External validation of models for predicting cumulative live birth over multiple complete cycles of IVF treatment.

STUDY QUESTION: Can two prediction models developed using data from 1999 to 2009 accurately predict the cumulative probability of live birth per woman over multiple complete cycles of IVF in an updated UK cohort? SUMMARY ANSWER: After being updated, the models were able to estimate individualized chances of cumulative live birth over multiple complete cycles of IVF with greater accuracy. WHAT IS KNOWN ALREADY: The McLernon models were the first to predict cumulative live birth over multiple complete cycles of IVF. They were converted into an online calculator called OPIS (Outcome Prediction In Subfertility) which has 3000 users per month on average. A previous study externally validated the McLernon models using a Dutch prospective cohort containing data from 2011 to 2014. With changes in IVF practice over time, it is important that the McLernon models are externally validated on a more recent cohort of patients to ensure that predictions remain accurate. STUDY DESIGN, SIZE, DURATION: A population-based cohort of 91 035 women undergoing IVF in the UK between January 2010 and December 2016 was used for external validation. Data on frozen embryo transfers associated with these complete IVF cycles conducted from 1 January 2017 to 31 December 2017 were also collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA). The predictive performances of the McLernon models were evaluated in terms of discrimination and calibration. Discrimination was assessed using the c-statistic and calibration was assessed using calibration-in-the-large, calibration slope, and calibration plots. Where any model demonstrated poor calibration in the validation cohort, the models were updated using intercept recalibration, logistic recalibration, or model revision to improve model performance. MAIN RESULTS AND THE ROLE OF CHANCE: Following exclusions, 91 035 women who underwent 144 734 complete cycles were included. The validation cohort had a similar distribution age profile to women in the development cohort. Live birth rates over all complete cycles of IVF per woman were higher in the validation cohort. After calibration assessment, both models required updating. The coefficients of the pre-treatment model were revised, and the updated model showed reasonable discrimination (c-statistic: 0.67, 95% CI: 0.66 to 0.68). After logistic recalibration, the post-treatment model showed good discrimination (c-statistic: 0.75, 95% CI: 0.74 to 0.76). As an example, in the updated pre-treatment model, a 32-year-old woman with 2 years of primary infertility has a 42% chance of having a live birth in the first complete ICSI cycle and a 77% chance over three complete cycles. In a couple with 2 years of primary male factor infertility where a 30-year-old woman has 15 oocytes collected in the first cycle, a single fresh blastocyst embryo transferred in the first cycle and spare embryos cryopreserved, the estimated chance of live birth provided by the post-treatment model is 46% in the first complete ICSI cycle and 81% over three complete cycles. LIMITATIONS, REASONS FOR CAUTION: Two predictors from the original models, duration of infertility and previous pregnancy, which were not available in the recent HFEA dataset, were imputed using data from the older cohort used to develop the models. The HFEA dataset does not contain some other potentially important predictors, e.g. BMI, ethnicity, race, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. WIDER IMPLICATIONS OF THE FINDINGS: Both updated models show improved predictive ability and provide estimates which are more reflective of current practice and patient case mix. The updated OPIS tool can be used by clinicians to help shape couples' expectations by informing them of their individualized chances of live birth over a sequence of multiple complete cycles of IVF. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. S.B. has a commitment of research funding from Merck. D.J.M. and M.B.R. declare support for the present manuscript from Elphinstone scholarship scheme at the University of Aberdeen and Assisted Reproduction Unit at Aberdeen Fertility Centre, University of Aberdeen. D.J.M. declares grants received by University of Aberdeen from NHS Grampian, The Meikle Foundation, and Chief Scientist Office in the past 3 years. D.J.M. declares receiving an honorarium for lectures from Merck. D.J.M. is Associate Editor of Human Reproduction Open and Statistical Advisor for Reproductive BioMed Online. S.B. declares royalties from Cambridge University Press for a book. S.B. declares receiving an honorarium for lectures from Merck, Organon, Ferring, Obstetric and Gynaecological Society of Singapore, and Taiwanese Society for Reproductive Medicine. S.B. has received support from Merck, ESHRE, and Ferring for attending meetings as speaker and is on the METAFOR and CAPRE Trials Data Monitoring Committee. TRIAL REGISTRATION NUMBER: N/A.

In vitro fertilisation for unexplained subfertility.

