Is home-based monitoring of ovulution to time frozen embryo transfer a cost-effective alternative for hospital-based monitoring of ovulation? Study protocol of the multicentre, non-inferiority Antarctica-2 randomised controlled trial

STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman’s point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN, SIZE, DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTEREST(S): The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017 DATE OF FIRST PATIENT’S ENROLMENT: 10 April 201

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STUDY QUESTION: What is the cost-effectiveness of in vitro fertilization(IVF) with conventional ovarian stimulation, single embryotransfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?. SUMMARY ANSWER: Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child. WHAT IS KNOWN ALREADY: IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF. STUDY DESIGN, SIZE, DURATION: We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were (sic)7187 for IVF-SET, (sic)8206 for IVF-MNC and (sic)5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences (sic)2117; 95% CI: (sic)1544-(sic)2657 and (sic)3136, 95% CI: (sic)2519-(sic)3754, respectively). The ICER for IVF-SET compared with IUI-COH was (sic)43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs. LIMITATIONS, REASONS FOR CAUTION: We only report on direct health care costs. The present analysis is limited to 12 months. WIDER IMPLICATIONS OF THE FINDINGS: Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate - a randomised controlled trial

Background: Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. Methods/Design: We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI. Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included. Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total). An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). Discussion: The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.Marleen J Nahuis, Nienke S Weiss, Fulco van der Veen, Ben Willem J Mol, Peter G Hompes, Jur Oosterhuis, Nils B Lambalk, Jesper MJ Smeenk, Carolien AM Koks, Ron JT van Golde, Joop SE Laven, Ben J Cohlen, Kathrin Fleischer, Angelique J Goverde, Marie H Gerards, Nicole F Klijn, Lizka CM Nekrui, Ilse AJ van Rooij, Diederik A Hoozemans, and Madelon van Wely

Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation

OBJECTIVES: To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child. DESIGN: Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial. SETTING: 17 centres in the Netherlands. PARTICIPANTS: Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility. INTERVENTIONS: Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation. MAIN OUTCOME MEASURES: The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality RESULTS: 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation). CONCLUSIONS: In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates.Trial registration Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.A J Bensdorp ... B W J Mol ... et al

Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility

BACKGROUND: Intrauterine insemination (IUI) combined with ovarian hyperstimulation (OH) has been demonstrated to be an effective form of treatment for subfertile couples. Several ovarian stimulation protocols combined with IUI have been proposed, but it is still not clear which stimulation protocol and which dose is the most cost-effective. OBJECTIVES: To evaluate ovarian stimulation protocols for intrauterine insemination for all indications. SEARCH STRATEGY: We searched for all publications which described randomised controlled trials comparing different ovarian stimulation protocols followed by IUI. We searched the Menstrual Disorders and Subfertility Group's Central register of Controlled Trials (CENTRAL). We searched the electronic databases of MEDLINE (January 1966 to present) and EMBASE (1980 to present). SELECTION CRITERIA: Randomised controlled trials only were considered for inclusion in this review. Trials comparing different ovarian stimulation protocols combined with IUI were selected and reviewed in detail. DATA COLLECTION AND ANALYSIS: Two independent review authors independently assess trial quality and extracted data. MAIN RESULTS: Forty three trials involving 3957 women were included. There were 11 comparisons in this review. Pregnancy rates are reported here since results of live birth rates were lacking.Seven studies (n = 556) were pooled comparing gonadotrophins with anti-oestrogens showing significant higher pregnancy rates with gonadotrophins (OR 1.8, 95% CI 1.2 to 2.7). Five studies (n = 313) compared anti-oestrogens with aromatase inhibitors reporting no significant difference (OR 1.2 95% CI 0.64 to 2.1). The same could be concluded comparing different types of gonadotrophins (9 studies included, n = 576). Four studies (n = 391) reported the effect of adding a GnRH agonist which did not improve pregnancy rates (OR 0.98 95% CI 0.6 to 1.6), although it resulted in significant higher multiple pregnancy rates (OR 2.9 95% CI 1.0 to 8). Data of three studies (n = 299) showed no convincing evidence of adding a GnRH antagonist to gonadotrophins (OR 1.5 95% CI 0.83 to 2.8). The results of two studies (n = 297) reported no evidence of benefit in doubling the dose of gonadotrophins (OR 1.2 95% 0.67 to 1.9) although the multiple pregnancy rates and OHSS rates were increased. For the remaining five comparisons only one or none studies were included. AUTHORS' CONCLUSIONS: Robust evidence is lacking but based on the available results gonadotrophins might be the most effective drugs when IUI is combined with ovarian hyperstimulation. When gonadotrophins are applied it might be done on a daily basis. When gonadotrophins are used for ovarian stimulation low dose protocols are advised since pregnancy rates do not differ from pregnancy rates which result from high dose regimen, whereas the chances to encounter negative effects from ovarian stimulation such as multiples and OHSS are limited with low dose gonadotrophins. Further research is needed for each comparison mad

