Publications by authors named "Nina la Cour Freiesleben"

25 Publications

  • Page 1 of 1

[Presence of SARS-CoV-2 in semen and the impact of COVID-19 onthe male reproductive system].

Ugeskr Laeger 2021 12;183(51)

This article reviews the current studies published on the transmission of SARS-CoV-2 in semen and the potential effect of COVID-19 on male fertility. The aim was to provide insight into different possible mechanisms of involvement of the male reproductive system by SARS-CoV-2 infection and to evaluate the studies investigating the presence of virus in semen. It is concluded that the likelihood of SARS-CoV-2 transmission through semen is low and that COVID-19 may negatively affect semen parameters, but that the impairment is probably short-termed.
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December 2021

[Intrauterine inseminationwith or without ovarian stimulationis often a first-choice treatment for infertility].

Ugeskr Laeger 2021 11;183(48)

In Denmark, intrauterine insemination (IUI) with or without ovarian stimulation is a common treatment for infertility. If strict cancellation criteria are met to reduce the risk of multiple pregnancies in ovarian stimulation cycles, IUI can be considered safe, less invasive and less costly compared to in vitro fertilisation. In 2019, a total of 9,322 homologous IUIs and 8,433 IUIs using donor sperm were performed in Denmark, and 2,000 children were expected to be born after the use of IUI. Thus, in this review we conclude that IUI is an effective treatment for infertility in selected patients.
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November 2021

Immediate versus postponed single blastocyst transfer in modified natural cycle frozen embryo transfer (mNC-FET): a study protocol for a multicentre randomised controlled trial.

BMJ Open 2021 10 27;11(10):e053234. Epub 2021 Oct 27.

Fertility Department 4071, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Introduction: Today, it is widespread practice to postpone frozen embryo transfer (FET) in a modified natural cycle (mNC) for at least one menstrual cycle after oocyte retrieval and failed fresh embryo transfer or freeze-all. The rationale behind this practice is the concern that suboptimal ovarian, endometrial or endocrinological conditions following ovarian stimulation may have a negative impact on endometrial receptivity and implantation. However, two recent systematic reviews and meta-analyses based on retrospective data did not support this practice. As unnecessary delay in time to transfer and pregnancy should be avoided, the aim of this study is to investigate if immediate single blastocyst transfer in mNC-FET is non-inferior to standard postponed single blastocyst transfer in mNC-FET in terms of live birth rate.

Methods And Analysis: Multicentre randomised controlled non-blinded trial including 464 normo-ovulatory women aged 18-40 years undergoing single blastocyst mNC-FET after a failed fresh or freeze-all cycle. Participants are randomised 1:1 to either FET in the first menstrual cycle following the stimulated cycle (immediate FET) or FET in the second or subsequent cycle following the stimulated cycle (postponed FET). The study is designed as a non-inferiority trial and primary analyses will be performed as intention to treat and per protocol.

Ethics And Dissemination: Ethical approval has been granted by the Scientific Ethical Committee of the Capital Region of Denmark (J-nr.: H-19086300). Data will be handled according to Danish law on personal data protection in accordance with the general data protection regulation. Participants will complete written consent forms regarding participation in the study and storage of blood samples in a biobank for future research. The study will be monitored by a Good Clinical Practice (GCP)-trained study nurse not otherwise involved in the study. The results of this study will be disseminated by publication in international peer-reviewed scientific journals.

Trial Registration Number: NCT04748874; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2021-053234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552140PMC
October 2021

Mental health indicators in pregnant women compared with women in the general population during the coronavirus disease 2019 pandemic in Denmark.

Acta Obstet Gynecol Scand 2021 Nov 21;100(11):2009-2018. Epub 2021 Sep 21.

Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic and the associated regulations issued to minimize risk of disease transmission seem to have had an impact on general mental health in most populations, but it may have affected pregnant women even more because of pregnancy-related uncertainties, limited access to healthcare resources, and lack of social support. We aimed to compare the mental health response among pregnant women with that in similarly aged women from the general population during the first wave of the COVID-19 pandemic.

Material And Methods: From April 14 to July 3, 2020, 647 pregnant women in their second trimester were enrolled in this study. For comparison, 858 women from the general Danish population (20-46 years) were sampled from an ongoing observational study. Participants responded to a questionnaire including six mental health indicators (concern level, perceived social isolation, quality of life, anxiety, mental health, and loneliness). Loneliness was measured using the UCLA Three-item Loneliness Scale and anxiety by the Common Mental Health Disorder Questionnaire 4-item Anxiety Subscale.

Results: The pregnant women had better scores during the entire study period for all mental health indicators, and except for concerns, social isolation, and mental health, the differences were also statistically significant. Pregnant women were more concerned about becoming seriously ill (40.2% vs. 29.5%, p < 0.001), whereas the general population was more concerned about economic consequences and prospects. Many pregnant women reported negative feelings associated with being pregnant during the COVID-19 pandemic and concerns regarding social isolation and regulation-imposed partner absence during hospital appointments and childbirth. All mental health indicators improved as Denmark began to reopen after the first wave of the pandemic.

Conclusions: Pregnant women exhibited lower rates of poor mental health compared with the general population. However, they were more concerned about becoming seriously ill, expressed negative feelings about being pregnant during the pandemic, and were worried about the absence of their partner due to imposed regulations. These finding may be taken into account by policy-makers during pandemics to balance specific preventive measures over the potential mental health deterioration of pregnant women.
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http://dx.doi.org/10.1111/aogs.14258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653239PMC
November 2021

Timely care for extrauterine pregnancies during the COVID-19 pandemic is needed.

Lancet Reg Health Eur 2021 Mar 20;2:100037. Epub 2021 Jan 20.

Department of Obstetrics and Gynaecology, The Fertility Clinic, Copenhagen University Hospital Hvidovre, DK-2650 Hvidovre, Denmark.

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http://dx.doi.org/10.1016/j.lanepe.2021.100037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816945PMC
March 2021

In vitro fertilisation (IVF) versus intracytoplasmic sperm injection (ICSI) in patients without severe male factor infertility: study protocol for the randomised, controlled, multicentre trial INVICSI.

BMJ Open 2021 06 24;11(6):e051058. Epub 2021 Jun 24.

Department of Obstetrics and Gynaecology, The Fertility Clinic, Copenhagen University Hospital Hvidovre, Hvidovre Hospital, Hvidovre, Denmark.

Introduction: Over the last decades, the use of intracytoplasmic sperm injection (ICSI) has increased, even among patients without male factor infertility. The increase has happened even though there is no evidence to support that ICSI results in higher live birth rates compared with conventional in vitro fertilisation (IVF) in cases with nonmale factor infertility. The lack of robust evidence on an advantage of using ICSI over conventional IVF in these patients is problematic since ICSI is more invasive, complex and requires additional resources, time and effort. Therefore, the primary objective of the IVF versus ICSI (INVICSI) study is to determine whether ICSI is superior to standard IVF in patients without severe male factor infertility. The primary outcome measure is first live birth from fresh and frozen-thawed transfers after one stimulated cycle. Secondary outcomes include fertilisation rate, ongoing pregnancy rate, birth weight and congenital anomalies.

Methods And Analysis: This is a two-armed, multicentre, randomised, controlled trial. In total, 824 couples/women with infertility without severe male factor will be recruited and allocated randomly into two groups (IVF or ICSI) in a 1:1 ratio. Participants will be randomised in variable block sizes and stratified by trial site and age. The main inclusion criteria are (1) no prior IVF/ICSI treatment, (2) male partner sperm with an expected count of minimum 2 million progressive motile spermatozoa following density gradient purification on the day of oocyte pick up and (3) age of the woman between 18 and 42 years.

Ethics And Dissemination: The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committee of the Capital Region of Denmark. Study findings will be presented, irrespectively of results at international conferences and submitted for publication in peer-reviewed journals.

Trial Registration Number: NCT04128904. Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2021-051058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231059PMC
June 2021

RUBIC (ReproUnion Biobank and Infertility Cohort): A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity.

Andrology 2021 11 18;9(6):1828-1842. Epub 2021 Jun 18.

Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Infertility affects 15%-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth.

Objectives: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up?

Material And Methods: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem.
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http://dx.doi.org/10.1111/andr.13063DOI Listing
November 2021

A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities.

Hum Reprod Update 2021 08;27(5):801-847

Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: In the decade following the introduction of ICSI, a higher prevalence of de novo chromosome abnormalities, in particular sex chromosome and autosomal structural abnormalities, as well as inherited abnormalities was described in children conceived by ICSI compared to both naturally conceived (NC) children and children conceived by standard IVF. The explanation for the observed increase in prevalence is not clear and has been suggested to reflect parental factors (e.g. age or sperm quality) or to be a result of the ICSI procedure itself. Over the years, the procedure, as well as the patient group, and indications for ICSI treatment have changed.