BACKGROUND: In vitro fertilisation (IVF) is a treatment for unexplained subfertility but is invasive, expensive, and associated with risks. OBJECTIVES: To evaluate the effectiveness and safety of IVF versus expectant management, unstimulated intrauterine insemination (IUI), and IUI with ovarian stimulation using gonadotropins, clomiphene citrate (CC), or letrozole in improving pregnancy outcomes. SEARCH METHODS: We searched following databases from inception to November 2021, with no language restriction: Cochrane Gynaecology and Fertility Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL. We searched reference lists of articles and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing effectiveness of IVF for unexplained subfertility with expectant management, unstimulated IUI, and stimulated IUI. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: IVF versus expectant management (two RCTs) We are uncertain whether IVF improves live birth rate (LBR) and clinical pregnancy rate (CPR) compared to expectant management (odds ratio (OR) 22.0, 95% confidence interval (CI) 2.56 to 189.37; 1 RCT; 51 women; very low-quality evidence; OR 3.24, 95% CI 1.07 to 9.8; 2 RCTs; 86 women; I2 = 80%; very low-quality evidence). Adverse effects were not reported. Assuming 4% LBR and 12% CPR with expectant management, these would be 8.8% to 9% and 13% to 58% with IVF. IVF versus unstimulated IUI (two RCTs) IVF may improve LBR compared to unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12; 2 RCTs; 156 women; I2 = 60%; low-quality evidence). We are uncertain whether there is a difference between IVF and IUI for multiple pregnancy rate (MPR) (OR 1.03, 95% CI 0.04 to 27.29; 1 RCT; 43 women; very low-quality evidence) and miscarriage rate (OR 1.72, 95% CI 0.14 to 21.25; 1 RCT; 43 women; very low-quality evidence). No study reported ovarian hyperstimulation syndrome (OHSS). Assuming 16% LBR, 3% MPR, and 6% miscarriage rate with unstimulated IUI, these outcomes would be 18.5% to 49%, 0.1% to 46%, and 0.9% to 58% with IVF. IVF versus IUI + ovarian stimulation with gonadotropins (6 RCTs), CC (1 RCT), or letrozole (no RCTs) Stratified analysis was based on pretreatment status. Treatment-naive women There may be little or no difference in LBR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.19, 95% CI 0.87 to 1.61; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 1.63, 95% CI 0.91 to 2.92; 2 RCTs; 221 women; I2 = 54%; low-quality evidence); or between IVF and IUI + CC (OR 2.51, 95% CI 0.96 to 6.55; 1 RCT; 103 women; low-quality evidence). Assuming 42% LBR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 26% LBR with IUI + gonadotropins (1 IVF to 1 IUI cycle), LBR would be 39% to 54% and 24% to 51% with IVF. Assuming 15% LBR with IUI + CC, LBR would be 15% to 54% with IVF. There may be little or no difference in CPR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.17, 95% CI 0.85 to 1.59; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 4.59, 95% CI 1.86 to 11.35; 1 RCT; 103 women; low-quality evidence); or between IVF and IUI + CC (OR 3.58, 95% CI 1.51 to 8.49; 1 RCT; 103 women; low-quality evidence). Assuming 48% CPR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 17% with IUI + gonadotropins (1 IVF to 1 IUI cycle), CPR would be 44% to 60% and 28% to 70% with IVF. Assuming 21% CPR with IUI + CC, CPR would be 29% to 69% with IVF. There may be little or no difference in multiple pregnancy rate (MPR) between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 0.82, 95% CI 0.38 to 1.77; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 0.76, 95% CI 0.36 to 1.58; 2 RCTs; 221 women; I2 = 0%; low-quality evidence); or between IVF and IUI + CC (OR 0.64, 95% CI 0.17 to 2.41; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in OHSS between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 6.86, 95% CI 0.35 to 134.59; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference in OHSS with 1 IVF to 1 IUI cycle (OR 1.22, 95% CI 0.36 to 4.16; 2 RCTs; 221 women; I2 = 0%; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.53, 95% CI 0.24 to 9.57; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in miscarriage rate between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 0.31, 95% CI 0.03 to 3.04; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference with 1 IVF to 1 IUI cycle (OR 1.16, 95% CI 0.44 to 3.02; 1 RCT; 103 women; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.48, 95% CI 0.54 to 4.05; 1 RCT; 102 women; low-quality evidence). In women pretreated with IUI + CC IVF may improve LBR compared with IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57; 1 RCT; 280 women; low-quality evidence). Assuming 22% LBR with IUI + gonadotropins, LBR would be 39% to 65% with IVF. IVF may improve CPR compared with IUI + gonadotropins (OR 14.13, 95% CI 7.57 to 26.38; 1 RCT; 280 women; low-quality evidence). Assuming 30% CPR with IUI + gonadotropins, CPR would be 76% to 92% with IVF. AUTHORS' CONCLUSIONS: IVF may improve LBR over unstimulated IUI. Data should be interpreted with caution as overall evidence quality was low.

Predicting cumulative live birth for couples beginning their second complete cycle of in vitro fertilization treatment.

STUDY QUESTION: Can we develop an IVF prediction model to estimate individualized chances of a live birth over multiple complete cycles of IVF in couples embarking on their second complete cycle of treatment? SUMMARY ANSWER: Yes, our prediction model can estimate individualized chances of cumulative live birth over three additional complete cycles of IVF. WHAT IS KNOWN ALREADY: After the completion of a first complete cycle of IVF, couples who are unsuccessful may choose to undergo further treatment to have their first child, while those who have had a live birth may decide to have more children. Existing prediction models can estimate the overall chances of success in couples before commencing IVF but are unable to revise these chances on the basis of the couple's response to a first treatment cycle in terms of the number of eggs retrieved and pregnancy outcome. This makes it difficult for couples to plan and prepare emotionally and financially for the next step in their treatment. STUDY DESIGN, SIZE, DURATION: For model development, a population-based cohort was used of 49 314 women who started their second cycle of IVF including ICSI in the UK from 1999 to 2008 using their own oocytes and their partners' sperm. External validation was performed on data from 39 442 women who underwent their second cycle from 2010 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data about all UK IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA) database. Using a discrete time logistic regression model, we predicted the cumulative probability of live birth from the second up to and including the fourth complete cycles of IVF. Inverse probability weighting was used to account for treatment discontinuation. Discrimination was assessed using c-statistic and calibration was assessed using calibration-in-the-large and calibration slope. MAIN RESULTS AND THE ROLE OF CHANCE: Following exclusions, 49 314 women with 73 053 complete cycles were included. 12 408 (25.2%) had a live birth resulting from their second complete cycle. Cumulatively, 17 394 (35.3%) had a live birth over complete cycles two to four. The model showed moderate discriminative ability (c-statistic: 0.65, 95% CI: 0.64 to 0.65) and evidence of overprediction (calibration-in-the-large = -0.08) and overfitting (calibration slope 0.85, 95% CI: 0.81 to 0.88) in the validation cohort. However, after recalibration the fit was much improved. The recalibrated model identified the following key predictors of live birth: female age (38 versus 32 years-adjusted odds ratio: 0.59, 95% CI: 0.57 to 0.62), number of eggs retrieved in the first complete cycle (12 versus 4 eggs; 1.34, 1.30 to 1.37) and outcome of the first complete cycle (live birth versus no pregnancy; 1.78, 1.66 to 1.91; live birth versus pregnancy loss; 1.29, 1.23 to 1.36). As an example, a 32-year-old with 2 years of non-tubal infertility who had 12 eggs retrieved from her first stimulation and had a live birth during her first complete cycle has a 46% chance of having a further live birth from the second complete cycle of IVF and an 81% chance over a further three cycles. LIMITATIONS, REASONS FOR CAUTION: The developed model was updated using validation data that was 6 to 12 years old. IVF practice continues to evolve over time, which may affect the accuracy of predictions from the model. We were unable to adjust for some potentially important predictors, e.g. BMI, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. These were not available in the linked HFEA dataset. WIDER IMPLICATIONS OF THE FINDINGS: By appropriately adjusting for couples who discontinue treatment, our novel prediction model will provide more realistic chances of live birth in couples starting a second complete cycle of IVF. Clinicians can use these predictions to inform discussion with couples who wish to plan ahead. This prediction tool will enable couples to prepare emotionally, financially and logistically for IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 16 February 2016.

