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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.

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 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.

STUDY QUESTIONAre perinatal outcomes following fresh blastocyst versus fresh cleavage stage embryo transfer (ET) different in singletons, twins, and between singleton siblings?SUMMARY ANSWERSingleton babies conceived following fresh blastocyst, versus cleavage stage, ET are less likely to be small for gestational age (SGA) or to have a congenital anomaly (a result confirmed by comparing singleton siblings), while singletons born following fresh blastocyst ET were at a higher risk of being large for gestational age (LGA) than their sibling born following fresh cleavage stage ET.WHAT IS KNOWN ALREADYBlastocyst stage transfer is now the preferred strategy in most IVF units. Previous studies have suggested that babies conceived through blastocyst transfer are at increased risk of preterm birth and LGA.STUDY DESIGN, SIZE, DURATIONA national population-based retrospective cohort study was performed using linked Human Fertilisation and Embryology Authority (HFEA) data on 130 516 IVF and ICSI livebirths occurring from 103 062 women between 2000 and 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSWe included women who had at least one singleton livebirth resulting from IVF/ICSI fresh embryo treatment, using their own eggs and partner’s sperm. A linked HFEA dataset was analysed using a multilevel framework, which accommodated repeated IVF cycles resulting in livebirths in the same woman. A population-averaged robust Poisson model was used for binary outcomes and a multinomial logistic regression model was used for categorical outcomes. Unadjusted and adjusted risk ratios (aRRs) (95% CI) were calculated.MAIN RESULTS AND THE ROLE OF CHANCEThere were 130 516 livebirths in 103 062 women, including 86 630 singletons, 43 886 twin births, and 5384 pairs of singleton siblings. In comparison with fresh cleavage stage ET, fresh blastocyst stage transfer in singletons was associated with a lower risk of low birthweight (aRR = 0.92; 95% CI 0.86, 0.99), lower risk of being SGA (0.83; 0.78, 0.89), and lower risk of congenital anomaly (0.79; 0.71, 0.89). This analysis did not show an increase in risk associated with preterm birth (1.00; 0.94, 1.06), high birthweight (0.99; 0.93, 1.06), LGA (0.99; 0.93, 1.05), and the chance of healthy singleton baby (1.00; 1.00, 1.02). Twins resulting from fresh blastocyst stage ET were at slightly higher risk of preterm birth (1.05; 1.02, 1.10) compared with twins conceived following fresh cleavage stage ET. There was insufficient evidence for an association with the other perinatal outcomes. Singleton siblings born following fresh blastocyst stage ET were at a higher risk of being LGA (1.57; 1.01, 2.46) and at lower risk of having a congenital anomaly (0.52; 0.28, 0.97) compared to their singleton siblings born following cleavage stage ET. There was some evidence of excess risk of preterm birth (1.42; 0.97, 2.23) associated with blastocyst stage transfer. However, we could not confirm an association between blastocyst stage ET and low birthweight (1.35; 0.81, 2.27), high birthweight (1.19; 0.80, 1.77), and the chance of being a healthy baby (0.97; 0.86, 1.09).LIMITATIONS, REASONS FOR CAUTIONThis was an observational study where we were unable to adjust for some key confounders, such as maternal smoking status and BMI, which may change from one pregnancy to another and are not recorded in the HFEA dataset.WIDER IMPLICATIONS OF THE FINDINGSIn the largest study of its kind, our analysis of singleton siblings, corrected for unmeasured, non-time varying maternal factors, confirms the previously reported association between blastocyst transfer and LGA babies, and shows a reduced risk of congenital anomaly following blastocyst transfer. Our sibling analysis did not confirm a decreased risk of low birthweight following blastocyst transfer. Overall, absolute risks are low and there is insufficient evidence to challenge the practice of extended culture of embryos.STUDY FUNDING/COMPETING INTEREST(S)This project is financed by an NHS Grampian Endowment Research Grant, project number 17/052. One of the authors, S.B., was the Editor in Chief of HROpen until 31 December 2022 and would have been in that role when the paper was first submitted. As an invited speaker, S.B. has received travel expenses, accommodation and honoraria from Merck, Organon, and Ferring. A.M. has received travel expenses, accommodation, and honoraria from Merck Serono, Cook Medical, Pharmasure, Gedeon Richter, and Ferring. D.J.M. is currently a HROpen Associate Editor.TRIAL REGISTRATION NUMBERN/A.

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.

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.

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.

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 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.

