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Item does not contain fulltext OBJECTIVE: To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis. DESIGN: Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis. SETTING: Reproductive medicine center in an university hospital. PATIENT(S): 158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients. INTERVENTION(S): Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively). MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) per started cycle. RESULT(S): The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n=1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P. CONCLUSION(S): From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low. CLINICAL TRIAL REGISTRATION NUMBER: NCT00866034.

study question: what is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? Summary answer: early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. What is known already: during ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. Study design, size, duration: this open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. Participants/materials, setting, methods: recombinant FSH (150–225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. Main results and the role of chance: there were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). Limitations, reasons for caution: the study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. Wider implications of the findings: the present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. Study funding/competing interests: this study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono

Objective To determine whether age or response to controlled ovarian hyperstimulation (COH) is a better predictor of IVF outcome in women≥40years. Design Retrospective analysis. Setting A transport IVF program. Patient(s) For patients undergoing IVF treatment the correlation between treatment outcome and age and response to COH was analyzed using the data of 2,588 consecutive cycles. Intervention(s) None. Main Outcome Measure(s) Pregnancy. Result(s) The incidence of poor ovarian response rises significantly with increasing age. Analysis of all cycles showed a significant decrease in clinical and ongoing pregnancy rate for women≥40years. Analysis of cycles with a good ovarian response showed no statistically significant differences for these parameters between women≥40years and those younger. A logistic regression analysis on pregnancy showed that ovarian response contributes more to the prediction of pregnancy than age. Conclusion(s) Patients aged≥40years with a good response to COH have a good prognosis for IVF treatment. The age limit for acceptance of patients should not be set at 40years. Instead, the response to COH can be used to predict candidates likely to have a successful IVF outcome.

Contains fulltext : 109739.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657.

Objectives: To compare efficacy, acceptability and patient preference of a single oral dose of fluconazole with a single intravaginal dose of 500 mg clotrimazole (medication groups) in women with vaginal candidosis visiting gynaecologists or general practitioners (study groups). Design : A comparative, randomized multicenter study. Events: Baseline visit and treatment, short-term follow-up after 1 week and long-term follow-up after 4 weeks. At each visit, symptoms were graded and cultures were obtained. Results: Symptomatic and mycological efficacy did not differ statistical significant in the medication groups or study groups. A complicated history regarding vaginal candidosis was more often found among gynaecologists, yielding poorer results of treatment. Patients preferred oral treatment over intra-vaginal treatment. Conclusions: No differences were found in the clinical and mycological efficacy of both drugs. Clinical results were related to parameters originating from the patients history, resulting in less favourable results in the study group of gynaecologists.

BACKGROUND: To test whether ovarian stimulation for in-vitro fertilization (IVF) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development, preimplantation genetic screening of embryos was employed in a prospective, randomized controlled trial, comparing two ovarian stimulation regimens. METHODS: Infertile patients under 38 years of age were randomly assigned to undergo a mild stimulation regimen using gonadotrophin-releasing hormone (GnRH) antagonist co-treatment (67 patients), which does not disrupt secondary follicle recruitment, or a conventional high-dose exogenous gonadotrophin regimen and GnRH agonist co-treatment (44 patients). Following IVF, embryos were biopsied at the eight-cell stage and the copy number of 10 chromosomes was analysed in 1 or 2 blastomeres. RESULTS: The study was terminated prematurely, after an unplanned interim analysis (which included 61% of the planned number of patients) found a lower embryo aneuploidy rate following mild stimulation. Compared with conventional stimulation, significantly fewer oocytes and embryos were obtained following mild stimulation ( P< 0.01 and

Objective: To assess the prevalence and etiology of the empty follicle syndrome (EFS). Design: Observational longitudinal study. Setting: Tertiary fertility centers. Patient(s): All patients beginning in vitro fertilization (IVF) treatment from December 2002 to November 2004 were included. Couples undergoing IVF with donor oocytes or participating in an experimental IVF study were excluded from analysis. Intervention(s): Identification of EFS cycles. Comparing ovarian hyperstimulation strategy, follicle count, and timing of human chorionic gonadotropin (hCG) for final oocyte maturation of the EFS cycles with normal IVF cycles. Main Outcome Measure(s): Number of follicles punctured, number of oocytes recovered, previous and future IVF attempts, and serum hormone levels. Result(s): Twenty-five of a total of 1,849 patients were identified with an EFS cycle. Reasons for occurrence of EFS cycles were mistiming of hCG for final oocyte maturation, premature ovulation, and poor ovarian response. None of the affected patients had experienced EFS cycles in earlier IVF attempts nor were there any recurrence in subsequent treatments. Conclusion(s): Accurate timing of induction of final oocyte maturation, properly scheduled ovarian hyperstimulation, instruction of patients and doctors, and full workup for IVF are essential for the successful recovery of oocytes. Occurrence of EFS in IVF can normally be attributed to a failure of at least one of these factors and probably rarely or never occurs otherwise.

