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Study Question: Does assisted reproduction, such as ovarian stimulation and/or laboratory procedures, have impact on perinatal outcomes of singleton live births compared to natural conception in couples with unexplained subfertility?Summary Answer: Compared to natural conception, singletons born after intrauterine insemination with ovarian stimulation (IUI-OS) had a lower birthweight, while singletons born after IVF had comparable birthweights, in couples with unexplained subfertility.What Is Known Already: Singletons conceived by assisted reproduction have different perinatal outcomes such as low birthweight and a higher risk of premature birth than naturally conceived singletons. This might be due to the assisted reproduction, such as laboratory procedures or the ovarian stimulation, or to an intrinsic factor in couples with subfertility.Study Design, Size, Duration: We performed a prospective cohort study using the follow-up data of two randomized clinical trials performed in couples with unexplained subfertility. We evaluated perinatal outcomes of 472 live birth singletons conceived after assisted reproduction or after natural conception within the time horizon of the studies.Participants/materials, Setting, Methods: To assess the possible impact of ovarian stimulation we compared the singletons conceived after IUI with FSH or clomiphene citrate (CC) and IVF in a modified natural cycle (IVF-MNC) or standard IVF with single embryo transfer (IVF-SET) to naturally conceived singletons in the same cohorts. To further look into the possible effect of the laboratory procedures, we put both IUI and IVF groups together into IUI-OS and IVF and compared both to singletons born after natural conception. We only included singletons conceived after fresh embryo transfers. The main outcome was birthweight presented as absolute weight in grams and gestational age- and gender-adjusted percentiles. We calculated differences in birthweight using regression analyses adjusted for maternal age, BMI, smoking, parity, duration of subfertility and child gender.Main Results and the Role Of Chance: In total, there were 472 live birth singletons. Of the 472 singleton pregnancies, 209 were conceived after IUI-OS (136 with FSH and 73 with CC as ovarian stimulation), 138 after IVF (50 after IVF-MNC and 88 after IVF-SET) and 125 were conceived naturally.Singletons conceived following IUI-FSH and IUI-CC both had lower birthweights compared to naturally conceived singletons (adjusted difference IUI-FSH -156.3 g, 95% CI -287.9 to -24.7; IUI-CC -160.3 g, 95% CI -316.7 to -3.8). When we compared IVF-MNC and IVF-SET to naturally conceived singletons, no significant difference was found (adjusted difference IVF-MNC 75.8 g, 95% CI -102.0 to 253.7; IVF-SET -10.6 g, 95% CI -159.2 to 138.1). The mean birthweight percentile was only significantly lower in the IUI-FSH group (-7.0 percentile, 95% CI -13.9 to -0.2). The IUI-CC and IVF-SET group had a lower mean percentile and the IVF-MNC group a higher mean percentile, but these groups were not significant different compared to the naturally conceived group (IUI-CC -5.1 percentile, 95% CI -13.3 to 3.0; IVF-MNC 4.4 percentile, 95% CI -4.9 to 13.6; IVF-SET -1.3 percentile, 95% CI -9.1 to 6.4).Looking at the laboratory process that took place, singletons conceived following IUI-OS had lower birthweights than naturally conceived singletons (adjusted difference -157.7 g, 95% CI -277.4 to -38.0). The IVF group had comparable birthweights with the naturally conceived group (adjusted difference 20.9 g, 95% CI -110.8 to 152.6). The mean birthweight percentile was significantly lower in the IUI-OS group compared to the natural group (-6.4 percentile, 95% CI -12.6 to -0.1). The IVF group was comparable (0.7 percentile, 95% CI -6.1 to 7.6).Limitations, Reasons For Caution: The results are limited by the number of cases. The data were collected prospectively alongside the randomized controlled trials, but analyzed as treated.Wider Implications Of the Findings: Our data suggest IUI in a stimulated cycle may have a negative impact on the birthweight of the child and possibly on pre-eclampsia. Further research should look into the effect of different methods of ovarian stimulation on placenta pathology and pre-eclampsia in couples with unexplained subfertility using naturally conceived singletons in the unexplained population as a reference.Study Funding/competing Interest(s): Both initial trials were supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (INeS 120620027, SUPER 80-83600-98-10192). The INeS study also had a grant from Zorgverzekeraars Nederland, the Dutch association of healthcare insurers (09-003). B.W.J.M. is supported by an NHMRC investigator Grant (GNT1176437) and reports consultancy for ObsEva, Merck Merck KGaA, Guerbet and iGenomix, outside the submitted work. A.H. reports grants from Ferring Pharmaceutical company (the Netherlands), outside the submitted work. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands), Ferring Pharmaceutics BV (the Netherlands) and Gedeon Richter (Belgium), he receives personal fees from educational activities for Ferring BV (the Netherlands) and for advisory and consultancy work for Roche and he receives research support grants from Merck Serono and Ferring Pharmaceutics BV, outside the submitted work. The remaining authors have nothing to disclose.Trial Registration Number: INeS study Trial NL915 (NTR939); SUPER Trial NL3895 (NTR4057). [ABSTRACT FROM AUTHOR]

