Meanwhile, new beneficial but also potential adverse effects are being hypothesized. Highest level evidence is available for the protective effect of folic acid on NTDs. Lower level evidence suggests other protective effects, but also some potential adverse effects, such as masking Vitamin B-12 deficiency, increasing twinning rates and an 'acceleration phenomenon' in pre-existing malignant neoplasms. While observational studies show lower cancer rates associated with increased folate intake, some case reports and animal experiments suggest opposite effects. Thus, public health policy makers are facing the question of balancing beneficial and potential adverse effects repeatedly. We propose that the scientific debate no longer focuses on NTDs alone, but that a comprehensive evaluation be undertaken by a public health authority with experience in complex meta-analyses and technology assessment.

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