Cui-Lan Li et al., Feasibility and effectiveness of unintended pregnancy prevention with low-dose mifepristone combined with misoprostol before expected menstruation, Hum. Reprod. (2015) 30 (12): 2794-2801. doi: 10.1093/humrep/dev239
Menstrual regulation revisited
It has been really difficult to select this month’s Editor’s Highlight. We have so many good studies in this issue! I decided to pick a study of the ‘alternative’ use of mifepristone/misoprostol, not for medical abortion but for ‘menstrual regulation’, to use that unpleasant euphemism. The combination of these drugs (200 mg mifepristone orally, followed by 800 µg misoprostol vaginally) has been studied extensively for medical abortion. Cui-Lan Li and co-workers from Guangzhou, China, now present a study of the effectiveness of administering low dose mifepristone (50 mg) orally one day before the expected menstruation and low-dose misoprostol (200 µg) orally on the date of the expected menstruation in women at risk of an unintended pregnancy. They recruited 650 healthy women who were seeking contraceptive advice after unprotected sexual intercourse, 15–45 years of age, with regular menstrual cycles (duration of 25–35 days) and regular sexual activity. The participants agreed not to use any other contraception method during the study period. Their study suggests that this regimen of menstrual regulation is effective and safe “in maintaining or restoring a non-pregnant status”: 50 mg mifepristone plus 200 µg misoprostol is efficacious for termination of ultra-early pregnancy (≤35 days of amenorrhea) in women who subsequently were shown to have had a positive hCG, with no obvious menstrual disturbance in non-pregnant women. The authors suggest cautiously that their regimen of menstrual regulation might have potential for routine contraception. This may still seem to be a bridge too far, but larger prospective studies of this new form of ‘menstrual regulation’ in unselected patients are warranted.
Elina Pohjoranta, Maarit Mentula, Mika Gissler, Satu Suhonen and Oskari Heikinheimo, Provision of intrauterine contraception in association with first trimester induced abortion reduces the need of repeat abortion – first-year results of a randomized controlled trial in Hum. Reprod. (2015) 30 (11): 2539-2546. doi: 10.1093/humrep/dev233
Insertion of an intrauterine device (IUD) immediately following an induced abortion below 12 weeks is more effective than prescribing oral contraceptives (OC). During the first year after the event the numbers of women requesting another abortion were 9/375 (2.4%) in the IUD group and 20/373 (5.4%) in the group randomized to receiving an OC prescription. The difference was significant. RCT’s are not always easy to perform, and this one definitely will have been no exception. Randomizing more than 750 women between IUDs and OCs after an induced abortion and following them up for (more than) a year will have put high demands on Elina Pohjoranta and her co-investigators and on the participants, and we owe them all for it. Theirs is an effort that results in findings that will contribute significantly to clinical practice from now onwards. Providing women with an IUD at the time of an induced abortion will decrease the need of subsequent abortions
Tjon-Kon-Fat R.I., et al., Is IVF—served two different ways—more cost-effective than IUI with controlled ovarian hyperstimulation? Hum. Reprod. (2015) 30 (10): 2331-2339., doi: 10.1093/humrep/dev193 Ah … how satisfying, RCT’s, Randomized Clinical Trials! Isn’t it wonderful that people are still prepared to make the (huge) effort to embark on them in these times of easy scoring, fast results and hurried progress? And how rewarding when the codes are broken and the analysis can start. Raissa Tjon-Kon-Fat, Alexandra Bensdorp and their 25 co-authors asked whether traditional IVF with conventional ovarian stimulation, single embryo transfer and subsequent cryo-cycles (IVF), or IVF in the modified natural cycle (IVF-MNC), or stimulated IUI (IUI-COH) are to be preferred from a cost-effectiveness point of view as a first line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception.
They found that both IVF strategies are significantly more expensive when compared to IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH the latter is the dominant strategy. I hope that NICE will notice.
S.D. Prien, C.E. Wessels and L.L. Penrose, Preliminary trials of a specific gravity technique in the determination of early embryo growth potential in Hum. Reprod. (2015) 30 (9): 2076-2083. doi: 10.1093/humrep/dev178
The weight of an embryo
As an editor of a scientific journal every now and then you bump into an exciting but unpredicted development. In the September issue of Human Reproduction you will find such a surprise: estimation of an embryo’s developmental potential by determining its specific gravity. Sam Prien and co-workers from Lubbock, Texas, USA, showed that average descent times of one cell mouse embryos in a Specific Gravity System (SGS) were different for embryos that stalled early versus those that developed to blastocysts. Significantly more embryos that dropped through the SGS developed to blastocyst than culture controls. In theory, this system will allow for early non-invasive differentiation between one cell embryos that will and that will not develop into blastocysts. The authors warn that the current in vitro study will need to be followed by fecundity studies prior to application to a human population. But be prepared, one day the maxim in the IVF unit may be: count your follicles and weigh your embryos.