Objective To establish the value of transcervical intrafallopian transfer of zygotes and the accuracy of fallopian cannulation. Design A prospective randomized study, comparing ultrasonically controlled transcervical intrafallopian transfer of zygotes with intrauterine transfer of cleaved embryos. Setting Department of IVF of the Rotterdam Academic Hospital. Patients One hundred forty-five patients with patent tubes entered the IVF program. Main Outcome Measure Pregnancy rates in both groups and ultrasound (US) assessment during fallopian cannulation and ET. Results Transvaginal cannulation of the tube appears not to be sufficiently accurate when performed without US guidance. Catheter damage occurred in many cases. The previously reported superior implantation rate after intrafallopian transfer in comparison with intrauterine transfer could not be confirmed. Conclusions Intrauterine transfer of cleaved embryos remains the method of choice in IVF.

The validity of the cumulative pregnancy rate (CPR) calculated by life-table approach, obtained in a transport in-vitro fertilization (IVF) programme, was tested by the determination of possible influence of selective drop-out of patients with a poor treatment prognosis. A cohort of 1211 patients who had a first IVF cycle was followed, and the CPR after three IVF cycles was assessed. First cycles of patients who discontinued treatment after failed IVF, and of those who did not achieve a pregnancy but proceeded to a subsequent cycle, were compared for fertilization rate and for occurrence of prognosticators of poor treatment outcome: oocyte yield < or =2, and replacement of

Prenatal cytogenetic analysis of 71 fetuses conceived by intracytoplasmic sperm injection (ICSI) resulted in the detection of nine (12.7%) chromosome aberrations including two cases of 47,XXY, four cases involving a 45,X cell line and three autosomal trisomies. Molecular analysis of the parental origin of the deleted or supernumerary chromosome was performed by using polymorphic microsatellite markers. Six cases involving a sex chromosome abnormality were found to be of paternal origin while the two trisomic cases that could be analysed were of maternal origin. Two cases involved the same infertile couple who had two consecutive ICSI pregnancies terminated because of a chromosome abnormality. The replaced embryos in both cases originated from a single batch of ICSI fertilized oocytes of which part was used to initiate the first pregnancy and part was cryopreserved and used to initiate the second pregnancy.

Objective To investigate whether the incidence and obstetric outcome of triplet pregnancies after IVF treatment justify strict limitation of the number of embryos to be replaced to two. Design Retrospective analysis. Setting A transport IVF program. Patient(s) All patients who had more than one embryo replaced. Intervention(s) None. Main Outcome Measure(s) Obstetric outcome, pregnancy. Result(s) High-order pregnancies occurred in 24 cases (23 triplets and 1 quadruplet). Three patients opted for selective embryo reduction (12.5%). Three triplet pregnancies spontaneously reduced to twins. Comparison of 18 triplets, reaching at least 20 weeks' gestation, with 54 twin pregnancies shows a higher perinatal mortality in the triplet group, causing 6 out of 18 patients to be confronted with at least one perinatal death. Triplets were born at a lower gestational age, had a lower birth weight, and a higher hospital admission rate of longer duration. Replacement of two, three, or four embryos did not lead to differences in pregnancy rates in the population studied. When a pregnancy occurred after replacement of three embryos, the risk of having a triplet pregnancy was 7.5%. Conclusion(s) The obstetric outcome of triplet pregnancies in our population indicates that triplet pregnancies after IVF treatment have to be prevented. Selective embryo reduction is acceptable for few patients only and can therefore not be seen as a solution. Replacement of three embryos results in triplet pregnancy in an unacceptably high percentage. Replacement of two embryos only gives acceptable IVF results and is the method chosen in the IVF program in Rotterdam to prevent triplet pregnancies. Fertil Steril ® 1997;67:290-5

