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Research question What are the obstetric and neonatal risks for women conceiving via frozen–thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method. Design A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies. Results Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference –124 g [–363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08–0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different. Conclusions The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.

It is known that lifestyle factors affect sporadic miscarriage, but the extent of this on RPL (recurrent pregnancy loss) is less well known. A systematic review and meta-analysis was performed to assess the associations between lifestyle factors and RPL. Studies that analysed RPL in the context of BMI, smoking, alcohol and caffeine intake were included. The primary and secondary outcomes were odds of having RPL in the general population and odds of further miscarriage, respectively. Underweight and women with BMI > 25 are at higher odds of RPL in the general population (OR 1.2, 95% CI 1.12–1.28 and OR 1.21, 95% CI 1.06–1.38, respectively). In women with RPL, having BMI > 30 and BMI > 25 has increased odds of further miscarriages (OR 1.77, 95% CI 1.25–2.50 and OR 1.35, 95% CI 1.07–1.72, respectively). The quality of the evidence for our findings was low or very low. Being underweight and BMI > 25 contributes significantly to increased risk of RPL (general population). BMI > 25 or BMI > 30 increases the risk of further miscarriages (RPL population). Larger studies addressing the effects of alcohol, cigarette smoking and caffeine on the risk of RPL with optimisation of BMI in this cohort of women are now needed.

Study question Which clinical parameters predict a high oocyte maturation rate in patients undergoing IVF treatment? Summary answer Time between oocyte collection and insemination demonstrated significant association with oocyte maturation and represents a parameter that could be optimised in IVF cycles. What is known already Oocyte maturation is an important factor determining IVF outcomes and can be a rate-limiting step for patients undergoing treatment. A number of clinical and laboratory variables may affect this process, including the choice of trigger prior to oocyte collection, and certain laboratory procedures. Identification of which of these are predictors of maturation in individual centres enables local protocols to be optimised. Study design, size, duration This is a retrospective study of 714 oocyte collections from 661 women between January 2020 to November 2020 treated in a large, single centre in the UK. Subsequent fertilisation on fresh oocytes consisted of 371 IVF and 343 ICSI cycles. Participants/materials, setting, methods Patient and treatment data was collected by clinical staff at time of treatment. Either GnRH agonist, hCG or double trigger were administered 36 hours before collection. Prior to ICSI, oocyte maturation was assessed by visualisation of polar body (PB) extrusion. After IVF, the number of 2PNs plus unfertilised oocytes with PB extrusion were assessed. Univariate analyses consisted of Mann-Whitney test, t-test, Fisher’s Exact test or ANOVA. Potential predictors were investigated by logistic regression. Main results and the role of chance The end point was maturation rate, defined as high (greater or equal to 70%) or low (less than 70%). Factors predictive of a high rate included insemination more than 4 hours after collection. Oocytes inseminated over 4 hours post-collection displayed significantly higher maturation rates than oocytes inseminated less than 2 hours after collection (69% and 61% respectively; P = 0.01). Oocytes inseminated between 2–4 hours also had higher maturation than those inseminated less than 2 hours post-collection, but this did not reach significance (67% and 61%, respectively; P = 0.06). Further, oocytes fertilised by ICSI had significantly higher maturation than conventional IVF (77% and 67%, respectively, P Limitations, reasons for caution Varying means of data collection across clinics and between clinical staff inevitably leads to provision of incomplete data and should be taken into consideration alongside interpretation. Prescription bias of specific triggers to certain patient demographics should be noted. Wider implications of the findings: Collectively, these results suggest that greater time between oocyte collection and insemination could be recommended to IVF clinics that wish to optimise their oocyte maturation. Triggering final maturation with GnRH agonist versus hCG or dual trigger did not have a significant effect on oocyte maturation when adjusted for confounders. Trial registration number Not applicable

Study question Do established donor and recipient clinical markers predict recipient clinical pregnancy and live birth rates (LBRs) in a vitrified oocyte donation programme? Summary answer Recipient BMI and previous miscarriages predicted cumulative LBR. Likelihood of clinical pregnancy and LBR was higher in recipients of donors aged 23–29 than donors 18–22. What is known already The influence of age on ovarian reserve underlies the upper limit of 35 years for UK donors. However, recent evidence suggests that oocyte aneuploidy rates follow an inverse U-shaped curve in relation to a woman’s age. Conflicting evidence exists regarding the impact of other donor-related factors including BMI, AMH, oocyte yield and prior reproductive history on recipient outcomes. Moreover, the effect of recipient age, BMI, and reproductive history on oocyte donation outcome remains unclear. Study design, size, duration Retrospective cohort study of 325 altruistic oocyte donors matched to a total of 511 recipients. Only first donations taking place between January 2017 and December 2019 were included. Participants/materials, setting, methods All oocyte donors were altruistic volunteers aged 18–35 with no prior infertility diagnosis. Donor and recipient screening for suitability and safety was carried out according to the Human Fertilisation Embryology Authority guidelines. Backward stepwise logistic regression was used to identify donor, recipient and embryology parameters predictive of recipient primary outcomes defined as clinical pregnancy and live birth, either cumulative or after the first embryo transfer (ET). Main results and the role of chance A total of 705 fresh and frozen/thawed ETs were performed, of which 76% were elective single embryo transfers (eSETs) of blastocysts (96.5%), resulting in a cumulative clinical pregnancy and LBR of 83.5% and 70.5% respectively after 3 ETs. Recipient BMI and previous miscarriages were predictors of cumulative LBR (p Limitations, reasons for caution The present study included only healthy oocyte donors, thus conclusions may not apply to subfertile or less healthy women. Male factors were not accounted for. Wider implications of the findings: We demonstrate the efficacy of vitrified oocyte donation treatment and identify recipient BMI, previous miscarriages and embryology parameters as predictors of cumulative LBR. Additionally, the choice of donors aged 18–22 instead of older donors is found not to be advantageous for increasing the chance of clinical pregnancy and live birth. Trial registration number Not applicable

