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Introduction: Pregnancy after frozen-thawed embryo transfer (FET) is a multifactorial process. Although embryo quality is a key factor in determining pregnancy, other factors, including maternal determinants, are also considered to be predictive. Even though an association between endometrial thickness measured by transvaginal ultrasound and pregnancy rates has been reported in patients undergoing various assisted reproductive technology treatments, whether endometrial thickness predicts achieving pregnancy after natural cycle FET (NC-FET) remains unclear., Material and Methods: In this cohort study, 463 patients allocated to the modified NC-FET (mNC-FET) arm of a previously published randomized controlled trial were included. Monitoring in mNC-FET cycles consisted of regular ultrasound scans, measuring both dominant follicle and endometrial thickness. When the dominant follicle reached a size of 16-20 mm, an injection of human chorionic gonadotrophin was administered and embryo thawing and transfer planned. No minimal endometrial thickness was defined below which transfer was to be deferred. The primary endpoint was ongoing pregnancy rate., Results: Overall, the ongoing pregnancy rate per started FET cycle was 12.5%. Multivariate regression analyses showed that embryo quality was the only significant predictor for ongoing pregnancy. Mean endometrial thickness did not differ between patients achieving ongoing pregnancy and those who did not (9.0 vs. 8.8 mm, p = 0.4). Comparable results were obtained with regard to clinical pregnancy, live birth and miscarriage rates. The area under the receiver operator curve was 0.5, indicating little discriminatory value of endometrial thickness., Conclusions: Given that endometrial thickness was not found to be predictive of pregnancy after mNC-FET, cancellation based on endometrial thickness alone may not be justified., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Study Question: Are live birth rates (LBRs) after artificial cycle frozen-thawed embryo transfer (AC-FET) non-inferior to LBRs after modified natural cycle frozen-thawed embryo transfer (mNC-FET)?, Summary Answer: AC-FET is non-inferior to mNC-FET with regard to LBRs, clinical and ongoing pregnancy rates (OPRs) but AC-FET does result in higher cancellation rates., What Is Already Known: Pooling prior retrospective studies of AC-FET and mNC-FET results in comparable pregnancy and LBRs. However, these results have not yet been confirmed by a prospective randomized trial., Study Design, Size and Duration: In this non-inferiority prospective randomized controlled trial (acronym 'ANTARCTICA' trial), conducted from February 2009 to April 2014, 1032 patients were included of which 959 were available for analysis. The primary outcome of the study was live birth. Secondary outcomes were clinical and ongoing pregnancy, cycle cancellation and endometrium thickness. A cost-efficiency analysis was performed., Participant/materials, Setting, Methods: This study was conducted in both secondary and tertiary fertility centres in the Netherlands. Patients included in this study had to be 18-40 years old, had to have a regular menstruation cycle between 26 and 35 days and frozen-thawed embryos to be transferred had to derive from one of the first three IVF or IVF-ICSI treatment cycles. Patients with a uterine anomaly, a contraindication for one of the prescribed medications in this study or patients undergoing a donor gamete procedure were excluded from participation. Patients were randomized based on a 1:1 allocation to either one cycle of mNC-FET or AC-FET. All embryos were cryopreserved using a slow-freeze technique., Main Results and the Role of Chance: LBR after mNC-FET was 11.5% (57/495) versus 8.8% in AC-FET (41/464) resulting in an absolute difference in LBR of -0.027 in favour of mNC-FET (95% confidence interval (CI) -0.065-0.012; P = 0.171). Clinical pregnancy occurred in 94/495 (19.0%) patients in mNC-FET versus 75/464 (16.0%) patients in AC-FET (odds ratio (OR) 0.8, 95% CI 0.6-1.1, P = 0.25). 57/495 (11.5%) mNC-FET resulted in ongoing pregnancy versus 45/464 (9.6%) AC-FET (OR 0.7, 95% CI 0.5-1.1, P = 0.15). χ(2) test confirmed the lack of superiority. Significantly more cycles were cancelled in AC-FET (124/464 versus 101/495, OR 1.4, 95% CI 1.1-1.9, P = 0.02). The costs of each of the endometrial preparation methods were comparable (€617.50 per cycle in NC-FET versus €625.73 per cycle in AC-FET, P = 0.54)., Limitations, Reasons for Caution: The minimum of 1150 patients required for adequate statistical power was not achieved. Moreover, LBRs were lower than anticipated in the sample size calculation., Wider Implications of the Findings: LBRs after AC-FET were not inferior to those achieved by mNC-FET. No significant differences in clinical and OPR were observed. The costs of both treatment approaches were comparable., Study Funding/competing Interests: An educational grant was received during the conduct of this study. Merck Sharpe Dohme had no influence on the design, execution and analyses of this study. E.R.G. received an education grant by Merck Sharpe Dohme (MSD) during the conduct of the present study. B.J.C. reports grants from MSD during the conduct of the study. A.H. reports grants from MSD and Ferring BV the Netherlands and personal fees from MSD. Grants from ZonMW, the Dutch Organization for Health Research and Development. J.S.E.L. reports grants from Ferring, MSD, Organon, Merck Serono and Schering-Plough during the conduct of the study. F.J.M.B. receives monetary compensation as member of the external advisory board for Merck Serono, consultancy work for Gedeon Richter, educational activities for Ferring BV, research cooperation with Ansh Labs and a strategic cooperation with Roche on automated anti Mullerian hormone assay development. N.S.M. reports receiving monetary compensations for external advisory and speaking work for Ferring BV, MSD, Anecova and Merck Serono during the conduct of the study. All reported competing interests are outside the submitted work. No other relationships or activities that could appear to have influenced the submitted work., Trial Registration Number: Netherlands trial register, number NTR 1586., Trial Registration Date: 13 January 2009., First Patient Included: 20 April 2009., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: What is the cost-effectiveness of in vitro fertilization (IVF) with conventional ovarian stimulation, single embryo transfer (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 €7187 for IVF-SET, €8206 for IVF-MNC and €5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences €2117; 95% CI: €1544-€2657 and €3136, 95% CI: €2519-€3754, respectively).The ICER for IVF-SET compared with IUI-COH was €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., Study Funding/competing Interests: The study was supported by a grant from ZonMw, the Netherlands Organization for Health Research and Development, (120620027) and a grant from Zorgverzekeraars Nederland, the Netherlands' association of health care insurers (09-003)., Trial Registration Number: Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© Bensdorp et al 2015.)

