Enthesitis in a European registry-based cohort of patients with psoriatic arthritis treated with tumour necrosis factor inhibitors: clinical burden, patient-reported outcomes, and treatment response.

OBJECTIVE: To explore the registration of enthesitis among biologic-naïve patients with psoriatic arthritis (PsA) initiating tumour necrosis factor inhibitor (TNFi) treatment across 12 European registries, compare the disease burden and patient-reported outcomes (PROs) between patients with and without enthesitis, and assess the enthesitis treatment response. METHOD: Demographics, clinical characteristics, and PROs at first TNFi (TNFi-1) initiation (baseline) were assessed in patients with PsA, diagnosed by a rheumatologist, with versus without assessment of entheses and between those with versus without enthesitis. Enthesitis scores and resolution frequency were identified at follow-up. RESULTS: Of 10 547 patients in the European Spondyloarthritis (EuroSpA) Research Collaboration Network initiating TNFi, 1357 underwent evaluation for enthesitis. Eight registries included a validated scoring system for enthesitis. At baseline, 874 patients underwent entheses assessment [Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 485 patients, Spondyloarthritis Research Consortium of Canada (SPARCC) 389 patients]. Enthesitis was detected by MASES in 170/485 (35%, mean score ± sd 3.1 ± 2.4) and by SPARCC in 236/389 (61%, 4 ± 3.4). Achilles enthesitis was most frequent, by both MASES (unilateral/bilateral 28%/9%) and SPARCC (48%/18%). MASES/SPARCC baseline and follow-up scores for TNFi-1 were available for 100/105 patients. Of these, 63 patients (63%) (MASES) and 46 (43.8%) (SPARCC) achieved resolution of enthesitis. The site-specific enthesitis resolution was overall lower at SPARCC sites (peripheral; 63-80%) than at MASES sites (mainly axial; 82-100%) following TNFi-1. Disease activity and PROs were worse in patients with versus without enthesitis. CONCLUSION: Entheseal assessments are only registered in a minority of patients with PsA in routine care. When assessed, enthesitis was common, and a substantial proportion demonstrated resolution following treatment with TNFi-1.

Danish translation and cultural adaptation of the Psoriatic arthritis UnclutteRed screening Evaluation (PURE-4) scale.

OBJECTIVES: Screening tools are needed to help to identify psoriatic arthritis in patients with psoriasis. The Psoriatic arthritis UnclutteRed screening Evaluation (PURE-4) questionnaire was developed for this purpose and has been shown to perform very well. The aim of this study was to translate and culturally adapt the PURE-4 scale into the Danish language. METHOD: The translational process followed the guidelines provided by the Mapi Research Trust, which include the following steps: forward translation, backward translation, cognitive interviews, and proofreading. Following the guidelines helps to maintain the content validity of the questionnaire and secures a translation that is both literally and culturally appropriate for the target population. RESULTS: All four items were modified throughout the translation process, involving mainly minor changes such as the addition of more colloquial words in the Danish version. The new Danish version of PURE-4 was reviewed and approved by the original developers. CONCLUSIONS: A Danish version of the PURE-4 questionnaire was produced. The translation and cultural adaptation of PURE-4 constitute the first step in the validation of the questionnaire in Danish patients with psoriasis.

Unsuccessful treatment of chronic norovirus infection with enteral immunoglobulin in patients with common variable immunodeficiency, case report.

Background: Norovirus gastroenteritis is commonly an acute infection that lasts 2-3 days, but in immunocompromised patients norovirus can cause a chronic gastroenteritis lasting for years. Norovirus replicates in the gastrointestinal tract, but the pathway of viral clearance is not yet known. Promising results of enterally administered immunoglobulin in the treatment of chronic norovirus gastroenteritis in immunocompromised patients have previously been published. Case presentation: We report two individuals with common variable immunodeficiency and chronic debilitating norovirus gastroenteritis. Both patients were treated with enterally administered immunoglobulin via a duodenal feeding tube as other treatment modalities have been unsuccessful. The patients did not experience any immediate or long-term benefit of enterally administered immunoglobulin. Conclusion: Despite previous case reports of successful treatment of chronic norovirus infection among immunocompromised patients with enterally administered immunoglobulin, these two patients experienced no benefit of the treatment. This demonstrates the need for further research in treatment of chronic norovirus infection in immunocompromised patients.

