Theodora C van Tilborg Simone C Oudshoorn Marinus J C Eijkemans Monique H Mochtar Ron J T van Golde Annemieke Hoek Walter K H Kuchenbecker Kathrin Fleischer Jan Peter de Bruin Henk Groen Madelon van Wely Cornelis B Lambalk Joop S E Laven Ben Willem J Mol Frank J M Broekmans Helen L Torrance on behalf of the OPTIMIST study group; Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis; Hum Reprod (2017) 32 (12): 2485-2495 DOI: https://doi.org/10.1093/humrep/dex321
Theodora C van Tilborg Helen L Torrance Simone C Oudshoorn Marinus J C Eijkemans Carolien A M Koks Harold R Verhoeve Annemiek W Nap Gabrielle J Scheffer A Petra Manger Benedictus C Schoot Alexander V Sluijmer Arie Verhoeff Henk Groen Joop S E Laven Ben Willem J Mol Frank J M Broekmans on behalf of the OPTIMIST study group; Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder; Human Reprod (2017) 32 (12): 2496–2505 DOI: https://doi.org/10.1093/humrep/dex318
Simone C Oudshoorn Theodora C van Tilborg Marinus J C Eijkemans G Jur E Oosterhuis Jaap Friederich Marcel H A van Hooff Evert J P van Santbrink Egbert A Brinkhuis Jesper M J Smeenk Janet Kwee Corry H de Koning Henk Groen Cornelis B Lambalk Ben Willem J Mol Frank J M Broekmans Helen L Torrance on behalf of the OPTIMIST study group; Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder; Human Reprod (2017) 32 (12): 2506–2514 DOI: https://doi.org/10.1093/humrep/dex319
BREAKING NEWS: Individualised FSH dosing for IVF does not improve live birth ratesThis month, in three episodes, we publish the results of the OPTIMIST study, the latest production of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynecology. The findings are important:
Elpida Fragouli Caroline McCaffrey Krithika Ravichandran Katharina Spath James A Grifo Santiago Munné Dagan Wells - Clinical implications of mitochondrial DNA quantification on pregnancy outcomes: a blinded prospective non-selection study - Hum Reprod (2017) 32 (11): 2340–2347 DOI: https://doi.org/10.1093/humrep/dex292
Elevated mitochondrial DNA associated with implantation failure.
Elpida Fragouli and her group showed that mitochondrial DNA (mtDNA) quantification has the potential to serve as a new biomarker of embryo viability. Increased mtDNA levels were found to be relatively uncommon among euploid blastocysts, but for affected blastocysts the clinical implications were dramatic: elevated mtDNA was accompanied by implantation failure in all cases in which it was detected.
JLH (Hans) Evers, Editor-in-Chief Human Reproduction
Joseph M. Letourneau Nikita Sinha Kaitlyn Wald Eve Harris Molly Quinn Tal Imbar Evelyn Mok-Lin A. Jo Chien Mitchell Rosen - Random start ovarian stimulation for fertility preservation appears unlikely to delay initiation of neoadjuvant chemotherapy for breast cancer - Hum Reprod (2017) 32 (10): 2123–2129 DOI: https://doi.org/10.1093/humrep/dex276
Fertility preservation does not affect time to chemotherapy in breast cancer patients.
Joseph Letourneau and coworkers from San Francisco, USA, in a retrospective study, found that random start of ovarian stimulation in the cycle is unlikely to delay initiation of neoadjuvant chemotherapy in breast cancer patients. Neoadjuvant chemotherapy is a widely accepted treatment for operable breast cancer and random-start ovarian stimulation is an increasingly-used modality for fertility preservation in these patients.
Overall, the average time from cancer diagnosis to the start of chemotherapy in this study was similar between the patients who did undergo ovarian stimulation and those who did not (38.1 ± 11.3 days versus 39.4 ± 18.5 days, P=0.672). Those that underwent ovarian stimulation were referred 9.4 ± 6.8 days after diagnosis versus 17.9 ± 15.3 days for those who did not undergo ovarian stimulation (P<0.001). We can counsel our patients that fertility preservation as a rule will not delay the start of chemotherapy.
