Parenthood among men diagnosed with cancer in childhood and early adulthood: trends over time in a Danish national cohort.

STUDY QUESTION: Is the rate of fatherhood among men diagnosed with cancer in childhood and early adulthood different from men without cancer, and, if so, have the differences changed over time? SUMMARY ANSWER: Men diagnosed with cancer have had significantly reduced rates of fatherhood compared with undiagnosed men; however, the rates of fatherhood among the cancer survivors have increased markedly over time. WHAT IS KNOWN ALREADY: The number of children and young adolescents who survive cancer has steadily increased over recent decades, with a current 5-year survival rate of approximately 80%. Consequently, life circumstances after cancer have gained increasing importance, including the desire among survivors to have children and a family. ARTs to aid reproduction among cancer survivors have been developed, and fertility preservation is increasingly a topic being discussed before undergoing cancer treatment. But the potential for fertility preservation differs dependent on age at diagnosis and type of cancer. Earlier studies have shown a decreased fertility rate among survivors of child and adolescent cancer compared to those diagnosed in early adulthood. STUDY DESIGN, SIZE, DURATION: This study is a national, register-based cohort study. Men diagnosed with cancer in childhood and early adulthood (<30 years of age) were registered in the Danish Cancer Register in 1978-2016 (n = 9353). According to the time of diagnosis, each cancer-diagnosed man was randomly matched with 150 undiagnosed men from the background population within the same birth year. The men were followed until having their first child, death, migration or the end of the study (31 December 2017) in medical registers and socio-demographic population registers. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fatherhood among the boys and young men diagnosed with cancer were compared with the age-matched comparison group in all statistical analyses. Cancer diagnoses were categorised as central nervous system (CNS) cancers, haematological cancers or solid cancers. Analyses were stratified by age at diagnosis (0-9, 10-19, 20-29 years) and time of diagnosis (1978-1989, 1990-1999, 2000-2009, 2010-2016). Death was incorporated as a competing risk in all analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The study population consisted of 9353 boys and young men diagnosed with cancer between 1978 and 2016 and 1 386 493 men in the age-matched comparison group. Those surviving CNS cancer as young men had the lowest hazard ratio (HR) of fatherhood compared with the age-matched comparison group (HR 0.67, 95% CI 0.57-0.79), followed by survivors of haematological cancers (HR 0.90, 95% CI 0.81-1.01), while the highest chance of fatherhood was among survivors of solid cancers (HR 1.16, 95% CI 1.12-1.20) with a slightly increased HR compared with undiagnosed males. The HR of becoming a father increased over time. From the first decade to the last decade 30 years later, the HR of becoming a father increased for solid tumours (HR 0.78, 95% CI 0.73-0.83 to HR 1.08, 95% CI 0.95-1.22), haematological cancers (HR 0.64, 95% CI 0.53-0.79 to HR 0.97, 95% CI 0.73-1.30) and CNS cancers (HR 0.44, 95% CI 0.34-0.57 to HR 0.98, 95% CI 0.49-1.95) compared to the age-matched comparison group. Also, when compared with the age-matched comparison group, men diagnosed with cancer when aged 20-29 years were more likely became fathers over the time of the study (HR 0.80, 95% CI 0.74-0.86 to HR 1.08, 95% CI 0.96-1.22). LIMITATIONS, REASONS FOR CAUTION: The study was based on register data, and information was not available about the men's fertility potential, whether they had a desire to have children and whether it was possible for them to find a partner. Information about fertility preservation, e.g. sperm freezing, could also have provided additional insights. Furthermore, information about diagnosis and ART treatment would have been beneficial. WIDER IMPLICATIONS OF THE FINDINGS: Information and education of male patients diagnosed with cancer about fertility preservation options and their chances to create their own family is crucial. Reassuringly, time trends showed more men with a previous cancer diagnosis becoming fathers in recent years than in earlier years, reflecting that survival and fertility preservation have improved over time. STUDY FUNDING/COMPETING INTEREST(S): R.S. received a PhD grant from the Rosa Ebba Hansen Foundation and from the Health Foundation (J.nr. 15-B-0095). The funding for the establishment of the DANAC II Cohort was obtained from the Rosa Ebba Hansen Foundation. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Assisted reproductive technology treatment and risk of breast cancer: a population-based cohort study.

