Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Is home-based monitoring of ovulation to time frozen embryo transfer a cost-effective alternative for hospital-based monitoring of ovulation? Study protocol of the multicentre, non-inferiority Antarctica-2 randomised controlled trial.

STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman's point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN SIZE DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS SETTING METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTERESTS: The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017. DATE OF FIRST PATIENT'S ENROLMENT: 10 April 2018.

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH).

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.

QTL mapping in diploid potato by using selfed progenies of the cross S. tuberosum × S. chacoense.

Usually, mapping studies in potato are performed with segregating populations from crosses between highly heterozygous diploid or tetraploid parents. These studies are hampered by a high level of genetic background noise due to the numerous segregating alleles, with a maximum of eight per locus. In the present study, we aimed to increase the mapping efficiency by using progenies from diploid inbred populations in which at most two alleles segregate. Selfed progenies were generated from a cross between S. tuberosum (D2; a highly heterozygous diploid) and S. chacoense (DS; a homozygous diploid clone) containing the self-incompatibility overcoming S locus inhibitor (Sli-gene). The Sli-gene enables self-pollination and the generation of selfed progenies. One F2 population was used to map several quality traits, such as tuber shape, flesh and skin color. Quantitative trait loci were identified for almost all traits under investigation. The identified loci partially coincided with known mapped loci and partially identified new loci. Nine F3 populations were used to validate the QTLs and monitor the overall increase in the homozygosity level.

Cervical length measured by transvaginal ultrasonography versus Bishop score to predict successful labour induction in term pregnancies.

OBJECTIVES: To compare the value of transvaginal ultrasonographic measurement of the cervical length versus the Bishop score, prior to induction of labour, in predicting the mode of delivery within four days. MATERIALS AND METHODS: This longitudinal study included 110 women (at term, singleton, vertex presentation) in whom induction of labour was performed at 37-42 weeks of gestation. Cervical length on transvaginal ultrasound and the Bishop score were assessed prior to induction according to standard protocol. Medical records were reviewed for relevant-- demographic and clinical data. Primary outcome criterion was successful vaginal delivery within 96 h. Univariate analyses and receiver operating characteristic (ROC) curves were used to examine differences between variables possibly predicting outcome. RESULTS: Of the 110 women 66 were nulliparous and 44 multiparous. Vaginal delivery within 96 h was successful in 48 (73%) nulliparous and in 40 (91%) multiparous women ( i.e. in 80% of the total population). The overall rate of caesarean delivery was 17%. THERE WAS A SIGNIFICANT DIFFERENCE BETWEEN NULLIPAROUS AND MULTIPAROUS WOMEN IN AGE, CERVICAL LENGTH (MEAN IN MM IN NULLIPAROUS WOMEN: 29.31, range: 5.00-56.00; in multiparous women: 37.04, range: 12.00-56.00), Bishop score and successful induction, but no significant difference between these subgroups in neonatal outcomes. Only the Bishop score in nulliparous women showed a significant relationship between this variable and predicting successful labour induction (area under the ROC curve 0.679; standard error 0.73; p < 0.05; 95% CI: 0.536-0.823). The best cut-off value for the Bishop score was 3, with a sensitivity of 56.3% and a specificity of 72.2%. CONCLUSION: In this study group significant independent prediction of vaginal delivery within 96 h is provided by the Bishop score but only in nulliparous women. Transvaginal ultrasonographic measurement of cervical length is not a significant independent predictor of vaginal delivery within 96 h.

The inheritance of chilling tolerance in tomato (Lycopersicon spp.).

During the past 25 years, chilling tolerance of the cultivated (chilling-sensitive) tomato Lycopersicon esculentum and its wild, chilling-tolerant relatives L. peruvianum and L. hirsutum (and, less intensively studied, L. chilense) has been the object of several investigations. The final aim of these studies can be seen in the increase in chilling tolerance of the cultivated genotypes. In this review, we will focus on low-temperature effects on photosynthesis and the inheritance of these traits to the offspring of various breeding attempts. While crossing L. peruvianum (male symbol) to L. esculentum (female symbol) so far has brought the most detailed insight with respect to physiological questions, for practical purposes, e.g., the readily cross ability, crossing programmes with L. hirsutum as pollen donor at present seem to be a promising way to achieve higher chilling-tolerant genotypes of the cultivated tomato. This perspective is due to the progress that has been made with respect to the genetic basis of chilling tolerance of Lycopersicon spp. over the past five years.

