Janet Kwee

Comparison of inter- and intra-cycle variability of anti-Müllerian hormone and antral follicle counts

BACKGROUND The antral follicle count (AFC) and anti-Müllerian hormone (AMH) both represent age-related follicular decline quite accurately, although long-term follow-up studies are still lacking. The best ovarian reserve test would need only a single, cycle-independent measurement to be representative. METHODS To compare the inter- and intra-cycle stability of AFC and AMH, we used age-adjusted intra-class correlation coefficients (ICCs). To measure inter-cycle stability across a number of up to four menstrual cycles, we used data, prospectively collected for the purpose of an other study, from 77 regularly cycling, infertile women aged 24-40 years. AMH and AFC values were measured on cycle day 3. To study intra-cycle variability, we used data from a prospective cohort study of 44 regularly cycling volunteers, aged 25-46 years and measured AMH and assessed the AFC (2-10 mm) every 1-3 cycle days. RESULTS Between menstrual cycles, AFC and AMH varied between 0 and 25 follicles (median 10), and 0.3 and 27.1 ng/ml (median 4.64). The difference in age-adjusted ICC between AMH [ICC, 0.89 (95% CI, 0.84-0.94)] and AFC [ICC, 0.71 (95% CI, 0.63-0.77)] was 0.18 (95% CI, 0.12-0.27). For the intra-cycle variation, 0-43 antral follicles (median 7) were counted per volunteer. The difference in age-adjusted ICC between AMH [ICC, 0.87 (95% CI, 0.82-0.91)] and AFC [ICC, 0.69 (95% CI, 0.46-0.82)] was 0.18 (95% CI, 0.034-0.42). CONCLUSIONS Serum AMH demonstrated less individual intra- and inter-cycle variation than AFCs and may therefore be considered a more reliable and robust means of assessing ovarian reserve in subfertile women.

Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

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

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.

Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles

OBJECTIVE To examine whether follicle loss due to ovarian aging is responsible for the occurrence of regular menstrual cycles in aging women with polycystic ovary syndrome (PCOS), the size of the FSH-sensitive follicle cohort was estimated by the exogenous follicle-stimulating hormone ovarian reserve test (EFORT) and related to the follicle count as measured by ultrasound. DESIGN Prospective study. SETTING Reproductive endocrinology unit of an academic medical center. PATIENT(S) Twenty-seven aging women with PCOS (35.8-49.4 years): 20 with regular menstrual cycles and 7 with oligomenorrhea or amenorrhea. INTERVENTION(S) EFORT and transvaginal ultrasound. MAIN OUTCOME MEASURE(S) Baseline (cycle day 2, 3, or 4) FSH, androstenedione (A), T, E(2), and inhibin B levels, the E(2) and inhibin B increment after the EFORT, and the follicle count. RESULT(S) After correction for the body mass index (BMI), the inhibin B increment was higher in the irregular menstrual group, but the E(2) increment did not differ significantly between the two groups. Ultrasound showed a median follicle count of 8.5 (4.0-18.0) in women with regular menstrual cycles (n = 16), compared with 18.0 (8.0-35.0) in irregularly menstruating women (n = 7). The follicle count was significantly correlated to the FSH-induced E(2) increment (r = 0.656) as well as to the inhibin B increment (r = 0.654). The regularly menstruating group was significantly older, had a higher basal FSH concentration, and had lower androgens than the irregularly menstruating group. CONCLUSION(S) The smaller follicle count, the older age, the higher FSH concentration, and the lower FSH-induced inhibin B increment found in women with PCOS and a regular menstrual cycle confirm that a decrease in the size of the follicle cohort due to ovarian aging is largely responsible for the regular menstrual cycles in aging PCOS women.

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

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).

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

BackgroundIn 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/designMulticenter 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.DiscussionThe results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment.Trial registrationNCT01242852

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. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number NTR2657. TRIAL REGISTRATION DATE 20 December 2010. DATE OF FIRST PATIENT’S ENROLMENT 12 May 2011.

Hysteroscopy before In-Vitro Fertilisation (inSIGHT): A Multicentre, Randomised Controlled Trial

Since the first successful live birth after in vitro fertilization (IVF) was reported in 1978, more than 5 million children have been born with the help of this and intracytoplasmic sperm injection (ICSI) procedures. However, only approximately 25% to 30% of cycles of IVF and ICSI lead to the birth of a child. The reasons for implantation failure are poorly understood. One major cause of implantation failure is abnormalities of the uterine cavity such as polyps, myoma, and adhesions. Hysteroscopy has been generally regarded as the standard procedure to detect these uterine abnormalities. It is thought to improve pregnancy rates in women scheduled for IVF by detection and surgical removal of uterine cavity abnormalities, dilatation of the cervical canal, or induction of inflammatory reactions in the endometriumby the procedure itself. Hysteroscopy is often performed routinely in infertile women scheduled for their first IVF cycle. However, there are no data from well-designed randomized controlled trials to support this practice. The inSIGHT trial is a pragmatic multicenter randomized clinical trial designed to determine whether routine hysteroscopy before the first IVF treatment cycle increases the live birth rate. The trial was conducted in 7 university hospitals and 15 large general hospitals in the Netherlands. Women eligible for the trial were infertile, scheduled to start their first IVF or ICSI treatment, had no previous hysteroscopy, and had a normal transvaginal ultrasound of the uterine cavity. Subjects were randomly assigned in a 1: 1 ratio to hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF followed by IVF (hysteroscopy group) or to immediate start of IVF treatment (immediate IVF group). Web-based randomization was done with a variable block size to allocate patients to groups and was stratified by center. The doctors, outcome assessors, and participants were not masked to the assigned group. The primary study outcome was an ongoing pregnancy (detection of a fetal heartbeat at > 12weeks of gestation) within 18 months of randomization and a live birth. Analysis was done according to intention to treat. Between May 25, 2011, and August 27, 2013, 750 women were randomized: 373 to the hysteroscopy group and 377 to the immediate IVF group. A live birth occurred during the trial period in 209 (57%) of 369 women in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group; the relative riskwas 1.06, with a 95% confidence interval of 0.93 to 1.20; P = 0.41. These findings demonstrate that hysteroscopy does not improve live birth rates in infertile women scheduled for their first IVF cycle, who have a normal transvaginal ultrasound of the uterine cavity. Therefore, routine hysteroscopy should not be performed in women with a normal transvaginal ultrasound.