Assessing couples' preferences for fresh or frozen embryo transfer: a discrete choice experiment.

STUDY QUESTION: What are couples' preferences for fresh embryo transfer versus freezing of all embryos followed by frozen embryo transfer and the associated clinical outcomes that may differentiate them? SUMMARY ANSWER: Couples' preferences are driven by anticipated chances of live birth, miscarriage, neonatal complications, and costs but not by the differences in the treatment process (including delay of embryo transfer linked to frozen embryo transfer and risk of ovarian hyperstimulation syndrome (OHSS) associated with fresh embryo transfer). WHAT IS KNOWN ALREADY: A policy of freezing all embryos followed by transfer of frozen embryos results in livebirth rates which are similar to or higher than those following the transfer of fresh embryos while reducing the risk of OHSS and small for gestational age babies: it can, however, increase the risk of pre-eclampsia and large for gestational age offspring. Hence, the controversy continues over whether to do fresh embryo transfer or freeze all embryos followed by frozen embryo transfer. STUDY DESIGN, SIZE, DURATION: We used a discrete choice experiment (DCE) technique to survey infertile couples between August 2018 and January 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: We asked IVF naïve couples attending a tertiary referral centre to independently complete a questionnaire with nine hypothetical choice tasks between fresh and frozen embryo transfer. The alternatives varied across the choice occurrences on several attributes including efficacy (live birth rate), safety (miscarriage rate, neonatal complication rate), and cost of treatment. We assumed that a freeze-all strategy prolonged treatment but reduced the risk of OHSS. An error components mixed logit model was used to estimate the relative value (utility) that couples placed on the alternative treatment approaches and the attributes used to describe them. Willingness to pay and marginal rates of substitution between the non-cost attributes were calculated. A total of 360 individual questionnaires were given to 180 couples who fulfilled the inclusion criteria, of which 212 were completed and returned Our study population included 3 same sex couples (2 females and 1 male) and 101 heterosexual couples. Four questionnaires were filled by one partner only. The response rate was 58.8%. MAIN RESULTS AND THE ROLE OF CHANCE: Couples preferred both fresh and frozen embryo transfer (odds ratio 27.93 and 28.06, respectively) compared with no IVF treatment, with no strong preference for fresh over frozen. Couples strongly preferred any IVF technique that offered an increase in live birth rates by 5% (P = 0.006) and 15% (P < 0.0001), reduced miscarriage by 18% (P < 0.0001) and diminished neonatal complications by 10% (P < 0.0001). Respondents were willing to pay an additional £2451 (95% CI 604 - 4299) and £761 (95% CI 5056-9265) for a 5 and 15% increase in the chance of live birth, respectively, regardless of whether this involved fresh or frozen embryos. They required compensation of £5230 (95% CI 3320 - 7141) and £13 245 (95% CI 10 110-16 380) to accept a 10 and 25% increase in the risk of neonatal complications, respectively (P < 0.001). Results indicated that couples would be willing to accept a 1.26% (95% CI 1.001 - 1.706) reduction in the live birth rate for a 1% reduction in the risk of neonatal complications per live birth. Older couples appeared to place less emphasis on the risk of neonatal complications than younger couples. LIMITATIONS, REASONS FOR CAUTION: DCEs can elicit intentions which may not reflect actual behaviour. The external validity of this study is limited by the fact that it was conducted in a single centre with generous public funding for IVF. We cannot rule out the potential for selection or responder bias. WIDER IMPLICATIONS OF THE FINDINGS: If a strategy of freeze all was to be implemented it would appear to be acceptable to patients, if either success rates can be improved or neonatal complications reduced. Live birth rates, neonatal complication rates, miscarriage rates, and cost are more likely to drive their preferences than a slight delay in the treatment process. The results of this study have important implications for future economic evaluations of IVF, as they suggest that the appropriate balance needs to be struck between success and safety. A holistic approach incorporating patient preferences for expected clinical outcomes and risks should be taken into consideration for individualized care. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. A.M. is the chief investigator of the randomized controlled trial 'Freeze all'. S.B. is an Editor in Chief of Human Reproduction Open. The other co-authors have no conflicts of interest to declare. Graham Scotland reports non-financial support from Merck KGaA, Darmstadt, Germany, outside the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Prioritizing IVF treatment in the post-COVID 19 era: a predictive modelling study based on UK national data.

