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1.  In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study 
BMJ Open  2013;3(9):e003507.
Objective
To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD).
Design
Cohort study.
Setting
Denmark.
Participants
All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription.
Main outcome measures
ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between-pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression.
Results
We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4).
Conclusions
This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD.
doi:10.1136/bmjopen-2013-003507
PMCID: PMC3780335  PMID: 24056487
2.  Prevalence of Antidepressant Use during Pregnancy in Denmark, a Nation-Wide Cohort Study 
PLoS ONE  2013;8(4):e63034.
Aim
The aim of this study was to assess the prevalence and patterns of exposure to antidepressants before, during and after pregnancy in a cohort including all pregnant women in Denmark between 1997 and 2010.
Methods
We performed a retrospective cohort study including 912 322 pregnancies. Information was retrieved from the Danish Birth Registry and The Register of Medicinal Product Statistics to identify women redeeming an antidepressant prescription during pregnancy. Exposure periods were based on standard treatment doses and dispensed pack sizes.
Results
We identified 19 740 pregnancies exposed to an antidepressant at some point during pregnancy. The rate of exposure increased from 0.2% in 1997 to 3.2% in 2010. We found that the rate of exposure was halved during the first 3 months of pregnancy. In contrast, we describe a clear increase in exposure after pregnancy among pre-delivery treatment-naïve women.
Conclusions
In spite of uncertainty concerning antidepressants’ safety during pregnancy we find a 16-fold increase in exposure rates between 1997 and 2010. The rates describe a sharp decrease in exposure during pregnancy that is probably caused by physicians’ hesitation to prescribe antidepressants and women’s fear of unwanted effects on the unborn child. More studies are needed to clarify the consequences of antidepressant discontinuation during pregnancy.
doi:10.1371/journal.pone.0063034
PMCID: PMC3636192  PMID: 23638179
3.  Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study 
Objective To investigate any association between selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy and congenital major malformations.
Design Population based cohort study.
Participants 493 113 children born in Denmark, 1996-2003.
Main outcome measure Major malformations categorised according to Eurocat (European Surveillance of Congenital Anomalies) with additional diagnostic grouping of heart defects. Nationwide registers on medical redemptions (filled prescriptions), delivery, and hospital diagnosis provided information on mothers and newborns. Follow-up data available to December 2005.
Results Redemptions for SSRIs were not associated with major malformations overall but were associated with septal heart defects (odds ratio 1.99, 95% confidence interval 1.13 to 3.53). For individual SSRIs, the odds ratio for septal heart defects was 3.25 (1.21 to 8.75) for sertraline, 2.52 (1.04 to 6.10) for citalopram, and 1.34 (0.33 to 5.41) for fluoxetine. Redemptions for more than one type of SSRI were associated with septal heart defects (4.70, 1.74 to 12.7)). The absolute increase in the prevalence of malformations was low—for example, the prevalence of septal heart defects was 0.5% (2315/493 113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than one type of SSRI.
Conclusion There is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy, particularly sertraline and citalopram. The largest association was found for children of women who redeemed prescriptions for more than one type of SSRI.
doi:10.1136/bmj.b3569
PMCID: PMC2749925  PMID: 19776103
4.  Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study 
BMJ Open  2012;2(3):e001148.
Objectives
To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart.
Design
Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry.
Setting
Denmark.
Participants
Pregnant women in Denmark between 1997 and 2009 and their offspring.
Primary outcome measures
For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy.
Results
The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage.
Conclusions
The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case.
Article summary
Article focus
Relationship between SSRIs and congenital malformations.
Focus on malformations of the heart.
Focus on women with paused treatment during pregnancy.
Key messages
Risks of congenital malformations of the heart are increased for infants whose mothers were exposed to an SSRI during the first trimester.
Risks of congenital malformations of the heart are not different for pregnancies exposed during the first trimester as for pregnancies with paused treatment during pregnancy.
The found risk increases are moderate in absolute terms.
Strengths and limitations of this study
Observational study—no causal relations.
Nationwide study, including all live births in the study period.