Parthenocarpic fruit development in tomato.

Parthenocarpic fruit development is a very attractive trait for growers and consumers. In tomato, three main sources of facultative parthenocarpy, pat, pat-2, pat-3/pat-4, are known to have potential applications in agriculture. The parthenocarpic fruit development in these lines is triggered by a deregulation of the hormonal balance in some specific tissues. Auxins and gibberellins are considered as the key elements in parthenocarpic fruit development of those lines. An increased level of these hormones in the ovary can substitute for pollination and trigger fruit development. This has opened up genetic engineering approaches for parthenocarpy that have given promising results, both in quality and quantity of seedless fruit production.

The integration of recombination and physical maps in a large-genome monocot using haploid genome analysis in a trihybrid allium population.

Integrated mapping in large-genome monocots has been carried out on a limited number of species. Furthermore, integrated maps are difficult to construct for these species due to, among other reasons, the specific plant populations needed. To fill these gaps, Alliums were chosen as target species and a new strategy for constructing suitable populations was developed. This strategy involves the use of trihybrid genotypes in which only one homeolog of a chromosome pair is recombinant due to interspecific recombination. We used genotypes from a trihybrid Allium cepa x (A. roylei x A. fistulosum) population. Recombinant chromosomes 5 and 8 from the interspecific parent were analyzed using genomic in situ hybridization visualization of recombination points and the physical positions of recombination were integrated into AFLP linkage maps of both chromosomes. The integrated maps showed that in Alliums recombination predominantly occurs in the proximal half of chromosome arms and that 57.9% of PstI/MseI markers are located in close proximity to the centromeric region, suggesting the presence of genes in this region. These findings are different from data obtained on cereals, where recombination rate and gene density tends to be higher in distal regions.

Biodiversity assessment based on cpDNA and crossability analysis in selected species of Allium subgenus Rhizirideum.

The chloroplast DNA diversity of 33 accessions belonging to 16 species of five sections in Allium subgenus Rhizirideum was studied by analysing the sequence of three fragments: the trnL-F intergenic spacer, the rps 16 intron and rbcL (rubisco large subunit). The three sections Cepa, Schoenoprasum and Rhizirideum, representing the majority of the included species, each possess a separate clade after phylogenetic analysis. Exceptions to this general rule are the placement of Allium pskemense (section Cepa) connected to Allium senescens (section Rhizirideum) and Alium roylei, taking an intermediate position between sections Cepa and Schoenoprasum. Both species were located in their own section after nuclear DNA analysis. A range of crossing experiments has been carried out. The different position of A. roylei when comparing cpDNA and nDNA diversity was not confirmed with the production of hybrid seeds after crossing A. roylei with species other than those of section Cepa. The different position of A. pskemense in the cpDNA and the nDNA tree can not be compared to its crossability, since only a few crossing experiments are reported for this species. The hypothesis that a shorter distance between two species in a cpDNA tree compared to their distance in a nDNA tree will indicate interfertility at a certain level, is neither confirmed nor rejected by the currently available results.

Residual ovarian activity during oral steroid contraception.

Steroid drugs with contraceptive properties have been available in the clinical setting for over four decades and are still subject to improvement. Estrogens, progestins and anti-progestins have been used alone or in various combinations, regimens and routes of administration to favour the balance between efficacy and undesirable effects. One of the most important changes in this respect is the gradual lowering of steroid dosage in commercially available contraceptives. Current steroid contraceptive pills still achieve the goal of suppression of pituitary-ovarian activity, but the margins for error are minimal. In this review the available data on modes of action and the effects on suppressing pituitary-ovarian activity by different forms of oral contraception are reassessed. Although pregnancy rates provide a crude measure of contraceptive efficacy, no benchmark for pituitary-ovarian inhibition is available to test the suppressive potential of contraceptive drugs. Consequently, many studies provide incomplete and/or incomparable results. For the further study of those forms of steroid contraception that rely predominantly on suppression of ovarian activity, prevention of dominant follicles selection should be the objective.

Improving cycle control in progestogen-only contraceptive pill users by intermittent treatment with a new anti-progestogen.