Objective And Rationale: The objective of this systematic review and meta-analysis was to assess the prevalence of chromosome abnormalities in ICSI pregnancies and children and to examine any potentially increased risk compared to standard IVF and NC.

Search Methods: Pubmed, Embase, Cochrane Libraries and Web of Science up to October 2020 were searched. Primary outcome measures were overall chromosome abnormalities and de novo abnormalities (including sex chromosome abnormalities and autosomal abnormalities). The secondary outcome was inherited abnormalities. We followed the PRISMA guidelines and relevant meta-analyses were performed.

Outcomes: The search included 4648 articles, out of which 27 met the inclusion criteria, and 19 were included in quantitative synthesis (meta-analyses). The prevalence of chromosome abnormalities varied considerably between studies, possibly explained by large differences in sample size and patient demographics. Only five studies were eligible for pooled analyses on adjusted data. All studies had a critical risk of bias. Results from pooled adjusted data showed no evidence of an increased risk of overall chromosome abnormalities when comparing ICSI to either standard IVF (aOR 0.75 (95% CI 0.41-1.38)) or NC (aOR 1.29 (95% CI 0.69-2.43)). In contrast, meta-analyses on unadjusted data showed an increased risk of overall chromosome abnormalities in ICSI compared to both standard IVF (OR 1.42 (95% CI 1.09-1.85)) and NC (OR 2.46 (95% CI 1.52-3.99)) and an increased risk of de novo abnormalities in ICSI compared to NC (OR 2.62 (95% CI 2.07-3.31)). Yet, based on a very low certainty of evidence, the conclusion remains, that no indication of an increased risk of chromosome abnormalities in ICSI offspring could be found. If an increased risk of chromosome abnormalities in selected ICSI offspring should exist, the absolute risk continues to be small.

Wider Implications: This review provides an extensive overview of the existing evidence on the relationship between ICSI and chromosome abnormalities in the offspring. We highlight the need for well-designed large, prospective, controlled studies with systematic cytogenetic testing. Existing data are limited and, in many cases, marred by critical levels of bias.
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http://dx.doi.org/10.1093/humupd/dmab005DOI Listing
August 2021

Embryo Morphokinetics and Blastocyst Development After GnRH Agonist versus hCG Triggering in Normo-ovulatory Women: a Secondary Analysis of a Multicenter Randomized Controlled Trial.

Reprod Sci 2021 10 13;28(10):2972-2981. Epub 2021 Apr 13.

The Fertility Clinic, Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, DK-2650, Hvidovre, Denmark.

Gonadotropin-releasing hormone agonist (GnRHa) for final oocyte maturation, along with vitrification of all usable embryos followed by transfer in a subsequent frozen-thawed cycle, is the most effective strategy to avoid ovarian hyperstimulation syndrome (OHSS). However, less is known about the ovulation induction triggers effect on early embryo development and blastocyst formation. This study is a secondary analysis of a multicenter, randomized controlled trial, with the aim to compare embryo development in normo-ovulatory women, randomized to GnRHa or human chorionic gonadotropin (hCG) trigger. In all, 4056 retrieved oocytes were observed, 1998 from the GnRHa group (216 women) and 2058 from the hCG group (218 women). A number of retrieved oocytes, mature and fertilized oocytes, and high-quality embryos and blastocysts were similar between the groups. A sub-analysis in 250 women enrolled at the main trial site including 2073 oocytes was conducted to compare embryo morphokinetics and cleavage patterns with EmbryoScope time-lapse system. In total, 1013 oocytes were retrieved from the GnRHa group (124 women) and 1060 oocytes were retrieved from the hCG group (126 women). Morphokinetic parameters and cleavage patterns were comparable between the groups. However, embryos derived from the GnRHa group were less likely to perform rolling during their development than the embryos from the hCG trigger group (OR = 0.41 (95%CI 0.25; 0.67), p-value 0.0003). The comparable results on embryo development and utilization rates between the GnRHa and hCG triggers is of clinical relevance to professionals and infertile patients, when GnRHa trigger and freeze-all is performed to avoid OHSS development. ClinicalTrials.gov Identifier: NCT02746562.
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http://dx.doi.org/10.1007/s43032-021-00564-9DOI Listing
October 2021

A qualitative study on couples' attitudes and concerns regarding a freeze all strategy in ART treatment.

Hum Fertil (Camb) 2021 Mar 5:1-14. Epub 2021 Mar 5.