STUDY QUESTION: Is there an increased risk of breast cancer among women after ART treatment including ovarian hormone stimulation? SUMMARY ANSWER: The risk of breast cancer was slightly increased among women after ART treatment compared to age-matched, untreated women in the background population, and the risk was further increased among women initiating ART treatment when aged 40+ years. WHAT IS KNOWN ALREADY: The majority of breast cancer cases are sensitive to oestrogen, and ovarian hormone stimulation has been suggested to increase the risk of breast cancer by influencing endogenous oestrogen levels. Previous studies on ART treatment and breast cancer have varied in their findings, but several studies have small sample sizes or lack follow-up time and/or confounder adjustment. Recent childbirth, nulliparity and higher socio-economic status are breast cancer risk factors and the latter two are also associated with initiating ART treatment. STUDY DESIGN, SIZE, DURATION: The Danish National ART-Couple II (DANAC II) cohort includes women treated with ART at public and private fertility clinics in 1994-2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with no cancer prior to ART treatment were included (n = 61 579). Women from the background population with similar age and no prior history of ART treatment were randomly selected as comparisons (n = 579 760). The baseline mean age was 33.1 years (range 18-46 years). Results are presented as hazard ratios (HRs) with corresponding CIs. MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up (median 9.69 years among ART-treated and 9.28 years among untreated), 5861 women were diagnosed with breast cancer, 695 among ART-treated and 5166 among untreated women (1.1% versus 0.9%, P < 0.0001). Using Cox regression analyses adjusted for nulliparity, educational level, partnership status, year, maternal breast cancer and age, the risk of breast cancer was slightly increased among women treated with ART (HR 1.14, 95% CI 1.12-1.16). All causes of infertility were slightly associated with breast cancer risk after ART treatment. The risk of breast cancer increased with higher age at ART treatment initiation and was highest among women initiating treatment at age 40+ years (HR 1.37, 95% CI 1.29-1.45). When comparing women with a first birth at age 40+ years with or without ART treatment, the increased risk among women treated with ART persisted (HR 1.51, 95% CI 1.09-2.08). LIMITATIONS, REASONS FOR CAUTION: Although this study is based on a large, national cohort of women, more research with sufficient power and confounder adjustment is needed, particularly in cohorts with a broad age representation. WIDER IMPLICATIONS OF THE FINDINGS: An increased risk of breast cancer associated with a higher age at ART treatment initiation has been shown. Ovarian stimulation may increase the risk of breast cancer among women initiating ART treatment when aged 40+ years. Age-related vulnerability to hormone exposure or higher hormone doses during ART treatment may explain the increased risk. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the DANAC II cohort was received from the Ebba Rosa Hansen Foundation. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Obstetric and perinatal risks in 4601 singletons and 884 twins conceived after fresh blastocyst transfers: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Are obstetric and perinatal outcomes in pregnancies after fresh blastocyst transfer (BT) comparable with those born after fresh cleavage stage transfer (CT) and spontaneous conception (SC)? SUMMARY ANSWER: Fresh BT is associated with a higher risk of placental and perinatal complications. WHAT IS KNOWN ALREADY: BT optimizes the selection of top-quality embryos and increases pregnancy and live birth rates per transfer compared to CT. However, concerns have been raised as extended culture duration may increase obstetric complications and impair perinatal outcomes. Previous studies have shown a higher risk of preterm birth (PTB) among infants born after BT compared with CT. Pregnancies after BT are also prone to a higher risk of same-sex twins after single embryo transfer (SET). STUDY DESIGN, SIZE, DURATION: A retrospective register-based cohort study used data from Denmark, Norway and Sweden including three cohorts: 56 557 singletons and 16 315 twins born after fresh IVF/ICSI cycles and 2 808 323 SC singletons in Denmark (birth years 1997-2014), Norway (2010-2015) and Sweden (2002-2015). Of the fresh IVF/ICSI singletons, 4601 were born after BT and 51 956 after CT. The twin cohort consisted of 884 fresh IVF/ICSI children born after BT and 15 431 fresh IVF/ICSI children born after CT. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from a large Nordic cohort of children born after ART and SC initiated by the Committee of Nordic ART and Safety (CoNARTaS). The CoNARTaS cohort was established by cross-linking National ART-, Medical Birth-, and National Patients Registers using the unique personal identification number, allocated to every citizen in the Nordic countries. Obstetric and perinatal outcomes after BT, CT and SC were compared using logistic regression analysis. For perinatal outcomes, we calculated gestational age based on the date of oocyte pick-up (OPU) and in sensitivity analyses on data from Denmark and Norway, we also calculated gestational age based on the second-trimester ultrasonography (US) scan. Risk of pregnancies with same-sex twins after SET was used as a proxy for risk of monozygotic twins. Adjustments were made for child's sex, birth year, parity (0 or >1), maternal age, body mass index, smoking, educational level, fertilization method (IVF/ICSI), the number of aspirated oocytes, SET and country. Information on educational level and the number of aspirated oocytes was not available for Norway. Children born after frozen embryo transfer were not included. The birth cohorts were restricted according to the year in which BT was introduced in the different countries. MAIN RESULTS AND THE ROLE OF CHANCE: A higher risk of placenta previa was found in singleton pregnancies after BT compared with CT (adjusted odds ratio [aOR] 2.11 [95% CI 1.76; 2.52]). Singletons born after BT had a higher risk of PTB (aOR 1.14 [95% CI 1.01; 1.29]) compared with CT singletons, when estimated based on OPU. Furthermore, an altered male/female ratio (aOR 1.13 [95% CI 1.06; 1.21]) with more males following BT compared with CT was seen. Risk of same-sex twins after SET was higher after single BT compared with single CT (aOR 1.94 [95% CI 1.42; 2.60]). LIMITATIONS, REASONS FOR CAUTION: Residual confounding cannot be excluded, in particular related to duration and cause of infertility that we could not adjust for due to lack of reliable data. WIDER IMPLICATIONS OF THE FINDINGS: Extended embryo culture to the blastocyst stage has the potential to compromise obstetric and perinatal outcomes in fresh cycles. These results are important since an increasing number of IVF/ICSI treatments are performed as BT. STUDY FUNDING/COMPETING INTEREST(S): NORDFORSK (project no: 71450). The Research Fund of Rigshospitalet, Copenhagen University Hospital. ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. Grants from Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation. The Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. None of the authors has any conflicts of interests to declare regarding this study. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Is the risk of imprinting disorders increased in children conceived after ART? SUMMARY ANSWER: We found an adjusted odds ratio (AOR) of 2.84 [95% CI: 1.34-6.01] for Beckwith-Wiedemann syndrome in ART children, while the risk of Prader-Willi syndrome, Silver-Russell syndrome or Angelman syndrome was not increased in children conceived after ART. WHAT IS KNOWN ALREADY: Earlier studies, most of them small, have suggested an association between ART and imprinting disorders. STUDY DESIGN, SIZE, DURATION: This was a binational register-based cohort study. All children conceived by ART in Denmark (n = 45 393, born between 1994 and 2014) and in Finland (n = 29 244, born between 1990 and 2014) were identified. The full background populations born during the same time periods in the two countries were included as controls. Odds ratios of imprinting disorders in ART children compared with naturally conceived (NC) children were calculated. The median follow-up time was 8 years and 9 months for ART children and 11 years and 9 months for NC children. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the national health registries in Denmark and Finland, we identified all children diagnosed with Prader-Willi syndrome (n = 143), Silver-Russell syndrome (n = 69), Beckwith-Wiedemann syndrome (n = 105) and Angelman syndrome (n = 72) born between 1994/1990 and 2014, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a total of 388 children diagnosed with imprinting disorders; 16 of these were conceived after ART. The overall AOR for the four imprinting disorders in ART children compared with NC children was 1.35 [95% CI: 0.80-2.29], but since eight ART children were diagnosed with Beckwith-Wiedemann syndrome, the AOR for this specific imprinting disorder was 2.84 [95% CI: 1.34-6.01]. The absolute risk of Beckwith-Wiedemann syndrome in children conceived after ART was still low: 10.7 out of 100 000 newborns. The risks of Prader-Willi syndrome, Silver-Russell syndrome and Angelman syndrome were not increased in children conceived after ART. LIMITATIONS, REASONS FOR CAUTION: Imprinting disorders are rare events and our results are based on few ART children with imprinting disorders. The aetiology is complex and only partly clarified, and the clinical diagnoses are challenged by a broad phenotypic spectrum. WIDER IMPLICATIONS OF THE FINDINGS: In the existing studies, results on the risk of imprinting disorders in children conceived after ART are ambiguous. This study adds that the risk of imprinting disorders in ART children is very small and perhaps restricted to Beckwith-Wiedemann syndrome. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (grant number: 71450), the Nordic Federation of Obstetrics and Gynecology (grant numbers: NF13041, NF15058, NF16026 and NF17043) and the Interreg Öresund-Kattegat-Skagerak European Regional Development Fund (ReproUnion project). The authors have no conflicts of interest related to this work. TRIAL REGISTRATION NUMBER: N/A.