Study question Does reducing estradiol levels with letrozole co-treatment during ovarian stimulation with gonadotropins for IVF impact endocrinological and reproductive outcome markers in expected normal responders? Summary answer Letrozole co-treatment maintained follicular phase physiological serum estradiol levels, increased gonadotropin and androgen levels, and increased progesterone in the luteal phase. What is known already Ovarian stimulation for IVF causes supraphysiologic estradiol levels, which exert pituitary suppression reducing gonadotropin stimulation of the corpus luteum. Furthermore, stimulation may increase progesterone in the late follicular phase, reported to impair clinical outcomes, through a putative effect on endometrial maturation and embryo-endometrial asynchrony. Co-treatment with the highly selective aromatase inhibitor letrozole during ovarian stimulation has been shown to reduce estradiol levels and FSH consumption in poor responders, but conflicting data in relation to oocyte yield and implantation rates. The impact of letrozole co-treatment on hormonal changes and reproductive outcome after co-treatment in normal responders remains to be clarified. Study design, size, duration A multicentre double-blinded randomised placebo-controlled trial conducted in 4 fertility clinics at university hospitals in Denmark from August 2016 to November 2018. 159 women were randomised and 129 completed the study; 67 women in the letrozole group and 62 women in the placebo group. The study was conducted in accordance with the Helsinki Declaration and the ICH-Good-Clinical-Practice. Data collection and reporting followed the guidelines of CONSORT to achieve transparent reporting of trials. Participants/materials, setting, methods Women with expected normal ovarian reserve received an antagonist IVF protocol with fixed-dose FSH and fresh single embryo transfer. Co-treatment consisted of once-daily 5 mg letrozole or placebo from the start of stimulation until the day of triggering final oocyte maturation with human chorionic gonadotropin. Serum was collected on 7 visits from stimulation start to 8 days after oocyte retrieval. Clinical pregnancy was determined with a viable foetus by vaginal ultrasound at gestational week 7. Main results and the role of chance The proportion of patients with progesterone >1.5 ng/ml in the late follicular phase was similar in the letrozole versus placebo group with 6% versus 0%, respectively (OR 0, 95 % CI [0;1.6], P =.12). Mid-luteal progesterone levels >30 ng/ml were observed in 59% versus 31%, respectively, of subjects in the letrozole and placebo group (OR 3.3, 95% CI [1.4;7.1], P =.005). Letrozole treatment decreased estradiol levels by 69% (95 % CI [60%;75%], P Limitations, reasons for caution The diurnal variation of progesterone has been confirmed since this study was completed, hence the timing of the blood samples was not standardized . However, bias is unlikely due to the randomized design. The study was not powered to show an effect on ongoing pregnancy rates. Wider implications of the findings Letrozole co-treatment during ovarian stimulation with gonadotropins maintained serum estradiol at physiological levels, increased follicular phase levels of gonadotropins and androgens, and luteal progesterone levels. These data indicate that letrozole co-treatment may ameliorate the detrimental impacts of gonadotropin stimulation during IVF in normal responders. Trial registration number NCT02939898 and NCT02946684

Study question Can cooling of embryos during the embryo transfer be alleviated with the use of a 37 °C temperature protective device covering the ET catheter? Summary answer Cooling of embryos during embryo transfer can be effectively alleviated by using a 37 °C pre-warmed temperature protective device covering the ET catheter. What is known already An optimized physicochemical environment is crucial for maintenance of normal homeostasis, metabolism, and spindle stability to minimize stress on gametes and embryos. During preimplantation embryo development, epigenetic reprogramming occurs and environmental stress factors including temperature can disrupt this critical process and potentially damage embryos. IVF laboratories use heated stages, warming blocks and incubators to control and maintain temperature within set control limits. However, it has recently been shown that during the ET procedure, the temperature of fluid in the catheter tip drops significantly. To date no means of preventing this has been reported, or to our knowledge, implemented. Study design, size, duration In this prospective controlled study, 100 simulated embryo transfer procedures were carried out at 5 European clinics. The catheters were loaded with medium according to clinic protocol. In 50, the transfer catheter was then transported to the clinician and handled according to standard practice, and in the other 50 the catheter was covered with the temperature protecting device after loading but otherwise handled identically. 10 control and 10 intervention procedures were performed at each clinic. Participants/materials, setting, methods The temperature inside the ET catheter tip (Wallace Sure View) was measured with a calibrated thermocouple probe (diameter of 0.25 mm) placed at the location of an embryo and monitored during standard operating ET procedures (control group), and with the ET catheter-syringe set inserted into a temperature protective device (37 °C pre-warmed aluminium core, 15x90 mm) allowing retraction of the ET catheter tip immediately after embryo loading (study group). No embryos were employed in this study. Main results and the role of chance During standard operating ET procedures (control group), a considerable variation was observed in the embryo loading temperature between clinics, ranging from 34 °C to 37 °C. A profound temperature drop down to 20.8 °C–25.6 °C was recorded within 20 seconds of loading the ET catheter and in all 5 clinics a very rapid decline in catheter tip temperature down to ambient temperature was observed regardless of environment, type of workstation, or standard operating ET procedures in use. In contrast, when the ET catheter-syringe set was placed into a 37 °C pre-warmed temperature protective device from the time of embryo loading until the end of the simulated ET procedure, the drop of temperature was minimal, effectively maintaining the temperature at the loading temperature of between 34 °C and 37 °C °C throughout the simulated ET procedure. The mean loss of temperature of 14.8 °C in the control group was reduced to just to 0.4 °C in the study group. The consistent and profound differences in catheter tip temperature between the control and device groups across repeated measurements at different sites indicate the findings to be robust. Limitations, reasons for caution Numerous permutations of laboratory culture systems exist and the equipment, consumables and procedure for ET, including time, are highly variable and operator dependent. Therefore, the results and conclusions of this study may not be universally applicable. Furthermore, the impact of embryo cooling during ET on live birth rate remains uncertain. Wider implications of the findings: The ET procedure represents a ‘weak link’ in temperature control from the IVF laboratory to the patient until the embryo is safely deposited into its physiological environment, the uterine cavity. We demonstrate the effectiveness of a novel device for maintaining the temperature during ET, which could potentially improve embryo viability. Trial registration number Not applicable