BACKGROUND Mild ovarian stimulation has emerged as an alternative to conventional IVF with the advantages of being more patient-friendly and less expensive. Inadequate data on pregnancy outcomes and concerns about the cycle cancellation rate (CCR) have prevented mild, or low-dose, IVF from gaining wide acceptance. OBJECTIVE AND RATIONALE To evaluate parallel-group randomised controlled trials (RCTs) on IVF where comparisons were made between a mild (≤150 IU daily dose) and conventional stimulation in terms of clinical outcomes and cost-effectiveness in patients described as poor, normal and non-polycystic ovary syndrome (PCOS) hyper-responders to IVF. SEARCH METHODS Searches with no language restrictions were performed using Medline, Embase, Cochrane central, Pre-Medicine from January 1990 until April 2020, using pre-specified search terms. References of included studies were hand-searched as well as advance access articles to key journals. Only parallel-group RCTs that used ≤150 IU daily dose of gonadotrophin as mild-dose IVF (MD-IVF) and compared with a higher conventional dose (CD-IVF) were included. Studies were grouped under poor, normal or hyper-responders as described by the authors in their inclusion criteria. Women with PCOS were excluded in the hyper-responder group. The risk of bias was assessed as per Cochrane Handbook for the included studies. The quality of evidence (QoE) was assessed according to the GRADE system. PRISMA guidance was followed for review methodology. OUTCOMES A total of 31 RCTs were included in the analysis: 15 in the poor, 14 in the normal and 2 in the hyper-responder group. Live birth rates (LBRs) per randomisation were similar following use of MD-IVF in poor (relative risk (RR) 0.91 (CI 0.68, 1.22)), normal (RR 0.88 (CI 0.69, 1.12)) and hyper-responders (RR 0.98 (CI 0.79, 1.22)) when compared to CD-IVF. QoE was moderate. Cumulative LBRs (5 RCTs, n = 2037) also were similar in all three patient types (RR 0.96 (CI 0.86 1.07) (moderate QoE). Risk of ovarian hyperstimulation syndrome was significantly less with MD-IVF than CD-IVF in both normal (RR 0.22 (CI 0.10, 0.50)) and hyper-responders (RR 0.47 (CI 0.31, 0.72)), with moderate QoE. The CCRs were comparable in poor (RR 1.33 (CI 0.96, 1.85)) and hyper-responders (RR 1.31 (CI 0.98, 1.77)) but increased with MD-IVF among normal responders (RR 2.08 (CI 1.38, 3.14)); all low to very low QoE. Although fewer oocytes were retrieved and fewer embryos created with MD-IVF, the proportion of high-grade embryos was similar in all three population types (low QoE). Compared to CD-IVF, MD-IVF was associated with less gonadotrophin use and lower cost. WIDER IMPLICATIONS This updated review provides reassurance on using MD-IVF not only for the LBR per cycle but also for the cumulative LBR, with moderate QoE. With risks identified with ‘freeze-all’ strategies, it may be time to recommend mild-dose ovarian stimulation for IVF for all categories of women i.e. hyper, poor and normal responders to IVF.

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.

Varicoceles are reported to be present in a significant proportion of men presenting with subfertility and are more common amongst this group than in the general population. Opinion still remains divided amongst clinicians managing male factor infertility as to whether varicoceles alter the probability of spontaneous conception and/or pregnancy and live birth rates after fertility treatment. The debate as to whether varicoceles should be treated or not has intensified in recent years. This is due to the concerns regarding the impact of varicoceles on not only conventional semen parameters, but also the potential effects that they may have at the cellular level (an increase in circulating reactive oxygen species (ROS) resulting in sperm DNA fragmentation, even when conventional semen parameters are within the normal reference ranges). It has been suggested that treating the varicocele may result in improvements in the semen parameters, the fertilization and pregnancy rates for both spontaneous pregnancy as well as following in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. ICSI can still be used for Assisted Reproduction Treatment (ART) in the presence of suboptimal semen parameters. However, it is an invasive and expensive technique with potential adverse effects on the offspring. As far as we are aware, there are no randomized controlled trials comparing the clinical/cost effectiveness of varicocele treatment versus the immediate use of ICSI on pregnancy rates. Previous modelling exercises are old and do not take into consideration current practices and trends such as rising female age and time to pregnancy. The conflicting advice that patients sometimes receive, challenges our commitment to evidence-based practice. The only way to resolve the controversy is to undertake an appropriately powered randomized trial, assessing clinical- and cost-effectiveness and the time to pregnancy following varicocele treatment and comparing this to a no treatment group.

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.

The treatment of unexplained infertility is a contentious topic that continues to attract a great deal of interest amongst clinicians, patients and policy makers. The inability to identify an underlying pathology makes it difficult to devise effective treatments for this condition. Couples with unexplained infertility can conceive on their own and any proposed intervention needs to offer a better chance of having a baby. Over the years, several prognostic and prediction models based on routinely collected clinical data have been developed, but these are not widely used by clinicians and patients. In this opinion paper, we propose a prognosis-based approach such that a decision to access treatment is based on the estimated chances of natural and treatment-related conception, which, in the same couple, can change over time. This approach avoids treating all couples as a homogeneous group and minimizes unnecessary treatment whilst ensuring access to those who need it early.

To study the association of donor sperm on perinatal outcomes of livebirths conceived via in vitro fertilization (IVF) when compared with partner sperm.Retrospective cohort study SETTING: National Human Fertilisation and Embryology Authority assisted reproductive technology registry PATIENTS: All live born singletons and twins conceived through IVF with or without intracytoplasmic sperm injection in the United Kingdom between 1991 and 2016 INTERVENTION(S): Donor sperm compared to partner sperm MAIN OUTCOME MEASURE(S): Perinatal outcomes were assessed. The primary outcomes were preterm and very preterm birth; low, very low, high, and very high birthweight; Secondary outcomes were congenital anomaly and health baby. These were assessed for singletons and twins separately.For singleton livebirths, compared to partner sperm, those conceived with donor sperm were at reduced odds of very preterm (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.63-0.91; adjusted OR [aOR], 0.80; 95% CI, 0.66-0.96), and preterm (OR, 0.90; 95% CI, 0.83-0.98; aOR, 0.93; 95% CI, 0.85-1.01) birth. For birthweight outcomes, donor sperm showed a reduced odds of low (OR, 0.83; 95% CI, 0.76-0.91; aOR, 0.86; 95% CI, 0.78-0.94) and an increased odds of high (OR, 1.15; 95% CI, 1.07-1.23; aOR, 1.09; 95% CI, 1.01-1.17) birthweight. There was no confirmed difference in the odds ratios of very low (OR, 0.88; 95% CI, 0.74-1.06; aOR, 0.94; 95% CI, 0.78-1.13) or very high (OR, 1.21; 95% CI, 1.04-1.40; aOR, 1.15; 95% CI, 0.98-1.34) birthweight. Liveborn twins conceived with donor sperm, compared to partner sperm, were at reduced odds of very low (OR, 0.76; 95% CI, 0.66-0.88; aOR, 0.83; 95% CI, 0.72-0.96) and low (OR, 0.87; 95% CI, 0.81-0.93; aOR, 0.91; 95% CI, 0.85-0.98) birthweight. There was a suggestion of a reduced odds of very preterm (OR, 0.81; 95% CI, 0.70-0.95; aOR, 0.86; 95% CI, 0.74-1.01) and preterm (OR, 0.93; 95% CI, 0.86-1.01; aOR, 0.96; 95% CI, 0.88-1.04) birth. There was considerable uncertainty around the ORs for high (OR, 0.73; 95% CI, 0.31-1.72; aOR, 0.72; 95% CI, 0.29-1.80) and very high (OR, 1.02; 95% CI, 0.39-2.67; aOR, 1.34; 95% CI, 0.50-3.60) birthweight.Although unmeasured confounding remains a possibility, as paternal age, body mass index, and smoking status were unavailable for analysis, women, couples, service providers can be reassured that IVF livebirths conceived with donor sperm have no greater chance of adverse outcomes when compared to partner sperm.