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).

Assisted reproductive technology treatment and risk of ovarian cancer-a nationwide population-based cohort study.

STUDY QUESTION: Does hormone stimulation during assisted reproductive technology (ART) treatment increase the risk of ovarian cancer? SUMMARY ANSWER: No increased risk of ovarian cancer was found among ART-treated women, with the exception of ART-treated women with endometriosis. WHAT IS KNOWN ALREADY: Previous studies on the association between ovarian stimulation during ART and ovarian cancer have shown conflicting results. The risk of ovarian cancer varies according to the cause of infertility, and only a few studies on ART treatment and risk of ovarian cancer have had sufficient data to address this issue. Endometriosis has been linked to an increased risk of ovarian cancer. STUDY DESIGN, SIZE, DURATION: Women undergoing ART treatment during 1994-2015 were registered in the Danish IVF register. Data were linked with data from the Danish Cancer Register and socio-demographic population registers using an individual person identification number assigned to people residing in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women undergoing ART treatment were age-matched with a random sample of the female background population and followed for up to 22 years. After relevant exclusions, the population consisted of 58 472 ART-treated women and 625 330 untreated women, all with no previous malignancies. Ovarian cancer risk was assessed using multivariable cox regression analyses with adjustment for educational level, marital status, parity and treatment year. Results are shown as hazard ratios (HRs) with corresponding CIs. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 393 (0.06%) women were diagnosed with ovarian cancer during follow-up (mean 9.7 years). Women treated with ART had an increased risk of ovarian cancer (HR 1.20, 95% CI 1.10-1.31), which diminished over time. The increased risk was apparent among women with female factor infertility (HR 1.36, 95% CI 1.25-1.48), whereas no female factor infertility was associated with a lower risk (HR 0.87, 95% CI 0.76-1.00). The risk was increased among women with endometriosis (HR 3.78, 95% CI 2.45-5.84), whereas no increased risk was found among ART-treated women with polycystic ovary syndrome, other female causes of infertility and unexplained infertility. LIMITATIONS, REASONS FOR CAUTION: The association between ART treatment and ovarian cancer is likely influenced by increased detection due to multiple ultrasound scans during ART treatment. WIDER IMPLICATIONS OF THE FINDINGS: Undergoing ART treatment without the presence of endometriosis was not associated with an increased risk of ovarian cancer, which is reassuring. Whether ART treatment increases the risk of ovarian cancer among women with endometriosis needs further investigation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the Danish National ART-couple II cohort was achieved from Ebba Rosa Hansen Foundation. The funders had no influence on data collection, analyses or results presented. The authors have no conflicts of interest to declare.

Prostate artery embolisation for benign prostatic hyperplasia: a systematic review and meta-analysis.