Study question Does adjuvant letrozole in ovarian stimulation (OS) for in vitro fertilization (IVF) decrease the uterine peristalsis frequency (UPF) prior to fresh embryo transfer (ET)? Summary answer Adjuvant letrozole in (OS) for IVF does not reduce the UPF significantly prior to fresh ET. What is known already Throughout the cycle UPF aids spermatozoa transport to the fallopian tube and may affect implantation. At fresh, ET UPF is negatively correlated with implantation- and clinical pregnancy rates and is believed to be modulated by estradiol and progesterone. High levels of estradiol, from multiple follicular development, in OS have been reported to increase UPF, whereas progesterone is considered to be utero-relaxant. The influence of androgens is unclear. Co-treatment with letrozole during gonadotropin OS limits the estradiol rise the supra-physiological estradiol and may therefore reduce UPF prior to fresh ET. Study design, size, duration: This single centre study was nested within a multicentre double blinded RCT investigating the impact of letrozole co-treatment during gonadotropin OS for IVF on late follicular and luteal estradiol, progesterone and testosterone levels. Between 2016 and 2017, 39 women expected normal responders were randomised to co-treatment with letrozole or placebo. Of these, 33 women completed this element of the study. The study was carried out according to the Helsinki Declaration and the ICH-Good-Clinical-Practice. Participants/materials, setting, methods Eligible women were randomised 1:1 to adjuvant treatment with letrozole 5 mg/day or placebo in an antagonist protocol using a fixed dose of recFSH 150 IU/day. Final maturation was triggered with rhCG 6,500 IU and luteal support with vaginal progesterone was administered from the day following oocyte aspiration. Less than one hour prior to fresh ET, six minute duration transvaginal ultrasound recordings of the uterus in sagittal section were performed and blood samples were drawn. Main results and the role of chance A total of 33 women completed the study (letrozole n = 17; placebo n = 16). Age, BMI, and ovarian reserve markers were similar between the groups. On day of ET, serum estradiol levels were significantly suppressed in the letrozole group to mean 867 ± 827 pmol/L compared to 3,110 ± 1,528 pmol/L in the placebo group (P Limitations, reasons for caution The limited sample size risks masking minor effects. Wider implications of the findings: The supra-physiological levels of estradiol were significantly supressed in the intervention group, but UPF prior to fresh ET was similar in both groups. UPF is not strongly correlated to luteal phase sex steroid levels. Any beneficial effect of adjuvant letrozole during OS is not through an impact of UPF. Trial registration number NCT02939898

Study question The aim of this study was to evaluate the influence of blastocoele re-expansion time of warmed vitrified blastocysts on clinical pregnancy outcome. Summary answer Clinical pregnancy rate was significantly higher after transfer of warmed vitrified blastocysts that were fully expanded within 2 hours post thaw. What is known already The number of blastocysts being vitrified worldwide has increased dramatically over recent years. A combination of factors has led to this including the introduction of vitrification, an increase in freeze-all policies, single embryo transfer and an increase in preimplantation genetic testing. Currently, blastocyst re-expansion after thawing is used to indicate the survival status of the blastocyst and when combined with the morphology of blastocyst can predict its reproductive potential. While time taken for blastocoele re-expansion has been proposed to be a biomarker of viability, its value in clinical practice remains unclear. Study design, size, duration This retrospective study analysed outcomes in patients who had frozen embryo transfers between June-December 2020. 233 embryos were reviewed with time-lapse to assess their blastocoele expansion post-warming and three groups were identified. The first included fully expanded blastocysts post-warming. The second group included partially expanded blastocysts and the third non-expanded blastocysts. In addition, the groups were subcategorised into two further categories depending on whether they took less or more than 2 hours to complete expansion. Participants/materials, setting, methods 233 vitrified/warmed embryos from 216 patients were analysed using time-lapse incubators. The first group included 134 blastocysts, of which 70 were fully expanded within 2 hours and 64 after 2 hours post thaw. The second group had 70 embryos of which 45 expanded partially within 2 hours and 25 after 2 hours. The third had 28 embryos that had no expansion within the first 2 hours (n = 20) or after 2 hours (n = 8). Main results and the role of chance Blastocysts were collapsed by laser prior to vitrification. Single blastocyst transfer was performed for all patients. The mean transferred embryo age was 32.1± 5.5 and the recipient’s was 37.5± 5.9. Fully expanded blastocysts (n = 70) within 2 hours demonstrated a clinical pregnancy rate (CPR) of 57% compared with 38% from those that expanded fully after 2 hours (n = 64) (p = 0.02). Blastocysts with some form of expansion (full or partial) within 2 hours post-warming (n = 115) were associated a significantly higher CPR compared to those expanding after 2 hours (n = 89). The CPR was 55% and 39% respectively (p = 0.02). Embryos that showed no expansion (n = 20) within the first 2 hours post thaw resulted in CPR of 28%. Interestingly, embryos that showed no expansion after 2 hours resulted in no pregnancy. When combining morphology as a selection criterion, expansion within 2 hours of thawing was associated with a CPR of 62.5% for ≥4AB embryos, 50% for BB embryos and 45% for poorer embryos ≤CB.In conclusion, failure of blastocoele expansion post 2 hours reduced by half the chances of clinical pregnancy (p = 0.03). Combination of the degree of re-expansion and embryo morphology is an important predictor tool to improve clinical outcomes in frozen embryo transfers. Limitations, reasons for caution This study uses a small sample size of patients. The data are observational and were retrospectively analysed so unknown confounders could not be assessed. The addition of more cycles and further multivariate analysis, is essential for confirmation of the findings. However, initial results are very reassuring. Wider implications of the findings: The degree of speed of re-expansion post warming should be used as a predictor for prioritisation of embryos for transfer. Owing to these preliminary findings there is rationale for a larger scale study combining other morphological indicators that could further assess implantation indicators and assist patient counselling Trial registration number Not applicable