Disease activity-guided tapering of biologics in patients with inflammatory arthritis: a pragmatic, randomized, open-label, equivalence trial.

OBJECTIVE: To evaluate whether disease activity-guided tapering of biologics compared to continuation as usual care enables a substantial dose reduction while disease activity remains equivalent. METHOD: In this pragmatic, randomized, open-label, equivalence trial, adults with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis in low disease activity on stable-dose biologics for ≥ 12 months were randomized 2:1 into either the tapering group, i.e. disease activity-guided prolongation of the biologic dosing interval until flare or withdrawal, or the control group, i.e. maintaince of baseline biologics with a possible small interval increase at the patients request. The co-primary outcome in the intention-to-treat population was met if superiority in ≥ 50% biologic reduction at 18 months was demonstrated and disease activity was equivalent (equivalence margins ± 0.5). RESULTS: Ninety-five patients were randomized to tapering and 47 to control, of whom 37% (35/95) versus 2% (1/47) achieved ≥ 50% biologic reduction at 18 months. The risk difference was statistically significant [35%, 95% confidence interval (CI) 24%-45%], while disease activity remained equivalent [mean difference 0.05, 95% CI -0.12-0.29]. A statistically significant flare risk was observed [tapering 41% (39/95) vs control 21% (10/47), risk difference 20%, 95% CI 4%-35%]; but, only 1% (1/95) and 6% (3/47) had persistent flare and needed to switch to another biological drug. CONCLUSIONS: Disease activity-guided tapering of biologics in patients with inflammatory arthritis enabled one-third to achieve ≥ 50% biologic reduction, while disease activity between groups remained equivalent. Flares were more frequent in the tapering group but were managed with rescue therapy.

Obstetric and perinatal risks after the use of donor sperm: A systematic review and meta-analysis.

Donor sperm is widely used in infertility treatments. The purpose of the study was to investigate, whether use of donor sperm in intrauterine insemination (IUI) or in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments affect maternal and perinatal risks compared with spontaneously conceived pregnancies or use of partner sperm in IUI, IVF or ICSI. We provide a systematic review and meta-analyses on the most clinically relevant obstetric and perinatal outcomes after use of donor sperm compared with partner sperm: hypertensive disorders of pregnancy, preeclampsia, low birth weight, and preterm birth. Our meta-analyses showed an increased risk for preeclampsia (pooled adjusted odds ratio (aOR) 1.77, 95% CI 1.26-2.48) and hypertensive disorders of pregnancy (pooled aOR 1.55, 95%, CI 1.20-2.00) in pregnancies resulting from IUI with donor sperm compared with IUI with partner sperm. No increased risk was seen for low birth weight or preterm birth after the use of donor sperm in IUI compared with the use of partner sperm in IUI. Subgroup analysis for singletons only did not change these results. The meta-analysis on low birth weight showed a lower risk after in IVF with donor sperm compared with IVF with partner sperm (pooled aOR 0.89, 95% CI 0.83-0.94). For hypertensive disorders of pregnancy, preeclampsia and preterm birth, no difference was found between IVF with donor sperm vs. partner sperm. Patients need to be informed about the moderately increased risk of hypertensive disorders of pregnancy and preeclampsia in pregnancies after IUI with donor sperm.

Complement C3d is not associated with axial spondyloarthritis and magnetic resonance imaging changes at the sacroiliac joint.

