Rob E. Bernardus

Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study *

In the present prospective study we compared, in terms of pregnancy rates, the differences between intrauterine insemination (IUI) of in vitro capacitated husbands semen and timed natural intercourse in spontaneous or clomiphene citrate (CC) stimulated cycles. A rapid urinary luteinizing hormone peak detection test was used for timing of ovulation. Forty patients suffering from longstanding infertility of male (n = 17), cervical (n = 2), and idiopathic (n = 21) origin were randomly assigned into four distinct treatment modalities during 4 consecutive cycles. A total of 132 cycles were analyzed. In 35 cycles treated with CC plus IUI, five conceptions were achieved, whereas three pregnancies occurred in 32 inseminated spontaneous cycles. Only 1 patient conceived after timed intercourse in 31 CC stimulated cycles, and no pregnancy resulted from 34 spontaneous cycles combined with timed intercourse. There was a statistically significant higher conception rate in cycles in which IUI was performed, whereas the use of CC does not seem to improve the pregnancy rate. Analysis of results for other modifying factors did not substantially affect the relative risk (odds ratio) of pregnancy.

17α-hydroxyprogesterone caproate for the prevention of adverse neonatal outcome in multiple pregnancies: a randomized controlled trial.

OBJECTIVE: To estimate whether administration of 17&agr;-hydroxyprogesterone caproate can prevent neonatal morbidity in multiple pregnancies by reducing the preterm birth rate. METHODS: We conducted a multicenter, double-blind, placebo-controlled randomized trial in 55 obstetric clinics in the Netherlands. Women with a multiple pregnancy were randomized to weekly injections of either 250 mg 17&agr;-hydroxyprogesterone caproate or placebo, starting between 16 and 20 weeks of gestation and continuing until 36 weeks of gestation. The main outcome measure was adverse neonatal outcome. Secondary outcome measures were gestational age at delivery and delivery before 28, 32, and 37 weeks of gestation. RESULTS: We randomized 671 women. A composite measure of adverse neonatal outcome was present in 110 children (16%) born to mothers in the 17&agr;-hydroxyprogesterone caproate group, and in 80 children (12%) of mothers in the placebo group (relative risk [RR] 1.34; 95% confidence interval [CI] 0.95–1.89). The mean gestational age at delivery was 35.4 weeks for the 17&agr;-hydroxyprogesterone caproate group and 35.7 weeks for the placebo group (P=.32). Treatment with 17&agr;-hydroxyprogesterone caproate did not reduce the delivery rate before 28 weeks (6% in the 17&agr;-hydroxyprogesterone caproate group compared with 5% in the placebo group, RR 1.04; 95% CI 0.56–1.94), 32 weeks (14% compared with 10%, RR 1.37; 95% CI 0.91–2.05), or 37 weeks of gestation (55% compared with 50%, RR 1.11; 95% CI 0.97–1.28). CONCLUSION: 17&agr;-hydroxyprogesterone caproate does not prevent neonatal morbidity or preterm birth in multiple pregnancies. CLINICAL TRIAL REGISTRATION: ISRCTN Register, www.isrctn.org, ISRCTN40512715. LEVEL OF EVIDENCE: I

Pregnancy rates after timed intercourse or intrauterine insemination after human menopausal gonadotropin stimulation of normal ovulatory cycles: a controlled study *

Forty-eight patients with male (n = 16) or idiopathic (n = 32) infertility were stimulated with human menopausal gonadotropin. Intrauterine insemination (IUI) or natural intercourse were performed after either human chorionic gonadotropin (hCG)-induced or spontaneous, urinary luteinizing hormone (LH) surge-monitored ovulation. A total of 148 cycles were analyzed. In 40 cycles treated with hCG-induced ovulation and IUI, 3 (7.5%) patients conceived, whereas 37 women accomplished natural intercourse after hCG-induced ovulation and 2 (5.5%) became pregnant. When inseminated after a spontaneous LH surge, 3 (8.8%) of 34 patients achieved a pregnancy; no conception occurred in 37 spontaneously ovulatory cycles combined with timed intercourse. Pregnancy rates did not substantially differ between the treatment modalities or between mono-ovulatory and polyovulatory cycles. The cycle characteristics between spontaneous ovulatory and hCG-induced cycles significantly did differ.

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.

Pituitary responsiveness after administration of a GnRH agonist depot formulation : decapeptyl CR

OBJECTIVE This study was focused on the pattern of LH release from the pituitary during the initial response to high dose GnRH agonist administration. Secondly, the pattern of LH release and the pituitary responsiveness to physiological and pharmacological stimulation during long‐term pituitary suppression by a high dose GnRH agonist was studied. In addition, the relation between serum agonist levels and pituitary function and responsiveness was investigated.

