Polycystic ovary syndrome and offspring risk of congenital heart defects: a nationwide cohort study.

STUDY QUESTION: Is maternal polycystic ovary syndrome (PCOS) associated with increased offspring risk of congenital heart defects? SUMMARY ANSWER: This study does not support a strong association between PCOS and an increased risk of congenital heart defects. WHAT IS KNOWN ALREADY: In addition to affecting reproductive health, PCOS may involve insulin resistance. Maternal pregestational diabetes is associated with an increased risk of congenital heart defects and therefore PCOS may increase the risk of congenital heart defects in the offspring. STUDY DESIGN, SIZE, DURATION: In this nationwide cohort study, we used data from Danish health registers collected from 1995 to 2018. The study included 1 302 648 offspring and their mothers. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were live singleton offspring born during the study period. Information on maternal PCOS and offspring congenital heart defects was obtained from the National Patient Register. Logistic regression analysis was used to compute prevalence (odds) ratio (PR) of the association between PCOS and offspring congenital heart defects. MAIN RESULTS AND THE ROLE OF CHANCE: Among 1 302 648 live-born singletons, 11 804 had a mother with PCOS. Of these, 143 offspring had a congenital heart defect (prevalence 121 per 10 000) as compared with 12 832 among mothers without PCOS (prevalence 99 per 10 000). The adjusted PR was 1.22, 95% CI 1.03-1.44 comparing prevalence of congenital heart defects in offspring of women with PCOS with offspring of women without. After adjusting for the potentially mediating effect of pregestational diabetes, the PR was 1.16, 95% CI 0.98-1.37. LIMITATIONS, REASONS FOR CAUTION: PCOS may be underdetected in the National Patient Register. However, we expect that the mothers that we identified with PCOS truly had PCOS, thus, the estimated associations are not likely to be affected by this misclassification. The study does not provide evidence to rule out a moderate or weak association. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide reassurance to clinicians counselling pregnant women with PCOS that the disease does not pose a markedly increased risk of offspring congenital heart defects. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Novo Nordisk Foundation. M.L. reports personal fees from Dansk Lægemiddel Information A/S outside the submitted work. The remaining authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Maternal and fetal human leukocyte antigen class Ia and II alleles in severe preeclampsia and eclampsia.

A line of investigations indicate that genes in the human leukocyte antigen (HLA) complex are involved in a successful acceptance of the semiallogeneic fetus during pregnancy. In this study, associations between specific HLA class Ia (HLA-A and -B) and class II (HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) alleles and the risk of developing severe preeclampsia/eclampsia were investigated in a detailed and large-scale study. In total, 259 women diagnosed with severe preeclampsia or eclampsia and 260 matched control women with no preeclampsia, together with their neonates, were included in the study. HLA genotyping for mothers and neonates was performed using next-generation sequencing. The HLA-DPB1*04:01:01G allele was significantly more frequent (Pc=0.044) among women diagnosed with severe preeclampsia/eclampsia compared with controls, and the DQA1*01:02:01G allele frequency was significantly lower (Pc=0.042) among newborns born by women with severe preeclampsia/eclampsia compared with controls. In mothers with severe preeclampsia/eclampsia, homozygosity was significantly more common compared with controls at the HLA-DPB1 locus (Pc=0.0028). Although the current large study shows some positive results, more studies, also with a functional focus, are needed to further clarify a possible role of the classical HLA genes in preeclampsia.

The role of filaggrin mutations during pregnancy and postpartum: atopic dermatitis and genital skin diseases.

Mutations in the epidermal filaggrin gene (FLG) are associated with skin barrier dysfunction (dry skin, less acidic skin, and fissured skin), and atopic dermatitis (AD) with a severe and persistent course. Because pregnancy and delivery further impairs normal skin barrier functions (immune suppression, mechanical stress), we studied the possible role of FLG mutations on the risk of AD flares, genital infections, and postpartum problems related to perineal trauma. FLG-genotyping was performed in a population-based sample of 1837 women interviewed in the 12th and 30th weeks of pregnancy and 6 months postpartum as part of the Danish National Birth Cohort study 1996-2002. We found that FLG mutations also influence pregnancy-related skin disease; thus, women with FLG mutations had an increased risk of AD flares during pregnancy (OR 10.5, 95% CI 3.6-30.5) and of enduring postpartum physical problems linked to perineal trauma during delivery (OR 11.1, 95% CI 1.1-107.7).

