Fertility Treatment and the Risk of Cardiovascular Diseases in the Offspring

Background: As 2-3% of all children are born with fertility treatment, the safety of the hormones used as part of this treatment is of great importance. Exposure to high doses of hormones such as gonadotropin or clomiphene in the early stage of fetal development can not be avoided. In studies conducted so far, inconclusive results on the association between these hormones and cardiovascular malformations in the offspring have been found. Objectives: The aim of this study was to examine whether hormones used in fertility treatments increase the risk of cardiovascular diseases in the offspring. Methods: We conducted a case-control study in which 132 children, having ≥ 3 prescriptions of cardiovascular drugs before their fifth birthday, were compared with 24856 controls. Information about drug use was retrieved from the prescription database IADB.nl. Primary exposure was defined as use of gonadotropin and other ovulation stimulants (ATC: G03), (anti) gonadotropin- releasing hormones (ATC: H01CA and H01CC) or analogues (ATC: L02AE). A subanalysis was limited to cases receiving ≥3 prescriptions for cardiovascular drugs during their first year of life. We applied regression analysis to compute odds ratios (ORs) and 95% confidence intervals (95% CI). Results: The percentage of exposure to hormones used in fertility treatment was 6.8% among cases compared to 3.5% among controls. After adjustments for age of the mother at delivery, gender of the child, and birth year, exposure to hormones is pointing to an increased risk for developing cardiovascular diseases (aOR [CI95%] 1.94 [0.98-3.84]). When limiting the analysis to cases below the age of 1 (n=86), the risk was significantly increased with aOR 2.67 (1.28-5.57). Conclusions: This study shows that hormones used in fertility treatments seem to increase the risk of cardiovascular diseases notably during the first year of life

Association between Incidence of Prescriptions for Alzheimer’s Disease and Beta-Adrenoceptor Antagonists:A Prescription Sequence Symmetry Analysis

Background: Alzheimer’s disease (AD) is the most common cause of dementia, with a growing number of patients worldwide. The association between AD and treatment with drugs targeting the beta-adrenergic receptor is controversial. The aim of this study is to assess the association between the initiation of AD medication and beta-adrenoceptor antagonists (beta-blockers) in adults. Materials and Methods: We conducted a prescription sequence symmetry analysis using the University of Groningen IADB.nl prescription database. We determined the order of the first prescription for treating AD and the first prescription for beta-blockers, with the dispensing date of the first prescription for AD defined as the index date. Participants were adults over 45 years old starting any AD medication and beta-blockers within two years. We calculated adjusted sequence ratios with corresponding 95% confidence intervals. Results: We identified 510 users of both AD and beta-blockers, and 145 participants were eligible. The results were compatible with either a significant decrease in the incidence of AD after using beta-blockers (adjusted sequence ratio (aSR) = 0.52; 95% CI: 0.35–0.72) or, conversely, an increase in beta-blockers after AD medication (aSR = 1.96; 95% CI: 1.61–2.30). Conclusions: There is a relationship between the use of beta-blockers and AD medications. Further research is needed with larger populations to determine whether drug therapy for AD increases the risk of hypertension or whether beta-blockers have potential protective properties against AD development.</p

Antidepressant medication and the risk of pregnancy-induced hypertension

Background: Increased activity of the sympatic nervous system could possibly cause pregnancy-induced hypertension (PIH). Previous studies have suggested that antidepressants could contribute to this increased activity. Objectives: To examine whether the use of antidepressants during pregnancy increases the risk of developing pregnancy-induced hypertension. Methods: This retrospective cohort study was conducted using the prescription database IADB.nl among nulliparous women with singleton pregnancies between 1994 and 2014 in the Netherlands. Exposure was defined as at least one dispensing record of an antidepressant (AD; ATC-code N06A) during the first 20 weeks of gestation. Excluded were women using antithrombotic agents, antidiabetic drugs, antimigraine drugs, and antihypertensive drugs during six months before pregnancy till twenty weeks of gestation. The outcome, PIH, was defined as at least one dispensed record of an antihypertensive drug (methyldopa, nifedipine, labetalol, ketanserin, nicardipine) after 20 weeks of gestation till 14 days after delivery. Odds ratios (OR) and their corresponding 95% confidence intervals (95%CIs) were estimated using logistic regression analysis, adjusting for maternal age, benzodiazepine and antibiotic use. Subanalyses were conducted for class of AD, duration of use of AD (1-30, ≥ 31 Defined Daily Doses (DDD)), and maternal age. As the exact duration of gestation was unknown, all analysis were conducted for 3 theoretical gestational ages (35, 37, 39 weeks). Results: 28020 women were included, of which 539 (1,92%) used antidepressants (gestational age 39 weeks). The risk of pregnancy induced hypertension doubled for women using an antidepressant (aOR [95%CI] 2.00[1.30-3.18]). Significant associations (OR [95% CI]) were also found for the subgroup SSRI (2,12 [1.28-3,50]), ≥ 31 DDDs (2.53 [1.58-4.85]) and maternal age of 30-34 years (2,59 [1,35-4,98]). Decreasing the theoretical gestational age showed comparable results. Conclusions: Use of ADs during the first 20 weeks of gestations 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