BACKGROUND: The safety and efficacy of the anti-progestogen Org 31710 in improving cycle control in healthy women using the desogestrel progestogen-only pill was investigated in this randomized, double-blind, placebo-controlled study. METHODS: A total of 103 women using the 75 micro g desogestrel progestogen-only pill daily also received either 150 mg Org 31710 or placebo once every 28 days, starting on day 1, for a duration of 4-7 treatment cycles. RESULTS: The percentage of women with bleeding or spotting (B/S) every day in the placebo group was on average 30% during the whole treatment period and no days without reported B/S occurred. In contrast, a cyclic pattern was observed for the Org 31710 group; a peak incidence of B/S was observed on day 3 or 4 of each cycle, followed by a sharp decrease on cycle days 9-15. Compared with controls, less subjects in the Org 31710 group reported irregular, frequent or prolonged bleeding. These differences were clearly observed in the initial cycles, but were somewhat less pronounced during the later cycles of the treatment period. A relatively high incidence of B/S episodes starting in the second section of the cycle was also observed. CONCLUSION: The addition of Org 31710 once a month improved cycle control in women using daily treatment with 75 micro g desogestrel.

FSH and ovarian response: spontaneous recovery of pituitary-ovarian activity during the pill-free period vs. exogenous recombinant FSH during high-dose combined oral contraceptives.

OBJECTIVE: Compare spontaneous recovery of pituitary-ovarian activity during the pill-free period following the correct use of low-dose oral contraceptives and subsequent ovarian function during the administration of exogenous recombinant FSH (recFSH) after switching to continued Lyndiol (2.5 mg lynestrenol + 0.05 mg ethinyl-oestradiol) medication. DESIGN: Prospective, randomized, group-comparative, single-centre study. Following the monitoring of the pill-free period (week 1) and subsequent treatment with Lyndiol (for a total of 5 weeks), all subjects were randomly allocated to one of four groups receiving daily FSH injections for 1 week [75, 150, 225 IU recFSH or 150 IU purified urinary FSH (uFSH)] during the fourth week of Lyndiol use. PATIENTS: Thirty-six healthy volunteers aged 18-39 years, prestudy oral contraceptive use for at least 3 months, cycle length between 24 and 35 days. MEASUREMENTS: Serum FSH, LH and oestradiol (E2) concentrations as well as transvaginal ultrasound assessment of the number and diameter of follicles > 2 mm were used to monitor pituitary ovarian function. RESULTS: At the start of the pill-free period following the prestudy contraceptive medication, 67% of the women presented with LH and FSH levels < 1 IU/l and only one follicle > 10 mm was observed. Initial levels of LH and FSH correlated (P < 0.05) with the extent of pituitary-ovarian activity during the pill-free period. At the end of the pill-free period a follicle > 10 mm had emerged in one subject only. During the first 3 days of Lyndiol use, seven women (19%) eventually showed at least one follicle > 10 mm. During combined exogenous FSH and Lyndiol administration, LH levels remained completely suppressed (< or = 0.5 IU/l) in all women studied. FSH levels and number and size of follicles increased with increasing doses of exogenous FSH in a dose-dependent manner. E2 levels remained low in all groups (< 150 pmol/l). During the week following FSH administration, FSH levels and E2 levels decreased gradually while the number of follicles > 10 mm still increased. CONCLUSIONS: We have confirmed that dominant follicles > 10 mm are present at the end of the pill-free period and during the first days after resumption of pill intake. Once follicles > 10 mm arose at the end of the pill-free period, continued use of Lyndiol did not reduce follicle diameters. One week of Lyndiol reduces pituitary-ovarian activity to levels observed after 3 weeks of low-dose pills. FSH administration during Lyndiol resulted in dose-dependent follicle growth despite extremely low LH levels. E2 secretion (56 +/- 51 pmol/l) occurred to a limited and variable extent along with extremely low serum LH concentrations. Recovery of pituitary-ovarian activity at the end of the pill-free period is comparable to FSH levels and follicle dynamics following 7 days of 75-150 IU/l recFSH.

Single monthly administration of the anti-progestagen Org 31710 in users of the 75 microg desogestrel progestagen-only pill: effects on pituitary-ovarian activity.