OBJECTIVE: To investigate the associations between complement C3d and inflammatory and structural changes by magnetic resonance imaging (MRI) at the sacroiliac joints (SIJ) suggestive of axial spondyloarthritis, according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, in patients with low back pain. METHOD: This was a cross-sectional study of patients referred to the Spine Centre of Southern Denmark owing to unspecified low back pain (Spines of Southern Denmark cohort). The patients were divided into three groups: group 1: patients fulfilling the ASAS criteria for axial spondyloarthritis (axSpA, n = 96); group 2: patients with either a positive MRI of the SIJ and no spondyloarthritis features, or a negative MRI of the SIJ but positive human leucocyte antigen-B27 and one spondyloarthritis feature (non-axSpA, n = 38); group 3: patients with unspecified low back pain for > 3 months (control group, n = 82). Complement C3d was measured with double-decker rocket immunoelectrophoresis and evaluated in relation to the group division and baseline findings by SIJ MRI. RESULTS: In total, 184 C3d analyses were performed. The mean ± sd level of C3d was 33.8 ± 8.1 AU/mL. There were no differences in C3d levels between the three patient groups, mean values being: axSpA = 34.3 ± 7.9 AU/mL, non-axSpA = 33.5 ± 6.9 AU/mL, and controls = 33.4 ± 9.2 AU/mL. The level of C3d was not related to MRI findings. CONCLUSIONS: In these patients, complement C3d was not associated with active or structural SIJ changes on MRI suggestive of axial spondyloarthritis.

Diagnosing axial spondyloarthritis by multidiciplinary team conference at 3.5 years' follow-up in a cohort of patients with disease features according to the ASAS criteria.

OBJECTIVES: During the past two decades, magnetic resonance imaging (MRI) has increasingly been used diagnostically in axial spondyloarthritis (axSpA), and in 2009 MRI was introduced in the Assessment of SpondyloArthritis Society (ASAS) classification criteria. In clinical practice, there is a risk of overdiagnosis if MRI findings are not related to clinical and biochemical findings. The aim of this study was to provide an estimate of the prevalence of axSpA in a cohort of clinical patients with low back pain and findings suggestive of axSpA according to ASAS through consensus diagnosis at a multi-disciplinary team (MDT) conference, and to describe the performance of the features included in the ASAS criteria. METHOD: Consensus diagnoses of axSpA at MDT conferences were retrospectively established at 3.5 years' follow-up in a cohort of 84 patients, initially referred with disease features according to the ASAS criteria. Patients were examined clinically regarding spondyloarthritis features, and biochemical tests and MRI of the sacroiliac joints and entire spine were performed at baseline and after a mean of 3.5 years. RESULTS: According to the MDT consensus, 25 patients (30%) of the total cohort had axSpA at follow-up; 40% of individuals who fulfilled the ASAS criteria at baseline had axSpA, and 37% at follow-up; 96% of axSpA patients according to the MDT consensus met the ASAS criteria at baseline and 92% at follow-up. CONCLUSION: Approximately one-third of the included patients had axSpA when evaluated at the MDT conference. The ASAS criteria had low predictive value, but high sensitivity at both baseline and follow-up.

Clinically decisive (dis)agreement in multidisciplinary team assessment of esophageal squamous cell carcinoma; a prospective, national, multicenter study.

BACKGROUND: Decisions regarding tumor staging, operability, resectability, and treatment strategy in patients with esophageal cancer are made at multidisciplinary team (MDT) conferences. We aimed to assess interobserver agreement from four national MDT conferences and whether this would have a clinical impact. METHODS: A total of 20 patients with esophageal cancer were included across all four upper gastrointestinal (GI) cancer centers. Fully anonymized patient data were distributed among the MDT conferences which decided on TNM category, resectability, operability, curability, and treatment strategy blinded to each other's decisions. The interobserver agreement was expressed as both the raw observer agreement and with Krippendorff's α values. Finally, a case-by-case evaluation was performed to determine if disagreement would have had a clinical impact. RESULTS: A total of 80 MDT evaluations were available for analysis. A moderate to near-perfect observer agreement of 79.2%, 55.8%, and 82.5% for TNM category was observed, respectively. Substantial agreement for resectability and moderate agreement for curability were found. However, an only fair agreement was observed for the operability category. The treatment strategies had a slight agreement which corresponded to disagreement having a clinical impact in 12 patients. CONCLUSIONS: Esophageal cancer MDT conferences had an acceptable interobserver agreement on resectability and TM categories; however, the operability assessment had a high level of disagreement. Consequently, the agreement on treatment strategy was reduced with a potential clinical impact. In future MDT conferences, emphasis should be on prioritizing the relevant information being readily available (operability, T & M categories) to minimize the risk of disagreement in the assessments and treatment strategies, and thus, delayed or suboptimal treatment.