OBJECTIVES: Prostate artery embolisation (PAE) is a new minimally invasive treatment for lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). The purpose of this study was to review the efficacy and safety of PAE in the treatment of BPH with LUTS. METHODS: A systematic review performed according to the PRISMA guidelines with a pre-specified search strategy for PubMed, Web of Science, Cochrane Library and Embase databases protocol (PROSPERO ID: CRD42017059196). Trials studying the efficacy of prostate artery embolisation to treat LUTS with more than ten participants and follow-up longer than 6 months were included by two independent authors. Outcomes investigated were International Prostate Symptom Score (IPSS), quality of life (QoL), International Index of Erectile Function (IIEF-5), prostate volume (PV), prostate-specific antigen (PSA), peak void flow (Qmax), post-void residual (PVR) and complications. To summarise mean change from baseline, a meta-analysis was done using the random-effects model. RESULTS: The search returned 210 references, of which 13 studies met the inclusion criteria, representing 1,254 patients. Patients in the included studies with data available for meta-analysis had moderate to severe LUTS and a mean IPSS of 23.5. Statistically significant (p value < 0.05) improvements of all investigated outcomes were seen at 12-month follow-up. Major complications were reported in 0.3% of the cases. CONCLUSIONS: Our findings suggest that PAE can reduce moderate to severe LUTS in men with BPH with a low risk of complications. KEY POINTS: • Prostate artery embolisation (PAE) improved International Prostate Symptom Score (IPSS) by 67%. • Major complications after PAE are very rare. • Use of cone-beam CT may reduce risk of non-target embolisation.

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.

Suction blister lesions and epithelialization monitored by optical coherence tomography.

BACKGROUND/PURPOSE: Our objective was to assess epithelialization of suction blister lesions by optical coherence tomography (OCT) and benchmark it to histology using epidermal thickness (ET) as the primary outcome. METHODS: Thirty-two healthy volunteers were recruited to Study 1 and 2. One 10-mm suction blister was raised on each buttock, and the blister roof was excised. Lesions were covered with moisture-retaining dressing. In Study 1, the lesions were OCT-scanned on day 0 (D0), D2 and D4 and excised for histological examination. In Study 2, the progress of epithelialization and skin barrier function were monitored to D14. RESULTS: ET increased from D0 to D2 by 46 µm (P<.001) and from D2 to D4 by 19 µm (P=.004). Compared with histology, OCT overestimated the presence of the epithelium (P<.0001) and ET on D4. Reliable measurements were obtained when the ET of the lesions reached the ET of the normal epidermis from D5-D7 and onwards. The ET development was reflected in decreased transepidermal water loss. CONCLUSION: We found that the OCT technique was poorly discriminative with respect to the neoepithelium and the moist lesion surface material in the early postinjury period. In the later stages, OCT seemed valuable for estimating the advancement of epithelialization.

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.

Microbubble detection and ultrasound-guided vacuum-assisted biopsy of axillary lymph nodes in patients with breast cancer.

AIMS: To assess the feasibility of undertaking microbubble-guided vacuum-assisted biopsy (VAB) of the sentinel lymph node (SLN) and determine its sensitivity in detecting metastases. Patient experience and the impact of VAB on subsequent axillary surgery were also evaluated. MATERIALS AND METHODS: Patients with a normal axillary ultrasound or benign core biopsy planned for surgical SLN biopsy were recruited. Part 1 of the study was used to establish the technique of ultrasound microbubble contrast to detect the SLN. In Part 2 microbubble detection of the SLN was followed by 13 G VAB. All patients subsequently had surgical histological correlation. RESULTS: One hundred and thirty-nine patients were recruited: 36 to Part 1 and 103 to Part 2. Of the 100 patients in Part 2 included for analysis, 82 (82%) underwent successful biopsy. Sensitivity for detecting metastases was 58.8% (95% confidence interval: 32.9%, 81.6%). The procedure was generally well tolerated; however, VAB interfered adversely with subsequent surgical SLN biopsy with surgeons reporting moderate or severe interference in 48% of patients and an additional 8.3% with complete failure of SLNB. CONCLUSION: It is possible to perform VAB of microbubble-detected SLNs. Although the sensitivity for detecting metastases was reasonable, the adverse effect on subsequent surgery was significant.

Infertile women below the age of 40 have similar anti-Müllerian hormone levels and antral follicle count compared with women of the same age with no history of infertility.

