Poul Thorsen

Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders

OBJECTIVES: Recent studies suggest that familial autoimmunity plays a part in the pathogenesis of ASDs. In this study we investigated the association between family history of autoimmune diseases (ADs) and ASDs/infantile autism. We perform confirmatory analyses based on results from previous studies, as well as various explorative analyses. METHODS: The study cohort consisted of all of the children born in Denmark from 1993 through 2004 (689 196 children). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry. Information on ADs in parents and siblings of the cohort members was obtained from the Danish National Hospital Register. The incidence rate ratio of autism was estimated by using log-linear Poisson regression. RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes. CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.

Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis

OBJECTIVE To assess the risk of juvenile-onset recurrent respiratory papillomatosis conferred by a maternal history of genital warts in pregnancy, and to identify additional cofactors such as the method of delivery (cesarean versus vaginal) and procedures or complications during pregnancy. METHODS A retrospective cohort design was used to evaluate maternal and infant characteristics associated with respiratory papillomatosis among Danish births between 1974 and 1993. Using data from Danish registries, we identified 3033 births with a maternal history of genital warts during pregnancy. Fifty-seven respiratory papillomatosis cases were identified by review of medical records from ear, nose, and throat departments. RESULTS Seven of every 1000 births with a maternal history of genital warts resulted in disease in the offspring, corresponding to a 231.4 (95% confidence interval 135.3, 395.9) times higher risk of disease relative to births without a maternal history of genital warts. In women with genital warts, delivery times of more than 10 hours were associated with a two-fold greater risk of disease. Cesarean delivery was not found to be protective against respiratory papillomatosis, and no other procedures or complications during pregnancy were observed to increase the risk of respiratory papillomatosis. CONCLUSION A maternal history of genital warts in pregnancy is the strongest risk factor for respiratory papillomatosis in the child. Future studies should examine the efficacy of genital wart treatment for the prevention of disease.

Pre-, peri- and neonatal risk factors for autism.

Objective. To identify pre‐, peri‐ and neonatal risk factors for pervasive developmental disorders (PDD). Methods. We searched the Medline database through March 2011 for relevant case–control and population‐based studies on pre‐, peri‐ and neonatal hazards related to PDD, including autism. We identified 85 studies for this review. Data were extracted systematically and organized according to risk factors related to family history, pregnancy, gestational age, delivery, birth milestones and the neonates condition at birth. Results. During the prenatal period, risk factors for PDD were advanced maternal or paternal ages, being firstborn vs. third or later, maternal prenatal medication use and mothers status as foreign born. During the perinatal and neonatal periods, the risk factors for PDD were preterm birth, breech presentation, planned cesarean section, low Apgar scores, hyperbilirubinemia, birth defect and a birthweight small for gestational age. The influence of maternal pre‐eclampsia, diabetes, vomiting, infections and stress during pregnancy requires further study in order to determine risk for PDD. Discussion. Despite evidence for the association of some pre‐, peri‐ and neonatal risk factors associated with PDD, it remains unclear whether these risks are causal or play a secondary role in shaping clinical expression in individuals with genetic vulnerability. A plausible hypothsesis is that improvements in obstetric and neonatal management have led to an increased rate of survivors with pre‐existing brain damage. Given the variety of risk factors, we propose that future studies should investigate combinations of multiple factors, rather than focusing on a single factor.

Cytokines Associated With Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants

OBJECTIVE. The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days. METHODS. For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21. RESULTS. Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1β, 6, 8, and 10 and interferon γ and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor β. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude. CONCLUSIONS. The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.