Study Question: What is the natural conception rate over the course of 12 months in couples with unexplained or mild male subfertility who are scheduled for fertility treatment and have a predicted unfavourable prognosis for natural conception?Summary Answer: The natural conception rate over the course of 12 months in couples who were allocated to treatment was estimated to be 24.5% (95% CI: 20-29%).What Is Known Already: After starting treatment, couples often perceive unsuccessful cycles as evidence of definitive failure even though they are still able to conceive naturally in between and after treatment. The magnitude of the natural conception rate for couples who chose to commence treatment is unknown, as is whether the calculated prognosis before commencing treatment is still applicable.Study Design, Size, Duration: We performed a secondary analysis of a randomized controlled trial including couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception. Couples were allocated to either three cycles IVF with single embryo transfer (SET), six cycles of IVF in a modified natural cycle (MNC) or six cycles of IUI with controlled ovarian hyperstimulation (IUI-COH). The detailed data collection in this trial allowed us to study the conception rates in periods that couples were not receiving treatment.Participants/materials, Settings, Methods: We split the dataset into periods during which couples were treated and periods during which they were not treated. Couples could conceive naturally in the periods before, in between and after treatment cycles. The outcome was ongoing pregnancy, thus natural conception rate refers to natural conception leading to ongoing pregnancy. We performed a Cox proportional hazards analysis with female age, duration of subfertility and a time-varying covariate with four categories: IVF-SET, IVF-MNC, IUI-COH and no treatment. We used this Cox model to estimate the natural conception rate over 12 months of no treatment.Main Results and the Role Of Chance: Out of 602 included couples, there were 342 ongoing pregnancies, of which 77 (23%) resulted from natural conception. The estimated natural conception rate over 12 months was 24.5% (95% CI: 20-29%) on cohort level. Estimated rates for female age varying between 18 and 38 years and duration of subfertility between 1 and 3 years ranged from 22 to 35%.Limitations, Reasons For Caution: We considered couples at risk for natural conception when not receiving treatment, whereas they might not have had periovulatory sexual intercourse. As couples were scheduled for treatment, it is possible that these couples were less inclined to try to conceive naturally, potentially leading to an underestimation of their natural conception rate if they kept trying to conceive.Wider Implications Of the Findings: Couples with unexplained subfertility who are about to start fertility treatment, still have about a one in four chance of ongoing pregnancy due to natural conception over 12 months. This information can add to the counselling of couples who commenced fertility treatment after failed cycles and to emphasize not to cease their natural attempts.Study Funding/competing Interest(s): The INeS trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch association of health care insurers (09-003). The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. No other potential conflicts of interest reported.Trial Registration Number: The INeS trial was registered at the Dutch trial registry (NTR 939). [ABSTRACT FROM AUTHOR]

Study Question: Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)?Summary Answer: We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility.What Is Known Already: A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI.Study Design, Size, Duration: We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples).Participants/materials, Setting, Methods: We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1.Main Results and the Role Of Chance: None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10).Limitations, Reasons For Caution: Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations.Wider Implications Of the Findings: We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples.Study Funding/competing Interest(s): The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest.Trial Registration Number: The trial was registered at the Dutch trial registry (NTR939). [ABSTRACT FROM AUTHOR]

