Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.

STUDY QUESTION: Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older? SUMMARY ANSWER: Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles. WHAT IS KNOWN ALREADY: In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting. STUDY DESIGN, SIZE, DURATION: A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the 'r-FSH and r-LH' and 'r-FSH only' groups respectively. LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment. WIDER IMPLICATIONS OF THE FINDINGS: Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older. STUDY FUNDING/COMPETING INTEREST(S): Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare. TRIAL REGISTRATION NUMBER: The trial was registered in the Dutch trial register (ISRCTN10841210).

Obstetric rupture of the rectovaginal septum and sphincter complex despite an intact perineum: report of three cases.

Obstetric injury comprising tearing of the rectovaginal septum, rectal mucosa, and anal sphincter complex with limited or no involvement of the perineal body may implicate the sudden appearance of an elbow, foot or head in the anal orifice during the second phase of labour. This complex type of obstetric injury is highly uncommon and reports have rarely been published. There are no guideliness as to how to respond to this obstetric emergency and there is no time for consultation. In order to reach clinical recommendations on repair and management of this unexpected obstetric injury for the midwife or obstetrician, we report three such cases. The three described cases with their corresponding sequence of events and interventions illustrate that successful repair of these types of injury can often be achieved. To minimize factors leading to long-term complications, repair requires the involvement of an experienced gynaecologist and sometimes even a colorectal surgeon.

[Alternative clinical-chemical laboratories: providers of incorrect or non-existant diagnoses]. / Alternatieve klinisch-chemische laboratoria: leveranciers van onjuiste of niet-bestaande diagnosen.

Until recently, alternative doctors and healers used to employ alternative ways of making their alternative diagnoses such as electro-acupuncture, iridiscopy, plantar reflexology, live blood analysis, aura reading and bioresonance methods. Two recent papers report the emergence of unjustified diagnoses, resulting from clinical chemistry testing in commercial laboratories with an alternative philosophy and character. Dutch law considers medicine to be a profession for which no special knowledge is demanded. Even incorrect diagnostic procedures and the diagnosis of non-existent diseases by these laboratories is not illegal, in spite of the resulting detrimental effects to the health and the purse of patients. Some would consider the Dutch law in this respect too liberal.

[Severe disciplinary measures in the Millecam case: important precedent for revising the rules of conduct by scientific associations and the KNMG]. / Strenge tuchtrechtelijke maatregelen in de zaak-Millecam: belangrijke jurisprudentie voor het aanscherpen van de gedragsregels door de wetenschappelijke verenigingen en de KNMG.

The popular 45-year-old Dutch actress Sylvia Millecam died in August 2001 from untreated advanced breast cancer. She refused standard medical treatment and sought solace in many alternative healers, including three medical physicians. The Dutch Healthcare Inspection accused the three physicians of malpractice and asked the Medical Disciplinary Tribunal to pass judgment. In April 2006 one physician was struck from the physician register and the other two were suspended for 1 year and 6 months, respectively. These unusually severe measures were based mainly on the fact that they had neglected professional standards as defined by specialty boards, they had presented themselves as professional physicians and they had not tried hard enough to convince Millecam of the need for standard treatment. The Tribunal did not accept the strong desire of the patient to undergo only alternative treatment as a defence. Notably, the judgment of the Tribunal seems to be more severe than the present bylaws of medical-scientific bodies and the Dutch Medical Association (KNMG), which are apparently too lenient regarding the use of alternative treatments by their members.

[Medical-scientific societies, quality control and disfunctional physicians]. / Medisch-wetenschappelijke verenigingen, kwaliteitscontrole en disfunctionerende artsen.

One doctor denied an existing fatal malignancy and diagnosed cancer in patients who did not have it. He and two other doctors gave the impression that they could cure patients by methods of which the efficacy has not been demonstrated. All three were members of a society for alternative medicine; two of them no longer are. The third, an internist, is still a member of his alternative scientific medical society, but of the Netherlands Association of Internal Medicine as well. A clinical chemist with a private laboratory that continually diagnoses nutritional deficiencies in a disputable way, and a neurologist who cooperates with a highly controversial American back physician were not expelled from their associations nor corrected by them. The Dutch Health Inspectorate is investigating dysfunctioning physicians and may well take action against them. The medical-scientific societies could well pay closer attention to their task of promoting the quality of the professional activities of their members.

[Information about cancer treatment and the media]. / Voorlichting over kankerbehandeling en de media.

A 'hopeful' development in cancer treatment (angiostatin) was reported in the Dutch press, which led to considerable disquiet amongst patients. There were no scientific articles that warranted this press publication. It has previously been stated that it is unethical for medical researchers to inform the press about treatments which have not been scrutinized by the medical community. The press on the other hand, should maintain a more responsible attitude toward medical claims and double-check medical information, even when it comes from renowned medical researchers. The main distinction between mainstream medicine and medical quackery is that the former is based on the results of controlled published research. When physicians propagate results in the popular press that have not been critically evaluated by the medical community, the distinction between quackery and mainstream medicine is undermined.

Alternative treatments in reproductive medicine: much ado about nothing. "The fact that millions of people do not master arithmetic does not prove that two times two is anything else than four": W.F. Hermans.

The popularity of alternative medicine certainly also affects patients suffering from infertility. Alternative medicine started in the seventies but there have always been unorthodox practitioners, treating infertile women and men. Some historical examples will be described. The claims made for alternative medicine in the lay press have not been accompanied by similar reports in the mainstream medical journals. Practitioners and advocates of alternative medicine have used several strategies to defend their position. These were mostly of a philosophical nature, but more recently the practitioners of alternative medicine admit that the effectiveness of their therapies should be proven in randomized trials, as is considered mandatory in regular medicine. There are very few well-designed papers on the effectiveness of alternative medicine with the exception of one kind of paper that is hard for editors of medical journals to resist: seemingly impeccable papers proving absurd claims, whose mechanisms of action are, for instance, completely incomprehensible. We argue that this type of paper should be rejected for publication and indeed offer explanations for their mere existence.