STUDY QUESTION: Do infertile patients below the age of 40 years have a lower ovarian reserve, estimated by anti-Müllerian hormone (AMH) and total antral follicle count (AFC), than women of the same age with no history of infertility? SUMMARY ANSWER: Serum AMH and AFC were not lower in infertile patients aged 20-39 years compared with a control group of the same age with no history of infertility. WHAT IS KNOWN ALREADY?: The management of patients with a low ovarian reserve and a poor response to controlled ovarian stimulation (COS) remains a challenge in assisted reproductive technologies (ART). Both AMH levels and AFC reflect the ovarian reserve and are valuable predictors of the ovarian response to exogenous gonadotrophins. However, there is a large inter-individual variation in the age-related depletion of the ovarian reserve and a broad variability in the levels of AMH and AFC compatible with conception. Women with an early depletion of the ovarian reserve may experience infertility as a consequence of postponement of childbearing. Thus, low ovarian reserve is considered to be overrepresented among infertile patients. STUDY DESIGN, SIZE, DURATION: A prospective cohort study including 382 women with a male partner referred to fertility treatment at Rigshospitalet, Copenhagen, Denmark during 2011-2013 compared with a control group of 350 non-users of hormonal contraception with no history of infertility recruited during 2008-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included patients and controls were aged 20-39 years. Women with polycystic ovary syndrome were excluded. On Cycle Days 2-5, AFC and ovarian volume were measured by transvaginal sonography, and serum levels of AMH, FSH and LH were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Infertile patients had similar AMH levels (11%, 95% confidence interval (CI): -1;24%) and AFC (1%, 95% CI: -7;8%) compared with controls with no history of infertility in an age-adjusted linear regression analysis. The prevalence of very low AMH levels (<5 pmol/l) was similar in the two cohorts (age-adjusted odds ratio: 0.9, 95% CI: 0.5;1.7). The findings persisted after adjustment for smoking status, body mass index, gestational age at birth, previous conception and chronic disease in addition to age. LIMITATIONS, REASON FOR CAUTION: The comparison of ovarian reserve parameters in women recruited at different time intervals could be a reason for caution. However, all women were examined at the same centre using the same sonographic algorithm and AMH immunoassay. WIDER IMPLICATIONS OF THE FINDINGS: This study indicates that the frequent observation of patients with a poor response to COS in ART may not be due to an overrepresentation of women with an early depletion of the ovarian reserve but rather a result of the expected age-related decline in fertility. STUDY FUNDING/COMPETING INTERESTS: The study received funding from MSD and the Interregional European Union (EU) projects 'ReproSund' and 'ReproHigh'. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Post-traumatic stress disorder symptoms and risk of hypertension over 22 years in a large cohort of younger and middle-aged women.

BACKGROUND: Post-traumatic stress disorder (PTSD) has been linked to hypertension, but most research on PTSD and hypertension is cross-sectional, and potential mediators have not been clearly identified. Moreover, PTSD is twice as common in women as in men, but understanding of the PTSD-hypertension relationship in women is limited. We examined trauma exposure and PTSD symptoms in relation to incident hypertension over 22 years in 47 514 civilian women in the Nurses' Health Study II. METHOD: We used proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for new-onset hypertension (N = 15 837). RESULTS: PTSD symptoms assessed with a screen were modestly associated with incident hypertension in a dose-response fashion after adjusting for potential confounders. Compared to women with no trauma exposure, women with 6-7 PTSD symptoms had the highest risk of developing hypertension (HR 1.20, 95% CI 1.12-1.30), followed by women with 4-5 symptoms (HR 1.17, 95% CI 1.10-1.25), women with 1-3 symptoms (HR 1.12, 95% CI 1.06-1.18), and trauma-exposed women with no symptoms (HR 1.04, 95% CI 1.00-1.09). Findings were maintained, although attenuated, adjusting for hypertension-relevant medications, medical risk factors, and health behaviors. Higher body mass index and antidepressant use accounted for 30% and 21% of the PTSD symptom-hypertension association, respectively. CONCLUSIONS: Screening for hypertension and reducing unhealthy lifestyle factors, particularly obesity, in women with PTSD may hold promise for offsetting cardiovascular risk.

Plasma uric acid concentrations and risk of ischaemic stroke in women.