STUDY QUESTION: Can we use prediction modelling to estimate the impact of coronavirus disease 2019 (COVID 19) related delay in starting IVF or ICSI in different groups of women? SUMMARY ANSWER: Yes, using a combination of three different models we can predict the impact of delaying access to treatment by 6 and 12 months on the probability of conception leading to live birth in women of different age groups with different categories of infertility. WHAT IS KNOWN ALREADY: Increased age and duration of infertility can prejudice the chances of success following IVF, but couples with unexplained infertility have a chance of conceiving naturally without treatment whilst waiting for IVF. The worldwide suspension of IVF could lead to worse outcomes in couples awaiting treatment, but it is unclear to what extent this could affect individual couples based on age and cause of infertility. STUDY DESIGN, SIZE, DURATION: A population-based cohort study based on national data from all licensed clinics in the UK obtained from the Human Fertilisation and Embryology Authority Register. Linked data from 9589 women who underwent their first IVF or ICSI treatment in 2017 and consented to the use of their data for research were used to predict livebirth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three prediction models were used to estimate the chances of livebirth associated with immediate treatment versus a delay of 6 and 12 months in couples about to embark on IVF or ICSI. MAIN RESULTS AND THE ROLE OF CHANCE: We estimated that a 6-month delay would reduce IVF livebirths by 0.4%, 2.4%, 5.6%, 9.5% and 11.8% in women aged <30, 30-35, 36-37, 38-39 and 40-42 years, respectively, while corresponding values associated with a delay of 12 months were 0.9%, 4.9%, 11.9%, 18.8% and 22.4%, respectively. In women with known causes of infertility, worst case (best case) predicted chances of livebirth after a delay of 6 months followed by one complete IVF cycle in women aged <30, 30-35, 36-37, 38-39 and 40-42 years varied between 31.6% (35.0%), 29.0% (31.6%), 23.1% (25.2%), 17.2% (19.4%) and 10.3% (12.3%) for tubal infertility and 34.3% (39.2%), 31.6% (35.3%) 25.2% (28.5%) 18.3% (21.3%) and 11.3% (14.1%) for male factor infertility. The corresponding values in those treated immediately were 31.7%, 29.8%, 24.5%, 19.0% and 11.7% for tubal factor and 34.4%, 32.4%, 26.7%, 20.2% and 12.8% in male factor infertility. In women with unexplained infertility the predicted chances of livebirth after a delay of 6 months followed by one complete IVF cycle were 41.0%, 36.6%, 29.4%, 22.4% and 15.1% in women aged <30, 30-35, 36-37, 38-39 and 40-42 years, respectively, compared to 34.9%, 32.5%, 26.9%, 20.7% and 13.2% in similar groups of women treated without any delay. The additional waiting period, which provided more time for spontaneous conception, was predicted to increase the relative number of babies born by 17.5%, 12.6%, 9.1%, 8.4% and 13.8%, in women aged <30, 30-35, 36-37, 38-39 and 40-42 years, respectively. A 12-month delay showed a similar pattern in all subgroups. LIMITATIONS, REASONS FOR CAUTION: Major sources of uncertainty include the use of prediction models generated in different populations and the need for a number of assumptions. Although the models are validated and the bases for the assumptions are robust, it is impossible to eliminate the possibility of imprecision in our predictions. Therefore, our predicted live birth rates need to be validated in prospective studies to confirm their accuracy. WIDER IMPLICATIONS OF THE FINDINGS: A delay in starting IVF reduces success rates in all couples. For the first time, we have shown that while this results in fewer babies in older women and those with a known cause of infertility, it has a less detrimental effect on couples with unexplained infertility, some of whom conceive naturally whilst waiting for treatment. Post-COVID 19, clinics planning a phased return to normal clinical services should prioritize older women and those with a known cause of infertility. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, Merck KGaA, Guerbet and iGenomics. S.B. is Editor-in-Chief of Human Reproduction Open. None of the other authors declare any conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

BACKGROUND: Monitoring of in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) is necessary to detect as well as reduce the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the optimal ovarian response needed for assisted reproduction treatment. Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation IVF and ICSI treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered.  OBJECTIVES: To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. SEARCH METHODS: In this update conducted in March 2020, two review authors searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, the National Research Register, and web-based trial registers. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. DATA COLLECTION AND ANALYSIS: Two review authors (IK, AW) independently selected the studies, extracted data and assessed risk of bias. We resolved disagreements by discussion. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. MAIN RESULTS: We did not identify any new eligible studies in this update in 2020. The evidence based on the six trials identified in 2014 remained unchanged. They included 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment. None of the six studies reported our primary outcome of live birth rate. Two studies presented pregnancy rate per initiated cycle and per embryo transfer, respectively. Four studies reported pregnancy rate per woman with pooled data; we are uncertain of the effect of monitoring with TVUS only versus combined monitoring on clinical pregnancy rate per woman (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests in women with a 36% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate using TVUS only would be between 31% and 46%. We are uncertain of any effect in the mean number of oocytes retrieved per woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).  We are uncertain whether monitoring with TVUS only versus combined monitoring affected the incidence of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that in women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate monitored by TVUS only would be between 2% and 8%. The cycle cancellation rate was similar in both arms of two studies (0/34 versus 1/31, 1/25 versus 1/25; OR 0.57; 95% CI 0.07 to 4.39; N = 115; I² = 0%; low quality evidence).  The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. AUTHORS' CONCLUSIONS: This review update found no new randomised trials. Evidence from the six studies previously identified did not suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. The choice of one or the other method may depend upon the convenience of its use, and the associated costs. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.

Laparoscopic supracervical hysterectomy versus endometrial ablation for women with heavy menstrual bleeding (HEALTH): a parallel-group, open-label, randomised controlled trial.