Infertility affects 1 in 7 couples. An etiological diagnosis is made to plan treatment. In a quarter no diagnosis can be established, hence a diagnosis of unexplained infertility is made. IF conception does not happen after an etiological diagnosis based treatment or unexplained infertility is diagnosed, in-vitro fertilisation (IVF) is the treatment of choice. Over last 4 decades IVF processes have evolved. There are better tests to predict ovarian response and a number of stimulations regimen to choose from. Better prediction means ovarian hyperstimulation can be predicted and minimised. Cryopreservation of gametes and embryos have become vert successful process, to the extent that policy of freeze all for all has been discussed. It is important that advances in this field are properly evaluated before being put in routine clinical practice for not only pregnancy rates but long term outcomes.

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 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

Being overweight or obese can have a negative impact on fertility outcomes. This systematic review updates randomized controlled trial (RCT) findings on the effectiveness of weight loss interventions in reducing weight and improving reproductive outcomes of women and men with overweight or obesity and infertility. Eligible studies, published since the last review, were identified by searching databases from March 20, 2016 until March 31, 2020. RCTs involving any type of lifestyle intervention were considered. Eight RCTs were identified and aggregated with seven RCTs included in our previous review. Meta-analyses revealed that women randomized to a combined diet and exercise intervention were more likely to become pregnant, risk ratio (RR) = 1.87 (95% CI 1.20, 2.93) and achieve a live birth RR = 2.20 (95% CI 1.23, 3.94), compared to women in control groups who received no or minimal intervention. This pattern was not replicated in trials where control groups received immediate access to assisted reproductive technology (ART). No eligible randomized trials involving men were identified. Data were largely obtained from small scale studies. Better designed, adequately powered, robust randomized trials are needed to better understand the effect of weight loss interventions on reproductive outcomes in both women and men.

To determine whether perinatal outcomes following frozen vs. fresh embryo transfer (ET) differ within singletons, within sets of twins, and between siblings.Population-based retrospective cohort study.Academic Medical School PATIENT(S): 200,075 live births in 151,561 women who underwent in vitro fertilization with frozen or fresh ET between 1992 and 2017.Gestational age at birth, birthweight, congenital anomaly, and healthy baby (≥37 weeks of gestation, birthweight 2,500-4,000 g, no congenital malformations).There were 200,075 live births in 151,561 women including 132,679 singletons, 33,698 sets of twins, and 5,723 pairs of singleton siblings. In singletons, frozen ET was associated with a lower risk of very preterm birth (adjusted relative risk [aRR], 0.83; 95% confidence interval [CI], 0.73, 0.94), preterm birth (aRR, 0.93; 95% CI, 0.88, 0.97), low birthweight (2,500 g) (aRR, 0.72; 95% CI, 0.68, 0.77), small for gestational age (aRR, 0.66; 95% CI, 0.62, 0.70) and congenital anomaly (aRR, 0.85; 95% CI, 0.78, 0.94), but higher risk of high birthweight (4,000 g) (aRR, 1.64; 95% CI, 1.58, 1.72) and large for gestational age (aRR, 1.62; 95% CI, 1.55, 1.70) in comparison with fresh ET. In twins, frozen ET was associated with lower risk of very preterm birth (aRR, 0.84; 95% CI, 0.73, 0.97), and low birthweight (aRR, 0.72; 95% CI, 0.68, 0.77), but with a higher chance of a healthy baby (aRR, 1.11; 95% CI, 1.06, 1.16) compared to fresh ET. Singletons conceived following frozen ET had a lower risk of low birthweight (aRR, 0.56; 95% CI, 0.44, 0.74) and being small for gestational age (aRR, 0.54; 95% CI, 0.42, 0.68) than a singleton sibling born after a fresh ET. Frozen ET also was associated with higher risk of high birthweight (aRR, 1.85; 95% CI, 1.54, 2.24) and being large for gestational age (aRR, 1.81; 95% CI, 1.50, 2.20), and also were less likely to be preterm (aRR, 0.81; 95% CI, 0.67, 0.99).Our key finding is that singletons born following a frozen ET are less likely to be small for gestational age than a singleton sibling born following fresh ET but are more likely to be large for gestational age.

