Ann Haerskjold

Caesarean Section and Hospitalization for Respiratory Syncytial Virus Infection: A Population Based Study

Background and objective: Hospitalization for respiratory syncytial virus (RSV) infection and asthma share common determinants, and meta-analyses indicate that children delivered by caesarean section (CS) are at increased risk of asthma. We aimed to investigate whether birth by CS is associated with an increased risk of hospitalization for RSV illness. Methods: This was a population-based national register-based cohort study, conducted between January, 1997 and June, 2003, which included all children born in Denmark and all hospitalizations for RSV disease in them from 0 to 23 months of age. We used Cox regression with adjustment for prematurity, asphyxia, birthweight, multiple births, single parenthood, maternal smoking during pregnancy, older siblings and asthma diagnoses up to 2 weeks before hospitalization for RSV infection, to compare the effects of acute or elective CS versus vaginal delivery, on subsequent hospitalization for RSV disease. A test for homogeneity was used to assess for effect over time. Results: 399,175 children with 10,758 hospitalizations for RSV illness were included; 31,715 were born by acute CS and 30,965 by elective CS. Adjusted hazard ratios for hospitalization for RSV infection in children born by acute CS and by elective CS were 1.09 (1.01–1.17) and 1.27 (1.19–1.36), respectively. The effect of elective CS remained unchanged throughout the first 2 years of life (P = 0.53), whereas the effect of acute CS was only present in the second year of life (P = 0.001). Conclusion: Delivery by caesarian section is associated with an increased risk of hospitalization for RSV infection. This effect continues at least throughout the first 2 years of life.

The Danish National Prescription Registry in studies of a biological pharmaceutical: palivizumab – validation against two external data sources

Background National prescription databases are important tools in pharmacoepidemiological studies investigating potential long-term adverse events after drug use. Palivizumab is a biological pharmaceutical used as passive prophylaxis against severe infection with respiratory syncytial virus in high-risk children. Objective To assess the registration of palivizumab in the Danish National Prescription Registry (DNPR) and to examine if palivizumab reimbursement data obtained from the Danish Health and Medicines Authority could serve as a supplement to data from the DNPR. Methods Registration of palivizumab exposure in the DNPR between 1999 and 2010 was compared to two external data sources: registration of palivizumab exposure in medical records, and palivizumab reimbursement data. Results During the study period, 182 children with palivizumab exposure were registered in the DNPR. A total of 207 children were registered for palivizumab reimbursement. The sensitivity of palivizumab registration in the DNPR was 26% (20%–34%), and the specificity of no palivizumab registration in the DNPR was 97% (94%–99%), with data from the medical record as the reference. Palivizumab registration sensitivity in reimbursement data was 29% (22%–36%), and the specificity of no palivizumab registration in the DNPR was 97% (94%–99%), with data from the medical record as the reference. Conclusion Exposure to palivizumab was underestimated in the DNPR. Reimbursement data are a readily accessible data supplement, which only slightly increased the sensitivity of palivizumab registration in the DNPR. Our findings underline the need to improve DNPR information concerning drugs administered in hospitals.

Use of palivizumab is underestimated in the Swedish Prescribed Drug Register - implications for register-based drug studies.

Background Register studies are a valuable tool, when monitoring the safety of drugs. The Swedish Prescribed Drug Register (PDR) was established in 2005 and keeps records of all prescribed drugs dispensed in community pharmacies. Drugs prescribed in-hospital are not registered on an individual level, which may hamper the validity of register-based studies on drugs potentially administered in-hospital. Objective The objective was to assess the ability of the PDR to identify children treated with the monoclonal antibody palivizumab, which is used for prophylaxis against respiratory syncytial virus (RSV) infection in children. Methods Palivizumab exposure as filled prescriptions recorded in the PDR was assessed by indication of treatment (preterm-born children, bronchopulmonary dysplasia, or hemodynamically significant heart disease) and presented as numbers and proportions. For a random sample of children with an indication for treatment and without record of palivizumab exposure in the drug register, numbers and proportions by indication of treatment as noted in medical records were presented. The extent of underreporting in the drug register was estimated by indication for treatment. Results Through the national health registers, 2,317 children were identified as being at risk for severe infection with RSV infection and 75% had no records indicating palivizumab exposure in the PDR. In a random sample of 176 children at high risk for RSV infection and with no records of palivizumab prescription fills in the PDR, 47% had been treated with palivizumab according to medical records. The PDR underestimated palivizumab treatment with 49% in children born preterm, 42% in children with bronchopulmonary dysplasia, and 23% in those with a hemodynamically significant heart disease. Conclusion Our findings underline the need of improving the information in the Swedish national registers concerning drugs administered in-hospital.