Pregnancy rate is significantly higher in in vitro fertilization procedure with spermatozoa isolated from nonliquefying semen in which liquefaction is induced by α-amylase

In 115 patients (group I) in which normal liquefaction of semen occurred, the fertilization rate of the yielded oocytes was 71.2% after standard in vitro fertilization procedure, and the viable pregnancy rate per patient per cycle was 13.0%. In a comparable group of 26 patients (group II), in which semen liquefaction did not occur spontaneously, alpha-amylase was added in order to liquefy the semen. In this group, the fertilization rate was 86.7% of the yielded oocytes, and the viable pregnancy rate per patient per cycle was 26.9% (P less than 0.05). It is concluded that alpha-amylase can be of use to liquefy nonliquefying semen, and that the resultant spermatozoa have a positive effect on pregnancy results.

Time schedules of intrauterine insemination after urinary luteinizing hormone surge detection and pregnancy results

A urinary luteinizing hormone (LH) test (LH Color, Organon, Oss, The Netherlands), was used to time intrauterine insemination in 177 cycles. Morning and evening urine samples were tested. In 58 women (33%) the test was positive in the morning urine sample. Fifteen of these patients were inseminated 8-10 h thereafter and one patient (6.7%) conceived. The remaining 43 women were inseminated the following day, 25-31 h after LH detection, and seven pregnancies (16.3%) ensued. In 119 cycles showing a positive urinary test in the evening sample, insemination was performed the next day, between 17 and 23 h after the LH surge, and 18 patients (15.1%) became pregnant. Statistical analysis showed no significant differences in pregnancy rates between the three different schedules, or in the time of insemination between conceptional and non-conceptional cycles within each group. Most ovulations occurred between 16 and 28 h after the positive test was observed. These findings suggest that while the lifespan of the gametes allows a relatively long period for fertilization, from 8 to 31 h after urinary LH surge detection, better results may be expected when inseminating about 24 (+/- 6) h after the positive test.

Identification of barriers for good adherence to a guideline on recurrent miscarriage

Objective. Guidelines on recurrent miscarriage are poorly implemented in daily clinical practice. To ensure proper implementation, we identified existing barriers and facilitators for guideline adherence according to professionals and patients. Design. Qualitative research. Setting. Two different regions in the Netherlands. Population. Forty‐two professionals: gynecologists, residents in obstetrics and gynecology, fertility doctors and clinical geneticists. Ten patients with recurrent miscarriage. Methods. Focus group interviews were performed with professionals and individual in‐depth interviews with patients. Reports from the interviews were analyzed and barriers were identified. Main Outcome Measures. Identified barriers, categorized in four domains, including characteristics of: (I) the guideline, (II) professionals, (III) patients, (IV) organization. Results. Ninety‐six barriers, at all four domains, were identified among professionals. The most frequently mentioned barriers were: guideline being too complicated in the consultancy room and finding it difficult to refuse demands of insistent patients. Patients mentioned 40 barriers, of which lack of up‐to‐date patient information and lack of detailed knowledge about family history were most frequently mentioned. Potential facilitators, such as an electronic decision tool and patient questionnaires prior to their first visit, were mentioned by both professionals and patients. All participants agreed that complete adherence to the guideline was theoretically achievable. Conclusions. Both professionals and patients experienced barriers and facilitators for guideline adherence in recurrent miscarriage. Guideline implementation strategies should take these identified barriers into account.

Timing oocyte collection in GnRH agonists down-regulated IVF and ICSI cycles: a randomized clinical trial

BACKGROUND The evidence underpinning the timing of an oocyte collection in IVF or ICSI is limited. The aim of this study was to assess the effect of the follicle diameter size of the dominant follicle on ongoing pregnancy rates. METHODS We conducted a randomized controlled trial, including women aged between 18 and 43 years who were scheduled for GnRH agonist down-regulated IVF/ICSI treatment in four assisted conception units. Women were randomized between timing oocyte collection when the leading follicle had a diameter of 22 mm or when the leading follicle had a diameter of 18 mm. The primary end-point was ongoing pregnancy, defined as a viable pregnancy at 12 weeks of gestation. RESULTS The trial had major problems with recruiting patients and after the planned 2 years of recruiting only half of the aimed 400 inclusions were obtained. We allocated 97 women to the 22-mm group and 93 women to the 18-mm group. In the 22-mm group more women reached an ongoing pregnancy (37 of 97 women, 38%) compared with the 18-mm group (22 of 93 women, 24%) resulting in a relative risk of 1.6 [95% confidence interval (CI): 1.03-2.5]. In a logistic regression analysis, the timing of oocyte collection, adjusted for female age, IVF/ICSI and centre, was still associated with ongoing pregnancy, although the association was no longer statistically significant (OR: 2.0; 95% CI: 0.96-4.2) CONCLUSIONS: This study suggests that delaying the timing of oocyte collection in IVF or ICSI results in better ongoing pregnancy rates, however, larger studies have to be performed to prove or refute these findings. TRIAL REGISTRATION ISRCTN24724622.

Comparison of early versus late initiation of GnRH antagonist co-treatment for controlled ovarian stimulation in IVF: a randomized controlled trial

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 INTEREST(S) 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. TRIAL REGISTRATION NUMBER www.clinicaltrials.gov, no. NCT00866034.