The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility

BACKGROUND Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART. Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate. This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. METHODS/DESIGN We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months. Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded. Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). DISCUSSION Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. TRIAL REGISTRATION Current Controlled Trials ISRCTN 52843371Alexandra J Bensdorp, Els Slappendel, Carolien Koks, Jur Oosterhuis, Annemieke Hoek, Peter Hompes, Frank Broekmans, Harold Verhoeve, Jan Peter de Bruin, Janne Meije van Weert, Maaike Traas, Jacques Maas, Nicole Beckers, Sjoerd Repping, Ben W Mol, Fulco van der Veen and Madelon van Wel

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

ALIFE2 study::low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia - study protocol for a randomized controlled trial

Background A large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome. Methods/Design Randomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone. Study population: pregnant women of less than 7 weeks’ gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both. Setting: multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate. Intervention: LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone. Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations. Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions. Discussion After an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study. The study website can be accessed via www.ALIFE2study.org. Trial registration The ALIFE2 study was registered on 19 March 2012 under registration number NTR336

Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN):A randomised, two-by-two factorial trial

Background: In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. Methods: In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. Findings: Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05–1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97–1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. Interpretation: In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. Funding: The Netherlands Organization for Health Research and Development

The value of chromosomal analysis in oligozoospermic men

Objective: To determine the prevalence of chromosomal abnormalities in relation to sperm concentration in subfertile oligozoospermic men. Design: Retrospective cohort study. Setting: Two teaching hospitals. Patient(s): We retrospectively studied all men who received chromosomal analysis prior to intracytoplasmic sperm injection (ICSI) treatment from 2000 to 2010 in two teaching hospitals. Intervention(s): None. Main Outcome Measure(s): The results of chromosomal analysis and semen analysis were recorded. The frequency of abnormal karyotypes was analyzed in relation to the sperm concentration, categorized as extreme oligozoospermia (>0 to 1 to 5 to 20 million/mL). Result(s): Among 582 male ICSI candidates, the rates of abnormal karyotypes were 1.2% (2/162), 2.2% (5/227), and 1.5% (2/130) for men with extreme, severe, and moderate oligozoospermia, respectively. No abnormalities were present in normospermic men. Conclusion(s): The risk of conceiving a viable child with unbalanced structural chromosomal abnormalities in men with oligozoospermia may not justify karyotyping. (Fertil Steril (R) 2012;98:1438-42. (C) 2012 by American Society for Reproductive Medicine.

Challenges in Removing the Essure® Device

We present a case about Essure® removal surgery in which the third markers of the device have torn off. The woman needed a second surgery for complete removal of the devices. Fluoroscopy during surgery is a good method to visualize the lost fragments. With fluoroscopy, a hysterectomy is not needed for complete removal. It is important to understand the structure of the device and to be aware of the four radiopaque markers during surgery and their removal

Pregnancy outcomes and prognostic factors from tubal sterilization reversal by sutureless laparoscopical re-anastomosis: a retrospective cohort study

BACKGROUND: Female sterilization is a widely used contraceptive method but in a small group of women, post-sterilization regret occurs. A dilemma for these women is the choice between surgical re-anastomosis and IVF. We evaluated the factors that affected pregnancy rate after laparoscopic tubal re-anastomosis for sterilization regret. METHODS: We included women who underwent a laparoscopic tubal re-anastomosis between January 1997 and March 2008 at Maxima Medical Centre, The Netherlands, in a retrospective cohort study. Microsurgical laparoscopic re-anastomosis was performed using a serosa-muscular fixation/biological glue technique. The primary outcome was time to clinical pregnancy (TTP). Other outcomes were ongoing pregnancy and ectopic pregnancy. We studied whether clinical characteristics, including age, fertility history, BMI, semen quality, remaining tubal length and type of anastomosis, could predict the chance of pregnancy. RESULTS: Data from 127 patients were analysed. The 40-month cumulative clinical pregnancy rate was 74%, whereas the ongoing pregnancy rate was 59%. There were five ectopic pregnancies (3.9%). Only age was found to influence the probability of a positive pregnancy test, hazard rate ratio (HRR): 0.32 [95% confidence interval (CI) 0.12-0.88] and ongoing pregnancy [HRR 0.21 (95% CI 0.05-0.87)]. Previous pregnancy increased pregnancy probability [HRR: 2.2 (95% CI 0.51-9.8)]. A total sperm motility count of <20 million was related to prolonged TTP. CONCLUSIONS: Sutureless laparoscopic tubal re-anastomosis is an effective treatment for women who regret sterilization. Age, previous pregnancies and sperm quality should be considered when counselling for tubal sterilization reversal versus IVF. A randomized prospective trial comparing success rates of surgical reversal and IVF after sterilization regret should be conducte

What is the fertility-enhancing effect of tubal flushing? A hypothesis article

Hysterosalpingographies (HSGs) have formed an essential part of the fertility workup for more than a century. More recently, tubal flushing, especially with oil-based contrast, has been shown to significantly improve the natural conception rates. Critically, the mechanism of this fertility-enhancing effect during tubal flushing is still unclear. This article postulates hypotheses, based on published and own research, on the potential mechanisms and root cause of tubal flushing fertility enhancement. Possible explanations for the increased fertility rates, especially with oil-based contrast, are divided into the biochemical and interfacial effects derived from the contrast properties. The biochemical effects may include the immunological response of the endometrium or peritoneum, the impact on the endometrial opioid receptors or the iodine content. The interfacial effects may include improvement of interfacial factors due to the lubricant effect or dislodgement of mucus debris within the Fallopian tubes. Impact StatementWhat is already known on this subject? Tubal flushing during hysterosalpingographies (HSGs) increases natural conception rates, and using oil-based over water-based contrast increases that effect even further. However, the underlying mechanism of the observed fertility-enhancing effect is still poorly understood. What do the results of this study add? This article postulates different hypotheses on the potential mechanisms and root cause of the fertility enhancement from tubal flushing. What are the implications of these findings for clinical practice and/or further research? We suggest additional research on the different hypotheses, intending to determine which subfertile women will benefit most from tubal flushing using oil-based contrast and at which stage of their subfertility. Furthermore, we suggest research on administering tubal flushing with oil-based contrast, besides in HSG