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E-mail: jlh.evers{at}mumc.nl
The ‘wooden spoon’ is a figurative trophy that people use to award to whoever comes last in any contest. In 1979, Archie Cochrane (1909–1988), the famous British epidemiologist, awarded a wooden spoon to the specialty of Obstetrics and Gynaecology for the worst use of research evidence in guiding clinical practice: the grand mystery of bringing forth new life was shrouded in arcane medical and midwifery rituals (Grimes, 2007
). Some of these traditions were not only inappropriate (electronic fetal heart rate monitoring), but even harmful (diethylstilboestrol). But, do we do much better nowadays? The very timely literature review by Ulla-Britt Wennerholm and co-workers in this issue of the journal (p. 2158) gives little hope. The most arresting sentence in their report on children born after cryopreservation is ‘There was no control group’, when they are referring to the largest study so far on vitrification of oocytes. Without controls, what does a mean singleton birthweight of 2920 g after oocyte vitrification tell us? Or for that matter, a 26% preterm delivery rate? We introduced IVF and ICSI without properly controlled comparison into our clinics, MESA, PESA, TESE, embryo freezing, blastocyst transfer, PGD, PGS and now vitrification of oocytes. Wennerholm and co-workers conclude that after 25 years of slow-freezing embryos, data concerning infant outcome ‘seem reassuring’. That is good news, but it is more due to good fortune than to proper validation of these techniques before their introduction into the clinic. The authors emphasize the urgent need for a careful assessment of (pre)clinical evidence and for properly controlled follow-up studies of neonatal outcome before the new freezing techniques will be added to our daily routines.
Klinefelter syndrome patients, with a 47,XXY karyotype, form 3% of the infertile male population. They are generally azoospermic due to primary testicular failure. Surgical extraction of spermatozoa from their tiny testes is unexpectedly successful in these patients, revealing post-meiotic germ cells in >50% of biopsies. FISH analysis has shown between 50% and 95% of normal spermatozoa but an increased incidence (compared with controls) of 24,XX and 24,XY hyper-haploid sperm cells (Staessen et al., 2003). Hyper-haploid spermatozoa may result from meiosis of 47,XXY spermatogonia (although their capacity to undergo meiosis has been disputed) or may be due to 47,XXY men harbouring rare patches of spermatogenesis in their testis, containing normal 46,XY germ cells that are susceptible to meiotic abnormalities. Roberta Sciurano and co-workers offer evidence in support of the latter hypothesis (p. 2353). Although they only sampled <1% of the total testicular tissue volume, they found spermatogenic foci, probably originating from clones of spermatogonia that have randomly lost one of their X chromosomes. Their findings offer an explanation for the surprisingly high rate of normal children following ICSI with ejaculated or surgically extracted sperm cells in non-mosaic Klinefelter patients.
We know that ART singletons fare less well than spontaneously conceived singletons. Regarding twins, the studies so far disagree. Michèle Hansen and co-workers (p. 2321) have now shown that also twins are at increased risk of preterm birth, low birthweight, NICU admissions, morbidity and mortality (compared with controls) and that they run an increased risk of hospital admission, which continues into their second (and perhaps even third) year of life. Important information that could only be obtained by comparison with suitable twin controls and that should be shared with prospective ART couples. The issue of ART twins also being at a disadvantage is compounded by the chorionicity problem. In order to address the concern of the differing proportions of monochorionic placentation in the two groups (and since information on zygosity and chorionicity was not available to them), Hansen not only compared their findings to the total population of spontaneously conceived twins in Western Australia, but also to a subgroup of unlike-sex spontaneously conceived twins. This further underlines the importance of choosing a correct comparison group. What Hansen could not do of course was differentiate between the role of ART and the role of the underlying subfertility in determining the differences in infant hospitalization rates, as has been done so elegantly by Romundstad et al. (2008). In the latter study, the patients served as their own controls.
The formidable professor Ivo Brosens (2007) from Leuven, Belgium, an icon in maternal–placental interaction research, was the first to find a significantly reduced risk of developing hypertensive disorders in pregnant endometriosis patients compared with matched controls. Increased angiogenic properties of endometrium in endometriosis patients (compared with controls) might lead to better placentation and therefore less need for compensatory hypertension. Ruth Hadfield and co-workers fail to confirm such reduction in hypertensive disorders in a population-based, longitudinal study of singleton pregnancies in 3239 endometriosis patients and 205 640 controls in New South Wales (p. 2348). A matter of choosing the right controls? A more robust—since prospective—study design? Chance? Another beautiful theory slain by ugly facts? To be continued ... .
Finally, why do most studies find a difference of 5% ongoing pregnancies in IVF cycles using GnRH analogues in favour of the agonists when compared with the antagonists? Not because of their affecting the capacity of the endometrium to support invasion of the embryo, and neither because of a detrimental effect on the invasive potential of the blastocyst in the early stages of implantation, say Petra Klemmt and co-workers (p. 2187), based on an elegant series of in vitro experiments. This leaves a negative effect of the antagonist on the pituitary–ovarian axis, or a direct disturbance of the delicate mechanisms involved in folliculogenesis and final oocyte maturation as possible explanations for the decrease in clinical pregnancy rate following GnRH antagonist protocols.
What the above studies have in common is that they illustrate the need for appropriate controls. Without comparison group, it is impossible and sometimes even dangerous to try and determine the added value of a new treatment. This issue of the journal offers many more such well-controlled studies. Let us hope Professor Cochrane receives Human Reproduction up there.
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Brosens IA, De Sutter P, Hamerlynck T, Imeraj L, Jao Z, Cloke B, Brosens JJ, Dhont M. Endometriosis is associated with a decreased risk of pre-eclampsia. Hum Reprod (2007) 22:1725–1729.
Grimes DA. Discovering the need for randomized controlled trials in obstetrics: a personal odyssey. James Lind Library 2007. www.jameslindlibrary.org (26 July 2009, date last accessed).
Romundstad LB, Romundstad PR, Sunde A, Von During V, Skjaerven R, Gunnell D, Vatten LJ. Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study. Lancet (2008) 372:737–743.[CrossRef][Web of Science][Medline]
Staessen C, Tournaye H, Van Assche E, Michiels A, Van Landuyt L, Devroey P, Liebaers I, Van Steirteghem A. PGD in 47,XXY Klinefelter syndrome patients. Hum Reprod Update (2003) 9:319–330.
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