BACKGROUND AND PURPOSE: Elevated plasma uric acid has been inconsistently associated with an increased risk of total stroke; however, data are sparse amongst women. The association between plasma uric acid concentrations and ischaemic stroke amongst women was examined and the effect modification by key cardiovascular risk factors was evaluated. METHODS: A nested case-control design with matching by age, race/ethnicity, smoking status, menopausal status, postmenopausal hormone therapy use, date of blood draw and fasting status was utilized amongst female participants of the Nurses' Health Study who provided blood samples between 1989 and 1990. Plasma uric acid was measured on stored blood samples. The National Survey of Stroke criteria were utilized to confirm 460 incident cases of ischaemic stroke by medical records from 1990 to 2006. Multivariable conditional logistic regression models were estimated. RESULTS: In matched analysis, risk of ischaemic stroke increased by 15% for each 1 mg/dl increase in plasma uric acid [95% confidence interval (CI) 3%-28%], but was no longer significant after adjustment for cardiovascular risk factors, particularly history of hypertension. The highest quartile of uric acid was significantly associated with greater risk of ischaemic stroke (relative risk 1.56; 95% CI 1.06-2.29, extreme quartiles) in matched analysis, but estimates were no longer significant after adjustment for cardiovascular risk factors (relative risk 1.43; 95% CI 0.93-2.18). Significant effect modification by key cardiovascular risk factors was not observed. CONCLUSIONS: Plasma uric acid levels were not independently associated with increased risk of ischaemic stroke in this cohort of women. Whilst plasma uric acid was associated with stroke risk factors, it was not independently associated with stroke risk.

Diets of deepwater oreos (Oreosomatidae) and orange roughy Hoplostethus atlanticus.

The diets of black oreo Allocyttus niger, smooth oreo Pseudocyttus maculatus, spiky oreo Neocyttus rhomboidalis and orange roughy Hoplostethus atlanticus were determined from examination of contents of 240, 311, 76 and 415 non-empty stomachs, from fishes sampled by bottom trawl on Chatham Rise to the east of South Island, New Zealand. Hoplostethus atlanticus had an opportunistic predatory strategy with a broad diet dominated by prawns and mesopelagic teleosts, but with substantial components of mysids and cephalopods. Pseudocyttus maculatus was strongly specialized on gelatinous zooplankton (jellyfish and salps). Allocyttus niger consumed mainly salps and hyperiid amphipods, and to a lesser extent fishes, prawns, mysids and copepods. Neocyttus rhomboidalis primarily consumed salps, along with mysids, euphausiids and fishes. Only P. maculatus did not exhibit significant ontogenetic variation in diet. The diets were also influenced by year and bottom depth. Differences in the distributions and diets of the four species probably reduce conflicts in resource use.

Ovarian reserve assessment in users of oral contraception seeking fertility advice on their reproductive lifespan.