Study Question: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility?Summary Answer: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic.What Is Known Already: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management.Study Design, Size, Duration: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded.Participants/materials, Setting, Methods: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions.Main Results and the Role Of Chance: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup.Limitations, Reasons For Caution: The dynamic prediction model needs to be validated in an external population.Wider Implications Of the Findings: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup.Study Funding/competing Interests: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests. [ABSTRACT FROM AUTHOR]

IUI is a first-line treatment for couples with unexplained or mild male subfertility and has become one of the most widely used fertility-enhancing treatments. The results of a recent trial comparing IVF to IUI, demonstrating similar live birth rates, have been used to build a case supporting the effectiveness of IUI. Yet, this conclusion might be somewhat premature, as the superiority of neither IUI nor IVF over no treatment has ever been proven. The evidence on the effectiveness and safety of IUI and IVF has been evaluated in two Cochrane reviews which both suggested that there is insufficient evidence to conclude that IUI or IVF is effective compared to sexual intercourse in couples with unexplained subfertility. Recommendations for clinical practice have been given in the most recent National Institute for Health and Care Excellence fertility guideline that advises not to offer IUI any longer and suggests 2 years of sexual intercourse followed by IVF. This recommendation has generated an ongoing debate, with only 4% of all gynecologists in the UK discontinuing the use of IUI. We feel that it is high time to provide proper scientific evidence for the effectiveness of IUI, or lack thereof, and invite the medical community to start RCTs comparing IUI to sexual intercourse. [ABSTRACT FROM AUTHOR]

Objective: Does ovarian hyperstimulation and/or the in vitro procedure of assisted reproduction affect neurodevelopmental and physical health of the offspring?, Study Design: Infertile couples were randomly allocated to intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH), modified natural cycle in vitro fertilization (IVF-MNC) or single embryo transfer IVF (IVF-SET). We compared neurodevelopmental and physical health in childhood (4-7 years). We used age-appropriate questionnaires to assess behavioral problems (Child Behavior Check List (CBCL)) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)). We measured body mass index Z-score, waist- and hip-circumference, body fat percentage, blood pressure Z-scores, pulse wave velocity, glucose, insulin, insulin resistance, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, and high sensitivity c-reactive protein. We compared groups by analysis of variance., Results: We examined 191 (57%) of the 333 children born in the study at a mean age of 5.5 years (range 4.0-7.6 years). We found no statistically significant differences between randomization groups in children's neurodevelopmental or physical health indices (all p-values > 0.05). Comparing the outcomes between actual method of conception, including a naturally conceived group, also did not show statistically significant differences., Conclusions: Although this follow-up study was not powered on childhood outcomes and limited power due to attrition may have hampered detection of subtle effects, we found no indications of differences in neurodevelopmental and physical health between ovarian hyperstimulation and/or the in vitro procedure of assisted reproduction. Future trials should be powered on child outcomes, and aim to optimize follow-up rates to provide answers that are more definitive., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Unlabelled: Summary, Objective: Uterine serous carcinoma (USC) is an aggressive, histological subtype of endometrial cancer with a poor prognosis. This study evaluates the additional effect of staging surgery above total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH+BSO) on the use of adjuvant therapy and subsequent survival outcomes in clinical early-stage USC patients., Materials and Methods: This retrospective cohort study includes 75 women treated for clinical early-stage USC., Results: In 33 (44%) clinical early-stage patients surgical staging was performed and 15 patients (45%) proved to have lymphatic or abdominal metastasis. Use of adjuvant therapy was similar in patients, both staged with no metastasis (n = 18) and patients who underwent TAH and BSO only (n = 42, p = 0.17). No significant survival difference was found between surgically staged and TAH+BSO patients., Conclusions: Surgical staging proved to be important to determine stage of disease and hence prognosis. Surgical staging did not lead to selective avoidance of adjuvant therapy in patients with no metastasis.

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.)