Validity of Childhood Autism in the Danish Psychiatric Central Register: Findings from a Cohort Sample Born 1990–1999

The purpose of this study was to assess the validity of the diagnosis of childhood autism in the Danish Psychiatric Central Register (DPCR) by reviewing medical records from 499 of 504 total children with childhood autism born 1990–1999. Based on review of abstracted behaviors recorded in case records from child psychiatric hospitals, case status determination was performed using a standardized coding scheme. In 499 children diagnosed with childhood autism in the DPCR, the diagnosis could be confirmed in 469 children (94%). Of the 30 non-confirmed cases, five were classified by the reviewers as non-autistic cases and the remaining 25 cases were either classified with another ASD diagnosis or the specific diagnosis was not possible to determine.

Few microorganisms associated with bacterial vaginosis may constitute the pathologic core: a population-based microbiologic study among 3596 pregnant women

OBJECTIVE To evaluate the association between various microorganisms isolated from the genital tract in pregnant women with bacterial vaginosis. STUDY DESIGN A cross-sectional population-based study among pregnant women addressed at their first antenatal visit before 24 full gestational weeks from the referring area of the Department of Obstetrics and Gynecology at Odense University Hospital, Denmark, from November 1992 to February 1994. The main outcome measures were prevalence of various microorganisms and statistical estimates of interactions (crude, adjusted, and relative odds ratios) between the microorganisms isolated from the lower genital tract in pregnant women with and without clinical diagnosis of bacterial vaginosis. RESULTS Three thousand five hundred ninety-six (3596) pregnant women were asked to participate. Of the 3596 pregnant women 3174 (88.4%) agreed to participate before 24 full gestational weeks. After controlling for the presence of other microorganisms, strong associations between Gardnerella vaginalis, anaerobic bacteria, Mycoplasma hominis, and present bacterial vaginosis were found. Similarly Lactobacillus spp. were found to be associated with the absence of bacterial vaginosis. The combination of G. vaginalis and anaerobic bacteria and/or M. hominis was found in 59.6% of the cases with bacterial vaginosis and in 3.9% of the cases without bacterial vaginosis (odds ratio 36.4, 95% confidence interval 27.8 to 47.8). The crude odds ratio was found to be as high as 74.8 (95% confidence interval 32.3 to 174.1) when the combination of G. vaginalis, M. hominis, anaerobic bacteria, and no Lactobacillus spp. was associated with bacterial vaginosis. CONCLUSION There is a microbial foundation for bacterial vaginosis, and it is possibly due to an intermicrobial interaction in which the microorganisms G. vaginalis, anaerobic bacteria, and M. hominis are dominating, indicating that these constitute the pathologic core of bacterial vaginosis.

Cerebral Palsy, Autism Spectrum Disorders, and Developmental Delay in Children Born After Assisted Conception: A Systematic Review and Meta-analysis

OBJECTIVE To assess the existing evidence of associations between assisted conception and cerebral palsy (CP), autism spectrum disorders (ASD), and developmental delay. DATA SOURCES Forty-one studies identified in a systematical PubMed and Excerpta Medica Database (EMBASE) search for articles published from January 1, 1996, to April 1, 2008. STUDY SELECTION Studies written in English comparing children born after assisted conception with children born after natural conception assessing CP, ASD, and developmental delay, based on original data with a follow-up of 1 year or more. Main Exposures In vitro fertilization (IVF) with or without intracytoplasmic sperm injection or ovulation induction with or without subsequent intrauterine insemination. MAIN OUTCOME MEASURES Cerebral palsy, ASD, and developmental delay. RESULTS Nine CP studies showed that children born after IVF had an increased risk of CP associated with preterm delivery. In our meta-analysis including 19 462 children exposed to IVF, we estimated a crude odds ratio of 2.18 (95% confidence interval, 1.71-2.77). Eight ASD studies and 30 studies on developmental delay showed inconsistent results. No studies assessed the risk of CP, ASD, or developmental delay in children born after ovulation induction exclusively. CONCLUSIONS Methodological problems were revealed in the identified studies, and the gaps in our knowledge about the long-term outcomes of children born after assisted conception are considerable, including a lack of information on the long-term consequences of ovulation induction. Possible associations with ASD and developmental delay need assessment in larger studies. Studies on assisted conception and CP from countries outside of Scandinavia are needed, including detailed information on time to pregnancy, underlying cause of infertility, and type of IVF treatment.