Stop the epidemiological bonanza! Scandinavian countries are famous for a lot of things. Among these are the Vikings, Lennart Nilsson, Abba, Borgen, warm smoked salmon, Pippi Langstrump, Arto Paasilinna and Arne Sunde, but also the apparent ease with which Nordic researchers link national databases. In this issue of Human Reproduction we present an example. The Norwegian Medical Birth Registry was linked with the Norwegian Cancer Registry by Marte Myhre Reigstad and coworkers, and the authors found no increased risk of cancer in women conceiving by IVF. A reassuring finding, although the two large administrative databases were not created for this purpose and caveats are appropriate, as acknowledged by the authors. And also by two independent experts who comment on the paper, in this same issue of Human Reproduction. Madelon van Wely recommends that instead of relying on administrative databases that were developed for other purposes, future epidemiological studies on cancer following ART should be aware of early detection bias in these studies and aim at large prospective databases with a long follow-up time that include all risk factors. David Grimes warns that in large database linkage studies “the more comparisons are made, the greater is the likelihood that something will pop up as statistically significant (even when no association exists)”. Geneticists have faced similar problems with Genome Wide Association Studies and came up with the STREGA statement on STrengthening the REporting of Genetic Association studies, an extension of the STROBE statement. It’s time people working with other large datasets consider developing a similar tool. We receive many database studies nowadays. What we do not want is to scare our vulnerable IVF patients once a week with a spurious claim that IVF causes yet another erratic type of disease in mother or child. Let the epidemiologists take their responsibility and develop that publishing guideline.
This highlight refers to four articles:
1- Johannes L.H. Evers, et al., The war on error, in Hum. Reprod. (2015) 30 (8): 1747-1748 doi:10.1093/humrep/dev146
2- David A. Grimes, Epidemiologic research with administrative databases: red herrings, false alarms and pseudo-epidemics in Hum. Reprod. (2015) 30 (8): 1749-1752 doi:10.1093/humrep/dev151
4- M.M. Reigstad et al., Cancer risk among parous women following assisted reproductive technology in Hum. Reprod. (2015) 30 (8): 1952-1963 doi:10.1093/humrep/dev124
‘Quickstarting’ oral contraceptives after emergency contraception is a good idea.
S.T. Cameron, C. Berger, L. Michie, C. Klipping and K. Gemzell-Danielsson in Hum. Reprod. (2015) 30 (7): 1566-1572. doi: 10.1093/humrep/dev115
The effects on ovarian activity of ulipristal acetate when ‘quickstarting’ a combined oral contraceptive pill: a prospective, randomized, double-blind parallel-arm, placebo-controlled study
The availability of emergency contraception (EC) provides women with a second chance to prevent an unintended pregnancy. The most effective form of EC is inserting an IntraUterine Contraceptive Device (IUCD). This has the added advantage of providing continued contraception if the woman wishes so. Inserting an IUCD ‘ad hoc’ however may not always be practical nor feasible. Of the medical forms of EC, ulipristal acetate (UPA) prevents significantly more pregnancies than levonorgestrel (LNG). Neither of these two medical alternatives provides continued protection however. In the present randomized clinical trial (RCT) Sharon Cameron and co-workers investigated what is the effect on ovarian activity of a preceeding intake of UPA when starting a combined oral contraceptive (COC) in the mid to late follicular phase of the cycle. This is a very important and timely issue and I wish to commend the authors for having investigated it, and for having investigated it so well, in the form of an RCT. The study - from Scotland, Sweden and The Netherlands - showed that UPA does not affect the ability of the COC to induce ovarian quiescence. The authors warn however that their study cannot exclude a possible impact of hormonal contraception on the ability of UPA to delay ovulation. Further research on the interaction of hormonal contraception and UPA is therefore required. And Human Reproduction will be ready to publish it.
Will an apple a day keep the doctor away?