Register-based study—no recall bias.
doi:10.1136/bmjopen-2012-001148
PMCID: PMC3378942  PMID: 22710132
5.  Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme 
Neuro-Oncology  2011;13(9):974-982.
Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials.
doi:10.1093/neuonc/nor077
PMCID: PMC3158014  PMID: 21764822
albendazole; animal models; antiparasitic; benzimidazole; drug discovery; glioblastoma; mebendazole; preclinical trial; tubulin
6.  Antidepressant exposure in pregnancy and risk of autism spectrum disorders 
Clinical Epidemiology  2013;5:449-459.
Background
Both the use of antidepressant medication during pregnancy and the prevalence of autism spectrum disorder have increased during recent years. A causal link has recently been suggested, but the association may be confounded by the underlying indication for antidepressant use. We investigated the association between maternal use of antidepressant medication in pregnancy and autism, controlling for potential confounding factors.
Methods
We identified all children born alive in Denmark 1996–2006 (n=668,468) and their parents in the Danish Civil Registration System. We obtained information on the mother’s prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register. In a cohort analysis, we estimated hazard ratios of autism spectrum disorders in children exposed to antidepressant medication during pregnancy compared with children who were not exposed, using Cox proportional hazards regression analysis. Furthermore, we estimated the risk for autism spectrum disorder in a sibling design.
Results
Children exposed prenatally to antidepressants had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2–1.9) for autism spectrum disorder compared with unexposed children. Restricting the analysis to children of women with a diagnosis of affective disorder, the adjusted hazard ratio was 1.2 (95% CI 0.7–2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted hazard ratio 1.1; 95% CI 0.5–2.3).
Conclusion
After controlling for important confounding factors, there was no significant association between prenatal exposure to antidepressant medication and autism spectrum disorders in the offspring.
doi:10.2147/CLEP.S53009
PMCID: PMC3832387  PMID: 24255601
antidepressants; depression; autism; autism spectrum disorder; childhood autism; pregnancy
7.  Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α 
Nature chemical biology  2010;6(11):829-836.
Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC50 of ~10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
doi:10.1038/nchembio.453
PMCID: PMC3681608  PMID: 20890287
8.  Low Birth Weight in Children Born to Mothers with Hyperthyroidism and High Birth Weight in Hypothyroidism, whereas Preterm Birth Is Common in Both Conditions: A Danish National Hospital Register Study 
European Thyroid Journal  2013;2(2):135-144.
Objectives
Maternal hyper- and hypothyroidism have been associated with increased risk of adverse pregnancy outcomes, but studies have led to inconsistent results. We aimed to identify children born to mothers with a hospital-recorded diagnosis of thyroid dysfunction in Denmark and to study the association with gestational age at delivery and birth weight of the child.
Study Design
Population-based cohort study using Danish nationwide registers. All singleton live births in Denmark between January 1, 1978 and December 31, 2006 were identified and stratified by maternal diagnosis of hyper- or hypothyroidism registered in the Danish National Hospital Register before January 1, 2007.
Results
Maternal first-time diagnosis of thyroid dysfunction before, during or after pregnancy was registered in 32,809 (2.0%) of the singleton live births (n = 1,638,338). Maternal diagnosis of hyperthyroidism (adjusted OR 1.22, 95% CI 1.15-1.30) and hypothyroidism (adjusted OR 1.17, 95% CI 1.08-1.27) were associated with increased risk of preterm birth. Moreover, birth weight in children born to mothers with a diagnosis of hyperthyroidism was lower (adjusted difference −51 g, 95% CI −58 to −43 g) and higher in relation to maternal hypothyroidism (adjusted difference 20 g, 95% CI 10-30 g). Hyperthyroidism was associated with small-for-gestational-age (adjusted OR 1.15, 95% CI 1.10-1.20) and hypothyroidism with large-for-gestational-age children (adjusted OR 1.24, 95% CI 1.17-1.31).