Cerebral palsy among children born after in vitro fertilization : The role of preterm delivery-a population-based, cohort study

OBJECTIVE. Our aim was to assess the incidence of cerebral palsy among children conceived with in vitro fertilization and children conceived without in vitro fertilization. METHODS. A population-based, cohort study, including all live-born singletons and twins born in Denmark between January 1, 1995, and December 31, 2000, was performed. Children conceived with in vitro fertilization (9255 children) were identified through the In Vitro Fertilization Register; children conceived without in vitro fertilization (394713) were identified through the Danish Medical Birth Register. Cerebral palsy diagnoses were obtained from the National Register of Hospital Discharges. The main outcome measure was the incidence of cerebral palsy in the in vitro fertilization and non-in vitro fertilization groups. RESULTS. Children born after in vitro fertilization had an increased risk of cerebral palsy; these results were largely unchanged after adjustment for maternal age, gender, parity, small-for-gestational age status, and educational level. The independent effect of in vitro fertilization vanished after additional adjustment for multiplicity or preterm delivery. When both multiplicity and preterm delivery were included in the multivariate models, preterm delivery remained associated strongly with the risk of cerebral palsy. CONCLUSIONS. The large proportions of preterm deliveries with in vitro fertilization, primarily for twins but also for singletons, pose an increased risk of cerebral palsy.

Differential Patterns of 27 Cord Blood Immune Biomarkers Across Gestational Age

OBJECTIVES. Inflammation has been associated with preterm delivery and adverse neonatal outcomes such as cerebral palsy and chronic lung disease. However, no study to date has simultaneously examined a wide range of inflammatory mediators and their relationship to gestational age. We sought to describe the distribution of immune biomarkers in cord blood across gestational age and to investigate the association between biomarker level patterns and preterm birth. PATIENTS AND METHODS. As part of a large-scale molecular epidemiological study of preterm birth conducted at Boston Medical Center, this study analyzed both clinical and biomarker data from 927 births. Twenty-seven biomarkers were simultaneously quantified by immunoassay. The associations between the quartiles of 27 biomarkers and 3 gestational groups (≤32, 33–36, and ≥37 weeks) were analyzed. Biomarkers found to be significant were further analyzed for dose-response correlation with preterm birth by logistic regression, adjusted for pertinent demographic and clinical factors. RESULTS. The 27 biomarkers could be classified into 1 of 3 groups: (1) biomarkers increased in preterm birth (interleukin [IL]-2, IL-4, IL-5, IL-8, IL-10, monocyte chemoattractant protein 1, macrophage inflammatory protein [MIP]-1α, MIP-1β, soluble IL-6 receptor α, tumor necrosis factor α, soluble tumor necrosis factor receptor I, and TREM-1 [triggering receptor expressed on myeloid cells 1]); (2) biomarkers decreased in preterm birth (brain-derived neurotrophic factor, IL-1β, IL-18, matrix metalloproteinase 9, and neurotrophin 3); and (3) biomarkers not associated with preterm birth (IL-6, IL-12, IL-17, granulocyte/macrophage colony-stimulating factor, interferon γ, macrophage migration inhibitory factor, neurotrophin 4, RANTES [regulated on activation, normal T-cell expressed and secreted], transforming growth factor β, and tumor necrosis factor β). CONCLUSIONS. Biomarkers have different directions of association with prematurity; for significant biomarkers, the strength of association increases with biomarker concentration. Our results provide important information that could be used to guide additional studies aimed at determining mechanisms that contribute to preterm birth.

Biomarkers for the prediction of preterm delivery

This structured review discusses the current literature on selected biomarkers and their ability to predict preterm delivery (PTD).