ESGO/ISUOG/IOTA/ESGE Consensus Statement on preoperative diagnosis of ovarian tumours.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the preoperative diagnosis of ovarian tumours, including imaging techniques, biomarkers and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the preoperative diagnosis of ovarian tumours and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when a consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the preoperative diagnosis of ovarian tumours and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

ESGO/ISUOG/IOTA/ESGE Consensus Statement on preoperative diagnosis of ovarian tumors.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the preoperative diagnosis of ovarian tumors, including imaging techniques, biomarkers and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the preoperative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the preoperative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

Declaración de consenso de ESGO/ISUOG/IOTA/ESGE sobre el diagnóstico preoperatorio de los tumores de ovario La Sociedad Europea de Oncología Ginecológica (ESGO), la Sociedad Internacional de Ecografía en Obstetricia y Ginecología (ISUOG), el Grupo Internacional de Análisis de Tumores de Ovario (IOTA) y la Sociedad Europea de Endoscopia Ginecológica (ESGE) elaboraron conjuntamente declaraciones de importancia para la práctica clínica y con base empírica sobre el diagnóstico preoperatorio de los tumores de ovario, a partir de imágenes, biomarcadores y modelos de predicción, entre otras técnicas. La ESGO/ISUOG/IOTA/ESGE designó a un grupo internacional multidisciplinar, que incluye a personas expertas de la práctica clínica y la investigación que han demostrado liderazgo y experiencia en el diagnóstico preoperatorio de los tumores de ovario y en el tratamiento de las pacientes con cáncer de ovario (19 personas expertas de toda Europa). También se incluyó en el grupo a una representante de las pacientes. Para garantizar que las declaraciones tenían una base empírica, se revisó la literatura actual y se valoró de forma crítica. Se redactaron declaraciones preliminares basadas en la revisión de la literatura pertinente. La totalidad del grupo debatió durante una teleconferencia cada declaración preliminar y se llevó a cabo una primera ronda de votaciones. Las declaraciones se eliminaron cuando no se obtuvo el consenso entre los miembros del grupo. Los votantes tuvieron la oportunidad de aportar comentarios/sugerencias a la par que sus votos. Las declaraciones se revisaron en consecuencia. Se llevó a cabo otra ronda de votaciones según las mismas reglas para que todo el grupo pudiera evaluar la versión revisada de las declaraciones. El grupo logró un consenso sobre 18 declaraciones. Esta Declaración de Consenso presenta estas declaraciones de la ESGO/ISUOG/IOTA/ESGE sobre el diagnóstico preoperatorio de los tumores de ovario y la evaluación de la carcinomatosis, junto con un resumen de la evidencia que apoya cada declaración.

Plasma levels of H- and L-ficolin are increased in axial spondyloarthritis: improvement of disease identification.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that primarily affects the axial skeleton. A predominance of innate versus adaptive immune responses have been reported in axSpA, indicating a prominent autoinflammatory component of the disease. Little is known about the lectin pathway proteins (LPPs) of the complement system in relation to axSpA. We have investigated LPPs in patients with axSpA and control individuals. Plasma samples were obtained from a cross-sectional cohort of 120 patients with a clinical diagnosis of axSpA and from 144 age- and gender-matched controls. The plasma concentrations of 11 LPPs were measured, using sandwich-type time-resolved immunofluorometric assays in patients and controls, and related to clinical diagnosis and disease activity. Three LPPs [H-ficolin (ficolin-3), L-ficolin (ficolin-2) and collectin liver 1 (CL-L1)] were significantly higher in axSpA patients than in controls (P < 0·0001) and one LPP, collectin kidney 1 (CL-K1), was significantly lower (P < 0·0001). Further, combining H- or L-ficolin concentrations above the 75th percentile of the respective H- or L-ficolin concentration measured in controls with human leucocyte antigen (HLA)-B27 positivity yielded axSpA diagnostic specificities of 99/99% and positive likelihood ratios of 68/62, respectively. H-ficolin and L-ficolin plasma concentrations were found to be elevated in axSpA patients regardless of time since diagnosis. H-ficolin and L-ficolin may represent diagnostic biomarkers for patients with axSpA and should be further evaluated. Our results showed no association between disease activity and the measured LPP concentrations. This result might be due to the cross-sectional design, and should be further investigated.