The Fertility Clinic, Section 4071, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

The freeze all strategy has become a promising alternative to fresh embryo transfer in fertility treatment almost eliminating late ovarian hyperstimulation syndrome (OHSS) in the segmented cycle. There is a lack of in-depth knowledge regarding patients' attitudes towards the freeze all strategy. The aim of this study was to explore the attitudes towards a freeze all strategy compared with fresh embryo transfer in assisted reproductive technology (ART) treatment among couples in a public health care setting. We conducted semi-structured qualitative interviews with ten couples already participants in a randomised controlled trial (RCT) and undergoing ART treatment. The couple's responses showed five themes: (i) Starting treatment provides needed relief; (ii) Treatment must be provided with humanity; (iii) Provision of information instigates positive attitudes towards treatment; (iv) Fresh treatment - 'The normal way'; and (v) Freeze all treatment - 'The new black'. When thorough information about treatment procedures and safety aspects regarding both the freeze all and fresh embryo transfer strategy is given prior to initiation of treatment, couples feel secure and content, regardless of which treatment strategy is finally applied. This qualitative study found that starting treatment could prompt longed-for relief, as professionals would now 'take over' and assist in meeting the couple's family building goals.
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http://dx.doi.org/10.1080/14647273.2021.1893838DOI Listing
March 2021

Identification of a unique epigenetic profile in women with diminished ovarian reserve.

Fertil Steril 2021 03 4;115(3):732-741. Epub 2020 Dec 4.

Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark.

Objective: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve.

Design: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment.

Setting: Private and university-based facilities for clinical services and research.

Patient(s): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC.

Intervention(s): None.

Main Outcome Measure(s): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations.

Result(s): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485).

Conclusion(s): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.009DOI Listing
March 2021

Treatment with the anti-IgE monoclonal antibody omalizumab in women with asthma undergoing fertility treatment: a proof-of-concept study-The PRO-ART study protocol.

BMJ Open 2020 11 12;10(11):e037041. Epub 2020 Nov 12.

Centre for Physical Activity Research, Rigshospitalet, Kobenhavn, Denmark.

Introduction: Asthma is associated with prolonged time to pregnancy and a higher need for fertility treatment. However, the mechanism underlying this association remains incompletely understood. Previous research points to asthma-driven systemic inflammation also affecting the reproductive organs and thereby fertility. The aim of this study was to determine if treatment with omalizumab prior to fertility treatment will increase pregnancy rate among women with asthma by decreasing the systemic asthma-related inflammation and, by that, to provide insight into the underlying mechanisms.

Methods And Analysis: This is an ongoing prospective multicentre randomised controlled trial planned to enrol 180 women with asthma recruited from fertility clinics in Denmark. The patients are randomised 1:1 to either omalizumab or placebo. The primary endpoint is the difference in pregnancy rate confirmed with ultrasound at gestational week 7 of pregnancy. The secondary endpoints are change in sputum and blood eosinophil cell count, change in biomarkers, change in microbiota, together with rate of pregnancy loss, frequency of malformations, pre-eclampsia, preterm birth, birth weight, small for gestational age and perinatal death between groups.

Ethics And Dissemination: The methods used in this study are of low risk, but if successful, our findings will have a large impact on a large group of patients as infertility and asthma are the most common chronic diseases among the young population. The study has been approved by the Ethics Committee-Danish national research ethics committee (H-18016605) and the Danish Medicines Agency (EudraCT no: 2018-001137-41) and the Danish Data Protection Agency (journal number: VD-2018486 and I-Suite number 6745). The test results will be published regardless of whether they are positive, negative or inconclusive. Publication in international peer-reviewed scientific journals is planned.

Trial Registration Number: NCT03727971.
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http://dx.doi.org/10.1136/bmjopen-2020-037041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662444PMC
November 2020

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns.

Obstet Gynecol 2021 01;137(1):49-55

Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Methods and Analysis, Statistics Denmark, Copenhagen, the Recurrent Pregnancy Loss Unit, the Capital Region, Rigshospitalet, Copenhagen University Hospital, Copenhagen, the Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, the Department of Obstetrics and Gynaecology, the Fertility Clinic, Copenhagen University Hospital Hvidovre, Hvidovre, the Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Hvidovre, the DNRF Center for Chromosome Stability (CCS), Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, the Fetal Medicine Unit, Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, and the Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Objective: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes.

Methods: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available.

Results: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies.