BACKGROUND: Heavy menstrual bleeding affects 25% of women in the UK, many of whom require surgery to treat it. Hysterectomy is effective but has more complications than endometrial ablation, which is less invasive but ultimately leads to hysterectomy in 20% of women. We compared laparoscopic supracervical hysterectomy with endometrial ablation in women seeking surgical treatment for heavy menstrual bleeding. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial in 31 hospitals in the UK, women younger than 50 years who were referred to a gynaecologist for surgical treatment of heavy menstrual bleeding and who were eligible for endometrial ablation were randomly allocated (1:1) to either laparoscopic supracervical hysterectomy or second generation endometrial ablation. Women were randomly assigned by either an interactive voice response telephone system or an internet-based application with a minimisation algorithm based on centre and age group (<40 years vs ≥40 years). Laparoscopic supracervical hysterectomy involves laparoscopic (keyhole) surgery to remove the upper part of the uterus (the body) containing the endometrium. Endometrial ablation aims to treat heavy menstrual bleeding by destroying the endometrium, which is responsible for heavy periods. The co-primary clinical outcomes were patient satisfaction and condition-specific quality of life, measured with the menorrhagia multi-attribute quality of life scale (MMAS), assessed at 15 months after randomisation. Our analysis was based on the intention-to-treat principle. The trial was registered with the ISRCTN registry, number ISRCTN49013893. FINDINGS: Between May 21, 2014, and March 28, 2017, we enrolled and randomly assigned 660 women (330 in each group). 616 (93%) of 660 women were operated on within the study period, 588 (95%) of whom received the allocated procedure and 28 (5%) of whom had an alternative surgery. At 15 months after randomisation, more women allocated to laparoscopic supracervical hysterectomy were satisfied with their operation compared with those in the endometrial ablation group (270 [97%] of 278 women vs 244 [87%] of 280 women; adjusted percentage difference 9·8, 95% CI 5·1-14·5; adjusted odds ratio [OR] 2·53, 95% CI 1·83-3·48; p<0·0001). Women randomly assigned to laparoscopic supracervical hysterectomy were also more likely to have the best possible MMAS score of 100 than women assigned to endometrial ablation (180 [69%] of 262 women vs 146 [54%] of 268 women; adjusted percentage difference 13·3, 95% CI 3·8-22·8; adjusted OR 1·87, 95% CI 1·31-2·67; p=0·00058). 14 (5%) of 309 women in the laparoscopic supracervical hysterectomy group and 11 (4%) of 307 women in the endometrial ablation group had at least one serious adverse event (adjusted OR 1·30, 95% CI 0·56-3·02; p=0·54). INTERPRETATION: Laparoscopic supracervical hysterectomy is superior to endometrial ablation in terms of clinical effectiveness and has a similar proportion of complications, but takes longer to perform and is associated with a longer recovery. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Physiological, hyaluronan-selected intracytoplasmic sperm injection for infertility treatment (HABSelect): a parallel, two-group, randomised trial.

BACKGROUND: Sperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment. METHODS: This parallel, two-group, randomised trial included couples undergoing an ICSI procedure with fresh embryo transfer at 16 assisted conception units in the UK. Eligible women (aged 18-43 years) had a body-mass index of 19-35 kg/m2 and a follicle-stimulating hormone (FSH) concentration of 3·0-20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18-55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (≥37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up. This trial is registered, number ISRCTN99214271. FINDINGS: Between Feb 1, 2014, and Aug 31, 2016, 2772 couples were randomly assigned to receive PICSI (n=1387) or ICSI (n=1385), of whom 2752 (1381 in the PICSI group and 1371 in the ICSI group) were included in the primary analysis. The term livebirth rate did not differ significantly between PICSI (27·4% [379/1381]) and ICSI (25·2% [346/1371]) groups (odds ratio 1·12, 95% CI 0·95-1·34; p=0·18). There were 56 serious adverse events in total, including 31 in the PICSI group and 25 in the ICSI group; most were congenital abnormalities and none were attributed to treatment. INTERPRETATION: Compared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Network meta-analyses in reproductive medicine: challenges and opportunities.

Network meta-analysis allows researchers to synthesise both direct and indirect evidence, thus enabling simultaneous comparisons of multiple treatments. A relatively recent addition to evidence synthesis in reproductive medicine, this approach has become increasingly popular. Yet, the underlying assumptions of network meta-analyses, which drive the validity of their findings, have been frequently ignored. In this article, we discuss the strengths and limitations of network meta-analyses. In addition, we present an overview of published network meta-analyses in reproductive medicine, summarize their challenges and provide insights into future research opportunities.

Inherited susceptibility to miscarriage: a nested case-control study of 31,565 women from an intergenerational cohort.

BACKGROUND: Miscarriage can be a devastating outcome for couples, and most miscarriages are unexplained. Many adverse obstetric outcomes (such as preeclampsia, preterm birth, and growth restriction) are thought to be inherited. It is possible that these conditions could share similar pathophysiologic mechanisms (such as endothelial dysfunction) with miscarriage. Therefore, it was hypothesized that there could be a susceptibility to miscarriage transmitted from mother to daughter. OBJECTIVE: This study aimed to investigate the association between a maternal history of miscarriage and the risk of miscarriage in daughters. STUDY DESIGN: A case-control study nested within an intergenerational cohort was conducted. Mother-daughter pairs were identified from the intergenerational cohort within the Aberdeen Maternity and Neonatal Databank, United Kingdom. A mother's history of miscarriage was the exposure. The primary outcome was miscarriage in daughters. There were 31,565 mother-daughter pairs who were eligible for inclusion. A population average model that used generalized estimating equations with robust standard errors was used to estimate the odds of a mother's history of miscarriage in daughters with a miscarriage compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multiadjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Daughters who miscarried had 11% greater odds of being born to mothers with a history of miscarriage (adjusted odds ratio, 1.11; 95% confidence interval, 1.01-1.22). Daughters with recurrent miscarriage (≥2) were also more likely to be born to a mother with a history of miscarriage (adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.49). CONCLUSION: There may be an inherited predisposition to miscarriage transmitted from mother to daughter. Future research should investigate genetic or familial environmental factors that may predispose women to miscarriage.

Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection.