STUDY QUESTION What is the cumulative incidence of live birth and mean time to pregnancy (by conception after IVF/ICSI or natural conception) in women experiencing unexplained recurrent implantation failure (RIF) following IVF/ICSI treatment? SUMMARY ANSWER In 118 women who had experienced RIF, the reported cumulative incidence of live birth during a maximum of 5.5 years follow-up period was 49%, with a calculated median time to pregnancy leading to live birth of 9 months after diagnosis of RIF. WHAT IS KNOWN ALREADY Current definitions of RIF include failure to achieve a pregnancy following IVF/ICSI and undergoing three or more fresh embryo transfer procedures of one or two high quality embryos or more than 10 embryos transferred in fresh or frozen cycles. The causes and optimal management of this distressing condition remain uncertain and a range of empirical and often expensive adjuvant therapies is often advocated. Little information is available regarding the long-term prognosis for achieving a pregnancy. STUDY DESIGN, SIZE, DURATION Two hundred and twenty-three women under 39 years of age who had experienced RIF without a known cause after IVF/ICSI treatment in two tertiary referral university hospitals between January 2008 and December 2012 were invited to participate in this retrospective cohort follow up study. PARTICIPANTS/MATERIALS, SETTING, METHODS All eligible women were sent a letter requesting their consent to the anonymous use of their medical file data and were asked to complete a questionnaire enquiring about treatments and pregnancies subsequent to experiencing RIF. Medical files and questionnaires were examined and results were analysed to determine the subsequent cumulative incidence of live birth and time to pregnancy within a maximum 5.5 year follow-up period using Kaplan Meier analysis. Clinical predictors for achieving a live birth were investigated using a Cox hazard model. MAIN RESULTS AND THE ROLE OF CHANCE One hundred and twenty-seven women responded (57%) and data from 118 women (53%) were available for analysis. During the maximum 5.5 year follow up period the overall cumulative incidence of live birth was 49% (95% CI 39–59%). Among women who gave birth, the calculated median time to pregnancy was 9 months after experiencing RIF, where 18% arose from natural conceptions. LIMITATIONS, REASONS FOR CAUTION Since only 57% of the eligible study cohort completed the questionnaire, the risk of response bias limits the applicability of the study findings. WIDER IMPLICATIONS OF THE FINDINGS This study reports a favorable overall prognosis for achieving live birth in women who have previously experienced RIF, especially in those who continue with further IVF/ICSI treatments. However since 51% did not achieve a live birth during the follow-up period, there is a need to distinguish those most likely to benefit from further treatment. In this study, no clinical factors were found to be predictive of those achieving a subsequent live birth. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the University Medical Center Utrecht, in Utrecht and the Academic Medical Centre, in Amsterdam. NSM has received consultancy and speaking fees and research funding from Ferring, MSD, Merck Serono, Abbott, IBSA, Gedion Richter, and Clearblue. During the most recent 5-year period BCJMF has received fees or grant support from the following organizations (in alphabetic order); Actavis/Watson/Uteron, Controversies in Obstetrics & Gynecology (COGI), Dutch Heart Foundation, Dutch Medical Research Counsel (ZonMW), Euroscreen/Ogeda, Ferring, London Womens Clinic (LWC), Merck Serono, Myovant, Netherland Genomic Initiative (NGI), OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter/Finox, Reproductive Biomedicine Online (RBMO), Roche, Teva, World Health Organisation (WHO). None of the authors have disclosures to make in relation to this manuscript.

STUDY QUESTION Does letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF reduce the proportion of women with premature progesterone levels above 1.5 ng/ml at the time of triggering final oocyte maturation? SUMMARY ANSWER The proportion of women with premature progesterone above 1.5 ng/ml was not significantly affected by letrozole co-treatment. WHAT IS KNOWN ALREADY IVF creates multiple follicles with supraphysiological levels of sex steroids interrupting the endocrine milieu and affects the window of implantation. Letrozole is an effective aromatase inhibitor, normalizing serum oestradiol, thereby ameliorating some of the detrimental effects of IVF treatment. STUDY DESIGN, SIZE, DURATION A randomized, double-blinded placebo-controlled trial investigated letrozole intervention during stimulation for IVF with FSH. The trial was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 129 women with expected normal ovarian reserve (anti-Müllerian hormone 8–32 nmol/l) completed an IVF cycle with fresh embryo transfer and received co-treatment with either 5 mg/day letrozole (n = 67) or placebo (n = 62), along with the FSH. Progesterone, oestradiol, FSH, LH and androgens were analysed in repeated serum samples collected from the start of the stimulation to the mid-luteal phase. In addition, the effect of letrozole on reproductive outcomes, total FSH consumption and adverse events were assessed. MAIN RESULTS AND THE ROLE OF CHANCE The proportion of women with premature progesterone >1.5 ng/ml was similar (6% vs 0% (OR 0.0, 95% CI [0.0; 1.6], P = 0.12) in the letrozole versus placebo groups, respectively), whereas the proportion of women with mid-luteal progesterone >30 ng/ml was significantly increased in the letrozole group: (59% vs 31% (OR 3.3, 95% CI [1.4; 7.1], P = 0.005)). Letrozole versus placebo decreased oestradiol levels on the ovulation trigger day by 68% (95% CI [60%; 75%], P < 0.0001). Other hormonal profiles, measured as AUC, showed the following results. The increase in LH in the letrozole group versus placebo group was 38% (95% CI [21%; 58%], P < 0.0001) and 34% (95% CI [11%; 61%], P = 0.006) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, testosterone increased by 79% (95% CI [55%; 105%], P < 0.0001) and 49% (95% CI [30%; 72%], P < 0.0001) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, the increase in androstenedione was by 85% (95% CI [59%; 114%], P < 0.0001) and 69% (95% CI [48%; 94%], P < 0.0001) in the follicular and luteal phases, respectively. The ongoing pregnancy rate was similar between the letrozole and placebo groups (31% vs 39% (risk-difference of 8%, 95% CI [−25%; 11%], P = 0.55)). No serious adverse reactions were recorded in either group. The total duration of exogenous FSH stimulation was 1 day shorter in the intervention group, significantly reducing total FSH consumption (mean difference −100 IU, 95% CI [−192; −21], P = 0.03). LIMITATIONS, REASONS FOR CAUTION Late follicular progesterone samples were collected on the day before and day of ovulation triggering for patient logistic considerations, and the recently emerged knowledge about diurnal variation of progesterone was not taken into account. The study was powered to detect hormonal variations but not differences in pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS Although the use of letrozole has no effect on the primary outcome, the number of women with a premature increase in progesterone on the day of ovulation triggering, the increased progesterone in the mid-luteal phase due to letrozole may contribute to optimizing the luteal phase endocrinology. The effect of letrozole on increasing androgens and reducing FSH consumption may be used in poor responders. However, the effect of letrozole on implantation and ongoing pregnancy rates should be evaluated in a meta-analysis or larger randomized controlled trial (RCT). STUDY FUNDING/COMPETING INTEREST(S) Funding was received from EU Interreg for ReproUnion and Ferring Pharmaceuticals, and Roche Diagnostics contributed with assays. N.S.M. and A.P. have received grants from Ferring, Merck Serono, Anecova and Gedeon Richter, and/or personal fees from IBSA, Vivoplex, ArtPred and SPD, outside the submitted work. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBERS NCT02939898 and NCT02946684 TRIAL REGISTRATION DATE 15 August 2016. DATE OF FIRST PATIENT’S ENROLMENT 22 August 2016.

