J.L.H. Evers

The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis

BACKGROUNDnThe influence of multifollicular growth on pregnancy rates in subfertile couples undergoing intrauterine insemination (IUI) with controlled ovarian hyperstimulation (COH) remained unclear.nnnMETHODSnRelevant papers were identified by searching MEDLINE, EMBASE and the Cochrane Library. A meta-analysis was performed and Mantel-Haenszel pooled odd ratios (ORs) and risk differences with 99% confidence intervals (CIs) were calculated to express the relation between the number of follicles and pregnancy rates.nnnRESULTSnWe included 14 studies reporting on 11 599 cycles. The absolute pregnancy rate was 8.4% for monofollicular and 15% for multifollicular growth. The pooled OR for pregnancy after two follicles as compared with monofollicular growth was 1.6 (99% CI 1.3-2.0), whereas for three and four follicles, this was 2.0 and 2.0, respectively. Compared with monofollicular growth, pregnancy rates increased by 5, 8 and 8% when stimulating two, three and four follicles. The pooled OR for multiple pregnancies after two follicles was 1.7 (99% CI 0.8-3.6), whereas for three and four follicles this was 2.8 and 2.3, respectively. The risk of multiple pregnancies after two, three and four follicles increased by 6, 14 and 10%. The absolute rate of multiple pregnancies was 0.3% after monofollicular and 2.8% after multifollicular growth.nnnCONCLUSIONSnMultifollicular growth is associated with increased pregnancy rates in IUI with COH. Since in cycles with three or four follicles the multiple pregnancy rate increased without substantial gain in overall pregnancy rate, IUI with COH should not aim for more than two follicles. One stimulated follicle should be the goal if safety is the primary concern, whereas two follicles may be accepted after careful patient counselling.

Intra-cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in couples with non-male subfertility

BACKGROUNDnIn vitro fertilisation (IVF) and embryo transfer as treatment for male factor infertility is associated with lower fertilisation and pregnancy rates than for other indications. Since the late 1980s several assisted fertilisation techniques have emerged and have been rapidly developed to try to enhance results for couples with male factor infertility, or to help couples with severe male factor for whom conventional IVF was not possible. The technique of partial zona dissection (PZD) was developed to increase the probability that a sperm capable of fertilisation comes in contact with the oocyte. Although this method improved conventional IVF results, the improvement was only marginal and relatively large numbers of sperm are still required. This drawback applied less to the subsequent technique of subzonal microinjection of spermatozoa into the perivitelline space (SUZI). However, for all of these techniques fertilisation rates remained low, rates of polyspermic fertilisation were increased, and cases with a very limited number of spermatozoa in the ejaculate could still not be treated. The advent of intra-cytoplasmatic sperm injection (ICSI) of a single sperm (or sperm head or nucleus) into the oocyte appears to be an important breakthrough.nnnOBJECTIVESnTo investigate whether ICSI improves fertilisation and/or pregnancy rates in comparison to other fertilisation techniques.nnnSEARCH STRATEGYnThe Menstrual Disorders and Subfertility Group search strategy (see Review Group details) was used to identify trials that had compared ICSI with other infertility techniques, such as PZD, SUZI, conventional IVF and additional IVF.nnnSELECTION CRITERIAnTrials were included if they compared the effects of these techniques on fertilisation and pregnancy outcomes. Only randomised studies were included in this review.nnnDATA COLLECTION AND ANALYSISnTen studies met the inclusion criteria for this review. Eight studies compared ICSI with conventional IVF. One study compared ICSI with SUZI and one study compared ICSI with additional IVF. Data was extracted independently by two reviewers. Where relevant data was missing or unclear, the authors had been consulted. Male participants were classified according to their semen parameters, i.e. normal semen (concentration >20 million per ml, motility >50%, morphology >14%), borderline semen (concentration 10-20 million per ml, motility 30-50%, morphology 4-14% normal forms) and very poor semen (concentration <10 million per ml, motility <30%, morphology <4% normal forms).nnnMAIN RESULTSnFor couples with normal semen there is no evidence of a difference in fertilisation rates per retrieved oocyte or pregnancy rates between ICSI and conventional IVF. On the other hand, for fertilisation rate per inseminated oocyte, ICSI appears to result in better outcomes than IVF for normal semen. For couples with borderline semen ICSI results in higher fertilisation rates (all) than IVF. Couples with very poor semen will have better fertilisation outcomes with ICSI than with SUZI or additional IVF.nnnREVIEWERS CONCLUSIONSnThere is evidence from this systematic review that fertilisation rates are significantly better with ICSI than IVF in couples with borderline semen. When the semen parameters are normal there is insufficient evidence of a difference in effectiveness between ICSI and IVF when retrieved oocytes were the unit of randomisation. However, there was a small but statistically significant increase in fertilisation rate when inseminated oocytes were the unit of randomisation. Total fertilisation rates were significantly reduced in ICSI cycles than IVF but there were no damaged oocytes in IVF cycles regardless of the semen parameters.