Cumulative live birth rate prognosis based on the number of aspirated oocytes in previous ART cycles.

STUDY QUESTION: Is the number of aspirated oocytes in the first ART cycle associated with the cumulative live birthrates (CLBR) in subsequent cycles? SUMMARY ANSWER: The number of aspirated oocytes in the first cycle was associated with CLBR in subsequent cycles. Previous treatment response predicts outcome in future cycles. WHAT IS KNOWN ALREADY: Previous reports have shown a positive association between the number of retrieved oocytes and live birthrate per fresh treatment cycle. This has also been shown for the CLBR in one complete ART-cycle, including possible subsequent frozen-thawed transfers (FER). It has been shown that women with less than five oocytes in the first cycle have poorer outcome within six complete cycles than women with more than 12 oocytes, suggesting that the number of aspirated oocytes in the first cycle may be reproduced in later cycles. However, other studies have shown that an initial low treatment response may be improved with increased gonadotrophin start-dose. STUDY DESIGN, SIZE, DURATION: The Danish National IVF-registry includes all ART treatments in public and private clinics since 1994. Treatment-cycles were cross-linked with the Medical Birth Registry, identifying treatment-related births and natural conception births. This national cohort study includes all women starting ART treatments with homologous eggs between 2002 and 2011, N = 30 486. Subjects were followed for up to four fresh ART-cycles including subsequent FER-cycles (=four complete cycles), until the first livebirth, or until December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The CLBR within 1-4 complete ART-cycles were calculated as the proportion of women with a livebirth, out of all women initiating ART-treatment, including drop-outs (no livebirth or no continued treatment within follow-up). In women with one year follow-up from last treatment, multivariate logistic regression analysis assessed impact of retrieved oocytes on CLBR, adjusting results for female age and cause of infertility. Hospital admission due to ovarian hyperstimulation syndrome (OHSS) was reported. MAIN RESULTS AND THE ROLE OF CHANCE: After one, two and three complete ART-cycles, the CLBRs attributable to ART treatment were 26.4% [95%CI 25.9-26.9], 42.6% [42.0-43.1] and 51.3% [50.7-51.9], respectively. The CLBR attributable to non-ART related conception (natural conception or intrauterine insemination) were 5.3% [5.0-5.6], 8.3% [8.0-8.7] and 10.6% [10.3-11.0], after one, two and three complete cycles. In women without a live birth in the first complete cycle, the number of aspirated oocytes predicted the outcome in the second and third cycle: When compared to women with 0-3 aspirated oocytes in the first cycle, the odds for live birth in the second and third cycle was 1.18 [1.07-1.30] for women with 4-9 aspirated oocytes in the first cycle, 1.41 [1.27-1.57] for women with 10-15 aspirated oocytes and 1.63 [1.42-1.88] for women with more than 15 aspirated oocytes. For women without a livebirth in the first and second cycle, the sum of aspirated oocytes predicted outcome in the third complete cycle. Women with a sum larger than six aspirated oocytes, had marked increased odds ratios for livebirth in the third complete cycle, compared to women with a sum of 0-6 oocytes in the first and second fresh cycle. Incidence of hospital-admission due to OHSS was 1.7% in the first cycle, decreasing to 1.3% and 1.0% in the second and third cycles. LIMITATIONS, REASONS FOR CAUTION: Although mandatory, there may be treatment-cycles not registered in the IVF-registry. Missing information in number of aspirated oocytes are most likely random losses of information. There were few observations in women with more than 15 aspirated oocytes and these birthrates should be interpreted cautiously. Information on gonadotrophin dose used for stimulation was not available, nor was information on dose adjustments in subsequent cycles. WIDER IMPLICATIONS OF THE FINDINGS: With these results we can counsel couples returning for fertility treatments, providing an age-stratified revised prognosis for chances of live birth and risk of OHSS, reflecting prior failed attempts and previous ovarian response. STUDY FUNDING/COMPETING INTEREST(S): This study was unconditionally funded by Ferring Pharmaceuticals and ReproUnion. The funders had no role in the study design, data collection and interpretation, or decision to submit the work for publication. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (J.nr. 2012-41-1330).