Nasopharyngeal bacterial carriage in young children in Greenland: a population at high risk of respiratory infections.

The incidence of childhood respiratory infections in Greenland is among the highest globally. We performed a population-based study of 352 Greenlandic children aged 0-6 years aiming to describe rates and risk factors for carriage of four key bacteria associated with respiratory infections, their antimicrobial susceptibility and inter-bacterial associations. Nasopharyngeal swabs were tested for Streptococcus pneumoniae grouped by serotypes included (VT) or not included (NVT) in the 13-valent pneumococcal conjugate vaccine, non-typable Haemophilus influenzae (NTHi), Staphylococcus aureus and Moraxella catarrhalis. S. pneumoniae was detected from age 2 weeks with a peak carriage rate of 60% in 2-year-olds. Young age and having siblings attending a daycare institution were associated with pneumococcal carriage. Overall co-colonization with ⩾2 of the studied bacteria was 52%. NTHi showed a positive association with NVT pneumococci and M. catarrhalis, respectively, M. catarrhalis was positively associated with S. pneumoniae, particular VT pneumococci, whereas S. aureus were negatively associated with NTHi and M. catarrhalis. Nasopharyngeal bacterial carriage was present unusually early in life and with frequent co-colonization. Domestic crowding increased odds of carriage. Due to important bacterial associations we suggest future surveillance of pneumococcal conjugate vaccine's impact on carriage in Greenland to also include other pathogens.

Mitochondrial dysfunction and risk of cancer.

BACKGROUND: Mitochondrial mutations are commonly reported in tumours, but it is unclear whether impaired mitochondrial function per se is a cause or consequence of cancer. To elucidate this, we examined the risk of cancer in a nationwide cohort of patients with mitochondrial dysfunction. METHODS: We used nationwide results on genetic testing for mitochondrial disease and the Danish Civil Registration System, to construct a cohort of 311 patients with mitochondrial dysfunction. A total of 177 cohort members were identified from genetic testing and 134 genetically untested cohort members were matrilineal relatives to a cohort member with a genetically confirmed maternally inherited mDNA mutation. Information on cancer was obtained by linkage to the Danish Cancer Register. Standardised incidence ratios (SIRs) were used to assess the relative risk of cancer. RESULTS: During 7334 person-years of follow-up, 19 subjects developed a primary cancer. The corresponding SIR for any primary cancer was 1.06 (95% confidence interval 0.68-1.63). Subgroup analyses according to mutational subtype yielded similar results, for example, a SIR of 0.94 (95% CI 0.53 to 1.67) for the m.3243A>G maternally inherited mDNA mutation, cases=13. CONCLUSIONS: Patients with mitochondrial dysfunction do not appear to be at increased risk of cancer compared with the general population.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect.

BACKGROUND: An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. OBJECTIVE: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. METHODS: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-ß. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. RESULTS: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. CONCLUSIONS: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect.

The effectiveness of BCG vaccination in preventing Mycobacterium tuberculosis infection and disease in Greenland.