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., Trial Registration Number: Netherlands Trial register NTR1449.

This study aimed to compare longitudinal serum concentrations of angiogenic implantation factors between ongoing singleton and twin pregnancies after double-embryo transfer and to investigate whether these are involved in sustained double implantation. Sixteen patients with an ongoing singleton and nine patients with an ongoing twin pregnancy after double-embryo transfer were included in this prospective observational study. Main outcome measures were concentrations of vascular endothelial growth factor-A (VEGF-A), inhibin A, glycodelin A, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein-3 (IGFBP-3) at baseline, during the IVF treatment and in early pregnancy. It appeared that VEGF-A concentrations prior to any treatment and at early implantation as well as body mass index (BMI) were higher in women who conceived a twin pregnancy (P = 0.04). Soon after implantation, inhibin A concentrations were higher in twin pregnancies (P=0.02). Secretion profiles of glycodelin A and members of the IGF family did not differ between singleton and twin pregnancies. VEGF-A appears to play a role in sustained double implantation. Furthermore a high BMI is associated with ongoing double implantation. Future studies should investigate the predictive value of VEGF-A for having an ongoing singleton or twin pregnancy., (2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The use of aspirin during in vitro fertilization (IVF) has been investigated for its effect on pregnancy rates after IVF. In most of these studies, aspirin administration was then prolonged throughout the first trimester of pregnancy. By inhibiting vasoconstriction, the use of low-dose aspirin in the first trimester could influence placentation and therefore prevent or delay development of hypertensive pregnancy complications, such as pregnancy-induced hypertension (PIH) and pre-eclampsia (PE)., Methods: This study involved the follow-up by questionnaires and hospital records of patients with an ongoing pregnancy in a prospective, randomized, double-blind, placebo-controlled trial on the effect of low-dose aspirin during IVF. Aspirin treatment was continued throughout the first trimester of pregnancy. The primary end-point of this follow-up study was the incidence of pregnancy complications. The original trial is registered with the Dutch Trial Register and as an International Standard Randomized Clinical Trial, No. ISRNCTM97507474., Results: There were 54 patients who had ongoing pregnancies in the original trial; 90.7% returned the questionnaire and all Dutch hospital records were retrieved. A significant difference was found in the incidence of hypertensive pregnancy complications: 3.6% in the aspirin group and 26.9% in the placebo group (P < 0.05), resulting in numbers-needed-to-treat (NNT) of 10.3 to prevent hypertensive complications in one pregnancy after IVF treatment., Conclusions: The incidence of hypertensive complications was significantly lower in the group of women treated with low-dose aspirin throughout IVF treatment and first trimester of pregnancy. These results suggest a potential benefit of low-dose aspirin during IVF and first trimester to prevent hypertensive pregnancy complications. The findings justify further investigation in placebo-controlled randomized trials.

Objective: To analyze whether the administration of low-dose aspirin during IVF treatment improves the uterine blood flow and improves ongoing pregnancy rates for non-tubal factor IVF patients with previous failed conception., Design: Prospective double-blind placebo-controlled trial., Setting: University fertility clinic., Patient(s): Non-tubal IVF patients with previous failed conception., Intervention(s): Daily 100 mg aspirin or placebo throughout an IVF treatment with a long GnRH-agonist stimulation protocol., Main Outcome Measure(s): Ongoing pregnancy rate, pulsatility index of the uterine artery., Result(s): Of 169 patients, 84 were assigned to aspirin treatment and 85 to placebo treatment. In the aspirin group, 28 patients (35.4%) had an ongoing pregnancy, and in the placebo group, 26 patients (31.0%) had an ongoing pregnancy. Multilevel analyses showed that the pulsatility index of the uterine artery was not affected by aspirin or placebo treatment., Conclusion(s): Low-dose aspirin administration during IVF treatment does not improve pregnancy rates of non-tubal factor IVF patients with previous failed conception, and it does not affect the arterial uterine blood flow.