Effect of Maternal Psoriasis on Pregnancy and Birth Outcomes: A Population-based Cohort Study from Denmark and Sweden

Studies on pregnancy and birth outcomes in women with psoriasis are scarce and the findings inconsistent. The effect of maternal psoriasis and its severity on the risk of adverse pregnancy and birth outcomes was examined. A cross-national population-based cohort study was performed using prospectively collected data from Denmark and Sweden. Singleton births in women with psoriasis were identified in the national health registers between April 2007 and December 2012 and classified according to disease severity. Lifestyle factors, co-morbidity, pregnancy and birth outcomes were evaluated. A total of 8,097 births were identified in 6,103 women with psoriasis and 964 births in 753 women with psoriatic arthritis. Increased risk of gestational diabetes, gestational hypertension, pre-eclampsia, elective and emergency caesarean delivery was found in women with psoriasis. The risks were higher for women with severe psoriasis, who also had an increased risk of pre-term birth and low birth weight. Pre-conception counselling to improve maternal, pregnancy and birth outcome is encouraged.

Children with hemodynamically significant congenital heart disease can be identified through population-based registers.

Background Epidemiological research is facilitated in Sweden by a history of national health care registers, making large unselected national cohort studies possible. However, for complex clinical populations, such as children with congenital heart disease (CHD), register-based studies are challenged by registration limitations. For example, the diagnostic code system International Classification of Diseases, 10th version (ICD-10) does not indicate the clinical significance of abnormalities, therefore may be of limited use if used as the sole parameter in epidemiological research. Palivizumab is indicated as a prophylactic treatment against respiratory syncytial virus infections in children with hemodynamically significant CHD. Aim The aim of the study reported here was to develop and validate an algorithm to identify children with hemodynamically significant CHD according to recommendations for palivizumab prophylaxis in register-based research. Methods By using a strategy of combining criteria for age at diagnosis, diagnostic codes, surgical procedure codes, and dispensing records, we created an algorithm to define the specific cases with hemodynamically significant CHD in which palivizumab could be advocated according to recommendations. Results The algorithm identified 928 children with hemodynamically significant CHD in the Swedish birth cohort born July 1, 2005 to December 31, 2010. A sensitivity (95% confidence interval) of 80% (70–88) for the algorithm was found by analyzing 121 children identified through local hospital data who were treated with palivizumab within a defined region and study period. The positive predictive value was estimated by medical record review in a random sample of 34 cases identified by the algorithm. In 79% (62–91) of these cases, the children were regarded as having hemodynamically significant CHD according to the recommendations for treatment with palivizumab. Conclusion It was possible to identify a subgroup of children with hemodynamically significant CHD using an epidemiological approach and an algorithm with high validity. Our results will enable well-powered national cohort studies of individuals with complex clinical conditions such as hemodynamically significant CHD.

The validity of register data to identify children with atopic dermatitis, asthma or allergic rhinoconjunctivitis

The incidence of atopic dermatitis, wheezing, asthma and allergic rhinoconjunctivitis has been increasing. Register‐based studies are essential for research in subpopulations with specific diseases and facilitate epidemiological studies to identify causes and evaluate interventions. Algorithms have been developed to identify children with atopic dermatitis, asthma or allergic rhinoconjunctivitis using register information on disease‐specific dispensed prescribed medication and hospital contacts, but the validity of the algorithms has not been evaluated. This study validated the algorithms vs gold standard deep telephone interviews with the caretaker about physician‐diagnosed atopic dermatitis, wheezing, asthma or allergic rhinoconjunctivitis in the child.