The fatty acid composition of human follicular fluid is important for oocyte development and for pregnancy following in vitro fertilization (IVF). This study investigated whether a dietary intervention that included an increase in marine omega-3 fatty acids, olive oil and vitamin D alters the fatty acid composition of human follicular fluid. The association of lifestyle factors with follicular fluid fatty acid composition was also investigated. Fifty-five couples awaiting IVF were randomized to receive the 6-week treatment intervention of olive oil for cooking, an olive oil-based spread, and a daily supplement drink enriched with vitamin D and the marine omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and 56 couples were randomized to receive placebo equivalents. Dietary questionnaires were completed, and samples of blood were taken before and after the intervention. Follicular fluid was collected at oocyte retrieval and the fatty acid profile assessed using gas chromatography. In the control group, individual fatty acids in red blood cells and follicular fluid were significantly correlated. Furthermore, a healthier diet was associated with a lower percentage of follicular fluid arachidonic acid. The follicular fluid of women in the treatment group contained significantly higher amounts of EPA and DHA compared to the control group, while the omega-6 fatty acids linoleic, γ-linolenic, dihomo-γ-linolenic, and arachidonic were lower. This is the first report of a dietary intervention altering the fatty acid composition of follicular fluid in humans. Further research is required to determine whether this intervention improves oocyte quality.

Research question: Is an online lifestyle coaching platform more effective at modifying periconceptional behaviours than standard advice offered by the UK National Health Service (NHS)? Design: Women with subfertility or recurrent miscarriage were recruited to a two-centre randomized controlled trial. They were randomized to either the online lifestyle coaching platform Smarter Pregnancy (intervention) or periconceptional advice provided by NHS websites (control). Participants completed a lifestyle questionnaire at baseline, 6, 12, 18 and 24 weeks, and the results were used to tailor lifestyle coaching in the intervention group. At baseline, 12 and 24 weeks, composite risk scores (CRS) were calculated. A lower CRS corresponds to a healthier lifestyle. Results: Of the 400 women recruited, 262 women were randomized (131 in each arm). At 12 weeks, a reduction in CRS (includes risk score for intake of folic acid, vegetables and fruits, smoking and alcohol) was observed in the intervention versus control arms. After correcting for baseline, the difference in the CRS between intervention and control was –0.47 (95% CI –0.97 to 0.02) at 12 weeks and –0.32 (95% CI –0.82 to 0.15) at 24 weeks. A statistically significant reduction in lifestyle risk scores was found in women with a body mass index (BMI) of 25 kg/m2 or above compared with those with a BMI below 25kg/m2. The odds of being pregnant at 24 weeks was increased in the intervention versus control (OR 2.83, 95% CI 0.35 to 57.76). Conclusions: The Smarter Pregnancy coaching platform is more effective in delivering lifestyle advice and modulating behaviours to support women with a history of subfertility or recurrent miscarriage than standard online NHS advice.

Introduction: There remains a need for a non-invasive, low-cost and easily accessible way of identifying women at risk of developing hypertensive disorders in pregnancy. This study evaluated the predictive value of longitudinal salivary uric acid measurement. Material and methods: Pregnant women (n = 137) from 20 weeks of gestation were recruited at St Richards Hospital, Chichester, UK, for this prospective cohort study. Weekly samples of salivary uric acid were analyzed until delivery. Information regarding pregnancy and labor were obtained from the patient’s record after delivery. Independent t tests were used to compare mean levels of salivary uric acid in women with hypertensive complications and adverse fetal outcomes with women with normal pregnancies. Main outcome measures were preeclampsia, pregnancy-induced hypertension, spontaneous preterm delivery and small-for-gestational-age babies. Results: From 21 weeks of gestation until delivery, levels of salivary uric acid increased significantly in women who subsequently developed preeclampsia and pregnancy-induced hypertension compared with women with normal pregnancies (preeclampsia—mean at gestational age 21-24, 95% confidence interval [95% CI] [mean GA21-24): 108 [63-185] vs 47 (39-55) µmol/L; P =.005; pregnancy-induced hypertension—mean GA21-24: 118 [54–258] vs 47 [39-55] µmol/L; P =.004). In women who had spontaneous preterm delivery, salivary uric acid levels increased significantly from 29 to 32 weeks of gestation compared with women with normal pregnancies (mean GA29-32: 112 (57-221) vs 59 (50-71) µmol/L; P =.04). In women who had babies small-for-gestational-age

Background Nearly a third of children in the UK are overweight, with the prevalence in the most deprived areas more than twice that in the least deprived. The aim was to develop a risk identification model for childhood overweight/obesity applied during pregnancy and early life using routinely collected population-level healthcare data. Methods A population-based anonymised linked cohort of maternal antenatal records (January 2003 to September 2013) and birth/early-life data for their children with linked body mass index (BMI) measurements at 4–5 years (n = 29,060 children) in Hampshire, UK was used. Childhood age- and sex-adjusted BMI at 4–5 years, measured between September 2007 and November 2018, using a clinical cut-off of ≥ 91st centile for overweight/obesity. Logistic regression models together with multivariable fractional polynomials were used to select model predictors and to identify transformations of continuous predictors that best predict the outcome. Results Fifteen percent of children had a BMI ≥ 91st centile. Models were developed in stages, incorporating data collected at first antenatal booking appointment, later pregnancy/birth, and early-life predictors (1 and 2 years). The area under the curve (AUC) was lowest (0.64) for the model only incorporating maternal predictors from early pregnancy and highest for the model incorporating all factors up to weight at 2 years for predicting outcome at 4–5 years (0.83). The models were well calibrated. The prediction models identify 21% (at booking) to 24% (at ~ 2 years) of children as being at high risk of overweight or obese by the age of 4–5 years (as defined by a ≥ 20% risk score). Early pregnancy predictors included maternal BMI, smoking status, maternal age, and ethnicity. Early-life predictors included birthweight, baby’s sex, and weight at 1 or 2 years of age. Conclusions Although predictive ability was lower for the early pregnancy models, maternal predictors remained consistent across the models; thus, high-risk groups could be identified at an early stage with more precise estimation as the child grows. A tool based on these models can be used to quantify clustering of risk for childhood obesity as early as the first trimester of pregnancy, and can strengthen the long-term preventive element of antenatal and early years care.