Conclusions
Based on Danish nationwide registers, both maternal hyper- and hypothyroidism were associated with increased risk of preterm birth. Actual birth weight of the child and birth weight for gestational age were low if the mother had a diagnosis of hyperthyroidism and high if the diagnosis was hypothyroidism.
doi:10.1159/000350513
PMCID: PMC3821508  PMID: 24783052
Thyroid disease; Hyperthyroidism; Hypothyroidism; Iodine; Pregnancy; Gestational age; Birth weight; Birth length; Danish National Hospital Register

9.  Maternal Characteristics of Women Exposed to Hypnotic Benzodiazepine Receptor Agonist during Pregnancy 
Background. There is little knowledge regarding the characteristics of women treated with hypnotic benzodiazepine receptor agonists (HBRAs) during pregnancy. In this large Danish cohort study, we characterize women exposed to HBRA during pregnancy. We determined changes in prevalence of HBRA use from 1997 to 2010 and exposure to HBRAs in relation to pregnancy. Methods. We performed a retrospective cohort study including 911,017 pregnant women in the period from 1997 to 2010. Information was retrieved from The Danish Birth Registry and The Registry of Medicinal Product Statistics to identify pregnant women redeeming a prescription of HBRAs. Results. We identified 2,552 women exposed to HBRAs during pregnancy, increasing from 0.18% in 1997 to 0.23% in 2010. Compared to unexposed women, exposed women were characterized by being older, with higher BMI, in their third or fourth parity, of lower income and education level, more frequently smokers, and more likely to be comedicated with antipsychotic, anxiolytic, or antidepressant drugs (P < 0.0001). Conclusion. Women using HBRAs during their pregnancy differ from unexposed women in socioeconomic factors and were more likely to receive comedication. The consumption of HBRAs was reduced during pregnancy compared to before conception.
doi:10.1155/2014/945621
PMCID: PMC4003742  PMID: 24817891
10.  Prenatal Antidepressant Exposure and Risk of Spontaneous Abortion – A Population-Based Study 
PLoS ONE  2013;8(8):e72095.
Purpose
To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.
Methods
From the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.
Results
Of the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10–1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80–1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.
Conclusion
We identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.
doi:10.1371/journal.pone.0072095
PMCID: PMC3756033  PMID: 24015208
11.  Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model▿  
No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 μM paromomycin or 27 μM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.
doi:10.1128/AAC.00207-08
PMCID: PMC2533469  PMID: 18591280
12.  Success of Senegal's first nationwide distribution of long-lasting insecticide-treated nets to children under five - contribution toward universal coverage 
Malaria Journal  2011;10:86.
Background
In 2009, the first national long-lasting insecticide-treated net (LLIN) distribution campaign in Senegal resulted in the distribution of 2.2 million LLINs in two phases to children aged 6-59 months. Door-to-door teams visited all households to administer vitamin A and mebendazole, and to give a coupon to redeem later for an LLIN.
Methods
A nationwide community-based two-stage cluster survey was conducted, with clusters selected within regions by probability proportional to size sampling, followed by GPS-assisted mapping, simple random selection of households in each cluster, and administration of a questionnaire using personal digital assistants (PDAs). The questionnaire followed the Malaria Indicator Survey format, with rosters of household members and bed nets, and questions on campaign participation.
Results
There were 3,280 households in 112 clusters representing 33,993 people. Most (92.1%) guardians of eligible children had heard about the campaign, the primary sources being health workers (33.7%), neighbours (26.2%), and radio (22.0%). Of eligible children, 82.4% received mebendazole, 83.8% received vitamin A, and 75.4% received LLINs. Almost all (91.4%) LLINs received during the campaign remained in the household; of those not remaining, 74.4% had been given away and none were reported sold. At least one insecticide-treated net (ITN) was present in 82.3% of all households, 89.2% of households with a child < 5 years and 57.5% of households without a child < 5 years. Just over half (52.4%) of ITNs had been received during the campaign. Considering possible indicators of universal coverage, 39.8% of households owned at least one ITN per two people, 21.6% owned at least one ITN per sleeping space and 34.7% of the general population slept under an ITN the night before the survey. In addition, 45.6% of children < 5 years, and 49.2% of pregnant women had slept under an ITN.