Objective: To compare the effectiveness of highly purified hMG with recombinant FSH (rFSH) in IVF-intracytoplasmic sperm injection patients who were treated with a GnRH agonist., Design: An open-label, prospective, randomized comparison of fixed gonadotropin regimens., Setting: Eighteen Dutch IVF centers., Patient(s): Six hundred twenty-nine patients who were selected for IVF-intracytoplasmic sperm injection., Intervention(s): Patients were randomized to receive either highly purified hMG or rFSH in a fixed dosage of 150 IU/d after GnRH-agonist suppression (long protocol)., Main Outcome Measure(s): Ongoing pregnancy rate per started cycle. Difference between the two treatment groups was tested by using odds ratios, including the 95% confidence limits (intention-to-treat sample), and by using the Fisher's exact test (per-protocol sample)., Result(s): The ongoing pregnancy rates per started cycle were 26.3% and 25.2% for highly purified hMG and rFSH, respectively (no statistically significant difference). Treatment with highly purified hMG resulted in statistically significantly fewer oocytes (n = 7.8) than did treatment with rFSH (n = 10.6). There were no differences with respect to fertilization rates and implantation rates. Cycles with highly purified hMG were statistically significantly less often canceled as a result of ovarian hyperresponse (2.0% vs. 6.0% for highly purified hMG and rFSH, respectively)., Conclusion(s): Compared with rFSH, highly purified hMG did not result in superiority in ongoing pregnancy rates in first-cycle IVF-intracytoplasmic sperm injection patients who were treated with a fixed dosage of 150 IU of gonadotropin per day. Compared with rFSH, treatment with highly purified hMG resulted in retrieval of fewer oocytes, a lower incidence of hyperresponse, and comparable pregnancy rates.

Objective: To evaluate the predictive value of serial uterine artery Doppler ultrasound for embryo implantation in in-vitro fertilization (IVF)-intracytoplasmic sperm injection (ICSI) cycles., Methods: This was a prospective observational study at the VU University Medical Center, Amsterdam. Patients with an indication for IVF or IVF-ICSI according to departmental protocol underwent controlled ovarian hyperstimulation followed by IVF or IVF-ICSI and embryo transfer and had serial Doppler ultrasound performed during this treatment cycle. Patient and cycle characteristics, number of conceptions and ongoing pregnancies and pulsatility index (PI) of both uterine arteries on different cycle days were assessed and results were compared between patients who conceived and those who did not., Results: Of the 102 patients enrolled into the study, 83 underwent embryo transfer. Of these, 41 became pregnant and 42 did not (Group 1). Of the 41 pregnancies, 30 were ongoing (Group 2) and 11 miscarried (Group 3). Between Groups 1, 2 and 3, linear regression revealed no significant difference between any of the variables examined except in the quality of transferred embryos. There was no significant difference in the mean PI of the left and right uterine arteries on any day of the cycle, or in the change in PI during the cycle. Receiver-operating characteristics curves derived to determine the performance of PI to predict pregnancy outcome supported our findings that the uterine artery PI is not a suitable marker for identifying patients with implantation failure. Multivariate analysis showed no relationship between pregnancy and PI between groups, but it did show a relationship between pregnancy and some patient and cycle characteristics., Conclusion: In an unselected group of patients undergoing IVF or IVF-ICSI and embryo transfer, serial Doppler ultrasound examination of the uterine artery does not discriminate between cycles resulting in ongoing pregnancy, miscarriage and no pregnancy., (Copyright (c) 2008 ISUOG. Published by John Wiley & Sons, Ltd.)

A pregnancy rate of approximately 15% per cycle renders the process of human reproduction inefficient. The cycle-dependent expression of molecules involved in the embryo-endometrial dialogue has lead to the identification of a 'window of implantation'. This is the unique temporal and spatial expression of factors that allows the embryo to implant (via signalling, appositioning, attachment and invasion) in a specific time frame of 48 h, 7-10 days after ovulation. Integrin molecules, L-selectin ligands, mucin-1, heparin-binding epidermal growth factor and pinopodes are involved in appositioning and attachment. The embryo produces cytokines and growth factors [interleukins, prostaglandins, vascular endothelial growth factor (VEGF)] and receptors for endometrial signals (leukaemia inhibitory factor receptor, colony stimulating factor receptor, insulin-like growth factors and heparin binding epidermal growth factor receptor). The immune system plays an important role. Immunomodulatory factors such as glycodelin, inhibin and interleukin prevent a graft-versus-host reaction. Angiogenesis controlled by VEGF and prostaglandins is needed for formation of a receptive endometrium and a placenta. Identification of these factors has led to their use as markers of implantation that may identify defects causing subfertility. An ideal marker of implantation is sensitive and specific, and easy to obtain without disturbing implantation. Glycodelin and leukaemia inhibitory factor (serum) and integrins and pinopodes (biopsies) are promising candidates.