Human Reproduction’s greatest hits: My personal top-10 of 6 years as a Human Reproduction editor
With expert support from Richard Sharpe, Dado Somigliana and Madelon van Wely as deputy editors, I have had the good fortune to serve this journal as an editor for 6 years. They have been good years, for me and for the journal. Our impact factor for the first time crossed the magic hurdle of 5, the number of full-text downloads multiplied into the (literally!) millions, and many papers reached impressive Altmetric scores. We were read. We were cited. We were viewed, discussed, tweeted, re-tweeted, liked, shared and recommended. People downloaded and printed our PDFs.
If you would ask me which papers touched a personal chord in these 6 years, I’d have to admit they were many. And I could easily have picked 25 or 50. But these 10 are definitely among my favourites, for various reasons; all inspiring, most challenging, some puzzling. Papers that I’m proud we published.
Natural conception varies by clinic from 8 to 44%—Tjon-Kon-Fat et al. Hum Reprod. 28:1391–1397.
Raïssa Tjon-Kon-Fat and co-workers performed a prospective cohort study in 21 clinics that together recruited 2916 couples and found that natural conception rates differed from as low as 8% to as high as 44% per year per clinic. The authors conclude: ‘We found significant inter-clinic differences in natural conception chances for subfertile couples, which remain after adjustment for well-recognized predictors and type of clinic and accounting for sampling variation. These findings may seem counterintuitive, as these couples did not receive active treatment’. ‘May seem counterintuitive’ is putting it mildly… I would say: perplexing.
The best management of women with endometriosis—Dunselman et al. Hum Reprod. 29:400–412.
For a journal, publishing clinical guidelines is a sure thing to attract attention and future citations. Gerard Dunselman is a clinician who has been involved all his life in what he used to call ‘the dreaded disease’. He has updated, in an exemplary effort, together with a seasoned group of expert peers, the ESHRE endometriosis guideline. Over all their combined years of practice, a wealth of clinical knowledge has accumulated in these endo-dinosaurs. Very generously they now share it, compare it to the best scientific evidence, and make us benefit from it. Overall, 83 recommendations answered 22 key questions on optimal management of the dreaded disease. Since its publication in 2014, the guideline has already been cited by other authors more than 750 times, and downloaded as full text more than 35 000 times. Overwhelming figures.
Scratching where it does not itch—Yeung et al. Hum Reprod. 29:2472–2481
If you read this in 2028, you might say ‘Huh…? Scratching? The intellectual bankruptcy of reproductive medicine?’ In November 2014, Tracy Yeung and her group from Hong Kong published an RCT of the effect of endometrial injury performed in the cycle preceding IVF treatment. The study was pre-registered, enrolled the required number of participants in the time period planned, and had one relevant primary endpoint, ongoing pregnancy rate. ‘Scratching’ the endometrium did not improve the ongoing pregnancy rate among unselected subfertile women undergoing IVF. On the contrary…
It is a genuine pleasure for an editor to publish a well designed, meticulously performed and carefully reported study like this. Of course, an RCT is costly and labour-intensive. And of course, the ‘believers’ will always succeed in unearthing a subgroup with a different response. Fact is that in those days, back in 2014, many ART practitioners had switched to endometrial ‘scratching’, just because of some tempting findings in a few small, underpowered, mostly observational studies. This study may have stopped some of them, but I predict it will require many more RCTs (and meta-analyses, and IPD meta-analyses)—and millions and millions of Euros—to repudiate those initial poor quality studies and convince the ‘believers’.
Baffling differences in ICSI usage—Dyer et al. Hum Reprod. 31:1588–1609.
Registry data are another sure thing to attract attention. But that’s not the reason I have included this article in my personal top-10. In 2016 we published the ICMART World Report on 2008–2009–2010, on 4.5 million ART cycles. Examining the data showed something completely unexpected: a substantial, unexplained over-use of ICSI for non-male infertility all over the world. It varied from 60% of all ART treatments in Asia to a whopping 98% in the Middle-East. Registry figures as benchmarks, very important.