Study question Are obstetric/perinatal outcomes different in singleton pregnancies following blastocyst-stage embryo transfer when compared to cleavage-stage embryo transfer and have results changed over time? Summary answer Pregnancies following blastocyst are consistently associated with higher risk of large for gestational age and lower risk of small for gestational age babies What is known already Extended embryo culture to blastocyst-stage is widely used to select best embryos in in vitro fertilisation (IVF) cycles to improve pregnancy rates. Transfer of blastocyst-stage embryos is increasing with this being the default strategy in most clinics. As blastocysts are kept in culture until day 5, 6 or 7 after oocyte fertilisation, there are suggestions that longer exposure to culture media may have a negative impact on pregnancy outcomes. More recent primary studies have challenged some of the initial findings. We therefore conducted an updated systematic review and cumulative meta-analysis (CMA) to examine if these results have changed over time. Study design, size, duration Systematic review of studies published between 1980 and 2020, followed by aggregated meta-analysis and CMA to track the accumulation of evidence over the period of time. Exposed group: singleton pregnancies following blastocyst transfer. Non-exposed group: singleton pregnancies following cleavage-stage transfer. Sub-group analyses were conducted on fresh and frozen-thawed embryo transfers. Perinatal (categories of preterm birth and birth weight) and obstetric outcomes (hypertensive disorders of pregnancy, gestational diabetes, c-section, placental anomalies) were compared between the groups. Participants/materials, setting, methods Medline, EMBASE, CINHAL, Web of Science, Cochrane Central Register of Clinical Trials and International Clinical Trials Registry Platform databases were searched. Relevant journals were searched for advance access publications. Critical Appraisal Skills Programme (CASP) checklists were used to assess study quality. Two independent reviewers extracted data in 2 × 2 tables. Aggregated and CMA were performed using Comprehensive Meta-Analysis software. Risk ratio (RR) with 95% confidence interval (CI) were calculated. Main results and the role of chance A total of 33 observational studies were included (n = 574,756 singleton pregnancies). Pregnancies following blastocyst-stage embryo transfer are associated with a higher risk of preterm birth (PTB) (RR 1.09; 95% CI 1.01–1.17), very preterm birth (VPTB) (RR 1.15; 95% CI 1.07–1.24), large for gestational age (LGA) babies (RR 1.13; 95% CI 1.08–1.19), c-section (RR 1.05; 95% CI 1.02–1.09), and with a lower risk of small for gestational age (SGA) babies (RR 0.86; 95% CI 0.81–0.93) as compared to singleton pregnancies following cleavage-stage embryo transfer. These findings were maintained in both fresh and frozen-thawed sub-groups for LGA and SGA. PTB was not significantly different in both sub-group analyses. The risk of VPTB was higher after blastocyst-stage embryo transfer only in the sub-group analysis of fresh embryo transfers (RR 1.17; 95% CI 1.09–1.27) and that of c-section only in the frozen-thawed sub-group (RR 1.08; 95% CI 1.04–1.12). No other statistically significant differences for the other outcomes were noted. The CMA suggests that for SGA and LGA subsequent studies have increased the precision of the point estimate with no change in the direction or magnitude of the treatment effect since 2014. Limitations, reasons for caution This analysis was constrained by the intrinsic limitations of observational studies with some of them receiving a CASP score < 10. Adjustment for confounders was not possible and a high degree of clinical and statistical heterogeneity was noted among studies. Wider implications of the findings: Blastocyst is associated with a higher risk of LGA and a lower risk of SGA with a stable body of evidence since 2014. We may need to revisit the default position of extending embryo culture and individualise care, until further high-quality data from individual-patient-data of large registries are available. Trial registration number Not applicable

Study question Are perinatal outcomes different in pregnancies conceived using donor sperm compared with those with partner sperm? Summary answer The perinatal outcomes of singleton and twin pregnancies conceived with donor sperm are better when compared to those conceived with partner sperm What is known already There has been a substantial increase in the use of donor sperm in the last 15 years across the world. A recent systematic review and meta-analysis has suggested that there is an increased risk of hypertensive disorders of pregnancy and small for gestational age babies from ART treatment using donor sperm compared to partner`s sperm. This meta-analysis was limited due to poor quality of primary studies often with small sample sizes. Study design, size, duration This is a retrospective cohort study on 196,293 singleton and 46,275 twin pregnancies from the Human Fertilisation and Embryology Authority (HFEA) anonymised dataset including all live births from 1991 to 2016. Outcomes were preterm birth ( < 37 weeks); very preterm birth ( < 32 weeks); very low, low, high and very high birth weight ( < 1500g, < 2500g, >4000g and >4500g respectively); congenital anomaly and healthy baby (term live birth with appropriate weight and no congenital anomaly). Participants/materials, setting, methods All pregnancies resulting in singleton or twin livebirth were included. Any cycle involving donor oocytes, PGD, gamete intra-fallopian transfer, ectopic pregnancy, miscarriage, stillbirth, or termination was excluded. Logistic regression and generalised estimating equations were used for analysis of singletons and twins, respectively. Odds ratios (aOR) with 95% confidence intervals (CI) for donor versus partner sperm were adjusted for maternal age, previous pregnancy, cause of infertility and year for all outcomes plus gestational age for birthweight. Main results and the role of chance Baseline characteristics for donor and partner sperm pregnancies were assessed for singleton and twin livebirths separately. In both analyses there were significant differences between donor and partner sperm pregnancies in terms of maternal age, previous pregnancy status and cause of infertility. Analysis of singleton births demonstrated an increased odds (aOR, 95% CI) of having a healthy baby (1.09, 1.05 - 1.12) and reduced odds of congenital anomaly (0.34, 0.29 - 0.39), very preterm birth (0.66, 0.58-0.75), preterm birth (0.81, 0.76-0.86), low birthweight 0.89 (0.83 - 0.96) in singleton births using donor sperm compared with those using partner sperm. There was, however, an increased odds of high birthweight (1.10, 1.05 - 1.16) and very high birthweight (1.16, 1.05-1.29) with donor sperm pregnancies. Analysis of twin births conceived with donor sperm also showed higher odds of having a healthy baby (1.07, 1.01 - 1.15) and lower odds of congenital anomaly (0.52, 0.39 - 0.68) compared with partner sperm. There were no statistically significant differences between the birthweight or birth gestation outcomes for twin pregnancies. Sensitivity analysis of only cases with complete outcome data showed no significant differences when compared to the primary analysis. Limitations, reasons for caution This is a retrospective study of a single nation’s routinely collected data. We could not adjust for confounders such as smoking, BMI and pregnancy complications such as pre-eclampsia, as they are not recorded in HFEA’s dataset. Wider implications of the findings Patients and clinicians can be reassured that donor sperm pregnancies are not at higher risk of adverse perinatal outcomes. In fact, they are more likely to result in a healthy baby. Worldwide registries should consider including maternal data to enable a better assessment of outcomes. Trial registration number Not applicable