Yu Han Chui et al. in Human Reproduction (2015) 30 (6): 1342-1351. doi: 10.1093/humrep/dev064
Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic. Consumption of fruits and vegetables, even if washed carefully before use, is a potential source of human pesticide exposure. Pesticides are supposed to combat disease in agriculture, but by the same token, decreasing a microorganism’s viability, they might combat sperm. And of course they do not disappear once the tomato is harvested or the pear is picked. Fruits and vegetables carry residual pesticides, some more, some less. Their consumption is positively related to urinary metabolite levels of pesticides. Substituting conventionally grown produce with eco-friendly organic produce decreases the urinary metabolite levels of such pesticides. In the current study, Yu Han Chiu and co-workers, from the Harvard School of Public Health in Boston, USA, classified fruits and vegetables according to their typical, average pesticide residue status in the US food supply, as determined by the US Department of Agriculture. Onions and grapefruit are in the low pesticide residue category, strawberries and spinach in the high. The investigators did confirm their primary hypothesis that consumption of large volumes of high pesticide residue fruits and vegetables was associated with a lower total sperm count, a lower ejaculate volume, and a lower percentage of morphologically normal sperm among men attending a fertility clinic. Intake of fruits and vegetables with low pesticide residue was associated with a higher percentage of normal sperm morphology. These findings suggest for the first time that exposure to what we believe to be small amounts of residual pesticides, through consumption of fruits and vegetables, may be intense enough to affect spermatogenesis in humans. An apple a day may keep the family doctor away, but not the fertility doctor.
What is the effect of a multifaceted intervention with participation of patients on improvement of patient-centredness in fertility care?
Aleida Huppelschoten, Willianne Nelen, Gert Westert, Ron van Golde, Eddy Adang, Jan Kremer. in Hum. Reprod. (2015) 30 (4): 973-986. doi: 10.1093/humrep/deu348
Improving patient-centredness in partnership with female patients: a cluster RCT in fertility care
Taking care of infertility couples means providing care that takes into account the preferences and needs of these patients, something which, also due to the work of these authors, has become known as ‘patient-centred infertility care’. The title of their paper may confuse readers, but the content is important. The authors point out that especially infertile patients who suffer from a high emotional burden of treatment could benefit from a more patient-centred approach. Improvement of patient-centred care is still needed, because effective strategies to come to improvement are lacking. That’s why they embarked on this ‘cluster RCT’ in 32 Dutch fertility clinics, covering about one third of all Dutch hospitals. After randomization, 16 clinics in the intervention group were exposed to a multifaceted improvement strategy for patient-centred fertility care for 1 year. This strategy comprised audit and feedback, educational outreach visits and patient-mediated interventions. The remaining 16 clinics in the control group performed care as usual. From the findings the authors conclude that their multifaceted intervention with participation of patients did not improve total patient-centredness scores by women in fertility care. However, scores on the continuity of care subscale were significantly higher in the intervention group compared to the control group, and the addition of three interaction terms to the model had a significant impact: being younger than 36 years, beginning treatment after the study had started, and using complementary and alternative medicine. I have not only highlighted this study for its findings, another reason for choosing it is to show that even in difficult areas of research, modern methods and challenging study designs can assist us in evaluating care and hence help our patients.
Underuse of modern methods of contraception: underlying causes of undesired pregnancies and the public health burden in 35 low and middle-income countries.
Saverio Bellizzi,Howard Sobel, Hiromi Obara and Marleen Temmerman from WHO Manila and Geneva. in Hum. Reprod. (2015) 30 (4): 973-986. doi: 10.1093/humrep/deu348
Human Reproduction publishes papers on pharmacological, medical, demographic and social aspects of contraception. This study by Saverio Bellizzi and co-workers compares the contraceptive use of almost 13,000 unintentionally pregnant women with that of more than 111,000 sexually active women who were neither pregnant nor desiring pregnancy, a titanic effort. The study question was: What is the contribution of the underuse of modern methods of contraception to the annual undesired pregnancies in 35 low and middle-income countries? Their study revealed that 15 million out of 16.7 million undesired pregnancies occurring annually in these countries could have been prevented with optimal use of modern methods of contraception. The study would suggest that a major reason why women in low and middle income countries report non-use of effective methods is lack of knowledge and fables and fallacies surrounding these methods. Education could play an important role here, but educational interventions that do not go hand in hand with affordability and availability of contraception are destined to fail. WHO has to be commended for embarking on an essential study like this. Now that we understand the problem and know the solution, who will take the next step?
Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency
Nao Suzuki, Nobuhito Yoshioka, Seido Takae, Yodo Sugishita, Midori Tamura, Shu Hashimoto, Yoshiharu Morimoto and Kazuhiro Kawamura in Hum. Reprod. (2015) doi: 10.1093/humrep/deu353
Successful fertility preservation in patients with primary ovarian insufficiency
At Human Reproduction, with every manuscript we receive, we ask ourselves three questions: Is it new? Is it true? Do I care? A properly conducted randomized clinical trial on a pristine procedure theoretically might show affirmative answers to all three questions, but such articles are rare. We don’t receive them on a daily basis. HR pretends to offer new science and should therefore also publish papers that may be less than perfect but offer exciting new ideas. This study by Nao Suzuki and co-workers from Kawasaki and Osaka in Japan is such a study. It is new, and you should care. It offers a first glimpse of a development that might one day lead to preventing childlessness in patients with primary ovarian insufficiency (POI). The authors retrieved ovarian cortical tissue from these patients and vitrified it. After thawing the tissue, it was cultured for 48 hours during which follicles were exposed to substances that cause activation of follicle growth. Little cubes of the tissue then were inserted beneath the serosa of the Fallopian tube during laparoscopy. Thirty-seven POI patients were included in the study. In 20, surgical pathology showed that there were still some follicles present in their biopsies. After vitrification, thawing and transplantation, nine of these 20 patients developed follicles and at ovum pick-up 24 oocytes were retrieved from six. Regular IVF followed, and embryo transfer was carried out in four patients. Three pregnancies ensued, as reflected in a rise of serum hCG. At the time of writing the report one miscarriage, one still on-going pregnancy and one successful delivery had occurred. There is still a long way to go, two ongoing pregnancies in 37 patients gives you a number needed to treat of 19. IF – and here is the big IF - IF the comparison group would have shown no pregnancies. And this is at the same time the weak point of the present study: it lacks a comparison group. But it is new, it may be true, and even if this study would only lead to a better understanding of POI it would deserve our attention.
Does oocyte banking for anticipated gamete exhaustion influence future relational and reproductive choices? A follow-up of bankers and non-bankers
D. Stoop, E. Maes, N.P. Polyzos, G. Verheyen, H. Tournaye and J. Nekkebroeck
in Hum. Reprod. (2015) 30 (2): 338-344. doi: 10.1093/humrep/deu317
Dominic Stoop and his co-workers investigated the relational status, reproductive choices and possible regret of a pioneer cohort of women who considered or performed oocyte banking for anticipated age-related infertility between 2009 and 2011. Of the 140 women, 86 (61%) indeed completed at least one cycle of cryopreservation. Of these, only 51% think at present that they will use their frozen eggs at some point in time. 95% of the bankers would do it again however, most preferably at a younger age. 96% would recommend the procedure to others. Bankers and non-bankers did not differ in terms of experiencing steady relations (48 vs. 55%), attempting conception (35 vs. 45%), and not conceiving within one year (17 vs. 15%). The Brussels VUB group has always excelled in careful long-term patient follow-up. In this study they show that oocyte banking for ‘social reasons’ offers reassurance to the women who did it, even if they were currently less likely to use their frozen eggs than expected at the time of retrieval. Bankers and non-bankers did not differ in current desire for a child, relational status and reproductive choices. The procedure did not appear to affect these women’s life choices in this small pilot group.
Time-lapse in the IVF-lab: how should we assess potential benefit?
S. Armstrong, A. Vail, S. Mastenbroek, V. Jordan and C. Farquhar in Hum. Reprod. (2015) 30 (1): 3-8. doi: 10.1093/humrep/deu250
Toys for the boys – continued
Reproductive Medicine is notorious for introducing unproven new procedures into the clinic. Based on a few small observational studies clinical implementation takes place rapidly and on a massive scale. The next thing your hear is that “it is no longer ethically appropriate to start a clinical trial now, since that would deprive the patient of an extra chance of a pregnancy”, or - even worse – “she is going for IVF anyhow, so why not prescribe her alpha-pipalonic-sulphate and allow her to increase her chances?”. And once everyone is doing it, it will be difficult to step back and do the proper trial: “Why would a patient take part in such a trial if she stands a 50% chance of not receiving the new drug?” At this place I have praised previous attempts to critically assess new procedures in ART such as PGS and “scratching” the endometrium. It didn’t bring me much fan mail. In the current issue of Human Reproduction, Sarah Armstrong and her co-workers shine their critical light on time-lapse monitoring of embryo development, the latest cash-cow of ART lab equipment manufacturers. We demand drug companies to provide evidence, in multimillion euro trials, that their drugs do more good than harm. Why do we allow manufacturers of lab equipment (and culture media for that matter) to get away with it and sell their “toys for the boys” without appropriate testing? Wouldn’t they themselves be interested in the answer to the question whether it is the ability of the system to accumulate “multiple, detailed, time-lapse images of embryos which can be utilised to select the highest quality embryo for transfer”, or whether it is the effect of improved culture conditions, minimised handling of the embryos, temperature and gas composition control, and not exposing the embryos to bench-top light microscopy? If you are interested – which I’m sure you are – check the January issue of Human Reproduction for Sarah Armstrong’s article. It’s free.