Conclusion: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection.
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http://dx.doi.org/10.1097/AOG.0000000000004199DOI Listing
January 2021

Effect of clindamycin and a live biotherapeutic on the reproductive outcomes of IVF patients with abnormal vaginal microbiota: protocol for a double-blind, placebo-controlled multicentre trial.

BMJ Open 2020 10 13;10(10):e035866. Epub 2020 Oct 13.

Department of Clinical Medicine, Aarhus Universitet, Aarhus, Denmark.

Introduction: Recent studies in in vitro fertilisation (IVF) patients have associated abnormal vaginal microbiota (AVM) with poor clinical pregnancy rates of 6%-9% per embryo transfer. The biological plausibility for this finding is hypothesised to be ascending infection to the endometrium which in turn hampers embryo implantation. New molecular based diagnosis may offer advantages compared to microscopical diagnosis of AVM which has huge inter-study variability ranging from 4 to 38%; however, the important question is whether screening and treatment of AVM would improve reproductive outcomes in IVF patients. Herein, we describe a protocol for an ongoing double-blind, placebo-controlled multicentre trial of IVF patients diagnosed with AVM and randomised in three parallel groups 1:1:1.

Methods And Analysis: This is a drug intervention study where IVF patients will be screened for AVM, using a qPCR assay targeting and . If positive, patients will be randomised to one of the three study arms. The first arm consists of clindamycin 300 mg ×2 daily for 7 days followed by vaginal CTV-05 until clinical pregnancy scan week 7-9. The second arm consists of clindamycin and placebo CTV-05, whereas patients in the third arm will be treated with placebo/placebo. We used a superiority design to estimate that active treatment in both arms will increase the primary outcome, clinical pregnancy rate per embryo transfer, from 20% to 40%. A potential difference between the two active arms was considered exploratory. With a power of 80% and an alpha at 5%, the sample size is estimated to be 333 patients randomised. A pre-planned interim analysis is scheduled at 167 patients randomised.

Ethics And Dissemination: All patients have to give informed consent. Dissemination of results is ensured in clinical trial agreements whether they be positive or not. Ethics committee, Central Denmark Region approved this protocol.

Trial Registration Number: ICH-GCP monitored trial, EudraCT 2016-002385-31; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-035866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554508PMC
October 2020

Biological and Clinical Rationale for Androgen Priming in Ovarian Stimulation.

Front Endocrinol (Lausanne) 2020 4;11:627. Epub 2020 Sep 4.

Laboratory of Reproductive Biology, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, Copenhagen, Denmark.

Androgen receptors are expressed by all stages of growing follicles, and follicular fluid androgen levels are positively correlated to granulosa cell androgen receptor and follicle-stimulating hormone (FSH) receptor expression. Thus, androgens may promote follicular growth, accumulation and/or responsiveness to gonadotropins. This is explored therapeutically in the concept of androgen priming, to improve the ovarian response to stimulation in assisted reproduction. Androgen effects may be achieved in two different ways, either directly by providing exogenous androgen or by providing luteinizing hormone (LH) activity [i.e., LH or human chorionic gonadotropin (hCG)] to stimulate local ovarian production of androgen. The androgen concentrations in follicular fluid by far exceed the levels in female circulation and it has recently been shown that there was no correlation between serum testosterone levels and follicular fluid androgen levels. There is some evidence that administration of exogenous dehydroepiandrosterone or testosterone increases live birth rates, but an optimal protocol has not been established and such adjuvant treatment should be considered experimental. Furthermore, studies exploring long-term administration of LH activity, achieving LH levels comparable to those seen in women with polycystic ovary syndrome, are awaited. The aim of the present review is to discuss critically the most suitable approach for androgen priming from a biological and clinical standpoint, and to evaluate current approaches and results obtained in clinical trials.
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http://dx.doi.org/10.3389/fendo.2020.00627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498541PMC
May 2021

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

BMJ 2020 08 5;370:m2519. Epub 2020 Aug 5.

Fertility Clinic, Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Hvidovre, Kettegaard Allé 30, Copenhagen DK-2650, Denmark.

Objective: To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.

Design: Multicentre, randomised controlled superiority trial.

Setting: Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.

Participants: 460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection.

Interventions: Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure.

Main Outcome Measures: The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle.

Results: Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group.

Conclusions: In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present.

Trial Registration: Clinicaltrials.gov NCT02746562.
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http://dx.doi.org/10.1136/bmj.m2519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399608PMC
August 2020

Pregnancy outcomes following oocyte donation.

Best Pract Res Clin Obstet Gynaecol 2021 Jan 15;70:81-91. Epub 2020 Jul 15.

