Roel Schats

Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost­ effectiveness analysis

BACKGROUND Couples affected by idiopathic subfertility or male subfertility have an estimated spontaneous conception rate of about 2% per cycle. Although various infertility treatments are available, counselling of a couple in their choice of treatment is difficult because of the lack of consistent data from good-quality comparative studies. We compared the results of treatment with intrauterine insemination (IUI) with those of in-vitro fertilisation (IVF), and did a cost-effectiveness analysis. METHODS In a prospective, randomised, parallel trial, 258 couples with idiopathic subfertility or male subfertility were treated for a maximum of six cycles of either IUI in the spontaneous cycle (IUI alone), IUI after mild ovarian hyperstimulation, or IVF. The primary endpoint was a pregnancy resulting in at least one livebirth after treatment. Cost-effectiveness based on real costs was studied by Markov chain analysis. FINDINGS 86 couples were assigned IUI alone, 85 IUI plus ovarian hyperstimulation, and 87 IVF. Ten couples dropped out before treatment began. Although the pregnancy rate per cycle was higher in the IVF group than in the IUI groups (12.2% vs 7.4% and 8.7%, respectively; p=0.09), the cumulative pregnancy rate for IVF was not significantly better than that for IUI. Couples in the IVF group were more likely than those in the IUI groups to give up treatment before their maximum of six attempts (37 [42%] drop-outs vs 13 [15%] and 14 [16%], respectively; p<0.01). The womans age was the only factor that influenced a couples chance of success. IUI was a more cost-effective treatment than IVF (costs per pregnancy resulting in at least one livebirth 8423-10661 Dutch guilders [US

Ovarian volume and antral follicle count for the prediction of low and hyper responders with in vitro fertilization

4511-5710] for IUI vs 27409 Dutch guilders [US

Borderline malignancy of the ovary and controlled hyperstimulation, a report of 2 cases.

14679] for IVF). INTERPRETATION Couples with idiopathic or male subfertility should be counselled that IUI offers the same likelihood of successful pregnancy as IVF, and is a more cost-effective approach. IUI in the spontaneous cycle carries fewer health risks than does IUI after mild hormonal stimulation and is therefore the first-choice treatment.

Contemporary Pharmacological Manipulation in Assisted Reproduction

BackgroundThe current study was designed to compare antral follicle count (AFC) and basal ovarian volume (BOV), the exogenous FSH ovarian reserve test (EFORT) and the clomiphene citrate challenge test (CCCT), with respect to their ability to predict poor and hyper responders.MethodsOne hundred and ten regularly menstruating patients, aged 18–39 years, participated in this prospective study, randomized, by a computer designed 4-blocks system study into two groups. Fifty six patients underwent a CCCT, and 54 patients underwent an EFORT. All patients underwent a transvaginal sonography to measure the basal ovarian volume and count of basal antral follicle. In all patients, the test was followed by a standard IVF treatment. The result of ovarian hyperstimulation during IVF treatment, expressed by the total number of follicles, was used as gold standard.ResultsThe best prediction of ovarian reserve (Y) was seen in a multiple regression prediction model that included, AFC, Inhibin B-increment in the EFORT and BOV simultaneously (Y = -3.161 + 0.805 × AFC (0.258-1.352) + 0.034 × Inh. B-incr. (0.007-0.601) + 0.511 BOV (0.480-0.974) (r = 0.848, p < 0.001). Univariate logistic regression showed that the best predictors for poor response were the CCCT (ROC-AUC = 0.87), the bFSH (ROC-AUC = 0.83) and the AFC (ROC-AUC = 0.83). Multiple logistic regression analysis did not produce a better model in terms of improving the prediction of poor response. For hyper response, univariate logistic regression showed that the best predictors were AFC (ROC-AUC = 0.92) and the inhibin B-increment in the EFORT (ROC-AUC = 0.92), but AFC had better test characteristics, namely a sensitivity of 82% and a specificity 89%. Multiple logistic regression analysis did not produce a better model in terms of predicting hyper response.ConclusionIn conclusion AFC performs well as a test for ovarian response being superior or at least similar to complex expensive and time consuming endocrine tests. It is therefore likely to be the test for general practise.

Effect of an oral contraceptive pill on follicular development in IVF/ICSI patients receiving a GnRH antagonist: a randomized study.

We report 2 patients who developed a borderline malignancy of the ovary after treatment with follicular stimulants in the context of an in vitro fertilisation (IVF) programme. In both cases, conservative surgery for the borderline malignancy was sufficient treatment. Ultimately, both patients became pregnant, 1 after IVF treatment and 1 without treatment, and both delivered healthy babies. In addition to the presentation of both cases, the literature concerning the possible risks of treating patients with high dosage, exogenously administered hormones is reviewed and the possible association between exogenous hormones and the risk of developing ovarian cancer is discussed.