Endocrine and ultrasound effects were studied of an intermittent (every 28 days) oral administration of 150 mg of the anti-progestagen Org 31710 during the continued daily use of 75 microg desogestrel (DSG) for progestagen-only contraception. A randomized, double-blind, placebo-controlled two-centre study was conducted in 50 healthy volunteers. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and progesterone concentrations, and follicle number and size were studied, as well as endometrial thickness, which was assessed by transvaginal sonography at least twice weekly during a single medication cycle (cycle 3-5). Forty-eight women were evaluated (Org 31710, n = 25; placebo, n = 23). Seven ovulations were observed in the treated group versus none in the placebo group. LH concentrations were higher on days 9 and 11 and oestradiol concentrations lower on day 3 in the treated group, irrespective of whether ovulation occurred. No parameter could predict ovulation. Endometrial thickness was greater on cycle days 7-13 and 19 in the treated group. However, within the Org 31710 group, no significant differences were found in volunteers who did or did not ovulate. Observed differences may be attributed to a competitive effect of Org 31710 with progestagen-induced suppression of the pituitary-ovarian axis, altered oestradiol feedback mechanisms, and/or altered receptor availability.

Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives.

This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by transvaginal sonography daily during the 7-day pill-free interval in 44 healthy volunteers using three different low-dose oral contraceptives. Healthy volunteers were enrolled using 20 micrograms ethinyl estradiol (EE) + 75 micrograms gestodene (GSD) (Harmonet, Wyeth-Lederle; n = 15), 20 micrograms EE + 150 micrograms desogestrel (DSG) (Mercilon, Organon n = 17), or 30 micrograms EE + 150 micrograms DSG (Marvelon, Organon, n = 12) given according to the usual regimen of one tablet daily during 3 weeks and 1 week pill-free interval. No ovulations were observed. Pituitary hormones were not statistically significantly different at the beginning of the pill-free interval between the study groups. FSH concentrations were significantly higher at the end of the pill-free interval in the 30 micrograms EE group compared with both 20 micrograms EE groups (7.0 [0.6-12.4] IU/L vs 4.9 [1.4-6.1] IU/L and 4.5 [2.4-7.4] IU/L; p = 0.001). In both 20 micrograms EE groups, a single persistent follicle (24 and 28 mm) was present in one subject. Follicle diameters were statistically significantly smaller at the beginning and at the end of the pill-free period in the 30 micrograms EE group compared with both 20 micrograms EE study groups. Dominant follicles (defined as follicle diameter > or = 10 mm) were observed at the end of the pill-free interval in both 20 micrograms EE groups (in 27% and 18% of women, respectively) but not in the 30 micrograms EE group. Finally, the area-under-the-curve for E2 was statistically significantly lower in the 30 micrograms EE group compared with both 20 micrograms EE groups. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 micrograms EE study groups.

PIP: This article reports on a study that evaluated pituitary-ovarian recovery in the pill-free interval during a period of use of one of three low-dose combined oral contraceptives (COC). 44 female volunteers using low-dose oral contraception were subdivided into three groups in this comparative study: 15 women used 20 mcg ethinyl estradiol (EE) + 75 mcg gestodene; 17 used 20 mcg EE + 150 mcg desogestrel; 12 used 30 mcg EE + 150 mcg desogestrel. No ovulations were observed. Pituitary hormone levels between the study groups were not significantly different at the beginning of the pill-free interval. Follicle-stimulating hormone (FSH) concentrations were significantly higher at the end of the pill-free interval in the 30 mcg EE group than in both 20 mcg EE groups. In each of the 20 mcg EE groups, a single persistent follicle (24 mm and 28 mm, respectively) was found in 1 subject. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval.

Cumulative pregnancy rates and selective drop-out of patients in in-vitro fertilization treatment.

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 <2 embryos. The CPR after three cycles was 54.9%. No differences were found in the first and second cycles of patients who continued treatment and those who dropped out. Selective drop-out of patients with a poor treatment prognosis was not found. Therefore, although calculations of CPR using life-table analysis generally overestimate the real probability of pregnancy after successive IVF cycles, the calculated CPR after three IVF cycles gives a reliable indication of the chance of occurrence of a pregnancy for the population studied.

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.

A triplet pregnancy after in vitro fertilization is a procedure-related complication that should be prevented by replacement of two embryos only.

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.

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.