The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark. Electronic address:

The use of oocyte donation (OD) has increased continuously over the last three decades, and it is now an indispensable part of assisted reproductive technology (ART). With OD, it has become possible to overcome the biological barrier of ovarian follicle pool depletion and the general age-related decline in fertility. This review contains a thorough appraisal of the safety of OD with an analysis of short-term pregnancy outcomes. Salient up-to-date evidence was evaluated, which revealed that in comparison with both IVF with autologous oocytes, and naturally conceived pregnancies, there is: (i) an increased risk of hypertensive disorders of pregnancy and preeclampsia; (ii) an increased risk of low birth weight and preterm birth and (iii) an increased risks of obstetric emergencies, following OD treatment. As a precaution, it is therefore highly encouraged to perform only single embryo transfer (SET) and to prescribe prophylactic low-dose aspirin during OD pregnancies.
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http://dx.doi.org/10.1016/j.bpobgyn.2020.07.008DOI Listing
January 2021

Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial.

BMJ Open 2019 12 15;9(12):e031811. Epub 2019 Dec 15.

The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Introduction: Despite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome.

Methods And Analysis: Multicentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18-41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed.

Ethics And Dissemination: The study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated.

Trial Registration Number: The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-031811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924851PMC
December 2019

The Effects of Simulation-based Transvaginal Ultrasound Training on Quality and Efficiency of Care: A Multicenter Single-blind Randomized Trial.

Ann Surg 2017 03;265(3):630-637

*Department of Obstetrics and Gynecology, Nordsjællands Hospital Hillerød, Hillerød, Denmark and Copenhagen Academy for Medical Education and Simulation, Capital Region and University of Copenhagen, Copenhagen, Denmark †Faculty of Health, Aarhus University, Aarhus, Denmark ‡Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark §Department of Obstetrics and Gynecology, Juliane Marie Centret, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark ¶Department of Obstetrics and Gynecology, Roskilde, University Hospital, Roskilde, Denmark ||Department of Obstetrics and Gynecology, Holbæk University Hospital, and Department of Obstetrics, Holbæk, Denmark and Gynecology, Naestved Hospital, University of Copenhagen, Copenhagen, Næstved, Denmark #Copenhagen Academy for Medical Education and Simulation, Capital Region and University of Copenhagen, Copenhagen, Denmark **Department of Obstetrics and Gynecology, Juliane Marie Centret, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Objective: To explore the effect of adding simulation-based transvaginal ultrasound training to trainees' clinical training compared with only clinical training on quality of and efficiency of care.

Background: Simulation-based ultrasound training may be an effective adjunct to clinical training, but no studies have examined its effects on quality and efficiency of care.

Methods: Trainees from 4 University Hospitals in East Denmark were included (N = 54). Participants were randomized to either simulation-based ultrasound training and clinical training (intervention group, n = 28), or to clinical training only (control group, n = 26).The primary outcome was patient-reported discomfort during transvaginal ultrasound examinations performed by study participants. Secondary outcomes included patient-reported perceived safety and confidence in ultrasound provider. Finally, the need for trainee supervision or repeated patient examinations was recorded.

Results: In total, 1150 patient ratings were collected. The intervention was associated with a reduction of patient discomfort by 18.5% [95% confidence interval (CI), 10.7-25.5; P < 0.001), and with a 7.9% (95% CI, 0.5-14.7; P = 0.04) increase in perceived safety. The intervention group participants received 11.1% (95% CI, 2.5-18.9) higher scores on patients' confidence compared with control group participants (P = 0.01). When the number of days of clinical training was doubled, the odds for trainee supervision or repeated patient examination was reduced by 45.3% (95% CI, 33.5-55.1) and 19.8% (95% CI, 4.1-32.9) in the intervention and control group, respectively (P = 0.005).

Conclusions: Simulation-based ultrasound training improved quality of care and reduced the need for repeated patient examination and trainee supervision.
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http://dx.doi.org/10.1097/SLA.0000000000001656DOI Listing
March 2017

Individualised gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A prospective, observational study.

Eur J Obstet Gynecol Reprod Biol 2017 Mar 9;210:76-82. Epub 2016 Dec 9.

The Fertility Clinic, Section 4071, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.

Objective: The aim of this study was to evaluate an individualised gonadotrophin starting dose regimen for women with anovulatory infertility.