Semen preparation techniques for intrauterine insemination

BACKGROUND: Semen preparation techniques for assisted reproduction, including intrauterine insemination (IUI), were developed to separate the motile morphological normal spermatozoa. Leucocytes, bacteria and dead spermatozoa produce oxygen radicals that negatively influence the ability to fertilize the egg. The yield of as many motile, morphologically normal spermatozoa as possible might influence treatment choices and therefore outcomes. OBJECTIVES: To compare the effectiveness of gradient, swim-up, or wash and centrifugation semen preparation techniques on clinical outcome in subfertile couples undergoing intrauterine insemination (IUI). SEARCH STRATEGY: We searched the Menstrual Disorders and Subfertility Group Trials Register (13 January 2007), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 2), MEDLINE (1966 to January 2007 ), EMBASE (1980 to January 2007), Science Direct Database (1966 to January 2007), National Research Register (2000 to 2007), Biological Abstracts (2000 to January 2007), CINAHL (1982 to October 2006) and reference lists of relevant articles. We also contacted experts and authors in the field. SELECTION CRITERIA: Parallel randomized controlled trials (RCTs) comparing the efficacy of semen preparation techniques used for subfertile couples undergoing IUI in terms of clinical outcome were included. DATA COLLECTION AND ANALYSIS: Two reviewer authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Five RCTs, including 262 couples in total, were included in the meta-analysis (Dodson 1998; Grigoriou 2005; Posada 2005; Soliman 2005; Xu 2000). Xu compared the three techniques; Soliman compared a gradient technique versus a wash technique; Dodson and Posada compared a gradient technique versus a swim-up technique; whereas Grigoriou compared swim-up versus a wash technique. No trials reported the primary outcome of live birth.There was no evidence of a difference between pregnancy rates (PR) for swim-up versus a gradient or wash and centrifugation technique (Peto OR 1.57, 95% CI 0.74 to 3.32; Peto OR 0.41, 95% CI 0.15 to 1.10, respectively); nor in the two studies comparing a gradient technique versus wash and centrifugation (Peto OR 1.76, 95% CI 0.57 to 5.44). There was no evidence of a difference in the miscarriage rate (MR) in two studies comparing swim-up versus a gradient technique (Peto OR 0.13, 95% CI 0.01 to 1.33). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend any specific preparation technique. Large high quality randomised controlled trials, comparing the effectiveness of a gradient and/ or a swim-up and/ or wash and centrifugation technique on clinical outcome are lacking. Further randomised trials are warrante

Spontaneous LH surges prior to hCG administration in unstimulated-cycle frozen-thawed embryo transfer do not influence pregnancy rates