TABLE OF CONTENTSIntroduction 345Materials and methods 346Ovarian hyperstimulation syndrome 346Adnexal torsion 349Complications of the transvaginal procedure 349Ectopic pregnancy 350Conclusion 351References 351Four different major clinical complications wereidentified in a retrospective analysis of 2495 in-vitrofertilization (IVF) cycles resulting in oocyte retrieval.The severe form of ovarian hyperstimulation syndrome(OHSS) occurred in 18 patients, giving a prevalence forthis complication of 0.7%. Seven (39%) of these 18 pa-tients had previously been diagnosed as having polycys-tic ovaries. Eleven patients were admitted withmoderate OHSS. Adnexal torsion was diagnosed in twopatients. Ovariectomy was considered necessary inboth cases. Complications of the transvaginal pro-cedure occurred in seven cases (0.3%): one patient hadan acute appendicitis with puncture holes in the appen-dix, six patients were admitted shortly after oocyte re-trieval with a pelvic inflammatory disease. Of the 624pregnancies obtained, 13 were ectopic, giving an ec-topic pregnancy rate of 2.1%. It is concluded that seri-ous clinical complications of IVF treatment are rare.However, patients should be counselled for the occur-rence of serious procedure-related complications be-fore entering an IVF programme.Key words: clinical complications/ectopic pregnancy/IVF/OHSSIntroductionIn-vitro fertilization (IVF) treatment is an elective pro-cedure. Clinical complications caused by the procedure aretherefore always iatrogenic. Although complications arereported to occur infrequently, counselling of patients onpossible complications of IVF treatment is necessary be-fore informed consent can be obtained. The incidence ofcomplications appears to differ between programmes andcould depend on various factors such as methods used forovarian stimulation, criteria used for cancellation of cycles,and techniques used for follicle aspiration and embryotransfer. Therefore, it seems advisable to inform patientsabout the incidence of clinical complications in the actualIVF programme they are about to join. To obtain data con-cerning the incidence of clinical complications leading tohospital admission in our transport IVF programme at theZuiderziekenhuis, Rotterdam, The Netherlands, a retro-spective analysis was carried out. In the population studied,four different major complications were identified: ovarianhyperstimulation syndrome (OHSS), adnexal torsion,pelvic inflammatory disease (PID) and ectopic pregnancy.The occurrence of high-order pregnancies is not discussedhere since this will be the subject of a separate paper. De-tailed reports have been published elsewhere on the occur-rence of a hepatitis-B infection related to the IVFlaboratory procedure (van Os et al., 1991). Psychologicalcomplications resulting from procedure-related stress ordisappointing treatment results can occur in IVF treatment.Although this aspect certainly needs attention, psychologi-cal reactions were not a subject of this study. Publicationson assisted reproduction that include information concern-ing complications are reviewed, and the findings of ourretrospective study are compared with these reports.

Transport in vitro fertilization (IVF) programs are operational in a lot of countries and especially popular in The Netherlands, where IVF activities are strictly regulated. Since the introduction of intracytoplasmic sperm injection (ICSI) in the IVF laboratory, many laboratories are now setting up this new technique, which necessitates major investments in terms of infrastructure and specialized personnel.We present a cost effective alternative, consisting of patient selection, preparation, and oocyte retrieval at one center and transport of oocytes to a second center, where the ICSI procedure and embryo transfer are performed. Since early 1994 several Dutch centers have a transport ICSI program running with the Gent University Infertility Center, and we wish to present the results of our cooperation with two major centers, comparing them to our local results, for the first 10 months of 1994. Patient selection was similar at all three centers: only couples with previously failed in vitro fertilization or having been refused for routine IVF were enrolled in the program. Stimulation schemes and follow-up of the stimulation were different at all three centers. Transport of oocytes was carried out in a transport box or by attaching the closed tubes containing the follicular aspirates to the chest of the husband. Transport times varied between 1.5 and 3 hr, depending on traffic conditions.Up to November 1, 1994, a total of 77 transport ICSI cycles and 294 own ICSI cycles were carried out. Although locally significantly more oocytes were retrieved and thus available for ICSI than in transport cycles, fertilization and pregnancy rates were not different between the two groups.These results suggest that long-distance transport of human oocytes seems not to be harmful to their capacity to be successfully injected and to further embryonic development and their implantation potential. Transport ICSI seems to be a valuable and cost-effective approach to treat high numbers of patients at a restricted number of highly specialized IVF laboratories, especially in countries where ICSI is not commonly available.