Over the last decade the use of frozen-thawed embryo transfer has substantially increased, and currently up to one in two embryos transferred has been cryopreserved. To support implantation, endometrial and embryo maturity are required to be synchronized. This can be achieved in various ways. The most commonly applied endometrial preparation methods are the "natural cycle," in which the sequential estrogen and P necessary for endometrial maturation are derived from the developing follicle, and the "artificial" cycle, in which these are sequentially administered. Review of the published data comparing these approaches does not identify a superior approach in terms of clinical outcomes. However, although the "natural cycle" avoids the need for luteal support, the artificial cycle provides more control over timing of ET, and the "modified" natural cycle, in which ovulation is triggered exogenously, may offer both of these advantages. The optimal monitoring strategy for freeze-thaw cycles remains unclear, because only a few studies have addressed this question. Further studies are also required to determine the ideal dosage, method of administration, and duration of estrogen and P supplementation in artificial cycle frozen embryo transfer.

Shared motherhood IVF treatment is becoming increasingly accepted among assisted reproductive techique practitioners and patients in Europe, although data on its overall efficiency remain scarce. This 6-year retrospective study from a single, private, UK HFEA-regulated centre included consecutive lesbian couples ( n = 121) undergoing shared motherhood IVF treatment (141 cycles). Recipients were more parous and had undergone more previous intrauterine insemination and IVF treatments than donor partners, who had slightly higher ovarian reserve markers than recipients. Indications in most cycles (60%) were non-medical. Most (79%) egg-providers were stimulated with gonadotrophin releasing hormone antagonist protocol, and no moderate or severe cases of ovarian hyperstimulation syndrome (OHSS) arose. A total of 172 fresh and vitrified-warmed embryo transfers were carried out: 70% at the blastocyst-stage and 58% involved a single embryo. Cumulative live birth rate per receiver was 60% (72/120), and twin delivery rate was 14% (10/72). Perinatal outcome parameters were better for singleton than twin pregnancies, although the latter also achieved generally favourable outcomes. No significant difference in cumulative outcomes were found between synchronized and non-synchronized cycles. Shared motherhood IVF combines ovarian stimulation with single blastocyst transfer to provide a safe and effective treatment modality offering reassuring obstetrical and perinatal outcomes.

Background: Childhood obesity is a serious public health challenge and identification of high-risk populations for early intervention to prevent its development is a priority. We aimed to systematically review prediction models for childhood overweight/obesity and critically assess the methodology of their development, validation and reporting. Methods: Medline and Embase were searched from their start dates to 31/12/16 for studies published in English describing the development and/or validation of a model that could predict the development of overweight and/or obesity between 1 to 13 years using maternal and early life factors using: {Pediatric Obesity/ OR Fetal Macrosomia/ OR [(child or childhood or children or p#ediatric* or infant* or toddler or embry* or prenatal* or neonat*).mp. AND (obes*.mp. OR overnutrition/ or obesity/ or overweight/ OR overweight.mp. OR over weight.mp.)]} AND [exp causality/ OR ((Reinforc* or Enabl* or predispos*) and factor*).mp. OR (risk* or predict* or causal* or prognos* or causation).mp.] AND [exp Maternal Behavior/ OR maternal.mp. OR mother*.mp. OR early life.mp.] Data were extracted using the Cochrane CHARMS checklist. The TRIPOD statement was used to assess transparency in reporting. Findings: Ten studies were identified that developed (one), developed and validated (seven) or externally validated an existing (two) prediction model. A median of 23 (interquartile range, 22 to 24) TRIPOD items out of 37 (31 for derivation/validation alone) were reported. Except one, all models were developed using automated variable selection methods. Four studies only included complete cases and two studies used multiple imputation to handle missing data. Maternal body mass index, birthweight and gender were the most commonly included predictors. Median AUROC was 0.78 in development/internal validation and 0.71 in external validation. Conclusion: It was not possible to combine the results due to considerable model heterogeneity. Some included models have not been externally validated or compared to existing models to assess performance. New methods are needed to combine findings from existing prediction models. Future prediction models need to be developed, validated and recalibrated to target populations using standard robust methods to refine the applicability of the resulting scores.