LH surges are the start of a period of optimal endometrial receptivity. Missing these surges in an unstimulated-cycle frozen-thawed embryo transfer (FET) based on ultrasound alone might lead to incorrect timing of embryo transfer. This prospective, non-randomized trial established the incidence and effect of spontaneous LH surges on ongoing pregnancy rates and assessed the use of ultrasound without LH monitoring in planning FET. All patients undergoing unstimulated-cycle FET in the study centre over a 2-year period were included in this analysis (n=233). All patients had regular menstrual cycles. Serum LH analysis took place before human chorionic gonadotrophin administration. The main outcome measure was ongoing pregnancy. LH surges occurred in over half of patients. Overall pregnancy rate was 34.3%. Relative risks for ongoing pregnancy for cycles with or without a spontaneous LH surge were not significantly different (ongoing pregnancy rate 33.4% versus 34.8%; RR 1.02, 95% CI 0.7-1.5). Based on these results, it was concluded that LH surges ?10 IU/l occurred in over 50% of patients, but LH surges demonstrated no significant effect on pregnancy rates. Single LH determination prior to ovulation induction in unstimulated-cycle FET does not seem to have added clinical value. LH surges are the start of a period of fertility. Missing these surges in natural-cycle frozen-thawed embryo transfer (FET) based on ultrasound alone might lead to incorrect timing of thawing and transferring. This can subsequently lead to diminished pregnancy rates. In this trial we established both the incidence and effect of these LH surges on ongoing pregnancy rates and assessed the use of ultrasound without LH monitoring in planning natural-cycle FET. Over a 2-year period, all patients undergoing natural-cycle FET in our centre were included in this analysis (n=233). All patients had a regular menstrual cycle. Analyses of the LH concentration took place before ovulation induction with human chorionic gonadotrophin in natural-cycle FET. The main outcome measure was ongoing pregnancy. LH surges occurred in over half of all patients. The overall pregnancy rate was 34.3%. No difference was found in pregnancy rates between patients with and without an LH surge. Based on these results, we concluded that LH surges occurred in over 50% of all patients, but these surges demonstrated no significant effect on pregnancy rates. Regular ultrasound evaluation of the dominant follicle alone seems to be an accurate method to plan natural-cycle FET.<br/

Intrauterine insemination versus Fallopian tube sperm perfusion in non-tubal subfertility: a systematic review based on a Cochrane review

BACKGROUND: The objective of this review was to compare the efficacy of Fallopian tube sperm perfusion (FSP) with intrauterine insemination (IUI) in the treatment of non-tubal subfertility. METHODS: The principles of the Cochrane Menstrual Disorders and Subfertility Group were employed. Only randomized controlled studies comparing FSP with IUI were included in this review. The main outcome measures included live birth rates and pregnancy rates per couple. RESULTS: Twenty-eight studies were found performing the comparison of interest. Overall six studies involving 474 couples were included in the meta-analysis. One study only assessed live birth rates, which resulted in no difference in outcome between FSP and IUI [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.39-3.53]. The results in pregnancy rate per couple revealed no statistically significant difference between FSP and IUI (OR 1.76, 95% CI 0.77-4.05). Subgroup analysis revealed that couples suffering from unexplained subfertility clearly benefit from FSP over IUI (OR 2.88, 95% CI 1.73-4.78). Excluding studies which used the Foley catheter for tubal perfusion resulted in a significant difference favouring FSP for all indications (OR 2.42, 95% CI 1.54-3.80). CONCLUSIONS: There is firm evidence that FSP gives rise to higher pregnancy rates in couples with unexplained subfertility and should therefore be advised in these couples. For other indications FSP has not been proven more effective compared with IUI. Results showed that the Foley catheter might not be effective for FSP. Future research should focus on comparing different types of catheter

The addition of GnRH antagonists in intrauterine insemination cycles with mild ovarian hyperstimulation does not increase live birth rates--a randomized, double-blinded, placebo-controlled trial

BACKGROUND: This multicenter, double-blinded RCT investigated the efficacy of GnRH antagonists in cycles with mild ovarian hyperstimulation (MOH) followed by IUI in subfertile women. METHODS: Couples diagnosed with unexplained, male factor subfertility or associated with the presence of minimal or mild endometriosis were randomized with a computer-generated list of numbers by a third party in a double-blinded setting to receive either a GnRH antagonists or a placebo in 12 institutional or academic hospitals. All women were treated with recombinant FSH in a low-dose step-up regimen starting on Day 2-4 of the cycle. A GnRH antagonist was added when one or more follicles of 14 mm diameter or more were visualized. When at least one follicle reached a size of >= 18 mm, ovulation was induced by hCG injection. A single IUI was performed 38-40 h later. Couples were offered a maximum of three consecutive cycles. The primary outcome of the trial was live births. Secondary outcomes were pregnancy rates, multiple pregnancy rates, miscarriages and ovarian hyperstimulation syndrome rate. RESULTS: A total of 233 couples were included from January 2006 to February 2009, starting 572 treatment cycles. Live birth rates were not significantly different between the group treated with GnRH antagonist (8.4%; 23/275) and the placebo group (12%; 36/297) (P = 0.30). Three twin pregnancies occurred in the GnRH antagonist group and two twin pregnancies in the placebo group. CONCLUSIONS: Adding a GnRH antagonist in cycles with MOH in an IUI program does not increase live birth rates. Dutch Trial Register no: NTR497