Conclusions
The nationwide integrated LLIN distribution campaign allowed household ITN ownership of one or more ITNs to surpass the RBM target of 80% set for 2010, though additional distribution strategies are needed to reach populations missed by the targeted campaign and to reach the universal coverage targets of one ITN per sleeping space and 80% of the population using an ITN.
doi:10.1186/1475-2875-10-86
PMCID: PMC3083382  PMID: 21489278
13.  Mebendazole in the treatment of helminthiasis. 
Mebendazole, a new broad-spectrum anthelmintic, was used to treat patients with nematode infections--ascariasis, trichuriasis and hookworm. The dosage for adults was 100 mg twice daily for 3 days and for children, 50 mg twice daily for 3 days. Pretreatment and post-treatment egg counts on stool specimens showed that after mebendazole there was a reduction of over 99% in egg count per gram of stool in all three types of infection. The overall cure rates for the infections were as follows: Ascaris lumbricoides, 86.8% (59/68); Trichuris trichiura, 86.0% (37/43); and hookworm, 85.7% (24/28). The drug was equally effective in light and heavy infections. No important side effect was noted with this drug. It is suggested that mebendazole is the drug of choice for trichuriasis and mixed nematode infection.
PMCID: PMC1878825  PMID: 974969
14.  Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study 
Objective To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).
Design Nationwide register based cohort study.
Setting Denmark, 1996-2011.
Participants 999 378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30 091; maternal use after birth, n=21 557; use in infants, n=6591), surgery for IHPS, and potential confounders.
Main outcome measures Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.
Results 880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and −0.11 (−0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (−0.31 to 0.50) and 0.67 (−0.06 to 2.02).
Conclusions Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.
doi:10.1136/bmj.g1908
PMCID: PMC3949411  PMID: 24618148
15.  Pinworms—Incidence, Predictability and Treatment with Thiabendazole 
California Medicine  1967;107(4):315-318.
One hundred-ninety-two children, ages 2 to 16 years, selected from the outpatient department medical clinic without regard to presenting complaint were examined by conventional cellulose tape specimens obtained at home. Twenty-four per cent of the patients were found to have pinworm ova present.
The physicians seeing the last 84 patients were asked to estimate the likelihood of enterobiasis in these children. By various means from history, physical examination or blood cell differential counts, estimates were slightly better than by chance.
Treatment of 185 patients in a random fashion with placebo, thiabendazole and pyrvinium pamoate resulted in negative tests three weeks after therapy, in 15, 92 and 95 per cent of patients, respectively. Transient side effects consisting of anorexia and vomiting were noted in all three groups, but were most pronounced in adults receiving thiabendazole.
PMCID: PMC1502768  PMID: 6062278
16.  Are familial factors underlying the association between socioeconomic position and prescription medicine? A register-based study on Danish twins 
BMJ Open  2013;3(11):e003292.
Objectives
Although well established, the association between socioeconomic position and health and health behaviour is not clearly understood, and it has been speculated that familial factors, for example, dispositional factors or exposures in the rearing environment, may be underlying the association. The objective was to compare prescription fillings within twin pairs who are partly or fully genetically identical and share childhood exposures.
Design
Twin cohort study.
Setting
Denmark.
Participants
Data from the Danish Twin Registry were linked to registers in Statistics Denmark and the Danish Registry of Medicinal Product statistics. A total of 8582 monozygotic (MZ) and 15 788 dizygotic same sex (DZSS) twins were included.
Outcome measures
Number of prescription fillings during follow-up (1995–2005) was analysed according to education and income. Results of unpaired and intrapair analyses were compared.
Results
An inverse social gradient in filling of prescriptions for all-purpose and system-specific drugs was observed in the unpaired analyses. In the intrapair analyses, associations were attenuated some in DZSS and more in MZ twins. Filling of drugs targeting the nervous system was still strongly associated with income in the intrapair analyses.