Study Design: We included 71 normogonadotrophic anovulatory infertile women in a prospective, observational study. All underwent one ovulation induction cycle in a flexible, low-dose step-up protocol. The gonadotrophin starting dose (75-150IU/day) was individualised according to a nomogram incorporating menstrual cycle pattern (oligo- or amenorrhoea), BMI, and mean ovarian volume. The number of women who fulfilled the criteria for human chorionic gonadotrophin (hCG) administration (one follicle ≥17mm or 2-3 follicles ≥15mm) was assessed.

Results: Of the 50 women (70.4%) who fulfilled the hCG criteria and underwent intrauterine insemination, 34 (47.9%) achieved monofollicular growth and 16 (22.5%) developed 2-3 mature follicles. Seventeen (23.9%) cycles were converted to in vitro fertilisation (IVF) due to the development of >3 mature follicles, and one (1.4%) cycle was cancelled due to risk of ovarian hyperstimulation syndrome. Baseline total antral follicle count was found to be significantly associated with fulfillment of the hCG criteria (OR 0.96, 95% CI: 0.92-0.99, P=0.01).

Conclusions: The nomogram-based dose regimen was not considered suitable for ovulation induction due to a tendency to overestimate the gonadotrophin starting dose. However, the model may serve as a mild IVF regimen, especially in women prone to excessive follicle growth.
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http://dx.doi.org/10.1016/j.ejogrb.2016.12.010DOI Listing
March 2017

Mono-ovulation in women with polycystic ovary syndrome: a clinical review on ovulation induction.

Reprod Biomed Online 2016 Jun 31;32(6):563-83. Epub 2016 Mar 31.

Fertility Clinic and Department of Gynecology/Obstetrics, Holbæk Hospital, Copenhagen University Hospital, Smedelundsgade 60, 4300 Holbæk, Denmark.

Polycystic ovary syndrome (PCOS) affects 5-10% of women of reproductive age and is the most common cause of anovulatory infertility. The treatment approaches to ovulation induction vary in efficacy, treatment duration and patient friendliness. The aim was to determine the most efficient, evidence-based method to achieve mono-ovulation in women diagnosed with PCOS. Publications in English providing information on treatment, efficacy and complication rates were included until September 2015. Systematic reviews, meta-analyses and randomized controlled trials were favoured over cohort and retrospective studies. Clomiphene citrate is recommended as primary treatment for PCOS-related infertility. It induces ovulation in three out of four patients, the risk of multiple pregnancies is modest and the treatment is simple and inexpensive. Gonadotrophins are highly efficient in a low-dose step-up regimen. Ovulation rates are improved by lifestyle interventions in overweight women. Metformin may improve the menstrual cycle within 1-3 months, but does not improve the live birth rate. Letrozole is effective for ovulation induction, but is an off-label drug in many countries. Ovulation induction in women with PCOS should be individualized with regard to weight, treatment efficacy and patient preferences with the aim of achieving mono-ovulation and subsequently the birth of a singleton baby.
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http://dx.doi.org/10.1016/j.rbmo.2016.03.006DOI Listing
June 2016

Dynamics and mechanisms of chemotherapy-induced ovarian follicular depletion in women of fertile age.

Fertil Steril 2010 Jun 1;94(1):156-66. Epub 2009 Apr 1.

The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objective: To study ovarian follicular dynamics during chemotherapy to understand the mechanisms behind chemotherapy-induced ovarian follicular depletion and to evaluate whether pretreatment levels of ovarian reserve markers were predictive of the posttreatment levels.

Design: Prospective clinical study.

Setting: University hospital fertility center.

Patient(s): Seventeen women (median age 30 years; range 19-35 years) undergoing chemotherapy.

Intervention(s): Patients were seen before, frequently during, and after chemotherapy, until 1 year after the end of treatment. Antral follicle count and levels of FSH, LH, E(2), anti-Müllerian hormone (AMH), and inhibin A and B were monitored at each visit.

Main Outcome Measure(s): The dynamics of the ovarian reserve markers during chemotherapy and factors predictive of posttreatment ovarian function.

Result(s): Anti-Müllerian hormone level (mean +/- 2 SEM) dropped from 2.7 +/- 1.0 to 1.1 +/- 0.6 and to 0.4 +/- 0.4 ng/mL immediately after one and two series of chemotherapy, respectively. Inhibin B and antral follicle count decreased after three series whereas FSH reached menopausal levels after four series. High pretreatment AMH levels predicted higher posttreatment AMH levels.