BACKGROUND Extended embryo culture to blastocyst stage is widely used in IVF and is the default strategy in most clinics. The last decade has witnessed a growing interest in obstetric–perinatal outcomes following blastocyst transfer. Recent studies have challenged the conclusions of systematic reviews that associate risks of preterm birth (PTB) and large for gestational age (LGA) babies with blastocyst transfer. A higher proportion of blastocysts is transferred as frozen-thawed embryos, which may also have added implications. OBJECTIVE AND RATIONALE The aim of this study was to conduct an updated systematic review of the obstetric–perinatal outcomes in singleton pregnancies following blastocyst-stage transfer compared to cleavage-stage transfer in IVF/ICSI cycles. Where deemed appropriate, data were combined in cumulative meta-analyses. SEARCH METHODS Data sources from Medline, EMBASE, CINAHL, Web of Science, the Cochrane Central Register of Clinical Trials and the International Clinical Trials Registry Platform (ICTRP) (1980–2020) were searched using combinations of relevant keywords. Searches had no language restrictions and were limited to human studies. Observational studies and randomized controlled trials comparing obstetric–perinatal outcomes between singleton pregnancies after blastocyst-stage transfer and those after cleavage-stage transfer in IVF/ICSI cycles were sought. Two independent reviewers extracted data in 2 × 2 tables and assessed the methodological quality of the relevant studies using the Critical Appraisal Skills Programme scoring. Cumulative meta-analyses were carried out with independent analysis of pregnancies after fresh and frozen embryo transfers, using the Comprehensive Meta-Analysis software. If provided by included studies, adjusted effect sizes were combined in a sensitivity analysis. OUTCOMES A total of 35 studies were included (n = 520 769 singleton pregnancies). Outcome data suggest singleton pregnancies following fresh blastocyst transfer were associated with higher risk of LGA (risk ratio (RR) 1.14; 95% CI 1.05–1.24) and very PTB (RR 1.17; 95% CI 1.08–1.26) compared to fresh cleavage-stage transfer. Singleton pregnancies following frozen blastocyst transfer were associated with higher risks of LGA (RR 1.17; 95% CI 1.08–1.27), PTB (RR 1.13; 95% CI 1.03–1.24) and caesarean section (RR 1.08; 95% CI 1.03–1.13) but lower risks of small for gestational age (RR 0.84, 95% CI 0.74–0.95) and perinatal mortality (RR 0.70; 95% CI 0.58–0.86). Increased risks of LGA and PTB after frozen blastocyst transfer persisted in the sensitivity analysis, which also showed a significantly increased risk of PTB after fresh blastocyst transfer. Cumulative meta-analyses revealed consistency in prevalence and magnitude of risks for a number of years. Data on other perinatal outcomes are still evolving. WIDER IMPLICATIONS While the available evidence is predominantly reassuring in the context of blastocyst-stage embryo transfer, observational data suggest that blastocyst transfer is associated with a higher risk of LGA. This holds true irrespective of fresh or frozen transfer. Meta-analysis of adjusted data showed an increased risk of PTB with fresh and frozen blastocyst transfer. However, the quality of available evidence ranges from low to very low. Although blastocyst-stage embryo transfer remains the default position in most centres, based on individual risk profile we may need to consider cleavage-stage embryo transfer in some to mitigate the risk of LGA/PTB.

Background: Embryos created following in-vitro fertilisation (IVF) are usually replaced within the uterus within a few days (fresh embryo transfer). It has been suggested that elective freezing of all embryos followed by transfer at a later date (freeze-all) could make treatment safer and more effective. The aim of this trial was to compare the clinical and cost-effectiveness of a strategy of freeze-all versus fresh embryo transfer. Methods: A two arm, non-blinded, parallel group pragmatic randomised trial was conducted across 18 IVF clinics in the UK. Couples undergoing IVF, where the woman was