Academic performance in adolescents aged 15-16 years born after frozen embryo transfer compared with fresh embryo transfer: a nationwide registry-based cohort study.

OBJECTIVE: To assess academic performance in singletons aged 15-16 years conceived after frozen embryo transfer (FET) compared with singletons born after fresh embryo transfer (ET) in Danish cohorts born from 1995 to 2001. DESIGN: Danish national registry-based cohort study. SETTING: Danish national registries. POPULATION: All 6495 singletons conceived after assisted reproductive technology (ART) treatment in Denmark from 1995 to 2001 [FET (n) = 423; fresh ET (n) = 6072]. METHODS: Mean test scores on a national standardised and international comparable grading-scale. Comparisons of test score were first made in univariate analysis (Model 1) and secondly in a multivariate linear model (Model 2) adjusting for relevant reproductive and socio-demographic covariates such as the occupational and educational level of the parents. Sensitivity analyses on FET-IVF (in vitro fertilisation) versus fresh ET-IVF and FET-ICSI (intracytoplasmic sperm injection) versus fresh ET-ICSI were made. Linear mixed models were used to account for the correlation in test scores of siblings for continuous outcome. MAIN OUTCOME MEASURES: Mean overall test score and test score in Danish, mathematics, English, and physics/chemistry. RESULTS: Crude and adjusted mean test scores were similar for adolescents conceived after FET compared with fresh ET. The crude mean difference was +0.11 (95% CI -0.11; 0.34), and the adjusted mean difference was +0.12 (95% CI -0.09; 0.34). CONCLUSIONS: Adolescents conceived after FET had similar academic performance at 15-16 of years of age compared with children conceived after fresh ET. TWEETABLE ABSTRACT: Using frozen embryos in fertility treatment does not affect school performance in Danish adolescents aged 15-16 years.

Structural progression rate decreases over time on serial radiography and magnetic resonance imaging of sacroiliac joints and spine in a five-year follow-up study of patients with ankylosing spondylitis treated with tumour necrosis factor inhibitor.

OBJECTIVE: To investigate temporal changes in structural progression assessed by serial conventional radiography and magnetic resonance imaging (MRI) of the sacroiliac joints (SIJs) and spine in patients with ankylosing spondylitis (AS) treated with tumour necrosis factor (TNF) inhibitor for 5 years. METHOD: Forty-two patients were included and 33 patients were followed for 5 years in a prospective investigator-initiated study. Conventional radiographs were required four times and MRI seven times. The modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS); Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ and Spine Inflammation, and SPARCC MRI SIJ Structural Score (SSS) for Fat, Erosion, Backfill, and Ankylosis; and the Canada-Denmark MRI scores for Spine Inflammation, Fat, Erosion, and New Bone Formation (NBF) were applied. RESULTS: Compared with baseline, MRI Inflammation had decreased significantly at week 22 (spine)/week 46 (SIJ) and thereafter. MRI SIJ Fat (from week 22), SIJ Ankylosis, Spine NBF, and mSASSS had increased significantly at week 46 and thereafter. SIJ Erosion had decreased from year 2. The annual progression rate in mSASSS was significantly higher during weeks 0-46 compared to week 46 to year 3. In multivariate regression analyses, baseline SIJ Inflammation and Backfill were independent predictors of 5 year progression in SIJ Ankylosis. Spine Erosion predicted progression in Spine NBF. Longitudinally, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, MRI Spine Inflammation, Fat, and Erosion scores were significantly associated with mSASSS. SIJ Inflammation, Fat, Erosion, and Backfill scores were longitudinally associated with SIJ Ankylosis. Structural progression was not associated with body mass index, smoking, or Assessment of SpondyloArthritis international Society Non-Steroidal Anti-Inflammatory Drug Index. CONCLUSION: In a 5 year follow-up study of patients with AS treated with TNF inhibitor, structural progression decreased over time.