STUDY QUESTION: To what extent does oral contraception (OC) impair ovarian reserve parameters in women who seek fertility assessment and counselling to get advice on whether their remaining reproductive lifespan is reduced? SUMMARY ANSWER: Ovarian reserve parameters defined by anti-Müllerian hormone (AMH), antral follicle count (AFC) and ovarian volume were found to be significantly decreased by 19% (95% CI 9.1-29.3%), 18% (95% CI 11.2-24.8%) and 50% (95% CI 45.1-53.7%) among OC users compared with non-users. WHAT IS KNOWN ALREADY: AMH and AFC have proved to be reliable predictors of ovarian ageing. In women, AMH declines with age and data suggest a relationship with remaining reproductive lifespan and age at menopause. OC may alter parameters related to ovarian reserve assessment but the extent of the reduction is uncertain. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of 887 women aged 19-46 attending the Fertility Assessment and Counselling Clinic (FACC) from 2011 to 2014 comparing ovarian reserve parameters in OC users with non-OC users. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FAC Clinic was initiated to provide individual fertility assessment and counselling. All women were examined on a random cycle day by a fertility specialist. Consultation included; transvaginal ultrasound (AFC, ovarian volume, pathology), a full reproductive history and AMH measurement. Women were grouped into non-users and users of OC (all combinations of estrogen-progestin products and the contraceptive vaginal ring). Non-users included women with an intrauterine device (IUD) or no hormonal contraception. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 887 women, 244 (27.5%) used OC. In a linear regression analyses adjusted for age, ovarian volume was 50% lower (95% CI 45.1-53.7%), AMH was 19% lower (95% CI 9.1-29.3%), and AFC was 18% lower (95% CI 11.2-24.8%) in OC users compared with non-users. Comparison of AMH at values of <10 pmol/l OC was found to have a significant negative influence on AMH (OR 1.6, 95% CI 1.1; 2.4, P = 0.03). Furthermore, we found a significant decrease in antral follicles sized 5-7 mm (P < 0.001) and antral follicles sized 8-10 mm (P < 0.001) but an increase in antral follicles sized 2-4 mm (P = 0.008) among OC users. The two groups (OC users versus non-users) were comparable regarding age, BMI, smoking and maternal age at menopause. LIMITATIONS, REASON FOR CAUTION: The study population comprised women attending the FAC Clinic. Recruitment was based on self-referral, which could imply a potential selection bias. Ovarian reserve was examined at a random cycle day. However, both AMH and AFC can be assessed independently of the menstrual cycle. The accuracy in predicting residual reproductive lifespan is still needed in both users and non-users of OC. WIDER IMPLICATIONS OF THE FINDINGS: OC has a major impact on the ovarian volume, and a moderate impact on AFC and AMH with a shift towards the smaller sized antral follicle subclasses. The most evident reduction occurs in the antral follicles of 5-7 and 8-10 mm with the highest number of AMH secreting granulosa cells. It is essential to be aware of the impact of OC use on ovarian reserve parameters when guiding OC users on their fertility status and reproductive lifespan. STUDY FUNDING/COMPETING INTERESTS: The FAC Clinic was established in 2011 as part of the ReproHigh collaboration. This study received funding through the Capital Region Research Fund and by EU-regional funding. There are no competing interests. TRIAL REGISTRATION NUMBER: The biobank connected to FAC Clinic is approved by the Scientific Ethical Committee (H-1-2011-081).

Trends in perinatal health after assisted reproduction: a Nordic study from the CoNARTaS group.

STUDY QUESTIONS: Has the perinatal outcome of children conceived after assisted reproductive technology (ART) improved over time? SUMMARY ANSWER: The perinatal outcomes in children born after ART have improved over the last 20 years, mainly due to the reduction of multiple births. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: A Swedish study has shown a reduction in unwanted outcomes over time in children conceived after ART. Our analyses based on data from more than 92 000 ART children born in four Nordic countries confirm these findings. STUDY DESIGN: Nordic population-based matched cohort study with ART outcome and health data from Denmark, Finland, Norway and Sweden. PARTICIPANTS, SETTING AND METHODS: We analysed the perinatal outcome of 62 379 ART singletons and 29 758 ART twins, born from 1988 to 2007 in four Nordic countries. The ART singletons were compared with a control group of 362 215 spontaneously conceived singletons. Twins conceived after ART were compared with all spontaneously conceived twins (n = 122 763) born in the Nordic countries during the study period. The rates of several adverse perinatal outcomes were stratified into the time periods: 1988-1992; 1993-1997; 1998-2002 and 2003-2007 and presented according to multiplicity. MAIN RESULTS AND ROLE OF CHANCE: For singletons conceived after ART, a remarkable decline in the risk of being born preterm and very preterm was observed. The proportion of ART singletons born with a low and very low birthweight also decreased. Finally, the stillbirth and infant death rates have declined among both ART singletons and twins. Throughout the 20 year period, fewer ART twins were stillborn or died during the first year of life compared with spontaneously conceived twins, presumably due to the lower proportion of monozygotic twins among the ART twins. LIMITATIONS, REASONS FOR CAUTION: We were not able to adjust for some potential confounders such as BMI, smoking, length or cause of infertility. The Nordic ART populations have changed over time, and in recent years, both less as well as severely reproductive ill couples are being treated. This may have affected the observed trends. WIDER IMPLICATIONS OF THE FINDINGS: It is assuring that data from four countries confirm an overall improvement over time in the perinatal outcomes of children conceived after ART. Furthermore, data show the beneficial effect of single embryo transfer, not only in regard to lowering the rate of multiples but also concerning the health of singletons. STUDY FUNDING/COMPETING INTERESTS: The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen and the Danish Agency for Science, Technology and Innovation has supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Federation of Obstetrics and Gynecology (NFOG). None of the authors has any competing interests to declare.