STUDY QUESTION Is it feasible to undertake a randomised controlled trial to establish whether surgical removal of endometrioma or not, improves live birth rates from IVF? SUMMARY ANSWER A randomised controlled trial (RCT) comparing surgery versus no surgery to endometrioma prior to IVF is only feasible in UK if an adaptive rather than traditional study design is used; this would minimise resource wastage and complete the trial in an acceptable time frame. WHAT IS KNOWN ALREADY There is wide variation in the management of endometriomas prior to IVF, with decisions about treatment being influenced by personal preferences. STUDY DESIGN, SIZE, AND DURATION This was a mixed-methods study consisting of an online survey of clinicians, a focus group and individual interviews with potential trial participants. PARTICIPANTS/MATERIALS, SETTING, METHODS Endometriosis and fertility experts across the UK were invited to participate in an online anonymised questionnaire. Potential future trial participants were recruited from a tertiary care fertility centre and invited to participate in either individual interviews or focus groups. MAIN RESULTS AND THE ROLE OF CHANCE Clinicians and potential trial participants confirmed the need for an RCT to inform the management of an endometrioma prior to IVF. There were 126 clinicians who completed the survey, and the majority (70%) were willing to recruit to a trial. Half of those who responded indicated that they see at least 10 eligible women each year. The main barriers to recruitment were waiting lists for surgery and access to public funding for IVF. One focus group (n = 7) and five interviews were conducted with potential trial participants (n = 3) and their partners (n = 2). The findings from these discussions highlighted that recruitment and retention in a potential RCT could be improved by coordination between IVF and surgical services such that an operation does not delay IVF or affect access to public funding. Live birth was considered the most important outcome with an improvement of at least 10% considered the minimum acceptable by both patients and clinicians. LIMITATIONS, REASONS FOR CAUTION This feasibility study captured views of clinicians across the UK, but as patients were from a single Scottish centre, their views may not be representative of other areas with limited public funding for IVF. WIDER IMPLICATIONS OF THE FINDINGS There is a need for an appropriately powered RCT to establish whether or not surgical treatment of endometrioma prior to IVF improves live birth rates. There are logistical issues to be considered due to limited number of participants, funding of IVF and waiting times. These could be overcome in a RCT by using an adaptive design which would include a prospectively planned opportunity for modification of specified aspects of the study design based on interim analysis of the data, coordination of IVF treatments and endometriosis surgeries and international collaboration. Similar principles could be used for other questions in fertility where a traditional approach for randomised trials is not feasible. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the NHS Grampian R&D pump priming fund (RG14437-12). S.B. is Editor-in-Chief of HROPEN, and A.W.H. is Deputy Editor of HROPEN. Neither was involved in the review of this manuscript. L.S. reports grants from CSO and NIHR to do endometriosis research, outside the submitted work. K.C. reports grants from NIHR/HTA and CSO during the conduct of the study. J.H.e., A.W.H., J.D., S.B.r., K.B., G.B., J.H.u. and K.G. report no conflict of interest.

Objective To study whether the growth trajectory of the first, second, and third trimester, birth, and 5 years of age differs between children born following fresh embryo transfer (fresh ET), frozen−thawed embryo transfer (FET), and children born after natural conception (NC). Design Historical cohort study of children. The analysis compared cross-sectional and longitudinal differences in measurement between individuals stratified by method of conception. Setting Not applicable. Patients Participants were born between 1997 and 2012 by NC (n = 65,683), fresh ET (n = 576), and FET (n = 179). Data were available for method of conception and fetal, maternal, and neonatal characteristics and measurements at 5 years. Intervention (s) None Main Outcome Measure(s) Size at first, second, and third trimester, birth, and 5 years. Result(s) In the longitudinal model, first trimester crown−rump length was significantly longer after fresh ET compared to NC. Second trimester head size was larger after fresh ET and after FET compared to NC. Birth weight was lower after fresh ET conception compared to FET. At 5 years of age, children conceived by fresh ET and FET were no heavier than peers conceived by NC. Conclusion(s) Individuals conceived by in vitro fertilization have significantly different antenatal growth trajectories during the first and second trimester compared to those conceived by NC, and differences persist at birth for weight and head size. The relevance of these different growth trajectories remains uncertain, and larger prospective studies are required.

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

Better imaging techniques will result in more women who are undergoing in vitro fertilization (IVF) being diagnosed with adenomyosis. Preliminary data suggest that adenomyosis may have implications for the outcome of IVF. However, available evidence is limited to data from retrospective studies with major inconsistencies in the diagnostic criteria used to confirm adenomyosis. Despite this uncertainty, a number of therapeutic modifications have been suggested to minimize the impact of adenomyosis in women undergoing IVF. In this brief report, we summarize current limitations in diagnosing adenomyosis and critically evaluate the available evidence on its impact on IVF outcomes. We set out a number of steps needed to generate the evidence to underpin the diagnosis, prognosis and effective treatment so that women undergoing IVF can be adequately counselled.

BACKGROUND Registry data from the Human Fertilisation and Embryology Authority (HFEA) show an increase of 40% in IUI and 377% in IVF cases using donor sperm between 2006 and 2016. OBJECTIVE AND RATIONALE The objective of this study was to establish whether pregnancies conceived using donor sperm are at higher risk of obstetric and perinatal complications than those conceived with partner sperm. As more treatments are being carried out using donor sperm, attention is being given to obstetric and perinatal outcomes, as events in utero and at delivery have implications for long-term health. There is a need to know if there is any difference in the outcomes of pregnancies between those conceived using donor versus partner sperm in order to adequately inform and counsel couples. SEARCH METHODS We performed a systematic review and meta-analysis of the outcomes of pregnancies conceived using donor sperm compared with partner sperm. Searches were performed in the OVID MEDLINE, OVID Embase, CENTRAL and CINAHL databases, including all studies published before 11 February 2019. The search strategy involved search terms for pregnancy, infant, donor sperm, heterologous artificial insemination, donor gametes, pregnancy outcomes and perinatal outcomes. Studies were included if they assessed pregnancies conceived by any method using, or infants born from, donor sperm compared with partner sperm and described early pregnancy, obstetric or perinatal outcomes. The Downs and Black tool was used for quality and bias assessment of studies. OUTCOMES Of 3391 studies identified from the search, 37 studies were included in the review and 36 were included in the meta-analysis. For pregnancies conceived with donor sperm, versus partner sperm, there was an increase in the relative risk (RR) (95% CI) of combined hypertensive disorders of pregnancy: 1.44 (1.17–1.78), pre-eclampsia: 1.49 (1.05–2.09) and small for gestational age (SGA): 1.42 (1.17–1.79) but a reduced risk of ectopic pregnancy: 0.69 (0.48–0.98). There was no difference in the overall RR (95% CI) of miscarriage: 0.94 (0.80–1.11), gestational diabetes: 1.49 (0.62–3.59), pregnancy-induced hypertension (PIH): 1.24 (0.87–1.76), placental abruption: 0.65 (0.04–10.37), placenta praevia: 1.19 (0.64–2.21), preterm birth: 0.98 (0.88–1.08), low birth weight: 0.97 (0.82–1.15), high birthweight: 1.28 (0.94–1.73): large for gestational age (LGA): 1.01 (0.84–1.22), stillbirth: 1.23 (0.97–1.57), neonatal death: 0.79 (0.36–1.73) and congenital anomaly: 1.15 (0.86–1.53). WIDER IMPLICATIONS The majority of our findings are reassuring, except for the mild increased risk of hypertensive disorders of pregnancy and SGA in pregnancies resulting from donor sperm. However, the evidence for this is limited and should be interpreted with caution because the evidence was based on observational studies which varied in their quality and risk of bias. Further high-quality population-based studies reporting obstetric outcomes in detail are required to confirm these findings.