The long-term prognosis for live birth in couples initiating fertility treatments.

STUDY QUESTION: What are the long-term chances of having a child for couples starting fertility treatments and how many conceive with ART, IUI and without treatment? SUMMARY ANSWER: Total 5-year live birthrates were strongly influenced by female age and ranged from 80% in women under 35-26% in women ≥40 years, overall, 14% of couples conceived naturally and one-third of couples starting treatments with intrauterine insemination delivered from that treatment. WHAT IS KNOWN ALREADY: Few studies report success rates in fertility treatments across a couple's complete fertility treatment history, across clinics, evaluating live births after insemination, ART and natural conceptions. STUDY DESIGN, SIZE, DURATION: This register-based national cohort study from Denmark includes all women initiating fertility treatments in public and private clinics with homologous gametes in 2007-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were identified in the Danish ART Registry and were cross-linked with the Medical Birth Registry to identify live births. Subfertile couples were followed 2 years (N = 19 884), 3 years (N = 14 445) and 5 years (N = 5165), or until their first live birth. Cumulative live birthrates were estimated 2, 3 and 5 years from the first treatment cycle, in all women, including drop-outs. Birthrates were stratified by type of first treatment (ART/IUI), mode of conception (ART/IUI/natural conception) and female age. MAIN RESULTS AND THE ROLE OF CHANCE: Within 5 years, in women aged <35 years (N = 3553), 35-39 years (N = 1156) and ≥40 years (N = 451), a total of 64%, 49% and 16% had a live birth due to treatment, respectively. Additionally, in women aged < 35 years, 35-39 years and ≥40 years, 16%, 11% and 10% delivered after natural conception, yielding total 5-year birthrates of 80%, 60% and 26%. In women starting treatments with IUI (N = 3028), 35% delivered after IUI within 5 years, 24% delivered after shift to ART treatments and 17% delivered after natural conception. Within 5 years from starting treatments with ART (N = 2137), 53% delivered after ART, 11% delivered after natural conception and 0.6% delivered after IUI. LIMITATIONS, REASONS FOR CAUTION: Birthrates are most likely higher compared to countries without national coverage of treatments and results are influenced by laws and regulations. Information on duration of infertility prior to treatment was not available. Future prospective intervention studies should focus on the role of expectant management. WIDER IMPLICATIONS OF THE FINDINGS: Our results can provide couples with a comprehensible age-stratified prognosis at start of treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was unconditionally funded by Ferring Pharmaceuticals and the Augustinus foundation. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: S.S.M. received an unconditional grant from Ferring Pharmaceuticals; A.A.H. has received personal fees from Ferring Pharmaceuticals not related to this work; A.N.A. reports grants and personal fees from Ferring Pharmaceuticals, personal fees from Merck Serono, grants and personal fees from MSD, outside the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (J.nr. 2012-41-1330).

Academic performance in adolescents born after ART-a nationwide registry-based cohort study.