Conclusion(s): Anti-Müllerian hormone and inhibin B levels immediately declined in response to chemotherapy, and the follicular target of chemotherapy appeared to be growing follicles. High pretreatment AMH levels were predictive of a higher posttreatment AMH level.
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http://dx.doi.org/10.1016/j.fertnstert.2009.02.043DOI Listing
June 2010

Vanishing twins: a predictor of small-for-gestational age in IVF singletons.

Hum Reprod 2007 Oct 29;22(10):2707-14. Epub 2007 Aug 29.

The Fertility Clinic, The Juliane Marie Center, Copenhagen University Hospital, Rigshopitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Background: The purpose of this study was to assess the effect of a vanishing twin on the risk of being small-for-gestational age (SGA) in in vitro fertilization (IVF) singletons.

Methods: The study included 642 survivors of a vanished co-twin, 5237 primary singletons and 3678 primary twins. The survivor cohort was subdivided according to gestational age at the time of vanishing to give groups of early (<8 weeks), intermediate (8-22 weeks) and late (>22 weeks) survivors.

Results: The rate of SGA infants was significantly higher in survivors than in singletons (OR: 1.50, 95%CI: 1.03-2.20) and a significant inverse correlation was observed between SGA and the gestational age at the time of vanishing (r = -0.10, P < 0.02). Also in term infants, the risk of birthweight <2500 g was higher in survivors than in singletons (OR: 1.71, 95%CI: 1.06-2.74). A similar increase in the rate of low birthweight in term survivors was seen with increasing gestational age at the time of vanishing (r = -0.12; P < 0.01). In multiple logistic regression analysis adjusting for maternal age, parity, child gender and pre-eclampsia, the vanishing of a co-twin (OR: 1.56, 95%CI: 1.06-2.27) and gestational age at the time of vanishing (OR: 2.08, 95%CI: 1.00-4.35) were the only significant predictors of being SGA.

Conclusions: IVF singletons with a vanished co-twin had a higher rate of SGA than singletons from a single gestation and the risk of SGA is increased with increasing gestational age at the time of vanishing.
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http://dx.doi.org/10.1093/humrep/dem225DOI Listing
October 2007

Consequences of vanishing twins in IVF/ICSI pregnancies.

Hum Reprod 2005 Oct 24;20(10):2821-9. Epub 2005 Jun 24.

The Fertility Clinic, The Juliane Marie Center, Copenhagen University Hospital, Rigshospitalet, Denmark.

Background: Spontaneous reductions are a possible cause of the increased morbidity in IVF singletons. The aim of this study was to assess incidence rates of spontaneous reductions in IVF/ICSI twin pregnancies and to compare short- and long-term morbidity in survivors of a vanishing co-twin with singletons and born twins.

Methods: We identified 642 survivors of a vanishing co-twin, 5237 singletons from single gestations and 3678 twins from twin gestations. All children originated from pregnancies detected by transvaginal sonography in gestational week 8. By cross-linkage with the national registries the main endpoints were prematurity, birth weight, neurological sequelae and mortality.

Results: Of all IVF singletons born, 10.4% originated from a twin gestation in early pregnancy. Multiple logistic regression analyses adjusted for maternal age, parity and ICSI treatment showed for birth weight <2500 g an odds ratio (OR) of 1.7 [95% confidence interval (CI) 1.2-2.2] and for birth weight <1500 g OR 2.1 (95% CI 1.3-3.6) in singleton survivors of a vanishing twin versus singletons from single gestations; corresponding figures were seen for preterm birth. This increased risk was almost entirely due to reductions that occurred at >8 weeks gestation. We found no excess risk of neurological sequelae in survivors of a vanishing co-twin versus the singleton cohort; however, OR of cerebral palsy was 1.9 (95% CI 0.7-5.2). Furthermore, we observed a correlation between onset of spontaneous reduction, i.e. the later in pregnancy the higher the risk of neurological sequelae (r = -0.09; P = 0.02). Adjusted OR of child death within the follow-up period was 3.6 (95% CI 1.7-7.6) in the survivor versus the singleton cohort.

Conclusions: One in 10 IVF singletons originates from a twin gestation. Spontaneous reductions that occur at >8 weeks gestation are one of the causes for the higher risk of adverse obstetric outcome in IVF singletons.
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http://dx.doi.org/10.1093/humrep/dei142DOI Listing
October 2005

[Streptococcus pyogenes as a cause of primary peritonitis].

Ugeskr Laeger 2004 Nov;166(49):4485-6

Amtssygehuset i Glostrup, Gynaekologisk-Obstetrisk Afdeling.

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November 2004
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