Conclusions
Familial factors seem to account for part of the observed social inequality in filling of prescription medicine.
doi:10.1136/bmjopen-2013-003292
PMCID: PMC3831100  PMID: 24227869
Epidemiology; Genetics; Social Medicine
17.  Initiation and Persistence to Statin Treatment in Patients with Diabetes Receiving Glucose-Lowering Medications 1997- 2006 
Aims:
Since 2001 guidelines recommend statin treatment in most patients with diabetes. We investigated secular changes in initiation and persistence to statin treatment during a 10-year period in a nationwide cohort of patients initiating glucose-lowering medication (GLM).
Methods:
All Danish citizens 30 years and older who claimed prescriptions of GLM between 1997 and 2006 were identified from nationwide registers of drug dispensing from pharmacies and hospitalizations, and followed until 2006. Statin treatment was registered if a prescription was claimed during the period. By logistic regression we analyzed factors related to initiation and persistence to statin treatment.
Results:
In total 128,106 patients were included. In 1997 only 7% of the patients receiving GLM claimed statins within the first year after GLM initiation. Despite increasing statin prescriptions the following years, only 62% were using statins at the end of follow up. The chance of ever receiving statins was lowest if not initiated within 180-days following the first purchase of GLM (OR 0.75, 95% CI 0.74-0.76). A previous myocardial infarction was associated with increased statin treatment (OR 4.51; 95% CI 4.31 - 4.71), while low income was associated with lower use of statins (OR 0.68; 95%CI 0.66-0.72). Between 75-85 % of the patients who initiated statins treatment were persistent to treatment by 2007.
Conclusions:
In spite of increasing use of statins in diabetes patients over time, many patients remain untreated. Early initiation of statin treatment in diabetic patients and focus on patients with low socioeconomic status is needed to give long-term benefits.
doi:10.2174/1874192400903010152
PMCID: PMC2793397  PMID: 20016749
Diabetes; Statins; compliance; epidemiology; lipids.
18.  Contribution of Integrated Campaign Distribution of Long-Lasting Insecticidal Nets to Coverage of Target Groups and Total Populations in Malaria-Endemic Areas in Madagascar 
In October 2007, Madagascar conducted a nationwide integrated campaign to deliver measles vaccination, mebendazole, and vitamin A to children six months to five years of age. In 59 of the 111 districts, long-lasting insecticidal nets (LLINs) were delivered to children less than five years of age in combination with the other interventions. A community-based, cross-sectional survey assessed LLIN ownership and use six months post-campaign during the rainy season. LLIN ownership was analyzed by wealth quintile to assess equity. In the 59 districts, 76.8% of households possessed at least one LLIN from any source and 56.4% of households possessed a campaign net. Equity of campaign net ownership was evident. Post-campaign, the LLIN use target of ≥ 80% by children less than five years of age and a high level of LLIN use (69%) by pregnant women were attained. Targeted LLIN distribution further contributed to total population coverage (60%) through use of campaign nets by all age groups.
doi:10.4269/ajtmh.2010.09-0597
PMCID: PMC2829903  PMID: 20207867
19.  Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e30850.
Background
Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.
Methodology/Principal Findings
To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.
Conclusions/Significance
Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.
doi:10.1371/journal.pone.0030850
PMCID: PMC3266299  PMID: 22295115
20.  Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence. 
Benzimidazoles have been widely used since the 1960s as anthelmintic agents in veterinary and human medicine and as antifungal agents in agriculture. More recently, selected benzimidazole derivatives were shown to be active in vitro against two protozoan parasites, Trichomonas vaginalis and Giardia lamblia, and clinical studies with AIDS patients have suggested that microsporidia are susceptible as well. Here, we first present in vitro susceptibility data for T. vaginalis and G. lamblia using an expanded set of benzimidazole derivatives. Both parasites were highly susceptible to four derivatives, including mebendazole, flubendazole, and fenbendazole (50% inhibitory concentrations of 0.005 to 0.16 microgram/ml). These derivatives also had lethal activity that was time dependent: 90% of T. vaginalis cells failed to recover following a 20-h exposure to mebendazole at 0.17 microgram/ml. G. lamblia, but not T. vaginalis, was highly susceptible to five additional derivatives. Next, we examined in vitro activity of benzimidazoles against additional protozoan parasites: little or no activity was observed against Entamoeba histolytica, Leishmania major, and Acanthamoeba polyphaga. Since the microtubule protein beta-tubulin has been identified as the benzimidazole target in helminths and fungi, potential correlations between benzimidazole activity and beta-tubulin sequence were examined. This analysis included partial sequences (residues 108 to 259) from the organisms mentioned above, as well as the microsporidia Encephalitozoon hellem and Encephalitozoon cuniculi and the sporozoan Cryptosporidium parvum. beta-tubulin residues Glu-198 and, in particular, Phe-200 are strong predictors of benzimidazole susceptibility; both are present in Encephalitozoon spp. but absent in C. parvum.