STUDY QUESTION: Is academic performance in adolescents aged 15-16 years and conceived after ART, measured as test scores in ninth grade, comparable to that for spontaneously conceived (SC) adolescents? SUMMARY ANSWER: ART singletons had a significantly lower mean test score in the adjusted analysis when compared with SC singletons, yet the differences were small and probably not of clinical relevance. WHAT IS KNOWN ALREADY: Previous studies have shown similar intelligence quotient (IQ) levels in ART and SC children, but only a few have been on adolescents. Academic performance measured with standardized national tests has not previously been explored in a complete national cohort of adolescents conceived after ART. STUDY DESIGN, SIZE, DURATION: A Danish national registry-based cohort including all 4766 ART adolescents (n = 2836 singletons and n = 1930 twins) born in 1995-1998 were compared with two SC control cohorts: a randomly selected singleton population (n = 5660) and all twins (n = 7064) born from 1995 to 1998 in Denmark. Nine children who died during the follow-up period were excluded from the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mean test scores on a 7-point-marking scale from -3 to 12 were compared, and adjustments were made for relevant reproductive and socio-demographic covariates including occupational and educational level of the parents. MAIN RESULTS AND THE ROLE OF CHANCE: The crude mean test score was higher in both ART singletons and ART twins compared with SC adolescents. The crude mean differences were +0.41 (95% CI 0.30-0.53) and +0.45 (95% CI 0.28-0.62) between ART and SC singletons and between ART and SC twins, respectively. However, the adjusted mean overall test score was significantly lower for ART singletons compared with SC singletons (adjusted mean difference -0.15 (95% CI -0.29-(-0.02))). For comparison, the adjusted mean difference was +2.05 (95% CI 1.82-2.28) between the highest and the lowest parental educational level, suggesting that the effect of ART is weak compared with the conventional predictors. The adjusted analyses showed significantly lower mean test scores in mathematics and physics/chemistry for ART singletons compared with SC singletons. Comparing ART twins with SC twins yielded no difference in academic performance in the adjusted analyses. Similar crude and adjusted overall mean test scores were found when comparing ART singletons and ART twins. LIMITATIONS, REASONS FOR CAUTION: Missing data on educational test scores occurred in 6.6% of adolescents aged 15-16 years for the birth cohorts 1995-1997, where all of the children according to their age should have passed the ninth grade exam at the time of data retrieval. As sensitivity analyses yielded no significant difference in the adjusted risk of having missing test scores between any of the groups, it is unlikely that this should bias our results. Adjustment for body mass index and smoking during pregnancy was not possible. WIDER IMPLICATIONS OF THE FINDINGS: As our results are based on national data, our findings can be applied to other populations. The findings of this paper suggest that a possible small negative effect of parental subfertility or ART treatment is counterbalanced by the higher educational level in the ART parents. STUDY FUNDING/COMPETING INTERESTS: The Danish Medical Association in Copenhagen (KMS) funded this study with a scholarship grant. None of the authors had any competing interests. TRIAL REGISTRATION NO STATISTICS DENMARK: 704676.

Obstetric and neonatal complications in pregnancies conceived after oocyte donation: a systematic review and meta-analysis.

BACKGROUND: Approximately 50 000 oocyte donation (OD) treatment cycles are now performed annually in Europe and the US. OBJECTIVES: To ascertain whether the risk of adverse obstetric and perinatal/neonatal outcomes is higher in pregnancies conceived by OD than in pregnancies conceived by conventional in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) or spontaneously. SEARCH STRATEGY: A systematic search was performed in the PubMed, Cochrane and Embase databases from 1982-2016. Primary outcomes were hypertensive disorders of pregnancy, pre-eclampsia (PE), gestational diabetes mellitus, postpartum haemorrhage, caesarean section, preterm birth, low birthweight and small for gestational age. SELECTION CRITERIA: Inclusion criteria were original studies including at least five OD pregnancies with a control group of pregnancies conceived by conventional IVF/ICSI or spontaneous conception, and case series with >500 cases reporting one or more of the selected complications. Studies not adjusting for plurality were excluded. DATA COLLECTION AND ANALYSIS: Thirty-five studies met the inclusion criteria. A random-effects model was used for the meta-analyses. MAIN RESULTS: For OD pregnancies versus conventional IVF/ICSI pregnancies the risk of PE was adjusted odds ratio (AOR) 2.11 (95% CI, 1.42-3.15) in singleton and AOR 3.31 (95% CI, 1.61-6.80) in multiple pregnancies. The risks of preterm birth and low birthweight in singletons were AOR 1.75 (95% CI, 1.39-2.20) and 1.53 (95% CI, 1.16-2.01), respectively. CONCLUSIONS: OD conceptions are associated with adverse obstetric and neonatal outcomes. To avoid the additional increase in risk from multiplicity, single-embryo transfer should be the choice of option in OD cycles. TWEETABLE ABSTRACT: Oocyte donation pregnancies have increased risk of a range of obstetric and neonatal complications.