M.H. Mochtar

Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis

BACKGROUND Recently, dopamine agonists were proposed as a prophylactic treatment for ovarian hyperstimulation syndrome (OHSS) in women at high risk in IVF/ICSI treatment cycles. METHODS We conducted a systematic review and meta-analysis of randomized trials comparing the prophylactic effect of the dopamine agonist, cabergoline, versus no treatment in IVF/ICSI cycles. Primary outcome was OHSS incidence per randomized woman. Secondary outcomes were live birth rate, ongoing pregnancy rate, clinical pregnancy rate and miscarriage rate. Searches (until September 2009) were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library and databases of abstracts. RESULTS Four randomized trials entailing 570 women were included. There was evidence of a statistically significant reduction in the incidence of OHSS in the cabergoline group (OR 0.41, 95% CI 0.25-0.66) with an absolute risk reduction of 12% (95% CI 6.1-18.2%), but there was no statistically significant evidence of a reduction in severe OHSS (OR 0.50, 95% CI 0.20-1.26). There was no evidence for a difference in clinical pregnancy rate (OR 1.07, 95% CI 0.70-1.62) and miscarriage rate (OR 0.31, 95% CI 0.03-3.07). CONCLUSION Prophylactic treatment with the dopamine agonist, cabergoline, reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.

Immobilisation versus immediate mobilisation after intrauterine insemination: randomised controlled trial

Objective To evaluate the effectiveness of 15 minutes of immobilisation versus immediate mobilisation after intrauterine insemination. Design Randomised controlled trial. Setting One academic teaching hospital and six non-academic teaching hospitals. Participants Women having intrauterine insemination for unexplained, cervical factor, or male subfertility. Interventions 15 minutes of immobilisation or immediate mobilisation after insemination. Main outcome measure Ongoing pregnancy per couple. Results 391 couples were randomised; 199 couples were allocated to 15 minutes of immobilisation after intrauterine insemination, and 192 couples were allocated to immediate mobilisation (control). The ongoing pregnancy rate per couple was significantly higher in the immobilisation group than in the control group: 27% (n=54) versus 18% (34); relative risk 1.5, 95% confidence interval 1.1 to 2.2 (crude difference in ongoing pregnancy rates: 9.4%, 1.2% to 17%). Live birth rates were 27% (53) in the immobilisation group and 17% (32) in the control group: relative risk 1.6, 1.1 to 2.4 (crude difference for live birth rates: 10%, 1.8% to 18%). In the immobilisation group, the ongoing pregnancy rates in the first, second, and third treatment cycles were 10%, 10%, and 7%. The corresponding rates in the mobilisation group were 7%, 5%, and 5%. Conclusion In treatment with intrauterine insemination, 15 minutes’ immobilisation after insemination is an effective modification. Immobilisation for 15 minutes should be offered to all women treated with intrauterine insemination. Trial registration Current Controlled Trials ISRCTN53294431.

Couples with unexplained subfertility and unfavorable prognosis: a randomized pilot trial comparing the effectiveness of in vitro fertilization with elective single embryo transfer versus intrauterine insemination with controlled ovarian stimulation

OBJECTIVE To evaluate the effectiveness of IVF with elective single embryo transfer (IVF-eSET) vs. IUI with controlled ovarian stimulation (IUI-COS) as an alternative treatment to reduce the risk for a multiple pregnancy. DESIGN Randomized pilot trial. SETTING Three academic and six teaching hospitals in the Netherlands. PATIENT(S) Couples with unexplained or mild male subfertility and an unfavorable prognosis for natural conception. INTERVENTION(S) One cycle of IVF-eSET or three cycles of IUI-COS. MAIN OUTCOME MEASURE(S) Ongoing pregnancy per couple. RESULT(S) We randomly allocated 116 women to IVF-eSET (n = 58) or IUI-COH (n = 58). There were 14 ongoing pregnancies (24%) in the IVF-eSET group and 12 pregnancies (21%) in the IUI-COS group (relative ratio 1.17; 95% confidence interval 0.60-2.30). There were two twin pregnancies in the IVF-eSET group (14%) and two twin pregnancies and one triplet pregnancy in the IUI-COH group (25%). CONCLUSION(S) In patients with unexplained or mild male subfertility and a poor prognosis for natural conception, one cycle of IVF-eSET might be as effective as three cycles of IUI-COS as primary treatment. Elective single embryo transfer does not seem an effective strategy in preventing multiple pregnancies in this particular population. In the future a strict SET policy (i.e., compulsory SET) might be an option. Our trial provides evidence for the feasibility and highlights the importance of a large definitive trial to determine the effectiveness and side effects of both strategies.