Cynthia M. Farquhar Marian G. Showell Emily A.E. Showell Penny Beetham Nora Baak Selma Mourad Vanessa M.B. Jordan - Clinical trial registration in fertility trials – a case for improvement? - Hum Reprod (2017) 32 (9): 1827-1834. DOI: https://doi.org/10.1093/humrep/dex251
Prospective trial registration in fertility research - a case for improvement
Cindy Farquhar and friends of the Auckland-based Cochrane group on Gynaecology and Fertility had a question: What is the prevalence of prospective trial registration in fertility journals? Do we do well? They decided to find out. Of the 693 fertility RCTs they retrieved, only 309 (44%) were registered. Of these 309 registered trials, not more than 21.7% were prospectively registered. Prospective trial registration varied considerably per country of origin. The highest frequency of prospective trial registration amongst the top ten publishing countries was 31%, in the Netherlands. F&S did better than HR. Why is prospective trial registration so important? In my Editorial in the May issue of Human Reproduction on the Texas Sharpshooter Fallacy I have explained the human tendency of seeing clustering of data where in reality there is none, the “Clustering Illusion”. Prospective trial registration prevents this: primary and secondary endpoints should be pre-specified, and all should be reported. A thorough explanation is required if a pre-specified endpoint is not discussed. The same holds for the secondary inclusion of unplanned endpoints. Pre-specified endpoints generally will lead to answering clinical questions; non-pre-specified endpoints, added at a later occasion, often after the data have been analysed, usually only lead the reader astray. They provide fake evidence.
H.A. Guidobaldi M. Cubilla A. Moreno M.V. Molino L. Bahamondes L.C. Giojalas - Sperm chemorepulsion, a supplementary mechanism to regulate fertilization - Hum Reprod (2017) 32 (8): 1560-1573. DOI: https://doi.org/10.1093/humrep/dex232
Chemo-repulsion of spermatozoa
This month I picked a truly fascinating paper, about eggs chasing sperms away. Motile cells, such as bacteria and amoebas, can swim or crawl along or against a chemical gradient. These processes are called ‘chemo-attraction’ and ‘chemo-repulsion’. The first, we know, is also operative in spermatozoa: a progesterone gradient may help the sperm cell to find the oocyte. Héctor Alejandro Guidobaldi and co-workers, from Córdoba, Argentina now have identified for the first time also chemo-repulsion in spermatozoa. Capacitated human spermatozoa are scared away by zinc (a cation released by the oocyte upon fertilization), and by synthetic Progesterone Receptor Ligands (sPRL, known for their contraceptive effect). Since the chemo-repelled spermatozoa are those that are capacitated – so set to fertilize the oocyte – it is tempting to speculate that this mechanism may prevent polyspermy under natural conditions, and fertilization under pharmacological treatment with sPRL. What we are witnessing in this issue of Human Reproduction may very well be the next step towards a new non-hormonal contraceptive.
S. S. Malchau, A.A. Hennings, A. Loft, S. Rasmussen, J. Forman, A. Nyboe Andersen, A. Pinborg - The long-term prognosis for live birth in couples initiating fertility treatments - Hum. Reprod. (2017) 32 (7). doi: 10.1093/humrep/dex096
80% cumulative live birth rate in young people after fertility treatment
I have selected this article from our July issue because it delivers such a wealth of high quality reference data. Within 5 years from starting fertility treatment in women below 35 years, 64% had had a live birth due to (any) treatment; in those that were 35-39 years, 49% did; and in those forty and over, 16%. In addition, in women below 35, 16% conceived naturally during treatment intervals; this figure was 10 and 11% in the older age groups. This yields surprisingly high total 5-year live birth rates of 80%, 60% and 26% in the respective age groups. Another interesting finding is that in women starting treatment with IUI, 35% delivered after IUI, whereas 24% delivered after switching to ART, and 17% delivered after natural conception. In other words, more than half of the women starting IUI were spared a demanding IVF treatment by performing a much simpler procedure.
Stephen A. Robert, Andy Vail - On the appropriate interpretation of evidence: the example of culture media and birth weight - Hum. Reprod. (2017) 32 (6). doi: 10.1093/humrep/dex081
Statistics is not your thing, you say?
This time I want to draw your attention not to a new original article, but to a highly educational Editorial Commentary in the June issue of Human Reproduction. Using a paper we published as a real life example, Stephen Roberts and Andy Vail illustrate the need for careful interpretation of trial results and for avoiding incorrect conclusions. Most of these faults relate to over-reliance on p-values and failure to properly consider effect sizes and confidence intervals. We have been paying attention to this before, also in this journal, for example in the paper by Leslie Farland and co-workers in 2016 - another must-read. Although the statistical principles of correct data analysis have been propagated for decades already, it is clear that as a scientific community we still have a long way to go. I encourage you to familiarize yourself with this lucid Editorial Commentary before embarking on your next clinical research endeavour. It reviews in clear English the most important interpretation errors that you need to be aware of when reporting your own (or appraising someone else’s) studies. Solid stuff, well written, discussing primary and secondary outcomes, multiple comparisons, statistical power, intention-to-treat and supplementary analyses. Mostly things you are familiar with of course, but here explained using a practical example from reproductive medicine. Which I always find more appealing. I genuinely enjoyed reading it.