BACKGROUND: Despite advances in ART, implantation and pregnancy rates per embryo transfer still remain low. IVF laboratories strive to ensure that the process of handling gametes in-vitro closely mimics the in-vivo environment. However, there remains a lack of knowledge regarding the in-vivo regulation and dynamic variation in biophysical parameters such as oxygen concentration, pH and temperature within the reproductive tract. OBJECTIVE AND RATIONALE: To undertake a systematic review of the current understanding of the physico-chemical parameters of oxygen tension (pO2), pH and temperature within the female reproductive tract, and their potential implications in clinical and pathological processes related to fertility and those pertaining to limited reproductive capacity. SEARCH METHODS: A comprehensive literature search was performed using electronic databases including Medline, Embase, Cochrane Library and Pubmed to identify original and review articles addressing the biophysical parameters (pO2, pH and temperature) in the female reproductive tract of any species. The search included all studies published between 1946 and November 2015. Search terms included ‘oxygen’, ‘pH’, ‘hydrogen ion concentration’, ‘acid base’ and others terms. We also used special features and truncations to identify synonyms and broaden the search. Studies were excluded if they only assessed embryo culture conditions, fetal acid-base status, oxidative stress, outcomes of pregnancy and measurements of these parameters in non-reproductive organs. OUTCOMES: Our search generated 18, 685 records and 60 articles were included. pO2 within the female reproductive tract shows cyclical variation and minute-to-minute oscillations which may be influenced by uterine contractility, hormones, the autonomic system, cardiac pulsatility, and myometrial and smooth muscle integrity. Fine balanced control of pO2 and avoidance of overwhelming oxidative stress is crucial for embryogenesis and implantation. The pH in the female reproductive tract is graduated, with lowest pH in the vagina (~pH 4.42) increasing towards the Fallopian tubes (~pH 7.94), reflecting variation in the site-specific microbiome and acid-base buffering at the tissue/cellular level. The temperature variation in humans is cyclical by day and month. In humans, it is biphasic, increasing in the luteal phase; with the caudal others terms. We also used special features and truncations to identify synonyms and broaden the search. Studies were excluded if they only assessed embryo culture conditions, fetal acid-base status, oxidative stress, outcomes of pregnancy and measurements of these parameters in non-reproductive organs. OUTCOMES: Our search generated 18, 685 records and 60 articles were included. pO2 within the female reproductive tract shows cyclical variation and minute-to-minute oscillations which may be influenced by uterine contractility, hormones, the autonomic system, cardiac pulsatility, and myometrial and smooth muscle integrity. Fine balanced control of pO2 and avoidance of overwhelming oxidative stress is crucial for embryogenesis and implantation. The pH in the female reproductive tract is graduated, with lowest pH in the vagina (~pH 4.42) increasing towards the Fallopian tubes (~pH 7.94), reflecting variation in the site-specific microbiome and acid-base buffering at the tissue/cellular level. The temperature variation in humans is cyclical by day and month. In humans, it is biphasic, increasing in the luteal phase; with the caudal region of the oviduct 1-2 degrees cooler than the cranial portion. Temperature variation is influenced by hormones, density of pelvic/uterine vascular beds and effectiveness of heat exchange locally, crucial for sperm motility and embryo development. We have identified significant deficiencies and inconsistencies in the methods used to assess these biophysical factors within the reproductive tract. We have suggested technological solutions including the development of methods and models for real time, in-vivo recordings of biophysical parameters. WIDER IMPLICATIONS: The notion of ‘back to nature’ in assisted conception suggested 20 years ago has yet to be translated into clinical practice. While the findings from this systematic review do not provide evidence to change current in-vitro protocols, it highlights our current inability to assess the in-vivo reproductive tract environment in real time. Data made available through future development of sensing technology in-utero may help provide new insights into how best to optimise the in-vitro embryo environment and allow for more precise and personalised fertility treatment.

Recent studies suggest that elevated late follicular phase progesterone concentrations after ovarian stimulation for IVF may result in embryo–endometrial asynchrony, reducing the chance of successful implantation after fresh embryo transfer. It remains unclear to what extent elevated late follicular phase progesterone levels may occur in unstimulated cycles before frozen–thawed embryo transfer, or what affect they may have on outcomes. In this cohort study, 271 patients randomized to the modified natural cycle arm of a randomized controlled trial comparing two endometrial preparation regimens underwent late follicular phase progesterone and LH testing. A receiver operating characteristic curve was constructed to identify a progesterone cut-off level with the best predictive value for live birth (progesterone level ≥4.6 nmol/l). A total of 24.4% of patients revealed an isolated elevated serum progesterone of 4.6 nmol/l or greater, and 44.3% showed an elevated progesterone level in association with a rise in LH. Neither endocrine disruption affected outcomes, with live birth rates of 12.9% versus 10.6% (OR 0.6, 95% CI 0.19 to 1.9) and 11.9% versus 17.5% (OR 1.6, 95% CI 0.79 to 3.1), respectively. Whether monitoring of progesterone and LH in natural cycle frozen–thawed embryo transfer has added clinical value should studied further.

The advent of vitrification has transformed the therapeutic landscape in assisted reproductive technology. Clear evidence for this is provided by the dramatic rise in the number of frozen embryo transfer (FET) cycles being carried out annually. In this review, we examine the reasons that underlie this trend and the current evidence that points to the place FET cycles will come to inhabit in the future. Safety issues have been central to the narrative around the clinical application of vitrification and, as the evidence base grows, the risk benefit balance will become clearer for different patient groups. These will include recipients of donor eggs, as in some centres the use of cryopreserved donor eggs now exceeds that of fresh oocytes. Efficient cryopreservation techniques have also affected international transport of gametes and embryos, increasing international access. The profound changes that vitrification has created promises to fulfil a prediction made by this journal's founding Editor, Bob Edwards, that embryo and cryopreservation would solve many of the challenges presented by assisted reproductive technology.

Research questionIs it feasible to perform a future definitive trial to determine the effectiveness of the positive reappraisal coping intervention (PRCI) in improving the psychological well-being of women with recurrent pregnancy loss (RPL) during the early stages of a new pregnancy?DesignThis mixed method study aimed to establish the feasibility of conducting a multicentre randomized controlled trial (RCT) to definitively test the effects of the PRCI on the psychological well-being of women with RPL. Participants (n = 75) were recruited to the study and at the point of a positive pregnancy test, 47 were randomized into two study groups. The intervention group received the PRCI and weekly questionnaire assessment (Hospital Anxiety and Depression Scale and Weekly Record Keeping Form [WRK]) to monitor psychological well-being; the control group received the same questionnaires. Nested within the RCT was a qualitative process evaluation (QPE) exploring participants’ subjective experience of study methods and the intervention. The study was conducted over a two-year period between 2014 and 2016.ResultsThis study successfully gathered knowledge about the feasibility aspects of conducting a future multicentre definitive study to determine the effects of the PRCI on the psychological well-being of women with RPL. Participants were receptive to its use and the intervention appeared to convey benefits with no apparent downside.ConclusionsThe study concluded that a definitive RCT of the PRCI is possible and that the model of care already has the potential to be made more widely available as a safe, low-cost, convenient and easily deliverable intervention to provide much-needed support to a vulnerable patient population.