Objective To investigate the feasibility of IVF treatment with minimal monitoring during ovarian hyperstimulation. Design Retrospective analysis and prospective study with real-time control group. Setting Transport IVF program with transport clinic and satellite clinics. Patients One hundred consecutive IVF cycles monitored at a transport clinic and 100 concurrent consecutive cycles monitored at satellite clinics, using the same stimulation-monitoring protocol and resulting in oocyte aspiration, are compared retrospectively for the number of ultrasound (US) measurements carried out during monitoring and for results of IVF treatment. No patient selection took place. After introduction of a minimal monitoring protocol at a transport clinic, a prospective study was started comparing 100 minimal monitoring cycles at a transport clinic with 100 concurrent conventional monitoring cycles at satellite clinics, all resulting in oocyte aspiration. Patients entered the retrospective or prospective study only once. In all cases the same laboratory facility was used. Monitoring of ovarian hyperstimulation was done with US measurements only. Cycles were canceled for impending ovarian hyperstimulation syndrome (OHSS) when >35 follicles were seen to develop during hyperstimulation. Results Retrospective analysis shows no difference for the average number of US measurements at transport and satellite clinics (2.8±0.9 and 3.0±1.0; mean±SD). No differences were found in the number of ongoing pregnancies obtained in the two groups: 22 and 18, respectively. One case of severe OHSS occurred in the satellite clinic group. Introduction of minimal monitoring at the transport clinic gives a significant reduction of the average number of US measurements at the transport clinic compared with satellite clinics, where conventional monitoring continued to be used (1.5±0.8 versus 2.8±0.9). Ongoing pregnancies at transport and satellite clinics numbered 33 and 26, respectively. In both groups one patient developed severe OHSS. Sixty-two percent of cycles at the transport clinic were monitored with one US measurement only. No cancellations for impending OHSS occurred during the study period. Conclusion A large group of patients need only one US measurement during monitoring of ovarian hyperstimulation. Minimal monitoring gives a useful further simplification of the clinical phase of IVF treatment, without adverse effects on treatment outcome and incidence of OHSS.

A prospective controlled study was performed to compare the PRs obtained after use of a uniform IVF culture medium containing a pasteurized serum protein solution or patient serum. The ongoing PRs per ET in the serum and the protein solution group were 32% and 28%, respectively (not significant). Culture of supernumerary embryos showed blastocyst formation and even hatching with both supplements. The PR will not drop when this protein solution is used as a protein supplement in IVF culture medium instead of patient serum.

Embryo transfer results after a 2 to 4 day period of embryo culture were compared. Two thousand two hundred ninety-seven ETs, performed in 1991 and 1992, were analyzed. Ongoing pregnancy rates after 2, 3, or 4 days of embryo culture were 23.3%, 21.9%, and 26.4%, respectively. Multiple pregnancy rates were 36.2%, 38.8%, and 32.6% per ongoing pregnancy for the three groups, respectively. The implantation rate of 73 cavitating morulae on day 4 was surprisingly high (41%) compared with that of other developmental stages. Transfer after 4 days of culture gives the ability to recognize embryos with a very high implantation potential.

To compare efficacy, safety and patient preference of a single oral dose of 150 mg fluconazole with a single intravaginal dose of 1200 mg miconazole in vaginal candidosis. To investigate the effect of treatment on Candida colonization of throat and rectum.Double-blind, double-dummy, parallel, randomized trial. Ninety-nine patients with symptomatic and mycologically verified candidosis were given 150 mg fluconazole with an intravaginal dummy, or 1200 mg miconazole with an oral dummy. Patients with an inadequate short-term response were given a second dose.At each visit a patient self assessment and an investigators' global assessment were recorded, and cultures were set up. Adverse events were recorded and laboratory tests were performed. Clinical cure or improvement (investigators' assessment) was obtained in 100% (short-term) and 95% (long term) of the fluconazole group and in 94% and 90%, respectively, of the miconazole group. Patients considered the treatment excellent or good in 81% (short-term) and 88% (long-term) in the fluconazole group and in 84% and 76%, respectively, of the miconazole group. Mycological cure was achieved in 98% (short-term) and 73% (long-term) of the fluconazole group and in 96% and 82% respectively in the miconazole group. The differences in results were not significant. Both treatments significantly reduced the number of positive rectal cultures: neither treatment had a significant effect on throat cultures. Four percent of the patients preferred intravaginal therapy.A single dose fluconazole is as safe and effective as a single dose of miconazole.