Kathrin Fleischer

Sex hormone‐binding globulin as a marker for the thrombotic risk of hormonal contraceptives

Summary.  Background: It takes many years to obtain reliable values for the risk of venous thrombosis of hormonal contraceptive users from clinical data. Measurement of activated protein C (APC) resistance via thrombin generation is a validated test for determining the thrombogenicity of hormonal contraceptives. Sex hormone‐binding globulin (SHBG) might serve as a marker for the risk of venous thrombosis, and can be easily and rapidly measured in routine laboratories.

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

Prediction model for obtaining spermatozoa with testicular sperm extraction in men with non-obstructive azoospermia

STUDY QUESTION Can an externally validated model, based on biological variables, be developed to predict successful sperm retrieval with testicular sperm extraction (TESE) in men with non-obstructive azoospermia (NOA) using a large nationwide cohort? SUMMARY ANSWER Our prediction model including six variables was able to make a good distinction between men with a good chance and men with a poor chance of obtaining spermatozoa with TESE. WHAT IS KNOWN ALREADY Using ICSI in combination with TESE even men suffering from NOA are able to father their own biological child. Only in approximately half of the patients with NOA can testicular sperm be retrieved successfully. The few models that have been developed to predict the chance of obtaining spermatozoa with TESE were based on small datasets and none of them have been validated externally. STUDY DESIGN, SIZE, DURATION We performed a retrospective nationwide cohort study. Data from 1371 TESE procedures were collected between June 2007 and June 2015 in the two fertility centres. PARTICIPANTS/MATERIALS, SETTING, METHODS All men with NOA undergoing their first TESE procedure as part of a fertility treatment were included. The primary end-point was the presence of one or more spermatozoa (regardless of their motility) in the testicular biopsies.We constructed a model for the prediction of successful sperm retrieval, using univariable and multivariable binary logistic regression analysis and the dataset from one centre. This model was then validated using the dataset from the other centre. The area under the receiver-operating characteristic curve (AUC) was calculated and model calibration was assessed. MAIN RESULTS AND THE ROLE OF CHANCE There were 599 (43.7%) successful sperm retrievals after a first TESE procedure. The prediction model, built after multivariable logistic regression analysis, demonstrated that higher male age, higher levels of serum testosterone and lower levels of FSH and LH were predictive for successful sperm retrieval. Diagnosis of idiopathic NOA and the presence of an azoospermia factor c gene deletion were predictive for unsuccessful sperm retrieval. The AUC was 0.69 (95% confidence interval (CI): 0.66-0.72). The difference between the mean observed chance and the mean predicted chance was <2.0% in all groups, indicating good calibration. In validation, the model had moderate discriminative capacity (AUC 0.65, 95% CI: 0.62-0.72) and moderate calibration: the predicted probability never differed by more than 9.2% of the mean observed probability. LIMITATIONS, REASONS FOR CAUTION The percentage of men with Klinefelter syndrome among men diagnosed with NOA is expected to be higher than in our study population, which is a potential selection bias. The ability of the sperm retrieved to fertilize an oocyte and produce a live birth was not tested. WIDER IMPLICATIONS OF THE FINDINGS This model can help in clinical decision-making in men with NOA by reliably predicting the chance of obtaining spermatozoa with TESE. STUDY FUNDING/COMPETING INTEREST This study was partly supported by an unconditional grant from Merck Serono (to D.D.M.B. and K.F.) and by the Department of Obstetrics and Gynaecology of Radboud University Medical Center, Nijmegen, The Netherlands, the Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, Den Bosch, The Netherlands, and the Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands. Merck Serono had no influence in concept, design nor elaboration of this study. TRIAL REGISTRATION NUMBER Not applicable.

The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI

Use of combined oral contraceptives is associated with a three- to six-fold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.

Effects of the contraceptive vaginal ring, the contraceptive transdermal patch and combined oral contraceptives on markers of hemostasis

This letter to the editor compares the results of two studies assessing the effect of switching from combined oral contraceptives to the combined contraceptive vaginal ring or transdermal patch on markers of hemostasis that have been related to the risk of venous thrombosis. One study found beneficial as well as unfavorable changes in markers and in contrast one study found only unfavorable prothrombotic effects. It states that the differences in outcomes between the studies might be explained by: difference in comparator oral contraceptive difference in laboratory methods and methodological differences. Copyright

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.

Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI : a multicentre trial and cost-effectiveness analysis

STUDY QUESTION Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment? SUMMARY ANSWER In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose. WHAT IS KNOWN ALREADY In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists. STUDY DESIGN, SIZE, DURATION Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping. PARTICIPANTS/MATERIALS, SETTING, METHODS In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results. LIMITATIONS, REASONS FOR CAUTION Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response. WIDER IMPLICATIONS OF THE FINDINGS Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB 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 autors have nothing to declare. TRIAL REGISTRATION NUMBER Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

The value of Anti-Müllerian hormone in low and extremely low ovarian reserve in relation to live birth after in vitro fertilization

OBJECTIVE To determine the relation of Anti-Müllerian hormone (AMH) with live birth after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in women with (extremely) low ovarian reserve. STUDY DESIGN This study was a retrospective cohort study in a Dutch tertiary fertility clinic. Between January 2009 and March 2012, AMH levels were measured in infertile women when ≥36 years of age or when showing clinical signs of diminished ovarian reserve, before they underwent IVF or ICSI treatment. Ultimately, 156 women with (extremely) low ovarian reserve were included and evaluated for cumulative live birth rates. Of each woman, only one treatment cycle was analyzed, either the one in which she became pregnant or her first treatment cycle if she did not reach pregnancy. The relation between AMH and live birth was evaluated with multivariable logistic regression analysis. A ROC curve was composed to evaluate the discriminative value of AMH in relation to live birth after IVF/ICSI. RESULTS Thirty-three out of 156 women (21.2%) gave live birth. Live birth was significantly lower in women with AMH ≤0.1ng/ml (4/37 women; 10.8%) or AMH >0.1-0.4ng/ml (7/42 women; 16.7%), compared to women with AMH >0.4-1.05ng/ml (22/77 women; 28.6%), p<0.001. Multivariable logistic regression revealed an association between the severity of low ovarian reserve and live birth (per 0.1ng/ml increase in AMH value, Odds ratio 1.21; 95% CI 1.07-1.36). CONCLUSIONS The level of AMH is related to live birth after IVF/ICSI in women with (extremely) low ovarian reserve. The live birth rate in women with AMH >0.4ng/ml was significantly higher than in women with AMH ≤0.4ng/ml. AMH could serve as a tool in the pre-treatment counseling for pregnancy and live birth chances in women with (extremely) low ovarian reserve.