Cumulative live birth rates in low-prognosis women

No external funds were obtained for the present study. The OPTIMIST study was funded by The Netherlands Organization for Health Research and Development (ZonMW number 171102020).Peer reviewedPublisher PD

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

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

Individualized versus standard FSH dosing in women starting IVF/ICSI:An RCT. Part 1: The predicted poor responder

STUDY QUESTION: Does an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI? SUMMARY ANSWER: In women with a predicted poor ovarian response (AFC <11) undergoing IVF/ICSI, an increased FSH dose (225/450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day). WHAT IS KNOWN ALREADY: In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered. STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC <11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC ≤ 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8–10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 511 women were randomized, 234 with an AFC ≤ 7 and 277 with an AFC 8–10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78–1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: €1099 (95%CI, 562–1591)], standard FSH dosing was the dominant strategy in our economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy. WIDER IMPLICATIONS OF THE FINDINGS: Since an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC <11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women

Influence of endometrial thickness on pregnancy rates in modified natural cycle frozen-thawed embryo transfer

Introduction: Pregnancy after frozen-thawed embryo transfer (FET) is a multifactorial process. Although embryo quality is a key factor in determining pregnancy, other factors, including maternal determinants, are also considered to be predictive. Even though an association between endometrial thickness measured by transvaginal ultrasound and pregnancy rates has been reported in patients undergoing various assisted reproductive technology treatments, whether endometrial thickness predicts achieving pregnancy after natural cycle FET (NC-FET) remains unclear. Material and methods: In this cohort study, 463 patients allocated to the modified NC-FET (mNC-FET) arm of a previously published randomized controlled trial were included. Monitoring in mNC-FET cycles consisted of regular ultrasound scans, measuring both dominant follicle and endometrial thickness. When the dominant follicle reached a size of 16–20 mm, an injection of human chorionic gonadotrophin was administered and embryo thawing and transfer planned. No minimal endometrial thickness was defined below which transfer was to be deferred. The primary endpoint was ongoing pregnancy rate. Results: Overall, the ongoing pregnancy rate per started FET cycle was 12.5%. Multivariate regression analyses showed that embryo quality was the only significant predictor for ongoing pregnancy. Mean endometrial thickness did not differ between patients achieving ongoing pregnancy and those who did not (9.0 vs. 8.8 mm, p = 0.4). Comparable results were obtained with regard to clinical pregnancy, live birth and miscarriage rates. The area under the receiver operator curve was 0.5, indicating little discriminatory value of endometrial thickness. Conclusions: Given that endometrial thickness was not found to be predictive of pregnancy after mNC-FET, cancellation based on endometrial thickness alone may not be justified

The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial.

Contains fulltext : 109856.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: In in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment a large drop is present between embryo transfer and occurrence of pregnancy. The implantation rate per embryo transferred is only 30%. Studies have shown that minor intrauterine abnormalities can be found in 11-45% of infertile women with a normal transvaginal sonography or hysterosalpingography. Two randomised controlled trials have indicated that detection and treatment of these abnormalities by office hysteroscopy after two failed IVF cycles leads to a 9-13% increase in pregnancy rate. Therefore, screening of all infertile women for intracavitary pathology prior to the start of IVF/ICSI is increasingly advocated. In absence of a scientific basis for such a policy, this study will assess the effects and costs of screening for and treatment of unsuspected intrauterine abnormalities by routine office hysteroscopy, with or without saline infusion sonography (SIS), prior to a first IVF/ICSI cycle. METHODS/DESIGN: Multicenter randomised controlled trial in asymptomatic subfertile women, indicated for a first IVF/ICSI treatment cycle, with normal findings at transvaginal sonography. Women with recurrent miscarriages, prior hysteroscopy treatment and intermenstrual blood loss will not be included. Participants will be randomised for a routine fertility work-up with additional (SIS and) hysteroscopy with on-the-spot-treatment of predefined intrauterine abnormalities versus the regular fertility work-up without additional diagnostic tests. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomisation. Secondary study outcome parameters are the cumulative implantation rate; cumulative miscarriage rate; patient preference and patient tolerance of a SIS and hysteroscopy procedure. All data will be analysed according to the intention-to-treat principle, using univariate and multivariate logistic regression and cox regression. Cost-effectiveness analysis will be performed to evaluate the costs of the additional tests as routine procedure. In total 700 patients will be included in this study. DISCUSSION: The results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment. TRIAL REGISTRATION: NCT01242852

Influence of endometrial thickness on pregnancy rates in modified natural cycle frozen-thawed embryo transfer

IntroductionPregnancy after frozen-thawed embryo transfer (FET) is a multifactorial process. Although embryo quality is a key factor in determining pregnancy, other factors, including maternal determinants, are also considered to be predictive. Even though an association between endometrial thickness measured by transvaginal ultrasound and pregnancy rates has been reported in patients undergoing various assisted reproductive technology treatments, whether endometrial thickness predicts achieving pregnancy after natural cycle FET (NC-FET) remains unclear. Material and methodsIn this cohort study, 463 patients allocated to the modified NC-FET (mNC-FET) arm of a previously published randomized controlled trial were included. Monitoring in mNC-FET cycles consisted of regular ultrasound scans, measuring both dominant follicle and endometrial thickness. When the dominant follicle reached a size of 16-20 mm, an injection of human chorionic gonadotrophin was administered and embryo thawing and transfer planned. No minimal endometrial thickness was defined below which transfer was to be deferred. The primary endpoint was ongoing pregnancy rate. ResultsOverall, the ongoing pregnancy rate per started FET cycle was 12.5%. Multivariate regression analyses showed that embryo quality was the only significant predictor for ongoing pregnancy. Mean endometrial thickness did not differ between patients achieving ongoing pregnancy and those who did not (9.0 vs. 8.8 mm, p = 0.4). Comparable results were obtained with regard to clinical pregnancy, live birth and miscarriage rates. The area under the receiver operator curve was 0.5, indicating little discriminatory value of endometrial thickness. ConclusionsGiven that endometrial thickness was not found to be predictive of pregnancy after mNC-FET, cancellation based on endometrial thickness alone may not be justified