STUDY QUESTION Can we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility? SUMMARY ANSWER Yes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis. WHAT IS KNOWN ALREADY Couples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations. STUDY DESIGN, SIZE, DURATION A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS A dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE A total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment. LIMITATIONS, REASONS FOR CAUTION We were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort. WIDER IMPLICATIONS OF THE FINDINGS For the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest.

Time-lapse imaging (TLI) systems for embryo incubation, assessment and selection are a novel technology available to in vitro fertilization (IVF) clinics. However, there is uncertainty about their clinical and cost-effectiveness and insufficient good quality evidence to warrant their routine use. Despite this, enthusiastic commercial marketing and slipping clinical equipoise have led to the widespread hasty introduction of this technology into practice, often at a considerable expense to the patient. We have reviewed the published literature and aim to summarize the strengths, weaknesses, opportunities and threats of these systems. These specialized incubators provide undisturbed embryo culture conditions and, by almost continuous monitoring of embryo development, generate morphokinetic parameters to aid embryo selection. They are thus hypothesized to improve outcomes following IVF. Although literature reports improved reproductive outcomes, these outcomes are largely surrogate and there is a paucity of studies reporting live births. The use of time lapse systems may reduce early pregnancy loss, increase elective single embryo transfers and limit multiple pregnancies through better embryo selection. However, the quality of the studies and hence the evidence so far, is low to moderate quality. We recommend further research producing robust high-quality evidence for and against the use of these systems.

Objective To explore obstetric and perinatal outcomes in singleton pregnancies occurring as a result of fresh and thawed frozen embryo transfer using anonymized Human Fertilisation and Embryology Authority data. Design Retrospective cohort study. Setting Not applicable. Patient(s) Singleton births after IVF/intracytoplasmic sperm injection cycles in the United Kingdom (1991–2011). Intervention(s) A total of 112,432 cycles (95,911 fresh and 16,521 frozen) were analyzed using multivariate logistic regression to explore associations between type of embryo transferred (frozen vs. fresh) and obstetric and perinatal outcomes. Relative risks (RRs) and their 99.5% confidence intervals (CIs) were calculated using Stata 14 MP, adjusting for potential confounders. Main Outcome Measure(s) Birth weight. Result(s) The adjusted RR (99.5% CI) of low birth weight [0.73 (0.66–0.80)] and very low birth weight [0.78 (0.63–0.96)] were all lower after frozen embryo transfer; however, RR of having a high birth weight baby was higher [1.64 (1.53–1.76)]. There was no difference in RR of preterm birth [0.96 (0.88–1.03)], very preterm birth [0.86 (0.70–1.05)], and congenital anomalies [0.86 (0.73–1.01)]. Conclusion(s) The findings of low birth and very low birth weight after thawed frozen embryo transfer are consistent with the literature and provide reassurance regarding the outcome of pregnancies after frozen embryo transfers. However, they highlight the possibility of high birth weight in these babies. Because these results are based on observational data, further evidence from randomized, controlled trials is needed before elective cryopreservation of all embryos is practiced in preference to the current practice of transfer of fresh embryos.

BACKGROUND The reproductive impact of adenomyosis and endometriosis is widely researched but the extent of these impacts remains elusive. It has been demonstrated that endometriosis, in particular, is known to result in subfertility but endometriosis and adenomyosis are increasingly linked to late pregnancy complications such as those caused by placental insufficiency. At the molecular level, the presence of ectopic endometrium perturbs the endometrial hormonal, cellular, and immunological milieu, negatively influencing decidualization, placentation, and developmental programming of the embryo. It is unclear if and how such early aberrant reproductive development relates to pregnancy outcomes in endometriosis and adenomyosis. OBJECTIVE AND RATIONALE The aims of this systematic review and meta-analysis were to (i) investigate the association of adenomyosis and endometriosis with fertility, obstetric, and neonatal outcomes of women through both assisted reproduction and natural conception and (ii) determine whether endometriosis disease subtypes have specific impacts on different stages of the reproductive process. SEARCH METHODS A systematic literature review of NHS evidence electronic databases and the Cochrane database identified all comparative and observational studies between 1980 and December 2018 in any language on adenomyosis and endometriosis with fertility, obstetric, and neonatal outcomes (23 search terms used). A total of 104 papers were selected for data extraction and meta-analysis, with use of Downs and Black standardized checklist to evaluate quality and bias. OUTCOMES We found that endometriosis consistently leads to reduced oocyte yield and a reduced fertilization rate (FR), in line with current evidence. Milder forms of endometriosis were most likely to affect the fertilization (FR OR 0.77, CI 0.63–0.93) and earlier implantation processes (implantation rate OR 0.76, CI 0.62–0.93). The more severe disease by American Society for Reproductive Medicine staging (ASRM III and IV) influenced all stages of reproduction. Ovarian endometriosis negatively affects the oocyte yield (MD −1.22, CI −1.96, −0.49) and number of mature oocytes (MD −2.24, CI −3.4, −1.09). We found an increased risk of miscarriage in both adenomyosis and endometriosis (OR 3.40, CI 1.41–8.65 and OR 1.30, CI 1.25–1.35, respectively), and endometriosis can be associated with a range of obstetric and fetal complications including preterm delivery (OR 1.38, CI 1.01–1.89), caesarean section delivery (OR 1.98 CI 1.64–2.38), and neonatal unit admission following delivery (OR 1.29, CI 1.07–1.55). WIDER IMPLICATIONS Adenomyosis and the subtypes of endometriosis may have specific complication profiles though further evidence is needed to be able to draw conclusions. Several known pregnancy complications are likely to be associated with these conditions. The complications are possibly caused by dysfunctional uterine changes leading to implantation and placentation issues and therefore could potentially have far-reaching consequences as suggested by Barker’s hypothesis. Our findings would suggest that women with these conditions should ideally receive pre-natal counselling and should be considered higher risk in pregnancy and at delivery, until evidence to the contrary is available. In order to expand our knowledge of these conditions and better advise on future management of these patients in reproductive and maternal medicine, a more unified approach to studying fertility and reproductive outcomes with longer term follow-up of the offspring and attention to the subtype of disease is necessary.

