Arie Verhoeff

The ovarian response as a predictor for successful in vitro fertilization treatment after the age of 40 years

OBJECTIVE To determine whether age or response to controlled ovarian hyperstimulation (COH) is a better predictor of IVF outcome in women > or = 40 years. 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 > or = 40 years. Analysis of cycles with a good ovarian response showed no statistically significant differences for these parameters between women > or = 40 years 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 > or = 40 years 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 40 years. Instead, the response to COH can be used to predict candidates likely to have a successful IVF outcome.

A comparison of in vitro fertilization results after embryo transfer after 2, 3, and 4 days of embryo culture

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.

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

BackgroundCosts 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/DesignMulticentre 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.DiscussionThe 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 registrationNTR2657

Treatment policy after poor fertilization in the first IVF cycle.

Purpose:The chance of recurrence of poor fertilization in a second in vitro fertilization (IVF) cycle was assessed.Methods:Total fertilization failure was defined, and the relationship between the fertilization rate and the number of motile sperm cells per milliliter of semen was assessed. Patients with a total fertilization failure or poor fertilization (20% or less of the oocytes fertilized) were divided into three subgroups with different chances of fertilization and were followed in a subsequent IVF cycle.Results:The recurrence rate of total fertilization failure was high in all three groups (45–70%), and poor fertilization frequently occurred in the second cycle (50–75%).Conclusions:Poor fertilization frequently recurs in the second IVF cycle. The use of intracytoplasmic sperm injection could be considered after fertilization of 20% or less of oocytes in the first cycle, irrespective of the number of motile sperm cells per milliliter of semen.

Elevated early follicular progesterone levels and in vitro fertilization outcomes: a prospective intervention study and meta-analysis

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.

Minimal monitoring of ovarian hyperstimulation: a useful simplification of the clinical phase of in vitro fertilization treatment

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.

Modulation of spontaneous myometrial activity in chronically instrumented ovariectomized sheep

The uterine electromyogram (EMG) and intrauterine pressure curves (IUP) were investigated as indicators of myometrial activity in chronically instrumented, ovariectomized ewes. Spontaneous electrical activity was characterized by rhythmic patterns of trains of bursts accompanied by IUP waves. Administration of adrenergic (propranolol or phentolamine) or cholinergic (atropine) blocking agents had no effect on spontaneous uterine activity. Both oxytocin and PGF2 alpha appeared to stimulate spontaneous myometrial activity. 17beta-Estradiol temporarily depressed uterine activity in a dose-dependent fashion. The period of relaxation was followed by a pronounced increase in activity. Progesterone treatment resulted in long-term suppression of myometrial activity. Oxytocin and PGF2alpha increased EMG and IUP activity during estradiol suppression but not after progesterone treatment. These results indicate that the myometrium is active in chronically instrumented, ovariectomized ewes. The autonomic nervous system or its receptors do not play a role in the maintenance of spontaneous myometrial activity, estradiol and progesterone suppress myometrical activity but by different mechanisms.

Comparison of results obtained with human serum and a protein solution as a supplement for in vitro fertilization culture medium.

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.

Transport intracytoplasmic sperm injection (ICSI): A cost-effective alternative

AbstractPurpose: 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. Methods: 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. Results: 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. Conclusions: 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.

A randomized, comparative study of a single oral dose of fluconazole versus a single topical dose of clotrimazole in the treatment of vaginal candidosis among general practitioners and gynaecologists

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.