Sara De Fanti Saverio Vicario Martin Lang Domenico Simone Cristina Magli Donata Luiselli Luca Gianaroli Giovanni Romeo - Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis - Hum. Reprod. (2017) 32 (5). doi: 10.1093/humrep/dex051
Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis
Sara De Fanti, Severio Vicario and co-workers from Bologna, Italy, studied what they call the “Purifying Selection on Mitochondrial DNA Variants” during human oogenesis. The question they asked was whether selection against mtDNA mutations occurs in human oocytes. They found evidence suggestive of the fact that “purifying selection” occurs for mtDNA mutations in human oocytes. It is operative between the expulsion of the 1st and the 2nd polar body. While either polar body is a good index of the nuclear genetic makeup of the oocyte, for mitochondrial genomes only the 2nd polar body appears to reflect the complete genetic status of the oocyte. This study is a fine example of how basic research – if confirmed – may have direct consequences for daily clinical practice.
S. Munné M. Alikani L. Ribustello P. Colls Pedro A. Martínez-Ortiz Referring Physician Group D.H. McCulloh - Euploidy rates in donor egg cycles significantly differ between fertility centers - Hum. Reprod. (2017) 32 (4). doi: 10.1093/humrep/dex031
Euploidy rates in donor egg cycles significantly differ between fertility centers
Santiago Munné and coworkers discovered a great difference in euploidy rates between 42 fertility clinics in the USA. They studied the incidence of chromosomal abnormalities in human embryos generated from donated (a strong point!) oocytes. A total of 1,645 donor oocyte cycles and 13,282 blastocyst biopsies were included in their retrospective cohort study. The average euploidy rate per cycle ranged from as low as 39% to as high as 82% per center. These are truly amazing differences that beg for further research into the clinical and lab practices that may be contributing to these (meiotic and/or mitotic) differences in euploidy rates. This both should increase our understanding of what exactly is happening at the chromosomal division level and it should provide us with opportunities for improving the clinical outcome of ART in general.
M. Toftager J. Bogstad K. Løssl L. Prætorius A. Zedeler T. Bryndorf L. Nilas A. Pinborg - Cumulative live birth rates after one ART cycle including all subsequent frozen–thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols - Hum. Reprod. (2017) 32 (3). doi: 10.1093/humrep/dew358
Cumulative live birth rate of one ART cycle plus all resulting freeze-thaw cycles
This month I would like to draw your attention to a fine paper by Mette Toftager and friends from Copenhagen, Denmark, who estimate the cumulative live birth rates after one complete ART cycle in women who had been included in an agonist/antagonist RCT. They were followed until all frozen embryos were used. The paper includes particularly clear graphical descriptive statistics and an exemplary flow-chart. It shows that the chance of at least one live birth after all fresh and frozen ET’s from the first ART cycle is 31-34%. It is similar in GnRH agonist and GnRH antagonist cycles. I recommend reading the paper, it offers many more interesting details, e.g. that the total number of deliveries from all FET cycles was significantly higher (p=0.01) in the antagonist group (19%) than in the agonist group (12%).
K. Lattes M.A. Checa R. Vassena M. Brassesco V. Vernaeve - There is no evidence that the time from egg retrieval to embryo transfer affects live birth rates in a freeze-all strategy - Hum. Reprod. (2017) 32 (2). doi: 10.1093/humrep/dew306
No reason to delay FET after freeze-all strategy
Karinna Lattes and colleagues from Barcelona, Spain, investigated retrospectively 512 freeze-all cycles and compared FETs that occurred in the first menstrual cycle following ovum pick-up (n=263) with those that occurred later (n=249). Live birth rates were not poorer when FET had been performed immediately following the pick-up cycle. Neither did they find a difference for biochemical pregnancy, clinical pregnancy, or pregnancy loss. According to these results there is no need to wait one or more cycles after freezing all embryos before performing FET.
Samer Tannus Weon-Young Son Ashley Gilman Grace Younes Tal Shavit Michael-Haim Dahan - The role of intracytoplasmic sperm injection in non-male factor infertility in advanced maternal age - Hum Reprod (2017) 32 (1): 119-124. DOI: https://doi.org/10.1093/humrep/dew298
ICSI doesn't beat age
Samer Tannus and colleagues from McGill, Montreal, Canada asked the question “Does ICSI improve reproductive outcomes compared to conventional IVF when used for non-male factor infertility in women aged 40 years and over?” They found that ICSI does not do better than IVF in older women when their partner’s sperm is normal. This is another confirmation of the fact that ICSI should not be used light-heartedly as an ‘add-on’ to IVF, except in case of male infertility. It constitutes overtreatment, offers no advantage and may even harm a couple’s chances. Who will be brave and do the RCT? We will publish it straightaway.