BACKGROUND: The BCG vaccine's ability to prevent Mycobacterium tuberculosis infection (MTI) remains highly debated. In Greenland, BCG vaccination was introduced in 1955, but was temporarily discontinued (1991-1996) due to nationwide policy changes. The study aimed to use the transient stop in BCG vaccination to evaluate the effect of vaccination on MTI prevalence and TB incidence. METHODS: MTI study: A cross-sectional study (2012), comprising East Greenlanders born during 1982-2006, evaluated the effect of BCG vaccination on MTI prevalence; a positive interferon γ release assay defined an MTI case. Associations were estimated using logistic regression. TB study: a cohort study covering the same birth cohorts with follow-up until 2012 evaluated the vaccine's effect on TB incidence. A personal identifier allowed for follow-up in the TB notification system. Associations were estimated using Cox regression. RESULTS: MTI study: Included 953 participants; 81% were BCG-vaccinated; 29% had MTI, 23% among vaccinated and 57% among non-vaccinated. BCG vaccination reduced the odds of MTI, OR 0.52 (95% CI 0.32 to 0.85), p=0.01. Vaccine effectiveness against MTI was 20%. TB study: Included 1697 participants followed for 21,148 person-years. 6% were notified with TB, 4% among vaccinated and 11% among non-vaccinated. BCG vaccination reduced the risk of TB, HR 0.50 (95% CI 0.26 to 0.95), p=0.03, yielding a vaccine effectiveness of 50%. CONCLUSIONS: BCG vaccination was effective in reducing both MTI and TB disease among children and young adults in a TB high-endemic setting in Greenland.

Risk of cancer in relatives of patients with myotonic dystrophy: a population-based cohort study.

BACKGROUND AND PURPOSE: Myotonic dystrophies (DM) are autosomal dominantly inherited neuromuscular disorders caused by unstable nucleotide repeat expansions. DM and cancer have been associated, but the pathogenesis behind the association remains unclear. It could relate to derived effects of the DM genotype in which case non-DM relatives of DM patients would not be expected to be at increased risk of cancer. To elucidate this, a population-based cohort study investigating risk of cancer in relatives of DM patients was conducted. METHODS: DM was identified using the National Danish Patient Registry and results of genetic testing. Information on cancer was obtained from the Danish Cancer Registry. A population-based cohort of 5 757 565 individuals with at least one relative was established using the Danish Family Relations Database based on kinship links in the Danish Civil Registration System. Familial aggregation of cancer was evaluated by (incidence) rate ratios (RRs) comparing the rate of cancer amongst relatives of patients with DM from 1977 to 2010 (exposed) with the rate of cancer amongst persons with a relative of the same type but without DM (non-exposed). RESULTS: In first-degree relatives of individuals with DM the adjusted RR of cancer was 0.89 (95% confidence interval 0.71-1.12) overall, and in stratified analyses 0.68 (0.37-1.12) before age 50 and 0.96 (0.74-1.23) at age 50 or older. CONCLUSIONS: The present study does not support an increased risk of cancer in non-DM relatives of DM patients suggesting that cancer and DM are associated through derived effects of the DM genotype.

Antibiotic use and risk of non-Hodgkin lymphomas.

Clinical case reports have suggested that specific bacterial infections are associated with certain non-Hodgkin lymphoma (NHL) subtypes. Epidemiological case-control studies have been conducted using antibiotics as a proxy for bacterial infections, but with inconclusive results. The aim of this study was, in a cohort design, based on the unique nationwide Danish registers, to investigate the association between use of antibiotics and the risk of NHL subtypes. On the basis of the Civil Registration System, we established a cohort of the entire adult (≥ 15 years) Danish population. Information on use of antibiotics came from the Danish Drug Prescription Registry and lymphoma diagnosis from the Danish Cancer Registry. Associations were assessed by adjusted rate ratios (RRs). In total, 13,602 patients were diagnosed with one of the NHL subtypes during 51.6 million person-years of follow-up (1995-2008). We observed positive associations between use of antibiotics and plasma cell myeloma [RR = 1.11, 95% confidence intervals (CIs) = 1.00-1.24], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (RR = 1.32, 95% CI = 1.20-1.45), mantle cell lymphoma (MCL) (RR = 1.40, 95% CI = 1.04-1.88) and anaplastic large T-cell lymphoma (ALCL) (RR = 1.83, 95% CI = 1.00-3.36). Among these, the increased risk of CLL/SLL, MCL and ALCL, respectively, did not vary by years since use, and only the risk of CLL/SLL risk differed by number of prescriptions. While causality could not be established in our study, an intriguing positive long-term association between antibiotic use and CLL/SLL risk was observed. To what extent these findings indicate a role for bacteria in lymphoma pathogenesis requires further investigation.

Trichuris suis ova therapy for allergic rhinitis does not affect allergen-specific cytokine responses despite a parasite-specific cytokine response.