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 recombinant LH on embryo quality: a randomized controlled trial in women with poor ovarian reserve

BACKGROUND Poor ovarian response is a common clinical problem, affecting up to 26% of IVF cycles. For these women, addition of recombinant luteinizing hormone (rLH) to ovarian hyperstimulation with recombinant FSH has a beneficial effect on ongoing pregnancy rates, but its effect on the yield of top-quality embryos is unknown. METHODS We conducted a randomized controlled trial in women expected to respond poorly under ovarian hyperstimulation during their first IVF cycle [all women aged 35-41 and women with FSH > 12 IU/ml and antral follicle count (AFC) ≤ 5]. Women were randomly allocated to rFSH and rLH (2:1 ratio) or rFSH alone (control group) after down-regulation with a GnRH agonist. The primary outcome was the proportion of top-quality embryos per woman on the day of transfer. Secondary outcomes were the number of stimulation days, the number of follicles ≥17 mm, the number of oocytes, the fertilization rate, the number of embryos, the number of women with ≥1 top-quality embryo, the biochemical, clinical and ongoing pregnancy rates and the miscarriage rate. RESULTS There were 116 women allocated to the rLH group and 128 allocated to the control group. The proportion of top-quality embryos per woman was 17% in the rLH group and 11% in the control group [mean difference 0.06; 95% confidence interval (CI) -0.01-0.14]. In the rLH and control groups respectively, 47 (41%) and 41 (32%) women had at least one top-quality embryo on the day of transfer (relative risk: 1.3, 95% CI 0.91-1.77). The ongoing pregnancy rate was 13 versus 12% (relative risk: 1.1; 95% CI 0.57-2.16) for the rLH group compared with the control group. CONCLUSIONS This study found no significant difference in embryo quality after the addition of rLH to rFSH for ovarian stimulation in women with poor ovarian reserve. CLINICAL TRIALS IDENTIFIER NTR1457.

IVF with planned single-embryo transfer versus IUI with ovarian stimulation in couples with unexplained subfertility: an economic analysis

Couples with unexplained subfertility are often treated with intrauterine insemination (IUI) with ovarian stimulation, which carries the risk of multiple pregnancies. An explorative randomized controlled trial was performed comparing one cycle of IVF with elective single-embryo transfer (eSET) versus three cycles of IUI-ovarian stimulation in couples with unexplained subfertility and a poor prognosis for natural conception, to assess the economic burden of the treatment modalities. The main outcome measures were ongoing pregnancy rates and costs. This study randomly assigned 58 couples to IVF-eSET and 58 couples to IUI-ovarian stimulation. The ongoing pregnancy rates were 24% in with IVF-eSET versus 21% with IUI-ovarian stimulation, with two and three multiple pregnancies, respectively. The mean cost per included couple was significantly different: €2781 with IVF-eSET and €1876 with IUI-ovarian stimulation (P<0.01). The additional costs per ongoing pregnancy were €2456 for IVF-eSET. In couples with unexplained subfertility, one cycle of IVF-eSET cost an additional €900 per couple compared with three cycles of IUI-ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. When IVF-eSET results in higher ongoing pregnancy rates, IVF would be the preferred treatment. Couples that have been trying to conceive unsuccessfully are often treated with intrauterine insemination (IUI) and medication to improve egg production (ovarian stimulation). This treatment carries the risk of multiple pregnancies like twins. We performed an explorative study among those couples that had a poor prognosis for natural conception. One cycle of IVF with transfer of one selected embryo (elective single-embryo transfer, eSET) was compared with three cycles of IUI-ovarian stimulation. The aim of this study was to assess the economic burden of both treatments. The Main outcome measures were number of good pregnancies above 12weeks and costs. We randomly assigned 58 couples to IVF-eSET and 58 couples to IUI-ovarian stimulation. The ongoing pregnancy rates were comparable: 24% with IVF-eSET versus 21% with IUI-ovarian stimulation. There were two multiple pregnancies with IVF-eSET and three multiple pregnancies with IUI-ovarian stimulation. The mean cost per included couple was significantly different, €2781 with IVF-eSET and €1876 with IUI-ovarian stimulation. The additional costs per ongoing pregnancy were €2456 for IVF-eSET. In couples with unexplained subfertility, one cycle of IVF-eSET costed an additional €900 per couple compared to three cycles of IUI-ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. We conclude that IUI-ovarian stimulation is the preferred treatment to start with. When IVF-eSET results in a higher ongoing pregnancy rate (>38%), IVF would be the preferred treatment.