BACKGROUND\ud Initial observational studies and a systematic review published 5 years ago have suggested that obstetric and perinatal outcomes are better in offspring conceived following frozen rather than fresh embryo transfers, with reduced risks of preterm birth, small for gestational age, low birth weight and pre-eclampsia. More recent primary studies are beginning to challenge some of these findings. We therefore conducted an updated systematic review and cumulative meta-analysis to examine if these results have remained consistent over time.\ud \ud OBJECTIVE AND RATIONALE\ud The aim of this study was to perform a systematic review and cumulative meta-analysis (trend with time) of obstetric and perinatal complications in singleton pregnancies following the transfer of frozen thawed and fresh embryos generated through in-vitro fertilisation.\ud \ud SEARCH METHODS\ud Data Sources from Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE and CINAHL (1984–2016) were searched using appropriate key words. Observational and randomised studies comparing obstetric and perinatal outcomes in singleton pregnancies conceived through IVF using either fresh or frozen thawed embryos. Two independent reviewers extracted data in 2 × 2 tables and assessed the methodological quality of the relevant studies using CASP scoring. Both aggregated as well as cumulative meta-analysis was done using STATA.\ud \ud OUTCOMES\ud Twenty-six studies met the inclusion criteria. Singleton babies conceived from frozen thawed embryos were at lower relative risk (RR) of preterm delivery (0.90; 95% CI 0.84–0.97) low birth weight (0.72; 95% CI 0.67–0.77) and small for gestational age (0.61; 95% CI 0.56–0.67) compared to those conceived from fresh embryo transfers, but faced an increased risk (RR) of hypertensive disorders of pregnancy (1.29; 95% CI 1.07–1.56) large for gestational age (1.54; 95% CI 1.48–1.61) and high birth weight (1.85; 95% CI 1.46–2.33). There was no difference in the risk of congenital anomalies and perinatal mortality between the two groups. The direction and magnitude of effect for these outcomes have remained virtually unchanged over time while the degree of precision has improved with the addition of data from newer studies.\ud \ud WIDER IMPLICATIONS\ud The results of this cumulative meta-analysis confirm that the decreased risks of small for gestational age, low birth weight and preterm delivery and increased risks of large for gestational age and high birth weight associated with pregnancies conceived from frozen embryos have been consistent in terms of direction and magnitude of effect over several years, with increasing precision around the point estimates. Replication in a number of different populations has provided external validity for the results, for outcomes of birth weight and preterm delivery. Meanwhile, caution should be exercised about embarking on a policy of electively freezing all embryos in IVF as there are increased risks for large for gestational age babies and hypertensive disorders of pregnancy. Therefore, elective freezing should ideally be undertaken in specific cases such as ovarian hyperstimulation syndrome, fertility preservation or in the context of randomised trials.

An improvement in long-term outcomes for malignancies and non-malignant conditions, together with a review of the NICE Guideline, has led to a need to provide clinical services to deal with the sequelae of disease, its treatment, and subsequent survival of young people diagnosed with cancer. In this article, we describe fertility preservation in an adolescent female diagnosed with Myelodysplastic/pre-malignant Clone with Monosomy 7 with pathophysiology like that of chronic myeloid leukaemia (CML) with known genetic markers in the tumour cells. We used random start controlled ovarian stimulation (COS) leading to oocyte collection and vitrification of metaphase II oocytes. Despite successful COS and vitrification, there remain numerous ethical considerations that merit more focussed discussion. Not least, in determining best practice for informed consent, but consideration of individualised protocols for ovarian stimulation, monitoring follicular development, together with prevention of ovarian hyperstimulation syndrome (OHSS) when considering most appropriate trigger for oocyte maturation. Random-start controlled ovarian stimulation and oocyte vitrification for adolescent girls diagnosed with cancer can be safely achieved through a collaborative, multidisciplinary and expert team approach. This case study offers a promising approach to fertility preservation, and would minimise the risk of introducing malignant cells after recovery.

One in 10 women reach menopause before they are 45 years of age, and 1 in 100 before 40. In most cases, poor ovarian response to gonadotrophins is a result of poor ovarian reserve. An early menopause is associated with long-term health risks. Identifying women at risk may allow appropriate measures to be instigated early. Women aged