BACKGROUND: Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied. OBJECTIVE: The aim was to investigate whether infection with the nematode parasite Trichuris suis alters systemic cytokine levels, cellular cytokine responses to parasite antigens and pollen allergens and/or the cytokine profile of allergic individuals. METHODS: In a randomized double-blinded placebo-controlled clinical trial (UMIN trial registry, Registration no. R000001298, Trial ID UMIN000001070, URL: http://www.umin.ac.jp/map/english), adults with grass pollen-induced allergic rhinitis received three weekly doses of 2500 Trichuris suis ova (n = 45) or placebo (n = 44) over 6 months. IFN-γ, TNF-α, IL-4, IL-5, IL-10 and IL-13 were quantified via cytometric bead array in plasma. Cytokines, including active TGF-ß, were also quantified in supernatants from peripheral blood mononuclear cells cultured with parasite antigens or pollen allergens before, during and after the grass pollen season for a sub-cohort of randomized participants (T. suis ova-treated, n = 12, Placebo-treated, n = 10). RESULTS: Helminth infection induced a Th2-polarized cytokine response comprising elevated plasma IL-5 and parasite-specific IL-4, IL-5 and IL-13, and a global shift in the profile of systemic cytokine responses. Infection also elicited high levels of the regulatory cytokine IL-10 in response to T. suis antigens. Despite increased production of T. suis-specific cytokines in T. suis ova-treated participants, allergen-specific cytokine responses during the grass pollen season and the global profile of PBMC cytokine responses were not affected by T. suis ova treatment. CONCLUSIONS AND CLINICAL RELEVANCE: This study suggests that cytokines induced by Trichuris suis ova treatment do not alter allergic reactivity to pollen during the peak of allergic rhinitis symptoms.

Ongoing tuberculosis transmission to children in Greenland.

Inuit in the Arctic are experiencing an increase in tuberculosis cases, reaching levels in Greenland comparable to high-incidence countries. This prompted us to study the level of tuberculosis transmission to Greenlandic children. Specifically, we estimated the current prevalence of Mycobacterium tuberculosis infection (MTI) and the underlying annual risk of MTI. 2,231 Greenlandic school children aged 5-17 yrs (∼25% of the Greenlandic population in the relevant age group) were tested for MTI using the tuberculin skin test and the QuantiFERON®-TB Gold in-tube test. Subjects with dual-positive results were considered infected and subjects with dual-negative results uninfected. The children with discordant test results were classified as probably having MTI and analysed separately. 8.1% of the children had dual-positive test results. The annual risk of MTI was estimated as 0.80% (95% CI 0.67-0.92%) giving a cumulative risk at the 18th birthday of 13.4%. The annual risk of MTI varied substantially by ethnicity (0.87% in Inuit children, 0.02% in non-Inuit children; p<0.001) and by location (0.13% on the west coast, 1.68% on the south coast; p<0.001). M. tuberculosis transmission occurs at a very high level in Inuit children with pronounced geographic differences emphasising the need for immediate public health interventions.

Trichinella infection in a hunting community in East Greenland.

Trichinella nativa infection (trichinellosis) is highly prevalent in Arctic wildlife, but the human burden of trichinellosis in present-day Greenland is unknown. The study aimed to determine Trichinella seroprevalence in an eastern Greenlandic hunting community and to evaluate risk factors for seropositivity. Overall, 998 inhabitants aged 10 years in the Ammassalik municipality were tested for Trichinella-specific IgG antibodies. Background information was obtained from questionnaires. Seropositivity was 1.4% in persons aged <40 years and increased to >12% in those aged 60 years. Older age, occupation as hunter or fisherman, and consumption of polar bear meat significantly increased the risk of Trichinella seropositivity. The seropositivity age pattern probably reflects changes in dietary preferences, but could also reflect mandatory meat inspection since 1966. However, preventive measures against Trichinella infection should be strengthened in Greenland.

EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma.