Low-dose aspirin in non-tubal IVF patients with previous failed conception: a prospective randomized double-blind placebo-controlled trial

Follicle-stimulating hormone (FSH) treatment to induce follicular development in anovulating women and multiple follicular development for assisted conception has been incorporated in almost all reproductive treatment cycles in the form of either urinary, purified urinary or recombinant preparations. Besides improved tolerance and theoretically lower chances of infection by prions, the latter may be more effective in terms of clinical pregnancy rates, FSH requirement and cost effectiveness. The low-dose, step-up protocol to induce monofollicular development, which is applied worldwide, has to compete with the equally effective but health economically beneficial step-down protocol. The long protocol using recombinant FSH 150 IU/day is advocated when using gonadotropin-releasing hormone (GnRH) agonists in in vitro fertilisation (IVF) or intracytoplasmatic sperm injection treatment. However, the current paradigmatic hyperstimulation came under scrutiny after the introduction of the GnRH antagonists, which allow milder and more convenient approaches with acceptable cancellation and pregnancy rates but lower requirements for FSH. Risk of ovarian hyperstimulation syndrome (OHSS) can be further eliminated if recombinant luteinising hormone (rLH) or GnRH agonists are used to trigger oocyte maturation and ovulation; the latter require pituitary responsiveness and are therefore excluded in agonist protocols.FSH and LH are both required for appropriate folliculo- and steroidogenesis. In hypogonadotropic women, the addition of LH (human menopausal gonadotropin, human chorionic gonadotropin or rLH) is therefore obligate to achieve appropriate follicular growth and pregnancy. The role of LH in ovulation induction is still a matter of debate, although in GnRH agonistic protocols there seems to be a ’‘therapeutic window’; levels that are too high or too low have detrimental effects on IVF outcome.To broaden the pharmaceutical armoury, recent efforts have been directed towards the development of novel GnRH antagonists and FSH preparations with optimal pharmacokinetic, pharmacodynamic and safety profiles. Alternative strategies with fewer adverse effects and higher benefit/cost ratios are under development. However, before the GnRH agonist is abandoned for the antagonist as standard therapy, the cause of the observed possible lower pregnancy rates with the latter need to be clarified. In addition, prospective studies investigating possible direct effects of GnRH analogues, optimal dose-finding studies and treatment regimens under different conditions, with or without pharmacological coadministration and for different indications, should be performed to optimise the efficacy and tailor treatment strategies to individual needs.

Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer

This randomized controlled study compared the effectiveness of a gonadotrophin releasing hormone (GnRH) antagonist protocol with or without oral contraceptive (OC) pretreatment on the number of oocytes retrieved in IVF or intracytoplasmic sperm injection (ICSI) patients. Sixty-four patients were randomized to start recombinant human FSH (r-hFSH) on day 2 or 3 after OC withdrawal (OC group) or on day 2 of a natural cycle (control group). From stimulation day 6 onwards, all patients were treated with daily (0.5 mg/ml) GnRH antagonist (Antide). OC pretreatment resulted in significantly lower starting concentrations of FSH, LH and oestradiol (P < 0.001) and a thinner endometrium (P < 0.0001). In the early stimulation period, fewer large follicles were found after OC pretreatment, leading to a significantly extended stimulation period (11.6 versus 8.7 days, P < 0.0001) with more follicles on the day of recombinant human chorionic gonadotrophin administration (15.4 versus 12.5, P = 0.02) and more oocytes retrieved (13.5 versus 10.2, P < 0.001) as compared with the control group. GnRH antagonist regimen, pretreated with OC, prevented the early endogenous FSH rise and improved follicular homogeneity, resulting in more oocytes. As a consequence of the extended treatment period, more rhFSH was required.

Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF: a meta-analysis with individual patient data

OBJECTIVE To analyze whether the administration of low-dose aspirin during IVF treatment improves the uterine blood flow and improves ongoing pregnancy rates for non-tubal factor IVF patients with previous failed conception. DESIGN Prospective double-blind placebo-controlled trial. SETTING University fertility clinic. PATIENT(S) Non-tubal IVF patients with previous failed conception. INTERVENTION(S) Daily 100 mg aspirin or placebo throughout an IVF treatment with a long GnRH-agonist stimulation protocol. MAIN OUTCOME MEASURE(S) Ongoing pregnancy rate, pulsatility index of the uterine artery. RESULT(S) Of 169 patients, 84 were assigned to aspirin treatment and 85 to placebo treatment. In the aspirin group, 28 patients (35.4%) had an ongoing pregnancy, and in the placebo group, 26 patients (31.0%) had an ongoing pregnancy. Multilevel analyses showed that the pulsatility index of the uterine artery was not affected by aspirin or placebo treatment. CONCLUSION(S) Low-dose aspirin administration during IVF treatment does not improve pregnancy rates of non-tubal factor IVF patients with previous failed conception, and it does not affect the arterial uterine blood flow.

Ultrasonographic evidence that bedrest after embryo transfer is useless.

IMPORTANCE Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up. OBJECTIVE To assess long-term risk of breast cancer after ovarian stimulation for IVF. DESIGN, SETTING, AND PARTICIPANTS Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group. EXPOSURES Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires. MAIN OUTCOMES AND MEASURES Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]). RESULTS Among 25,108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes). CONCLUSIONS AND RELEVANCE Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

An unexpected guest in follicular fluid

STUDY QUESTION Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients? SUMMARY ANSWER The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women. WHAT IS KNOWN ALREADY Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion. STUDY DESIGN, SIZE, DURATION We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n = 131 treated with aspirin, n = 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n = 187) and preterm delivery (n = 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30-0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22-1.7) and OR 0.52 (95% CI 0.16-1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35-4.4) and OR 1.6 (95% CI 0.51-5.0), respectively. LIMITATIONS, REASONS FOR CAUTION We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis. WIDER IMPLICATIONS OF THE FINDINGS Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted.