Early pregnancy outcomes of IVF cycles using donor versus partner sperm: analysis of 1 376 454 cycles recorded by the Human Fertilisation and Embryology Authority (1991-2016).

STUDY QUESTION: Are the early pregnancy outcomes of IVF pregnancies conceived with donor sperm different to those conceived with partner sperm? SUMMARY ANSWER: Pregnancies conceived with donor sperm have a lower odds of early pregnancy loss and ectopic pregnancy compared to pregnancies conceived with partner sperm. WHAT IS KNOWN ALREADY: The number of cycles using donor sperm has risen significantly in recent years. Adverse early pregnancy outcomes have a negative impact on women and their partners. The evidence available to date regarding early pregnancy outcomes for pregnancies conceived with IVF donor sperm is limited by low numbers and lower-quality studies. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study of 1 376 454 cycles conceived with either donor or partner sperm between 1991 and 2016 as recorded in the Human Fertilisation and Embryology Authority (HFEA) Register. PARTICIPANTS/MATERIALS, SETTING, METHODS: The HFEA has recorded data on all fertility treatments carried out in the UK from 1991 onwards, and it publishes this data in an anonymized form. This study assessed the outcomes of all pregnancies conceived with donor sperm and compared them to those conceived with partner sperm among IVF cycles recorded in the HFEA anonymized dataset from 1991 to 2016. Cycles that included intrauterine insemination, donor oocytes, preimplantation genetic testing, oocyte thaw cycles and alternative fertility treatments were excluded. The outcomes of interest were biochemical pregnancy, miscarriage, ectopic pregnancy, stillbirth and live birth. Logistic regression was used to adjust for confounding factors including age of the female partner, cause of infertility, history of previous pregnancy, fresh or frozen cycle, IVF or ICSI, number of embryos transferred, and year of treatment. Results are reported as adjusted odds ratios (aOR) and 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE: This study found reductions in the odds of biochemical pregnancy (aOR 0.82, 95% CI 0.78-0.86), miscarriage (aOR 0.93, 95% CI 0.89-0.97), and ectopic pregnancy (aOR 0.77, 95% CI 0.66-0.90) among pregnancies as a result of the use of donor sperm as opposed to partner sperm. LIMITATIONS, REASONS FOR CAUTION: This study is retrospective and limited by the constraints of routinely collected data. No data were available for maternal characteristics such as BMI, smoking and partner age, which could all be potential confounders. Clustering of multiple pregnancies within women could not be accounted for as the data are reported only at the cycle level with no maternal identifiers. WIDER IMPLICATIONS OF THE FINDINGS: This study has demonstrated that there are no increased risks of adverse pregnancy outcome with donor sperm pregnancies. The reduction in miscarriage in pregnancies using donor sperm suggests that sperm could have a role in miscarriage, as the selection process for being accepted as donor is stringent. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. C.A. has received funding from Ferring to attend a UK meeting for trainees in reproductive Medicine. A.M. has received funding from Ferring, Cook, Merck Serono, Geodon Ritcher, and Pharmasure for speaking at, or attending, meetings relating to reproductive medicine. She has also participated in a Ferring advisory board. S.B. has received grants from Tenovus and the UK Medical Research Council. She has also been supported with a Medical Research Scotland PhD studentship. TRIAL REGISTRATION NUMBER: N/A.

A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

The optimal route of progesterone administration for luteal phase support in a frozen embryo transfer: a systematic review.

OBJECTIVE: To investigate the optimal route of progesterone administration for luteal phase support in a frozen embryo transfer. DESIGN: Systematic review. PATIENTS: Women undergoing frozen embryo transfer (FET). INTERVENTIONS: We conducted an extensive database search of Medline (PubMed), Embase, Web of Science, and Cochrane Trials Register using relevant keywords and their combinations to find randomized controlled trials (RCTs) comparing the routes (i.e., oral, vaginal, intramuscular) of progesterone administration for luteal phase support (LPS) in artificial FET. MAIN OUTCOME MEASURES: Clinical pregnancy, live birth, miscarriage. RESULTS: Four RCTs with 3245 participants undergoing artificial endometrial preparation (EP) cycles during FET were found to be eligible. Four trials compared vaginal progesterone with intramuscular progesterone and two trials compared vaginal progesterone with oral progesterone. One study favored of vaginal versus oral progesterone for clinical pregnancy rates (RR 0.45, 95% CI 0.22-0.92) and other study favored intramuscular versus vaginal progesterone for clinical pregnancy rates (RR 1.46, 95% CI 1.21-1.76) and live birth rates (RR 1.62, 95% CI 1.28-2.05). Tabulation of overall evidence strength assessment showed low-quality evidence on the basis that for each outcome-comparison pair, there were deficiencies in either directness of outcome measurement or study quality. CONCLUSION: There was little consensus and evidence was heterogeneous on the optimal route of administration of progesterone for LPS during FET in artificial EP cycles. This warrants more trials, indirect comparisons, and network meta-analyses. PROPERO NO: CRD42021251017.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

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.

Subclinical hypothyroidism and antithyroid autoantibodies in women with subfertility or recurrent pregnancy loss: Scientific Impact Paper No. 70 June 2022: Scientific Impact Paper No. 70 June 2022.

The thyroid is a gland located in the neck and is important for many processes in the body. Problems with the thyroid gland are common in women of reproductive age. It is essential to have a normal working thyroid gland in order to achieve a successful pregnancy. One of the most common problems with the thyroid is underactivity (known as hypothyroidism). An early, mild form of an underactive thyroid is called subclinical hypothyroidism. Often people with this condition do not have any symptoms. Another common problem is thyroid autoimmunity. Here, the immune system attacks the thyroid gland, sometimes leading to the development of abnormal thyroid function. This can be diagnosed by the presence of proteins in the bloodstream called antibodies. Mild thyroid problems and the presence of high levels of thyroid antibodies have been linked to miscarriage and premature birth. There is debate in medicine about whether there should be routine testing of thyroid function both in the general population and in individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or repeated miscarriages. This Scientific Impact Paper provides information on thyroid testing and the management of mild thyroid problems and thyroid antibodies in women with a history of subfertility or recurrent miscarriages, using the latest evidence and guidelines. It concludes that there may be a role for treating these women with thyroxine tablets (the hormone produced by the thyroid gland) when subclinical hypothyroidism is present, and gives guidance on the cut-off levels for treatment.

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.

Are we managing women with Recurrent Miscarriage appropriately? A snapshot survey of clinical practice within the United Kingdom.

The aim of this study was to evaluate clinicians' views of managing women with first-trimester Recurrent Miscarriage within the UK compared with RCOG guidance. An online survey of 150 Association of Early Pregnancy Units members was conducted using SurveyMonkey™. Analysis was limited to UK-based respondents (102). Of the three key investigations, 98% performed antiphospholipid antibodies (APA) screening, 93.1% performed karyotyping for subsequent miscarriages and 86.3% performed a pelvic ultrasound routinely. Other routine investigations included inherited thrombophilias (65.7%), thyroid function tests (51.9%), diabetes mellitus screening (35.3%), parental karyotyping (34.3%), androgen profile (25.5%), 3-D ultrasound (17.6%), hysteroscopy (12.7%), hysterosalpingogram (9.8%), Vitamin D (7.8%), peripheral natural killer cells (2.9%) and uterine natural killer cells (2.9%). APA-positive women were offered treatment by 97.1%; however, 23.5% routinely offered treatment for APA-negative women. Other treatments offered routinely included progesterone (27.5%) and metformin (1.9%). Most clinicians managed RM as recommended by RCOG, however we have highlighted considerable deviation from the RCOG guidelines.IMPACT STATEMENTWhat is already known on this subject? Recurrent miscarriage (RM) can cause significant distress to women and their partners prompting referrals for investigation and management of this condition. Although UK national clinical guidance exists published by RCOG, the adherence to the guidance in clinical practice is not known.What do the results of this study add? This study shows that most clinicians performed investigations recommended by RCOG when managing women with RM. However, we have highlighted considerable variation of practice; many additional investigations were routinely performed and a quarter of clinicians offered treatments outside the RCOG guidance.What are the implications of these findings for clinical practice and/or further research? This paper demonstrates considerable variation of practice across the UK. Clinical practice may continue to vary whilst there are separate guidelines available from different professional organisations worldwide. Collaboration to produce a general consensus could reduce the variation in the care that these women receive.

Mild versus conventional ovarian stimulation for IVF in poor responders: a systematic review and meta-analysis.

Mild ovarian stimulation is a treatment option for poor responders in IVF treatment. Our updated review evaluated mild IVF solely from randomized controlled trials (RCTs) that used genuine low-dose gonadotrophin (≤150 IU daily) alone or in combination with oral medications, comparing it with conventional-dose (>150 IU/ daily) IVF for poor responders. Electronic searches on MEDLINE, Embase, The Cochrane Central Register of Controlled Trials and PreMEDLINE, and hand searches from 2002 up to 31 January 2019, identified 14 RCTs, which were compiled with the above inclusion criteria. The risk of bias (ROB) and quality of evidence (QOE) were assessed as per Cochrane Collaboration. Meta-analyses found no difference in live birth rate (four RCTs, n = 1057, RR 0.91, CI 0.66 to 1.25) (moderate QOE), ongoing pregnancy rate (six RCTs, n = 1782, RR 1.01, CI 0.86 to 1.20) (moderate-high QOE) and cycle cancellation rates (14 RCTs, n = 2746, RR 1.38, CI 0.99 to 1.92) (low QOE). Fewer oocytes and embryos were obtained from mild IVF; however, the number and proportion of high-grade embryos were similar. Mild IVF resulted in reduced gonadotrophin use and cost. The inference remained unchanged when smaller studies with ROB were excluded, or whether gonadotrophin alone or combination with oral medication was used. The evidence of equal efficacy from a pooled population, which was adequately powered for live birth, supported a mild IVF strategy for poor responders in preference to more expensive conventional IVF. Although clinical heterogeneity remained a limiting factor, it increased the generalizability of the findings.

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.

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.

In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction.

BACKGROUND: Polycystic ovarian syndrome (PCOS) occurs in 4% to 7% of all women of reproductive age and 50% of women presenting with subfertility. Subfertility affects 15% to 20% of couples trying to conceive. A significant proportion of these women ultimately need assisted reproductive technology (ART). In vitro fertilisation (IVF) is one of the assisted reproduction techniques employed to raise the chances of achieving a pregnancy. For the standard IVF technique, stimulating follicle development and growth before oocyte retrieval is essential, for which a large number of different methods combining gonadotrophins with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist are used. In women with PCOS, the supra-physiological doses of gonadotrophins used for controlled ovarian hyperstimulation (COH) often result in an exaggerated ovarian response, characterised by the development of a large cohort of follicles of uneven quality, retrieval of immature oocytes, and increased risk of ovarian hyperstimulation syndrome (OHSS). A potentially effective intervention for women with PCOS-related subfertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). So far, the only data available have derived from observational studies and non-randomised clinical trials. OBJECTIVES: To assess the effectiveness and safety of IVM followed by IVF or ICSI versus conventional IVF or ICSI among women with PCOS undergoing assisted reproduction. SEARCH METHODS: This is the second update of this review. We performed the search on 17 April 2018.The search was designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist, for all published and unpublished randomised controlled trials (RCTs).We searched the the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials and the Open Grey database for grey literature from Europe. We made further searches in the National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with PubMed and Google for any recent trials that have not yet been indexed in the major databases. SELECTION CRITERIA: All RCTs on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS, irrespective of language and country of origin. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact the authors of studies for which data were missing. Our primary outcomes were live birth per woman randomised and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found two RCTs suitable for inclusion in the review and six ongoing trials that have not yet reported results. Both included studies were published as abstracts in international conferences.Both studies were at unclear or high risk of bias for most of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.There were no data on the primary outcomes of this review, namely live birth per woman randomised and miscarriage.Both studies reported clinical pregnancy rate: there was evidence of an effect between IVM and IVF, favouring the former (odds ratio 3.10, 95% confidence interval 1.06 to 9.00; 71 participants; 2 studies; I2 = 0%; very low-quality evidence). The incidence of OHSS was zero in both studies in both groups.There were no data for the other outcomes specified in this review. AUTHORS' CONCLUSIONS: Though promising data on the in vitro maturation (IVM) technique have been published, unfortunately there is still no evidence from properly conducted randomised controlled trials upon which to base any practice recommendations regarding IVM before in vitro fertilisation (IVF) or intracytoplasmic sperm injection for women with polycystic ovarian syndrome. Regarding our secondary outcomes, very low-quality evidence showed that clinical pregnancy was higher with IVM when compared to IVF, whereas the incidence of ovarian hyperstimulation syndrome was zero in both studies in both groups. We are awaiting the results of six ongoing trials and eagerly anticipate further evidence from good-quality trials in the field.

Routine serum thyroid-stimulating hormone testing-optimizing pre-conception health or generating toxic knowledge?

Monitoring subclinical hypothyroidism (SCH) in women is believed to be important in terms of preventing overt hypothyroidism and optimizing the health and cognitive development of their children. Current systematic reviews have suggested an association between maternal SCH and adverse obstetric and neonatal outcomes. However, initiating the administration of thyroxine during pregnancy has failed to demonstrate appreciable health benefits. Hence there are calls by professional endocrine societies for optimizing serum thyroid-stimulating hormone (TSH) levels pre-conception. The strategy of ensuring that serum TSH levels are below 2.5 mIU/l during the pre-conception period has generated considerable uncertainty partly because the recommended level of <2.5 mIU/l is lower than those previously used to define the condition and partly due to uncertainty about the best screening programme clinicians can use in this context. Recalibrating the expected normal peri-conceptional range of serum TSH (<2.5 mIU/l), will have a significant impact on clinical services due to an inevitable increase in numbers of women diagnosed with SCH who will need to be investigated, treated and monitored. Serum TSH fulfils the criteria for a screening test and oral thyroxine is an inexpensive drug. Therefore, there is no reason to believe that screening cannot be undertaken in all women planning to conceive. Yet this approach will miss women whose pregnancies are unplanned and generate anxiety, further tests and many more prescriptions for thyroxine, coupled with the need for lifelong monitoring in affected women. A number of existing and ongoing randomized trials have evaluated the use of thyroxine in women with infertility or miscarriage with detectable thyroid auto-antibodies. These are unlikely to answer the question whether routine pre-conception testing for SCH in asymptomatic women is beneficial. Routine screening of women at risk of pregnancy and optimization of their thyroid status could result in significant health benefits for their offspring. Alternatively this approach could prove to be an expensive way of generating toxic knowledge resulting in anxiety, increased drug use and potential harm. Only large, appropriately designed studies can reveal the answer.

Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation.

BACKGROUND: Gonadotropins are the most commonly used medications for controlled ovarian stimulation in in vitro fertilisation (IVF). However, they are expensive and invasive, and are associated with the risk of ovarian hyperstimulation syndrome (OHSS). Recent calls for more patient-friendly regimens have led to growing interest in the use of clomiphene citrate (CC) and aromatase inhibitors with or without gonadotropins to reduce the burden of hormonal injections. It is currently unknown whether regimens using CC or aromatase inhibitors such as letrozole (Ltz) are as effective as gonadotropins alone. OBJECTIVES: To determine the effectiveness and safety of regimens including oral induction medication (such as clomiphene citrate or letrozole) versus gonadotropin-only regimens for controlled ovarian stimulation in IVF or intracytoplasmic sperm injection (ICSI) treatment. SEARCH METHODS: We searched the following databases: Cochrane Gynaecology and Fertility Group Specialised Register (searched January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL CRSO), MEDLINE (1946 to January 2017), Embase (1980 to January 2017), and reference lists of relevant articles. We also searched trials registries ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch/Default.aspx). We handsearched relevant conference proceedings. SELECTION CRITERIA: We included randomized controlled trials (RCTs). The primary outcomes were live-birth rate (LBR) and OHSS. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias. We calculated risk ratios (RR) and Peto odds ratio (OR) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MD) for continuous outcomes. We analyzed the general population of women undergoing IVF treatment and (as a separate analysis) women identified as poor responders. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We included 27 studies in the updated review. Most of the new trials in the updated review included poor responders and evaluated Ltz protocols. We could perform meta-analysis with data from 22 studies including a total of 3599 participants. The quality of the evidence for different comparisons ranged from low to moderate. The main limitations in the quality of the evidence were risk of bias associated with poor reporting of study methods, and imprecision.In the general population of women undergoing IVF, it is unclear whether CC or Ltz used with or without gonadotropins compared to use of gonadotropins along with gonadotropin-releasing hormone (GnRH) agonists or antagonists resulted in a difference in live birth (RR 0.92, 95% CI 0.66 to 1.27, 4 RCTs, n = 493, I2 = 0%, low-quality evidence) or clinical pregnancy rate (RR 1.00, 95% CI 0.86 to 1.16, 12 RCTs, n = 1998, I2 = 3%, moderate-quality evidence). This means that for a typical clinic with 23% LBR using a GnRH agonist regimen, switching to CC or Ltz protocols would be expected to result in LBRs between 15% and 30%. Clomiphene citrate or Ltz protocols were associated with a reduction in the incidence of OHSS (Peto OR 0.21, 95% CI 0.11 to 0.41, 5 RCTs, n = 1067, I2 = 0%, low-quality evidence). This means that for a typical clinic with 6% prevalence of OHSS associated with a GnRH regimen, switching to CC or Ltz protocols would be expected to reduce the incidence to between 0.5% and 2.5%. We found evidence of an increase in cycle cancellation rate with the CC protocol compared to gonadotropins in GnRH protocols (RR 1.87, 95% CI 1.43 to 2.45, 9 RCTs, n = 1784, I2 = 61%, low-quality evidence). There was moderate quality evidence of a decrease in the mean number of ampoules used,) and mean number of oocytes collected with CC with or without gonadotropins compared to the gonadotropins in GnRH agonist protocols, though data were too heterogeneous to pool.Similarly, in the poor-responder population, it is unclear whether there was any difference in rates of live birth (RR 1.16, 95% CI 0.49 to 2.79, 2 RCTs, n = 357, I2 = 38%, low-quality evidence) or clinical pregnancy (RR 0.85, 95% CI 0.64 to 1.12, 8 RCTs, n = 1462, I2 = 0%, low-quality evidence) following CC or Ltz with or without gonadotropin versus gonadotropin and GnRH protocol. This means that for a typical clinic with a 5% LBR in the poor responders using a GnRH protocol, switching to CC or Ltz protocols would be expected to yield LBRs between 2% to 14%. There was low quality evidence that the CC or Ltz protocols were associated with an increase in the cycle cancellation rate (RR 1.46, 95% CI 1.18 to 1.81, 10 RCTs, n = 1601, I2 = 64%) and moderate quality evidence of a decrease in the mean number of gonadotropin ampoules used and the mean number of oocytes collected, though data were too heterogeneous to pool. The adverse effects of these protocols were poorly reported. In addition, data on foetal abnormalities following use of CC or Ltz protocols are lacking. AUTHORS' CONCLUSIONS: We found no conclusive evidence indicating that clomiphene citrate or letrozole with or without gonadotropins differed from gonadotropins in GnRH agonist or antagonist protocols with respect to their effects on live-birth or pregnancy rates, either in the general population of women undergoing IVF treatment or in women who were poor responders. Use of clomiphene or letrozole led to a reduction in the amount of gonadotropins required and the incidence of OHSS. However, use of clomiphene citrate or letrozole may be associated with a significant increase in the incidence of cycle cancellations, as well as reductions in the mean number of oocytes retrieved in both the general IVF population and the poor responders. Larger, high-quality randomized trials are needed to reach a firm conclusion before they are adopted into routine clinical practice.

Cumulative live birth rates after one or more complete cycles of IVF: a population-based study of linked cycle data from 178,898 women.

STUDY QUESTION: What is the chance of a live birth following one or more linked complete cycles of IVF (including ICSI)? SUMMARY ANSWER: The chance of a live birth after three complete cycles of IVF was 42.3% for treatment commencing from 1999 to 2007. WHAT IS KNOWN ALREADY: IVF success has generally been reported on the basis of live birth rates after a single episode of treatment resulting in the transfer of a fresh embryo. This fails to capture the real chance of having a baby after a number of complete cycles-each involving the replacement of fresh as well as frozen-thawed embryos. STUDY DESIGN, SIZE AND DURATION: Population-based observational cohort study of 178 898 women between 1992 and 2007. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included all women who commenced IVF treatment at a licenced clinic in the UK as recorded in the Human Fertilisation and Embryology Authority (HFEA) national database. Exclusion criteria included women whose treatment involved donor insemination, egg donation, surrogacy and the transfer of more than three embryos. Cumulative rates of live birth, term (>37 weeks) singleton live birth, and multiple pregnancy were estimated for two time-periods, 1992-1998 and 1999-2007. Conservative estimates assumed that women who did not return for IVF would not have the outcome of interest while optimal estimates assumed that these women would have similar outcome rates to those who continued IVF. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 71 551 women commenced IVF treatment during 1992-1998 and an additional 107 347 during 1999-2007. After the third complete IVF cycle (defined as three fresh IVF treatments-including replacement of any surplus frozen-thawed embryos), the conservative CLBR in women who commenced IVF during 1992-1998 was 30.8% increasing to 42.3% during 1999-2007. The optimal CLBRs were 44.6 and 57.1%, respectively. After eight complete cycles the optimal CLBR was 82.4% in the latter time period. The conservative rate for multiple pregnancy per pregnant woman fell from 31.9% during the earlier time period to 26.2% during the latter. LIMITATIONS AND REASON FOR CAUTION: Linkage of all IVF treatments to individual women was conducted. However, it was not possible to identify with certainty in all cases the episode of ovarian stimulation which generated some of the frozen embryos. Cumulative live birth rates could not be calculated for women who started treatment beyond 2007 as follow-up data were incomplete in some of them. Following a change in legislation in 2008, linked data were only made available for research in women who gave formal consent for this purpose. BMI and ethnicity could not be reported: these demographics are not recorded in the HFEA database. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate, at a national level, the chances of live birth in couples undergoing a number of complete (fresh and frozen) IVF cycles. They reflect improvements in reproductive technology and a more conservative embryo transfer policy. Although most couples in the UK still do not receive three complete IVF cycles; assuming no barriers to continuation of IVF treatment, around 83% of women receiving IVF would achieve a live birth by the eighth complete cycle, similar to the natural live birth rate in a non-contraception practising population. Our results support the call from NICE to develop consistent IVF policies based on three complete cycles. STUDY FUNDING/COMPETING INTERESTS: 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. S.B. reports grants from Chief Scientist Office Scotland during the conduct of the study. His institution has received support from Pharmaceutical companies (for educational seminars), which is not related to the submitted work. D.J.M., A.M. and A.J.L. have no conflicts of interest to declare.

Should we be promoting embryo transfer at blastocyst stage?

Improved laboratory standards and better culture media have made extended culture to blastocyst stage a reality to identify embryos with maximum implantation potential. The strategy of extended culture has become more popular across the world at a time when regulatory bodies have emphasized the need to increase the uptake of elective single embryo transfer, minimize complications associated with multiple births and aim for a healthy singleton live-birth as the preferred outcome in IVF. New data on perinatal outcomes suggest that pregnancies after embryo transfer at blastocyst stage are associated with a higher risk of preterm delivery, large for gestational age babies, monozygotic twins and altered sex ratio compared with those following embryo transfers at cleavage stage. In addition, concerns have been raised of increased congenital anomalies and epigenetic modifications with embryo transfer at blastocyst stage. Twenty-four years on from the first embryo transfer at blastocyst stage, we examine the reasons for extended embryo culture, evaluate the risks and benefits of this strategy and suggest the need to reconsider this policy in the interests of fetal safety.

Cumulative live birth rate: time for a consensus?

Traditionally, IVF success rates have been reported in terms of live birth per fresh cycle or embryo transfer. With the increasing use of embryo freezing and thawing it is essential that we report not only outcomes following fresh but also those after frozen embryo transfer as a complete measure of success of an IVF treatment. Most people agree that an individual's chance of having a baby following fresh and frozen embryo transfer should be described as cumulative live birth rate. However, views on the most appropriate parameters required to calculate such an outcome have been inconsistent. There is an additional dimension-time for all frozen embryos to be used up by a couple, which can influence the outcome. Given that cumulative live birth rate is generally perceived to be the preferred reporting system in IVF, it is time to have an international consensus on how this statistic is calculated, reported and interpreted by stakeholders across the world.

Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction.

BACKGROUND: Gonadotrophin-releasing hormone agonists (GnRHa) are commonly used in assisted reproduction technology (ART) cycles to prevent a luteinising hormone surge during controlled ovarian hyperstimulation (COH) prior to planned oocyte retrieval, thus optimising the chances of live birth. OBJECTIVES: To evaluate the effectiveness of the different GnRHa protocols as adjuncts to COH in women undergoing ART cycles. SEARCH METHODS: We searched the following databases from inception to April 2015: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2015, Issue 3), MEDLINE, EMBASE, CINAHL, PsycINFO, and registries of ongoing trials. Reference lists of relevant articles were also searched. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any two protocols of GnRHa used in in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles in subfertile women. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed trial eligibility and risk of bias, and extracted the data. The primary outcome measure was number of live births or ongoing pregnancies per woman/couple randomised. Secondary outcome measures were number of clinical pregnancies, number of oocytes retrieved, dose of gonadotrophins used, adverse effects (pregnancy losses, ovarian hyperstimulation, cycle cancellation, and premature luteinising hormone (LH) surges), and cost and acceptability of the regimens. We combined data to calculate odds ratios (OR) for dichotomous variables and mean differences (MD) for continuous variables, with 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methods. MAIN RESULTS: We included 37 RCTs (3872 women), one ongoing trial, and one trial awaiting classification. These trials made nine different comparisons between protocols. Twenty of the RCTs compared long protocols and short protocols. Only 19/37 RCTs reported live birth or ongoing pregnancy.There was no conclusive evidence of a difference between a long protocol and a short protocol in live birth and ongoing pregnancy rates (OR 1.30, 95% CI 0.94 to 1.81; 12 RCTs, n = 976 women, I² = 15%, low quality evidence). Our findings suggest that in a population in which 14% of women achieve live birth or ongoing pregnancy using a short protocol, between 13% and 23% will achieve live birth or ongoing pregnancy using a long protocol. There was evidence of an increase in clinical pregnancy rates (OR 1.50, 95% CI 1.18 to 1.92; 20 RCTs, n = 1643 women, I² = 27%, moderate quality evidence) associated with the use of a long protocol.There was no evidence of a difference between the groups in terms of live birth and ongoing pregnancy rates when the following GnRHa protocols were compared: long versus ultrashort protocol (OR 1.78, 95% CI 0.72 to 4.36; one RCT, n = 150 women, low quality evidence), long luteal versus long follicular phase protocol (OR 1.89, 95% CI 0.87 to 4.10; one RCT, n = 223 women, low quality evidence), when GnRHa was stopped versus when it was continued (OR 0.75, 95% CI 0.42 to 1.33; three RCTs, n = 290 women, I² = 0%, low quality evidence), when the dose of GnRHa was reduced versus when the same dose was continued (OR 1.02, 95% CI 0.68 to 1.52; four RCTs, n = 407 women, I² = 0%, low quality evidence), when GnRHa was discontinued versus continued after human chorionic gonadotrophin (HCG) administration in the long protocol (OR 0.89, 95% CI 0.49 to 1.64; one RCT, n = 181 women, low quality evidence), and when administration of GnRHa lasted for two versus three weeks before stimulation (OR 1.14, 95% CI 0.49 to 2.68; one RCT, n = 85 women, low quality evidence). Our primary outcomes were not reported for any other comparisons.Regarding adverse events, there were insufficient data to enable us to reach any conclusions except about the cycle cancellation rate. There was no conclusive evidence of a difference in cycle cancellation rate (OR 0.95, 95% CI 0.59 to 1.55; 11 RCTs, n = 1026 women, I² = 42%, low quality evidence) when a long protocol was compared with a short protocol. This suggests that in a population in which 9% of women would have their cycles cancelled using a short protocol, between 5.5% and 14% will have cancelled cycles when using a long protocol.The quality of the evidence ranged from moderate to low. The main limitations in the evidence were failure to report live birth or ongoing pregnancy, poor reporting of methods in the primary studies, and imprecise findings due to lack of data. Only 10 of the 37 included studies were conducted within the last 10 years. AUTHORS' CONCLUSIONS: When long GnRHa protocols and short GnRHa protocols were compared, we found no conclusive evidence of a difference in live birth and ongoing pregnancy rates, but there was moderate quality evidence of higher clinical pregnancy rates in the long protocol group. None of the other analyses showed any evidence of a difference in birth or pregnancy outcomes between the protocols compared. There was insufficient evidence to make any conclusions regarding adverse effects.