PMCID: PMC284688  PMID: 7811023
21.  Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration 
Frontiers in Oncology  2012;2:137.
Pyrvinium pamoate (PP) is an FDA-approved classical anthelmintic, but is now attracting particular attention as an anti-cancer drug after recent findings of its potent cytotoxicity against various cancer cell lines only during glucose starvation, as well as its anti-tumor activity against hypovascular pancreatic cancer cells transplanted in mice. The molecular mechanisms by which PP promotes such preferential toxicity against cancer cells are currently under extensive investigation. PP suppressed the NADH-fumarate reductase system that mediates a reverse reaction of the mitochondrial electron-transport chain complex II in anaerobic organisms such as parasitic helminthes or mammalian cells under tumor microenvironment-mimicking hypoglycemic/hypoxic conditions, thereby inhibiting efficient ATP production. PP also inhibited the unfolded protein response induced by glucose starvation, thereby inhibiting the proliferation of pancreatic cancer cells. Even under normoglycemic/normoxic conditions, PP suppressed the mitochondrial electron-transport chain complex I and thereby STAT3, inhibiting the proliferation of myeloma/erythroleukemia cells. Here, we review accumulating knowledge on its working mechanisms and evaluate PP as a novel anti-cancer drug that targets mitochondrial respiration.
doi:10.3389/fonc.2012.00137
PMCID: PMC3462317  PMID: 23061049
hypoglycemia; hypoxia; electron-transport chain; NADH-fumarate reductase; STAT3; unfolded protein response; Wnt signaling; androgen receptor
22.  Clarithromycin in Early Pregnancy and the Risk of Miscarriage and Malformation: A Register Based Nationwide Cohort Study 
PLoS ONE  2013;8(1):e53327.
Background
The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformations.
Methods
We conducted a nationwide cohort study including all women in Denmark with a known conception between 1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital malformations among users of clarithromycin compared to non-users.
Results
We identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401 women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring with malformations after exposure to clarithromycin.
Conclusions
We found an increased hazard of miscarriage but no increased prevalance of having offspring with malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous studies in animals and humans. However, further research is required to explore the possible effect of treatment indication on the associations found.
doi:10.1371/journal.pone.0053327
PMCID: PMC3534696  PMID: 23301061
23.  Developmental Enamel Defects in Children Prenatally Exposed to Anti-Epileptic Drugs 
PLoS ONE  2013;8(3):e58213.
Objective
Some anti-epileptic drugs (AED) have well-known teratogenic effects. The aim of the present study was to elucidate the effect of prenatal exposure to AED and the risk of enamel defects in the primary and permanent dentition.
Methods
A total of 38 exposed and 129 non-exposed children, 6–10 years of age, were recruited from the Aarhus Birth Cohort and the Department of Neurology, Viborg Regional Hospital, Denmark. Medication during pregnancy was confirmed by the Danish Prescription Database. All children had their teeth examined and outcomes in terms of enamel opacities and enamel hypoplasia were recorded.
Results
Children prenatally exposed to AED have an increased prevalence of enamel hypoplasia (11% vs. 4%, odds ratio (OR) = 3.6 [95% confidence interval (CI): 0.9 to 15.4]), diffuse opacities (18% vs. 7%, OR = 3.0; [95% CI: 1.0 to 8.7, p<0.05]), and numerous (>3) white opacities (18% vs. 10%, OR = 2.2; [95% CI: 0.8 to 6.1]) in the primary dentition. In the permanent dentition, an increased risk of numerous (>3) white opacities (34% vs. 12%, OR = 3.3; [95% CI: 1.3 to 8.4]) was found.