Euploidy in donor eggs varies greatly between centres—Munné et al. Hum Reprod. 32:743–749.
See Tjon-Kon-Fat’s 2013 paper above; in 2017 the mystery increased. Santiago Munné and co-workers discovered a pronounced difference in euploidy rates between 42 US fertility clinics referring to the same central laboratory. They studied the incidence of chromosomal abnormalities in human embryos stemming from donated (!) oocytes. A total of 1645 cycles and 13 282 blastocyst biopsies were included. The average euploidy rate/cycle ranged from as low as 39% to as high as 82% per centre. These are truly mind-blowing 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 occurring in the very early phases of embryonic life. What is happening with the delicate process of chromosome division? How do external factors disturb it?
80% cumulative live birth rate in young people after fertility treatment—Malchau et al. Hum Reprod. 32:1439–1449
I have selected this article from our July 2017 issue because it delivers such a wealth of high quality reference data, and because it illustrates how the correct use of administrative databases (as opposed to data dredging) may benefit clinicians. Within 5 years of starting fertility treatment in women below 35 years, 64% 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 two 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 resorting to a much simpler procedure (that allows in vivo conception and makes couples feel more in control). Maybe IUI should not be abandoned that easily after all?
Chemo-repulsion of spermatozoa—Guidobaldi et al. Hum Reprod. 32:1560–1573
Eggs chasing sperms away, that’s something! We know chemo-attraction is operative in spermatozoa: a progesterone gradient may help the sperm find the oocyte. Héctor Guidobaldi and co-workers now have identified 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). Since the ‘to-be-chemo-repelled’ spermatozoa are those that are capacitated—and thus 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 may very well be the next step towards a new non-hormonal contraceptive. And remember, you first read it here, in Human Reproduction.
Elevated mitochondrial DNA associated with implantation failure of euploid blastocysts—Fragouli et al. Hum Reprod. 32:2340–2347
Sometimes you have to stick your neck out. Elpida Fragouli and her group did. They showed, in a small retrospective study, that mitochondrial DNA (mtDNA) quantification may have the potential to serve as a new biomarker of embryo viability. Increased mtDNA levels were found to be relatively uncommon (5%) among euploid blastocysts, but for those blastocysts affected, the clinical implications were dramatic: embryos with high mtDNA do not easily implant. Nine of 199 morphologically normal, euploid blastocysts had elevated mtDNA levels, none of the nine implanted. A tiny study giving off a provocative novel signal. (i) Is it new? Unquestionably. (ii) Is it true? Wait and see. (iii) Do I care? Most definitely. And that’s why we decided to publish it.
Lifelong effects of having been in an IVF culture dish for 2–3 days—Roseboom. Hum Reprod. 33:546–552
David Barker—against much initial opposition—suggested that foetal adaptations to environmental cues might be the cause of health disturbances later in life. John Dumoulin—against much initial opposition—proposed that even before the foetal period, embryonic exposure to ‘environmental cues’ might affect later life. One of my last Editor’s choices was a truly thought provoking paper, ‘Developmental plasticity and its relevance to assisted human reproduction’ by Professor Tessa Roseboom. She is a world expert on the adult consequences of being exposed prenatally to famine in the Dutch hunger winter of 1944–1945. Who better to look from the outside at our daily ART practices, with all their ‘environmental cues’ to the early pre-implantation embryo, and the (epi)genetic modifications they may provoke?
Protect us from poor-quality medical research—ESHRE Capri Workshop Group. Hum Reprod. 33:770–776.
Much of the published medical research is flawed, cannot be replicated and/or has limited to no utility. This article presents an overview of the current landscape of biomedical research, identifies problems associated with common study designs and considers potential solutions. Randomized clinical trials, observational studies, systematic reviews and meta-analyses are discussed in terms of their inherent strengths, limitations and potential ways of improving their conduct, analysis and reporting. The present inflated emphasis on statistical significance needs to be replaced by sound study design, transparency and willingness to share data with a clear commitment towards improving the quality and utility of clinical research. If you read only one article this month (or this year), make it this one.
Fare thee well.