BACKGROUND: Approximately 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV). The Inuit in Greenland have a high incidence of EBV-associated nasopharyngeal carcinoma. METHODS: We conducted a population-based case-control study comparing gastric carcinomas in Greenland and in Denmark. RESULTS: The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations. CONCLUSION: The findings of this study argue against a general susceptibility to EBV-associated carcinomas among the Inuit.

Three-year incidence of AIDS in five cohorts of HTLV-III-infected risk group members.

The incidence of the acquired immune deficiency syndrome (AIDS) among persons infected with human T-lymphotropic virus type III (HTLV-III) was evaluated prospectively among 725 persons who were at high risk of AIDS and had enrolled before October 1982 in cohort studies of homosexual men, parenteral drug users, and hemophiliacs. A total of 276 (38.1 percent) of the subjects were either HTLV-III seropositive at enrollment or developed HTLV-III antibodies subsequently. AIDS had developed in 28 (10.1 percent) of the seropositive subjects before August 1985. By actuarial survival calculations, the 3-year incidence of AIDS among all HTLV-III seropositive subjects was 34.2 percent in the cohort of homosexual men in Manhattan, New York, and 14.9 percent (range 8.0 to 17.2 percent) in the four other cohorts. Out of 117 subjects followed for a mean of 31 months after documented seroconversion, five (all hemophiliacs) developed AIDS 28 to 62 months after the estimated date of seroconversion, supporting the hypothesis that there is a long latency between acquisition of viral infection and the development of clinical AIDS. This long latency could account for the significantly higher AIDS incidence in the New York cohort compared with other cohorts if the virus entered the New York homosexual population before it entered the populations from which the other cohorts were drawn. However, risk of AIDS development in different populations may also depend on the presence of as yet unidentified cofactors.

Post-transfusion mortality among recipients of ABO-compatible but non-identical plasma.

BACKGROUND AND OBJECTIVES: The consequences of ABO-compatible non-identical plasma for patient outcome have not been studied in randomized clinical trials or large cohort studies and use varies widely in the absence of evidence-based policies. We investigated if transfusion with compatible instead of identical plasma confers any short-term survival disadvantage on the recipients. MATERIALS AND METHODS: The cohort of all 86 082 Swedish patients who received their first plasma transfusion between 1990 and 2002 was followed for 14 days and the risk of death in patients exposed to compatible non-identical plasma compared to recipients of only identical plasma. RESULTS: After adjustment for potential confounding factors, there was an increased mortality associated with exposure to ABO-compatible non-identical plasma, with the excess risk mostly confined to those receiving 5 or more units (relative risk, 1.15; 95% confidence interval, 1.02-1.29). Stratification by blood group indicated higher risks in group O recipients, especially when the compatible plasma was from a group AB donor. CONCLUSIONS: This study suggests that ABO-compatible non-identical plasma is less safe than identical plasma. Subanalyses by blood group suggest a role for circulating immune complexes. Our findings may have policy implications for improving transfusion safety.

Rare and Common Variants Conferring Risk of Tooth Agenesis.

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Human antibody recognition of Anisakidae and Trichinella spp. in Greenland.

High levels of total IgE are observed among children in Greenland. To evaluate the extent to which Anisakidae and Trichinella spp. contribute to the high total IgE level, an ELISA and a western blot were developed for the detection of IgG antibodies to Anisakidae, based on excretory/secretory antigens from Anisakidae larvae. Western blots with Anisakidae and Trichinella antigens discriminated between Anisakidae and Trichinella infections, enabling cross-reactivity between the two parasite infections to be eliminated. Serum samples from 1012 children in Greenland were analysed for specific antibodies to Anisakidae and Trichinella. Eleven children were IgG-positive for Trichinella and nine were IgG-positive for Anisakidae, indicating a relatively low prevalence of both infections among children in Greenland. Faecal samples from 320 children were also examined for other intestinal parasites. Enterobius vermicularis was found in one sample and Blastocystis hominis in 32 samples, but no other intestinal parasites were identified. In total, 304 children had elevated total IgE levels. There was a significant association between Trichinella seropositivity and high levels of total IgE, but not between Anisakidae seropositivity and total IgE. The data indicate that parasitic infections alone do not explain the high level of total IgE observed among children in Greenland.