Conclusions
The present study shows that children prenatally exposed to AED have an increased risk of developing numerous teeth with white opacities in their primary and permanent dentition. In addition, they also have an increased risk of developing diffuse opacities and enamel hypoplasia in their primary teeth.
doi:10.1371/journal.pone.0058213
PMCID: PMC3592922  PMID: 23520494
24.  Existing data sources for clinical epidemiology: The Danish National Database of Reimbursed Prescriptions 
Clinical Epidemiology  2012;4:303-313.
The Danish health care system provides partial reimbursement of most prescription medications in Denmark. The dispensation of prescription medications is registered in administrative databases. Each time a prescription is redeemed at a pharmacy, an electronic record is generated with information related to the user, prescriber, the pharmacy, and the dispensed drug. The National Health Service gathers this information for administration of the drug reimbursement plan. Recently, this information became the basis for the establishment of a new research database, the Danish National Database of Reimbursed Prescriptions (DNDRP). In this paper, we review the content, coverage, quality, linkage, access, and research possibilities of this new database. The database encompasses the reimbursement records of all reimbursed drugs sold in community pharmacies and hospital-based outpatient pharmacies in Denmark since 2004. On average, approximately 3.5 million users are recorded in the database each year. During the coverage period, the number of annual prescription redemptions increased by 15%. Most dispensed prescriptions are in the categories “alimentary tract and metabolism”, “cardiovascular system”, “nervous system”, and “respiratory system”. Individuals are identified by the unique central personal registration (CPR) number assigned to all persons born in or immigrating to Denmark. The new database fully complies with Denmark’s Act on Processing of Personal Data, while avoiding additional restrictions imposed on data use at the Danish National Prescription Registry, administered by Statistics Denmark. Most importantly, CPR numbers are reversibly encrypted, which allows re-identification of drug users; furthermore, the data access is possible outside the servers of Statistics Denmark. These features open additional opportunities for international collaboration, validation studies, studies on adverse drug effects requiring review of medical records, studies involving contact to general practitioners, and linkage of prescription data to other clinical and research databases. The DNDRP thus is a valuable data source for pharmacoepidemiological research.
doi:10.2147/CLEP.S37587
PMCID: PMC3508607  PMID: 23204870
Denmark; patient registration; pharmacoepidemiology; registry-based research
25.  Maternal use of Loratadine during pregnancy and risk of hypospadias in offspring 
To examine the risk of hypospadias after exposure to loratadine and other antihistamines during pregnancy, we conducted a population-based case-control study in four Danish counties, which account for 30% of the Danish population (~1.6 M). We obtained data on maternal use of antihistamines from prescription databases, and data on birth outcomes from the Danish Medical Birth Registry (MBR) and the Hospital Discharge Registry (HDR). A total of 65,383 male births with a full prescription history of the mother in the study period from 1989-2002 were available for analysis. Within this cohort, we identified cases with a diagnosis of hypospadias, and 10 selected controls per case without such a diagnosis (matched on birth month, gender and year of birth). We identified 227 cases of hypospadias recorded in the HDR within six months postpartum and 2270 controls. One case (0.4%) and eight (0.4%) controls were exposed to loratadine in the first trimester and up to 30 days before the time of conception. The adjusted odds ratio (OR) for hypospadias among users of loratadine relative to non-users was 1.4 (95% CI: 0.2-11.2) and the corresponding OR for other antihistamines was 1.9 (95% CI: 0.7-5.7). In this study, maternal exposure to loratadine did not appear to be associated with an increased risk of hypospadias when compared with other antihistamines, although it should be noted that the statistical precision of the risk estimates might be limited.
PMCID: PMC1415837  PMID: 16575420
Hypospadias; Loratadine; pregnancy; drug safety; case-control studies

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