Acid-suppressive drug use during pregnancy and the risk of atopic dermatitis: A crossover study within the clinical practice research database

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

Atopic diseases and the risk of developing ulcerative colitis

Background: Although auto-immune diseases and atopic diseases seem to be caused by different malfunctions in the immunological pathways, there is an increasing body of evidence for cross regulation between the two pathways. Research showed that patients suffering from atopic diseases are at greater risk of developing for instance inflammatory bowel diseases. Objectives: The aim of this study was to examine to what extent the risk of developing ulcerative colitis is increased in atopic patients. Methods: We conducted a case-control study using data of patients, aged 18-50 years, from the prescription database IADB.nl. Cases were defined as new users of aminosalicylic acid preparations (ATC: A07EC); the first line treatment for ulcerative colitis. Controls were matched on gender and age at the index date. Excluded were rheumatic patients. Prevalence rates of atopic diseases were based on the use of either ≥2 prescriptions for dermal (atopic dermatitis), inhaled (asthma) or nasal (allergic rhinitis) corticosteroids within 12 months before the index date. Logistic regression analysis was used to estimate odds ratios (OR) and their corresponding 95% confidence intervals (95% CIs). Results: A total of 2022 cases and 202200 controls were included in the study (38.4% male; mean age 36.3 years). All three atopic diseases, asthma, allergic rhinitis, and atopic dermatitis were associated with ulcerative colitis with ORs of 3.11 (2.66-3.64), 2.69 (2.33-3.12), and 3.59 (3.23-3.99), respectively. Conclusions: This study shows a clear increased risk of developing ulcerative colitis among patients receiving medication for atopic diseases

Association of attention-deficit/hyperactivity disorder and atopic diseases:a case-control study

Background: Data on the association between attention-deficit/hyperactivity disorder (ADHD) and atopic diseases have been inconclusive. We assessed whether children using ADHD medication are more likely to receive drug treatment for asthma, allergic rhinitis, and/or eczema than children not using ADHD medication. Methods: We conducted a retrospective nested case-control study among children between 6 and 12 years of age using the IADB.nl prescription database. Cases were defined as children with at least two prescriptions of methylphenidate within 12 months. Cases were matched to four controls on age, sex, and area code. We further assessed the exposure of parental use of medication for ADHD and atopic diseases as a predicting parameter on receiving ADHD medication in childhood. Conditional logistic regression analysis was applied to obtain odds ratios and corresponding 95 % confidence intervals (CI). Results: We identified 4257 children, drug-treated for ADHD, and 17,028 controls. Drug treatment for asthma, allergic rhinitis, and eczema were more common in cases than controls with odds ratios of 1.4 (95 % CI 1.3-1.6), 1.4 (95 % CI 1.1-1.8) and 1.3 (95 % CI 1.1-1.5), respectively. Association of parental use of medication for atopy on receiving ADHD medication in the offspring (OR: 1.1: 95 % CI 1.0-1.2) was higher in cases compared to controls, but lower than the association between medication for atopy and ADHD in the child (OR: 1.4: 95 % CI 1.2-1.5) (p = 0.006). Conclusion: This study provides further evidence on the hypothesis that ADHD is associated with atopic diseases. Our results suggest that the association may have a genetic component

Trigeminovascular effects of propranolol in men and women, role for sex steroids

Objective : Assess whether propranolol modulates the trigeminovascular system in both men and women. Methods : We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to Tmax) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2–1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20–39 years old). Results : Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. Interpretation : Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system