Palivizumab Exposure and the Risk of Autoimmune Disease: A Cross-National Cohort Study

BackgroundTreatment with biologic pharmaceuticals may be associated with an increased risk of immune-mediated disease. Palivizumab is a humanized monoclonal antibody designed to provide passive immunity against respiratory syncytial virus infection. Palivizumab is primarily used in preterm children known to be immunologically immature. The long-term effect of palivizumab in terms of autoimmune diseases has not yet been investigated.AimOur objective was to investigate whether exposure to palivizumab was associated with the development of autoimmune diseases in children.MethodsThis was a population-based cohort study including data from 769,523 Danish children born between 1 January 1999 and 31 December 2010 and data from 581,742 Swedish children born between 1 July 2005 and 31 December 2010.ResultsOf the 1,351,265 children included, 1192 (0.09 %) were exposed to palivizumab. Nine cases of autoimmune disease were diagnosed among palivizumab-exposed children during the period of observation. Among the children exposed to palivizumab, one child in Denmark developed inflammatory bowel disease; in Sweden, children developed juvenile arthritis (one child), diabetes mellitus (two children), celiac disease (four children), and inflammatory bowel disease (one child). The risk of autoimmune disease was not significantly increased after palivizumab exposure (hazard ratio adjusted for age and country: 1.54; 95 % confidence interval 0.80–2.95).ConclusionThe risk of autoimmune disease was not increased after palivizumab exposure. Given the small number of incident cases of autoimmune disease observed, this finding should be interpreted with caution.

The Use and Safety of TNF Inhibitors during Pregnancy in Women with Psoriasis: A Review

Psoriasis is a chronic immune-mediated inflammatory disease affecting women of childbearing potential. Biologic agents, notably Tumor Necrosis Factor inhibitors (TNFi), are the only current non-contraindicated systemic treatment option during pregnancy. TNFi comprised of complete immunoglobulin G (IgG) antibodies antibodies (adalimumab, golimumab, and infliximab) actively cross the placenta from the second trimester and are detectable in the child up to one year postpartum. Data on safety of TNFi are conflicting; however a trend towards drug-specific harm has been reported, with increased risk of congenital malformations and preterm birth. TNFi exposure may alter the immune system of the infant towards hypersensitivity and reduced response to intracellular infections. Confounding by indication should be considered, as chronic inflammatory disease itself may pose a risk of adverse pregnancy outcomes. The quality of the current evidence is very low and no studies specifically address TNFi safety in women with psoriasis. Nonetheless, risks associated with TNFi treatment must be balanced against the as-yet uncertain risk of adverse outcomes in infants born to women with severe psoriasis. We searched PubMed using Medical Subject Headings (MeSH) terms and identified relevant studies and guidelines. Herein, we present the current knowledge of the use and safety of TNFi during pregnancy in women with psoriasis.

Palivizumab Exposure and the Risk of Atopic Dermatitis, Asthma and Allergic Rhinoconjunctivitis: A Cross-National, Population-Based Cohort Study

BackgroundPalivizumab is a humanized monoclonal antibody designed to provide passive immunity against respiratory syncytial virus. It is prescribed to children at high risk for severe infection with respiratory syncytial virus. However, little is known about the risk of the immune-mediated diseases atopic dermatitis, asthma, and allergic rhinoconjunctivitis after palivizumab exposure.AimOur objective was to investigate whether exposure to palivizumab was associated with atopic dermatitis, asthma, or allergic rhinoconjunctivitis in childhood.MethodsThis was a cross-national population-based cohort study including data from 769,523 Danish children born 1 January 1999–31 December 2010 and 581,742 Swedish children born 1 July 2005–31 December 2010. Since palivizumab is only indicated for children at the highest risk, sub-cohorts of preterm children, children with bronchopulmonary dysplasia, and children with hemodynamic significant heart disease were defined.ResultsOf the 1,351,265 children included, 1192 (0.09%) were exposed to palivizumab. An increased risk of asthma after palivizumab exposure was observed in the total birth cohort (hazard ratio [HR] 1.49; 95% confidence interval [CI] 1.32–1.68) and in the sub-cohort of preterm children (HR 1.24; 95% CI 1.07–1.44). However, post hoc analyses using the propensity score to balance confounding factors found no increased risk of asthma in preterm children (HR 0.91; 95% CI 0.56–1.48). No increased risks of atopic dermatitis (HR 1.18; 95% CI 0.94–1.48) or allergic rhinoconjunctivitis (HR 1.14; 95% CI 0.92–1.42) were observed.ConclusionExposure to palivizumab neither increased the risk of atopic disease nor protected against asthma.