BACKGROUND: Transfer of more than one embryo during in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) increases multiple pregnancy rates resulting in an increased risk of maternal and perinatal morbidity. Elective single embryo transfer offers a means of minimising this risk, but this potential gain needs to be balanced against the possibility of jeopardising the overall live birth rate (LBR). OBJECTIVES: To evaluate the effectiveness and safety of different policies for the number of embryos transferred in infertile couples undergoing assisted reproductive technology cycles. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group specialised register of controlled trials, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to March 2020. We handsearched reference lists of articles and relevant conference proceedings. We also communicated with experts in the field regarding any additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different policies for the number of embryos transferred following IVF or ICSI in infertile women. Studies of fresh or frozen and thawed transfer of one to four embryos at cleavage or blastocyst stage were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial eligibility and risk of bias. The primary outcomes were LBR and multiple pregnancy rate. The secondary outcomes were clinical pregnancy and miscarriage rates. We analysed data using risk ratios (RR), Peto odds ratio (Peto OR) and a fixed effect model. MAIN RESULTS: We included 17 RCTs in the review (2505 women). The main limitation was inadequate reporting of study methods and moderate to high risk of performance bias due to lack of blinding. A majority of the studies had low numbers of participants. None of the trials compared repeated single embryo transfer (SET) with multiple embryo transfer. Reported results of multiple embryo transfer below refer to double embryo transfer. Repeated single embryo transfer versus multiple embryo transfer in a single cycle Repeated SET was compared with double embryo transfer (DET) in four studies of cleavage-stage transfer. In these studies the SET group received either two cycles of fresh SET (one study) or one cycle of fresh SET followed by one frozen SET (three studies). The cumulative live birth rate after repeated SET may be little or no different from the rate after one cycle of DET (RR 0.95, 95% CI (confidence interval) 0.82 to 1.10; I² = 0%; 4 studies, 985 participants; low-quality evidence). This suggests that for a woman with a 42% chance of live birth following a single cycle of DET, the repeated SET would yield pregnancy rates between 34% and 46%. The multiple pregnancy rate associated with repeated SET is probably reduced compared to a single cycle of DET (Peto OR 0.13, 95% CI 0.08 to 0.21; I² = 0%; 4 studies, 985 participants; moderate-quality evidence). This suggests that for a woman with a 13% risk of multiple pregnancy following a single cycle of DET, the risk following repeated SET would be between 0% and 3%. The clinical pregnancy rate (RR 0.99, 95% CI 0.87 to 1.12; I² = 47%; 3 studies, 943 participants; low-quality evidence) after repeated SET may be little or no different from the rate after one cycle of DET. There may be little or no difference in the miscarriage rate between the two groups. Single versus multiple embryo transfer in a single cycle A single cycle of SET was compared with a single cycle of DET in 13 studies, 11 comparing cleavage-stage transfers and three comparing blastocyst-stage transfers.One study reported both cleavage and blastocyst stage transfers. Low-quality evidence suggests that the live birth rate per woman may be reduced in women who have SET in comparison with those who have DET (RR 0.67, 95% CI 0.59 to 0.75; I² = 0%; 12 studies, 1904 participants; low-quality evidence). Thus, for a woman with a 46% chance of live birth following a single cycle of DET, the chance following a single cycle of SET would be between 27% and 35%. The multiple pregnancy rate per woman is probably lower in those who have SET than those who have DET (Peto OR 0.16, 95% CI 0.12 to 0.22; I² = 0%; 13 studies, 1952 participants; moderate-quality evidence). This suggests that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following a single cycle of SET would be between 2% and 4%. Low-quality evidence suggests that the clinical pregnancy rate may be lower in women who have SET than in those who have DET (RR 0.70, 95% CI 0.64 to 0.77; I² = 0%; 10 studies, 1860 participants; low-quality evidence). There may be little or no difference in the miscarriage rate between the two groups. AUTHORS' CONCLUSIONS: Although DET achieves higher live birth and clinical pregnancy rates per fresh cycle, the evidence suggests that the difference in effectiveness may be substantially offset when elective SET is followed by a further transfer of a single embryo in fresh or frozen cycle, while simultaneously reducing multiple pregnancies, at least among women with a good prognosis. The quality of evidence was low to moderate primarily due to inadequate reporting of study methods and absence of masking those delivering, as well as receiving the interventions.

Family history and risk of miscarriage: A systematic review and meta-analysis of observational studies.

INTRODUCTION: Miscarriage, a spontaneous pregnancy loss at <24 weeks' gestation, is a common complication of pregnancy but the etiologies of miscarriage and recurrent miscarriage are not fully understood. Other obstetric conditions such as preeclampsia and preterm birth, which may share similar pathophysiology to miscarriage, exhibit familial patterns, suggesting inherited predisposition to these conditions. Parental genetic polymorphisms have been associated with unexplained miscarriage, suggesting there could be a genetically inherited predisposition to miscarriage. This systematic review and meta-analysis of observational studies aimed to assess the association between family history of miscarriage and the risk of miscarriage in women. MATERIAL AND METHODS: A systematic review and meta-analysis of observational studies was carried out in accordance with Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Electronic searches using databases (MEDLINE, EMBASE and CINAHL) were carried out to identify eligible studies from 1946 until 2019. Observational studies (cohort or case-control) were included. Human studies only were included. Participants were women of reproductive age. Exposure was a family history of one or more miscarriage(s). The primary outcome was miscarriage in women. Abstracts were screened and data were extracted by two independent reviewers. Study quality was assessed using Critical Appraisal Skills Program (CASP) tools. Data were pooled from individual studies using the Mantel-Haenszel method to produce pooled odds ratios (ORs) with 95% confidence intervals (95% CI). Systematic review registration number (PROSPERO): CRD42019127950. RESULTS: Thirteen studies were identified in the systematic review; 10 were eligible for inclusion in the meta-analysis. Twelve studies reported an association between family history of miscarriage and miscarriage in women. In all, 41 287 women were included in the meta-analysis. Women who miscarried were more likely to report a family history of miscarriage (pooled unadjusted OR 1.90, 95% CI 1.37-2.63). Overall study quality and size varied, with few adjusting for confounding factors. Results should be interpreted with caution as the associations presented are based on unadjusted analyses only. CONCLUSIONS: Women who miscarry may be more likely to have a family history of miscarriage. Further research is required to confirm or refute the findings.

Consequences of being overweight or obese during pregnancy on diabetes in the offspring: a record linkage study in Aberdeen, Scotland.