The effect of elevated progesterone levels before HCG triggering in modified natural cycle frozen-thawed embryo transfer cycles

Recent studies suggest that elevated late follicular phase progesterone concentrations after ovarian stimulation for IVF may result in embryo–endometrial asynchrony, reducing the chance of successful implantation after fresh embryo transfer. It remains unclear to what extent elevated late follicular phase progesterone levels may occur in unstimulated cycles before frozen–thawed embryo transfer, or what affect they may have on outcomes. In this cohort study, 271 patients randomized to the modified natural cycle arm of a randomized controlled trial comparing two endometrial preparation regimens underwent late follicular phase progesterone and LH testing. A receiver operating characteristic curve was constructed to identify a progesterone cut-off level with the best predictive value for live birth (progesterone level ≥4.6 nmol/l). A total of 24.4% of patients revealed an isolated elevated serum progesterone of 4.6 nmol/l or greater, and 44.3% showed an elevated progesterone level in association with a rise in LH. Neither endocrine disruption affected outcomes, with live birth rates of 12.9% versus 10.6% (OR 0.6, 95% CI 0.19 to 1.9) and 11.9% versus 17.5% (OR 1.6, 95% CI 0.79 to 3.1), respectively. Whether monitoring of progesterone and LH in natural cycle frozen–thawed embryo transfer has added clinical value should studied further

Hysteroscopy before in-vitro fertilisation (inSIGHT) : A multicentre, randomised controlled trial

BACKGROUND: Hysteroscopy is often done in infertile women starting in-vitro fertilisation (IVF) to improve their chance of having a baby. However, no data are available from randomised controlled trials to support this practice. We aimed to assess whether routine hysteroscopy before the first IVF treatment cycle increases the rate of livebirths. METHODS: We did a pragmatic, multicentre, randomised controlled trial in seven university hospitals and 15 large general hospitals in the Netherlands. Women with a normal transvaginal ultrasound of the uterine cavity and no previous hysteroscopy who were scheduled for their first IVF treatment were randomly assigned (1:1) to either hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF (hysteroscopy group) or immediate start of the IVF treatment (immediate IVF group). Randomisation was done with web-based concealed allocation and was stratified by centre with variable block sizes. Participants, doctors, and outcome assessors were not masked to the assigned group. The primary outcome was ongoing pregnancy (detection of a fetal heartbeat at >12 weeks of gestation) within 18 months of randomisation and resulting in livebirth. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01242852. FINDINGS: Between May 25, 2011, and Aug 27, 2013, we randomly assigned 750 women to receive either hysteroscopy (n=373) or immediate IVF (n=377). 209 (57%) of 369 women eligible for assessment in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group had a livebirth from a pregnancy during the trial period (relative risk 1·06, 95% CI 0·93-1·20; p=0·41). One (<1%) woman in the hysteroscopy group developed endometritis after hysteroscopy. INTERPRETATION: Routine hysteroscopy does not improve livebirth rates in infertile women with a normal transvaginal ultrasound of the uterine cavity scheduled for a first IVF treatment. Women with a normal transvaginal ultrasound should not be offered routine hysteroscopy. FUNDING: The Dutch Organisation for Health Research and Development (ZonMW)

Do female age and body weight modify the effect of individualized FSH dosing in IVF/ICSI treatment? A secondary analysis of the OPTIMIST trial

Introduction: The OPTIMIST trial revealed that for women starting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment, no substantial differences exist in first cycle and cumulative live birth rates between an antral follicle count (AFC)-based individualized follicle-stimulating hormone (FSH) dose and a standard dose. Female age and body weight have been suggested to cause heterogeneity in the effect of FSH dose individualization. The objective of the current study is to evaluate whether these patient characteristics modify the effect of AFC-based individualized FSH dosing in IVF/ICSI treatment. Material and methods: A secondary data-analysis of the OPTIMIST trial. Women initiating IVF/ICSI treatment were classified as predicted poor (AFC 0-7), suboptimal (AFC 8-10) or hyper responders (AFC >15), and randomly allocated to a standard FSH dose (150 IU/d) or an individualized FSH dose (450, 225 or 100 IU/d for predicted poor, suboptimal and hyper responders, respectively). In each predicted response category, logistic regression models with interaction terms were used to evaluate the presence of effect modification. The first cycle was analyzed, and the primary outcomes were first complete cycle live birth rate (including fresh plus frozen-thawed embryo transfers) and ovarian hyperstimulation syndrome (OHSS) risks. Results: No effect modification was revealed in the predicted poor (n = 234) and suboptimal (n = 277) responders. In the predicted hyper responders (n = 521), the effect of the individualized FSH dose on the first cycle live birth rate was modified by female age (P = 0.02) and the effect on OHSS risks was modified by body weight (P = 0.02). A dose reduction from 150 to 100 IU/d generally decreased the OHSS risks in predicted hyper responders, but also reduced the chance of a live birth in young women, and had no beneficial impact on OHSS risks in women with a relatively low body weight. Conclusions: In women with a predicted hyper response undergoing IVF/ICSI treatment, female age and body weight seem to modify the effect of FSH dose individualization. Although a reduced FSH starting dose generally decreases the OHSS risks, it may also reduce the chance of a live birth, specifically for young women. Future studies could consider these findings when investigating the optimal approach to reduce OHSS risks while maintaining the probability of a live birth for predicted hyper responders in IVF/ICSI treatment