Intra-venous fluids preventing severe ovarian hyperstimulation syndrome

BACKGROUND Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic condition that occurs after the administration of human menopausal gonadotrophin (hMG) with or without gonadotrophin releasing hormone (GnRH) agonists. OHSS is a threat to every woman undergoing ovulation induction and is potentially lethal in its severest form. Severe OHSS is characterised by growth of multiple large follicles with massive extravascular protein rich fluid shift. This may lead to hypovolaemia, haemoconcentration, oliguria, and electrolyte disturbance. Human albumin solutions are now used in the management of shock and other conditions in which restoration of blood volume is urgent, the acute management of burns, and clinical situations associated with hypoproteinaemia. Recently, a number of clinical trials with conflicting results have been reported in which albumin has been tested as a possible way for preventing the severe form of OHSS. OBJECTIVES To review the effectiveness of human albumin administration in prevention of severe ovarian hyperstimulation syndrome. SEARCH STRATEGY The Menstrual Disorders and Subfertility Group literature search strategy was used to identify randomised trials that had compared the use of human albumin with placebo or no treatment in the prevention of severe ovarian hyperstimulation syndrome. A diverse search strategy was employed, including handsearching of core journals from 1966 to November 2001, searching bibliographies of relevant trials, MEDLINE, EMBASE, PsychLIT and CINAHL databases, the MDSG specialised register, abstracts from North American and European meetings and contact with authors of relevant papers. SELECTION CRITERIA Trials were included if they compared the effect of human albumin with placebo or no treatment on relevant outcomes. Only randomised controlled studies were included in this review. DATA COLLECTION AND ANALYSIS Seven randomised controlled trials were identified, five of which met our inclusion criteria and enrolled 378 women (193 in the albumin treated group and 185 in the control group). Trials under consideration were evaluated for methodological quality and appropriateness for inclusion without consideration of their results.The five included trials were single-centre parallel randomised controlled studies. Relevant data were extracted independently by two reviewers using the standardized data extraction sheet. Validity was assessed in terms of method of randomisation, completeness of follow-up, presence or absence of crossover and co-intervention. DATA SYNTHESIS 2x2 tables were generated for all relevant outcomes. Odds ratios were calculated using the Peto modified Mantel-Haenszel technique. MAIN RESULTS Meta-analysis of the five included trials demonstrated significant reduction in severe ovarian hyperstimulation syndrome on administration of human albumin (odds ratio was 0.28 (95% CI 0.11 to 0.73). Relative risk was 0.35 (0.14 - 0.87) and absolute risk reduction was 5.5. For every 18 women at risk of severe OHSS, albumin infusion will save one more case. There was no evidence of an increase in the pregnancy rate (odds ratio was 1.09, (95% CI 0.65 to 1.83) REVIEWERS CONCLUSIONS: This review shows a clear benefit from administration of intra-venous albumin at the time of oocyte retrieval in prevention of severe OHSS in high-risk cases. Whether the NNT would justify the routine use of albumin infusion in cases at risk of severe OHSS needs to be judged by clinical decision makers.

Melanoma risk after ovarian stimulation for in vitro fertilization

STUDY QUESTIONnDo women treated with ovarian stimulation for IVF have an increased risk of melanoma?nnnSUMMARY ANSWERnOvarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up.nnnWHAT IS KNOWN ALREADYnAlthough exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group.nnnSTUDY DESIGN, SIZE, DURATIONnIn 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnThe cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database.nnnMAIN RESULTS AND THE ROLE OF CHANCEnIn total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21).nnnLIMITATIONS, REASONS FOR CAUTIONnDespite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses.nnnWIDER IMPLICATIONS OF THE FINDINGSnOur results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence.nnnSTUDY FUNDING/COMPETING INTERESTnThis study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.