AIMS/HYPOTHESIS: Maternal obesity in pregnancy is associated with cardiovascular disease and mortality rate in the offspring. We aimed to determine whether maternal obesity is also associated with increased incidence of type 2 and type 1 diabetes in the offspring, independently of maternal diabetes as a candidate mechanistic pathway. METHODS: Birth records of 118,201 children from 1950 to 2011 in the Aberdeen Maternity and Neonatal Databank were linked to Scottish Care Information-Diabetes, the national register for diagnosed diabetes in Scotland, to identify incident and prevalent type 1 and type 2 diabetes up to 1 January 2012. Maternal BMI was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on offspring outcomes was tested using time-to-event analysis with Cox proportional hazards regression to compare outcomes in offspring of mothers in underweight, overweight or obese categories of BMI, compared with offspring of women with normal BMI. RESULTS: Offspring of obese (BMI ≥30 kg/m2) and overweight (BMI 25-29.9 kg/m2) mothers had an increased hazard of type 2 diabetes compared with mothers with normal BMI, after adjustment for gestation when weight was measured, maternal history of diabetes before pregnancy, maternal history of hypertension, age at delivery, parity, socioeconomic status, and sex of the offspring: HR 3.48 (95% CI 2.33, 5.06) and HR 1.39 (1.06, 1.83), respectively. CONCLUSIONS/INTERPRETATION: Maternal obesity is associated with increased incidence of type 2 diabetes in the offspring. Evidence-based strategies that reduce obesity among women of reproductive age and that might reduce the incidence of diabetes in their offspring are urgently required.

Perinatal outcomes in singleton live births after fresh blastocyst-stage embryo transfer: a retrospective analysis of 67 147 IVF/ICSI cycles.

STUDY QUESTION: Are perinatal outcomes different between singleton live births conceived from fresh blastocyst transfer and those following the transfer of fresh cleavage-stage embryos? SUMMARY ANSWER: Fresh blastocyst transfer does not increase risks of preterm birth (PTB), low/high birth weight or congenital anomaly and does not alter the sex ratio at birth or prejudice the chance of having a healthy baby. WHAT IS KNOWN ALREADY: Extended embryo culture is currently considered the best option for embryo selection, but concerns have been raised about increased risks of preterm delivery and large-for-gestational-age (LGA) babies. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study based on data from the Human Fertilisation and Embryology Authority (HFEA) anonymised and cycle-based dataset in the UK between 1999 and 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Baseline characteristics were compared between in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) blastocyst-stage and cleavage-stage embryo transfer cycles using the χ2 test for categorical/dichotomised covariates and the Mann-Whitney test for continuous covariates. Statistical significance was set at <0.005. Poisson regression and multinomial logistic regression were used to establish relationships between perinatal outcomes and blastocyst-stage embryo transfer or cleavage-stage embryo transfer. Risk ratios (RRs), adjusted risk ratios (aRRs) and their 99.5% confidence intervals (CIs) were calculated as a measure of strength of associations. Results were adjusted for clinically relevant covariates. A sub-group analysis included women undergoing their first IVF/ICSI treatment. The level of significance was set at <0.05, and 95% CIs were calculated in the sub-group analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Of a total of 67 147 IVF/ICSI cycles, 11 152 involved blastocyst-stage embryo(s) and 55 995 involved cleavage-stage embryo(s). The two groups were comparable with regards to the risk of PTB (aRR, 1.00; 99.5% CI, 0.79-1.25), very-preterm birth (VPTB) (aRR, 1.00; 99.5% CI, 0.63-1.54), very-low birth weight (VLBW) (aRR, 0.84; 99.5% CI, 0.53-1.34), low birth weight (LBW) (aRR, 0.92; 99.5% CI, 0.73-1.16), high birth weight (HBW) (aRR, 0.94; 99.5% CI, 0.75-1.18) and very-high birth weight (VHBW) (aRR, 1.05; 99.5% CI, 0.66-1.65). The risk of congenital anomaly was 16% higher in the blastocyst-stage group than in the cleavage-stage group, but this was not statistically significant (aRR, 1.16; 99.5% CI, 0.90-1.49). The chance of having a healthy baby (born at term, with a normal birth weight and no congenital anomalies) was not altered by extended culture (aRR, 1.00; 99.5% CI, 0.93-1.07). Extended culture was associated with a marginal increase in the chance having a male baby in the main cycle-based analysis (aRR, 1.04; 99.5% CI, 1.01-1.09) but not in the sub-group analysis of women undergoing their first cycle of treatment (aRR, 1.04; 95% CI, 1.00-1.08). In the sub-group analysis, the risk of congenital anomalies was significantly higher after blastocyst-stage embryo transfer (aRR, 1.42; 95% CI, 1.12-1.81). LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of observational data and inability to adjust for key confounders, such as maternal smoking status and body mass index (BMI), which were not recorded in the HFEA dataset. As the main analysis was cycle-based and we were unable to link cycles within women undergoing more than one IVF/ICSI cycle, we undertook a sub-group analysis on women undergoing their first treatment cycle. WIDER IMPLICATIONS OF THE FINDINGS: Our findings should reassure women undergoing blastocyst-stage embryo transfer. For the first time, we have shown that babies born after blastocyst transfer have a similar chance of being healthy as those born after cleavage-stage embryos transfer. STUDY FUNDING/COMPETING INTEREST(S): The research activity of Dr Nicola Marconi was funded by the scholarship 'A. Griffini-J. Miglierina', Fondazione Comunitaria del Varesotto, Provincia di Varese, Italy. The authors do not have any competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Treatment-independent live birth after in-vitro fertilisation: a retrospective cohort study of 2,133 women.