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

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

Women's perspectives regarding subcutaneous injections, costs and live birth rates in IVF

BACKGROUND The addition of recombinant LH (rLH) to controlled ovarian hyperstimulation (COH) shows a beneficial effect on ongoing pregnancy rates in poor responder women, with an increase of ongoing pregnancy rate. Next to this possible beneficial effect, there are two potential drawbacks of adding rLH to COH; women have to administer extra injections, and daily rLH injections generate additional costs. We therefore investigated womens perspectives on an additional injection of rLH with respect to live birth rates (LBR) and out-of-pocket costs in a discrete choice experiment. METHODS Women eligible for IVF were asked to choose between treatments that differed in LBR after one IVF cycle, the amount of self-administered injections and out-of-pocket costs or reimbursement. The relative weights that women place on these attributes were estimated with a logistic regression model. To test for heterogeneity of preferences among women, patient characteristics were included in the model. RESULTS Two-hundred and thirty-four women were asked to participate in the study. In total, 223 women responded (response rate 95%) and 206 questionnaires were analysed. An increase of one daily injection did not alter womens treatment preference. LBR and costs did have a significant (P < 0.001) impact on womens choice of IVF treatment. Patient characteristics significantly influenced the effect of costs on womens preferences. CONCLUSIONS One extra daily injection will not cause a woman to refrain from a certain IVF treatment. However, to compensate for the out-of-pocket costs of this extra daily injection, the expected LBR should at least be 6%.

Endometrial thickness in women undergoing IUI with ovarian stimulation. How thick is too thin? A systematic review and meta-analysis

STUDY QUESTION Is pre-ovulatory endometrial thickness (EMT) in women with unexplained subfertility undergoing IUI with ovarian stimulation (OS) associated with pregnancy chances? SUMMARY ANSWER We found no evidence for an association between EMT and pregnancy chances. WHAT IS KNOWN ALREADY It has been suggested that OS with clomiphene citrate (CC) results in a lower EMT than with gonadotrophins or aromatase inhibitors, but the clinical consequences in terms of pregnancy are unclear. STUDY DESIGN, SIZE, DURATION We performed a systematic review and meta-analysis of studies comparing CC, gonadotrophins or aromatase inhibitors in an IUI program reporting on EMT and pregnancy rates in women with unexplained subfertility. PARTICIPANTS/MATERIALS, SETTING, METHODS We searched MEDLINE, EMBASE and the non-MEDLINE subset of PubMed from inception to 28th June 2016 and cross-checked references of relevant articles. Outcome measures were clinical pregnancy rate and mean pre-ovulatory EMT. We calculated mean differences (MD) with 95% CIs with a fixed effect model, and in case of heterogeneity with an I2 > 50% a random effect model. We performed a meta-regression analysis to determine if stimulating drugs interacted with the estimated effect of EMT. MAIN RESULTS AND THE ROLE OF CHANCE Our search retrieved 1563 articles of which 23 were included, totaling 3846 women. There were 17 RCTs and 6 cohort studies. The average study quality was low and there was considerable to substantial statistical heterogeneity. Seven studies provided data on EMT in relation to pregnancy. There was no evidence of a difference in EMT between women who conceived and women that did not conceive (1525 women, MDrandom: 0.51 mm, 95% CI: -0.05 to 1.07). Women treated with CC had a significantly thinner EMT than women treated with gonadotrophins (two studies, MD: -0.33, 95% CI: -0.64 to -0.01). There was no evidence of a difference in EMT when comparing CC with letrozole (five studies, MDrandom: -0.84, 95% CI: -1.97 to 0.28). The combination of CC plus gonadotrophins resulted in a slightly thinner endometrium than letrozole (nine studies, MDrandom: -0.79, 95% CI: -1.37 to -0.20). Letrozole resulted in a thinner EMT than gonadotrophins (two studies, MDrandom: -1.31, 95% CI: -2.08 to -0.53). LIMITATIONS, REASONS FOR CAUTION The overall quality of the included studies was low to moderate. We found considerable to substantial heterogeneity in the comparisons, hampering firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS We found no evidence for an association between EMT and pregnancy rates during IUI -OS. As a consequence, canceling IUI cycles because of a thin endometrial lining may negatively affect clinical care. Although we found some evidence for very small differences in EMT when comparing various drugs, we cannot make inferences on their effect on pregnancy chances since these differences may be coincidental. STUDY FUNDING/COMPETING INTEREST(S) None. REGISTRATION NUMBER N/A.

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.