STUDY QUESTION: What is the chance of a treatment-independent live birth following IVF (including ICSI) treatment? SUMMARY ANSWER: Over 5 years of follow-up, the treatment-independent live birth rate was 17% in unsuccessfully treated women and 15% in those who had a live birth after IVF. WHAT IS KNOWN ALREADY: A limited number of studies have investigated the chance of treatment-independent conception following completion of IVF, but most of them have been based on surveys with poor response rates and limited sample sizes. STUDY DESIGN, SIZE, DURATION: This is a population-based, retrospective cohort study of 2133 women who received IVF treatment between 1998 and 2011 at a single regional IVF Unit and were followed for a minimum of 1 year and maximum of 15 years after their last IVF or ICSI treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included all women, residing in the north-east of the UK, who attended the Aberdeen Fertility Clinic and received IVF treatment between 1998 and 2011. Clinical and diagnostic information of all women was linked with treatment and pregnancy outcome data. A total of 2133 women were divided into two groups: (i) those who achieved a live birth following successful IVF or ICSI treatment (n = 1060) and (ii) those in whom treatment was unsuccessful i.e. resulted in either no pregnancy or pregnancy loss (n = 1073). The two groups were followed from the date of the last embryo transfer until the first treatment-independent live birth or 31 December 2012, whichever came first. The primary outcome was the treatment-independent live birth rate at 1, 2.5, 5 and 10 years of follow-up. Cox regression was used to determine factors associated with treatment-independent live birth in each group. MAIN RESULTS AND THE ROLE OF CHANCE: Within 5 years of follow-up, the treatment-independent live birth rate was 17% (95% CI, 15-19%) among women whose IVF or ICSI treatment was unsuccessful and 15% (95% CI, 12-17%) among women whose treatment resulted in live birth. In both groups, shorter duration of infertility, younger female age and IVF as compared to ICSI were associated with a higher chance of achieving treatment-independent live birth. Among unsuccessfully treated women, the chance of post-IVF live birth was reduced in those with tubal factor infertility. Three or more previous IVF or ICSI embryo transfers were associated with a lower chance of treatment-independent live birth among successfully treated women. LIMITATIONS, REASONS FOR CAUTION: The study was conducted in a single fertility centre, which could compromise the generalizability of the findings. Moreover, data were unavailable on the women's use of contraception or active attempts to get pregnant, both of which could influence treatment-independent live birth rates. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a better understanding of the long-term prognosis for treatment-independent live birth after completion of IVF or ICSI treatment. The results will inform women of their chances of a treatment-independent live birth following failed or successful treatment and the factors that are associated with it. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Inherited predisposition to stillbirth: an intergenerational analysis of 26,788 mother-daughter pairs.

BACKGROUND: Previous evidence suggests that placental dysfunction, which includes preeclampsia, is inherited from mother to daughter, but heritability of stillbirth has never been investigated. OBJECTIVE: The purpose of this study was to investigate whether there is an inherited predisposition to stillbirth that is transmitted from mother to daughter. STUDY DESIGN: We carried out a nested case-control study within the intergenerational cohort held in the Aberdeen Maternity and Neonatal Databank. All mothers who had at least 1 daughter in Aberdeen, United Kingdom, between 1949 and 2000 were included. Mother-daughter pairs were linked with the use of the Scottish Community Health Index number. The main exposure was the mother's history of stillbirth. The primary outcome was stillbirth in any of the daughter's pregnancies. A population average model that used generalized estimating equations with robust standard errors was used to estimate odds of a mother's history of stillbirth in daughters with a stillbirth compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multi-adjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Among the daughters, 384 had a history of ≥1 stillbirths (cases); 26,404 only ever had livebirths (control subjects). We found no statistically significant association between mothers' history of stillbirth (adjusted odds ratio, 0.63; 95% confidence interval, 0.24-1.63) or miscarriage (adjusted odds ratio, 1.01; 95% confidence interval, 0.71-1.42) and stillbirth in daughters. CONCLUSION: This is the first study to investigate an inherited predisposition to stillbirth. There was no evidence of an inherited predisposition to stillbirth transmitted from mother to daughter.

Interventions for unexplained infertility: a systematic review and network meta-analysis.

BACKGROUND: Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI,  and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making. OBJECTIVES: To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility. SEARCH METHODS: We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials. SELECTION CRITERIA: We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (or combined with ICSI). DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence. MAIN RESULTS: We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%. AUTHORS' CONCLUSIONS: There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.

Contraception after pregnancy.

Whatever the outcome, pregnancy provides the opportunity to offer effective contraception to couples motivated to avoid another pregnancy. This narrative review summarizes the evidence for health providers, drawing attention to current guidelines on which contraceptive methods can be used, and when they should be started after pregnancy, whatever its outcome. Fertility returns within 1 month of the end of pregnancy unless breastfeeding occurs. Breastfeeding, which itself suppresses fertility after childbirth, influences both when contraception should start and what methods can be used. Without breastfeeding, effective contraception should be started as soon as possible if another pregnancy is to be avoided. Interpregnancy intervals of at least 6 months after miscarriage and 1-2 years after childbirth have long been recommended by the World Health Organization in order to reduce the chance of adverse pregnancy outcome. Recent research suggests that this may not be necessary, at least for healthy women <35 years old. Most contraceptive methods can be used after pregnancy regardless of the outcome. Because of an increased risk of venous thromboembolism associated with estrogen-containing contraceptives, initiation of these methods should be delayed until 6 weeks after childbirth. More research is required to settle the questions over the use of combined hormonal contraception during breastfeeding, the use of injectable progestin-only contraceptives before 6 weeks after childbirth, and the use of both hormonal and intrauterine contraception after gestational trophoblastic disease. The potential impact on the risk of ectopic pregnancy of certain contraceptive methods often confuses healthcare providers. The challenges involved in providing effective, seamless service provision of contraception after pregnancy are numerous, even in industrialized countries. Nevertheless, the clear benefits demonstrate that it is worth the effort.

Study protocol: E-freeze - freezing of embryos in assisted conception: a randomised controlled trial evaluating the clinical and cost effectiveness of a policy of freezing embryos followed by thawed frozen embryo transfer compared with a policy of fresh embryo transfer, in women undergoing in vitro fertilisation.

BACKGROUND: Infertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman's ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time - especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25-30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby. METHODS: E-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and < 42 years, with at least three good quality embryos are randomly allocated to receive either a fresh or thawed frozen embryo transfer. The primary outcome is a healthy baby, defined as a term, singleton, live birth with appropriate weight for gestation. Cost effectiveness will be calculated from a healthcare and societal perspective. DISCUSSION: E-Freeze will determine the relative benefits of fresh and thawed frozen embryo transfer in terms of improving the chance of having a healthy baby. The results of this pragmatic study have the potential to be directly transferred to clinical practice. TRIAL REGISTRATION: ISRCTN registry: ISRCTN61225414 . Date assigned 29/12/2015.