Background In England, 9.5% of children aged 4–5 years and 20.1% aged 10–11 years are obese, with the prevalence in the most deprived areas being more than twice as that in the least deprived. There is evidence illustrating the developmental origins of obesity, but it focuses on individual risk factors and comes mostly from research birth cohorts which are not necessarily representative of the wider population. There is no system-based early identification of childhood obesity risk at pregnancy stage and onwards.The aim was to develop and validate a risk identification system for childhood obesity using existing routinely collected maternal and early-life population-level healthcare data in Hampshire. Methods Studying Lifecourse Obesity PrEdictors (SLOPE) study is an anonymised population-based linked cohort of maternal antenatal and delivery records for all births taking place at University Hospital Southampton 2003–2018, and child health records including information on postnatal growth, type of feeding and childhood body mass index (BMI) up to 14 years. Childhood age- and sex- adjusted BMI at 4–5 years was used to define the outcome of overweight and obesity in the models. Logistic regression models together with multivariable fractional polynomials were used to select model predictors and to identify transformations of continuous predictors that best predict the outcome. Predictive accuracy was evaluated by assessing model discrimination and calibration. Results Childhood BMI was available for approximately 30000 children aged 4–5 years (9% obese). Models were developed in stages, incorporating data collected at first antenatal booking appointment, birth and early life predictors. The area under the curve (AUC) was lowest (0.64) for the model only incorporating maternal predictors from the booking appointment and highest for the model incorporating all factors up to weight at 2 years for predicting outcome at 4–5 years (0.82 for overweight and obesity and 0.89 for obesity excluding overweight). Maternal predictors included BMI, smoking status at first antenatal appointment, age and ethnicity. Early life predictors included birthweight, gender, breastfeeding and weight at 1 or 2 years of age. Although AUC was lower for the booking models, maternal predictors remained consistent across the models, thus high-risk groups could be identified at an early stage with more precise estimation as the child grows. Conclusion This prediction modelling can be used to identify and quantify clustering of risk for childhood obesity as early as the first trimester of pregnancy, and can strengthen the long-term preventive element of antenatal and early years care.

Background Maternal obesity during pregnancy increases the risk of large-for-gestational age (LGA) infant and childhood obesity. We aimed to investigate the association between maternal weight change between consecutive pregnancies and risk of having a LGA baby. Methods A population-based cohort of routinely collected antenatal health-care data between Jan 1, 2003, and Dec 31, 2017, at University Hospital Southampton, UK, was used. No age restriction was applied, and records of all women with their first two singleton livebirth pregnancies were analysed. Regression analysis was used to examine the association between interpregnancy change in maternal body-mass index (BMI) measured at first antenatal appointment of each pregnancy and LGA (adjusted for age, ethnicity, educational qualification, infertility treatment, smoking, employment status, infant sex, gestational diabetes in current pregnancy, and interpregnancy interval). We also stratified by maternal BMI category and LGA outcome in first pregnancy. Findings 15 940 records were analysed. 2548 women (16%) lost weight and 7607 (48%) gained weight (≥1 BMI unit) between pregnancies. LGA incidence was 7% (n=1109) in first and 13% (2106) in second pregnancies; and was 12% (315) in women who lost weight and 12% (690) in women whose weight remained stable between pregnancies compared with 14% (1101) in women who gained weight. Normal-weight and overweight women who gained weight had an increased risk of LGA after having a non-LGA baby in the first pregnancy (adjusted odds ratio 1·37 [95% CI 1·16–1·61], p Interpretation Losing weight after LGA birth in overweight women reduces the risk of subsequent LGA, whereas gaining weight increases its risk in women with no previous history of LGA. Avoiding weight gain between pregnancies is an important preventive measure to achieve better maternal and offspring outcomes. Funding Supported by a University of Southampton Primary Care and Population Sciences PhD studentship (to NZ), the Academy of Medical Sciences, and the Wellcome Trust ( grant no: AMS_HOP001\1060 to NAA ).

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 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.

ObjectiveTo investigate how women experience the initial period of a new pregnancy after suffering recurrent miscarriage (RM).DesignA qualitative study, nested within a randomised controlled feasibility study of a coping intervention for RM, used semi-structured face-to-face interviews. Interviews were audio-recorded, transcribed verbatim and analysed using a thematic network approach.SettingParticipants were recruited from the Recurrent Miscarriage Clinic and Early Pregnancy Unit in two tertiary referral hospitals in the UK.Participants14 women with RMs and who had previously participated in the randomised controlled trial (RCT) feasibility component of the study were recruited.ResultsSeven organising themes emerged from the data: (1) turmoil of emotions, (2) preparing for the worst, (3) setting of personal milestones, (4) hypervigilance, (5) social isolation, (6) adoption of pragmatic approaches, (7) need for professional affirmation.ConclusionsThe study established that for women with a history of RM, the waiting period of a new pregnancy is a traumatic time of great uncertainty and emotional turmoil and one in which they express a need for emotional support. Consideration should be given to the manner in which supportive care is best delivered within the constraints of current health service provision.Trial registration numberISRCTN43571276

Objective To study the impact of increased dietary intake of omega-3 fatty acids, vitamin D, and olive oil for 6 weeks before in vitro fertilization (IVF) or IVF–intracytoplasmic sperm injection (ICSI) on morphokinetic markers of early embryo development. Design A double-blinded randomized controlled trial. Setting Academic IVF unit in the United Kingdom. Patient(s) A total of 111 couples undergoing IVF or IVF-ICSI were recruited. Interventions(s) Fifty-five couples received the 6-week study intervention of a daily supplement drink enriched with omega-3 fatty acids and vitamin D plus additional olive oil and olive oil–based spread, and 56 couples received the control intervention. Main Outcome Measure(s) The primary end point for the study was the time taken for completion of the second cell cycle after fertilization (CC2). Secondary end points included time to complete the third and fourth cell cycles (CC3 and CC4), the synchrony of the second and third cell cycles (S2 and S3), and the day 3 and day 5 Known Implantation Data Scores (KIDScores). Result(s) There was no difference in CC2 between the two groups. However, CC4 was accelerated in the study group compared with the control group, and a significantly shortened S3 as well as an increase in KIDScore on day 3 were observed, indicating improved embryo quality in the study group. Conclusion(s) This study demonstrates that a short period of dietary supplementation alters the rate of embryo cleavage. Further research is required to investigate the mechanisms that regulate this effect, and whether the impact on embryo development translates into improved clinical outcomes. Clinical Trial Registration Number ISRCTN50956936

Introduction Until recently, limited options for preserving fertility in order to delay childbearing were available. Although egg freezing and successful thawing is now possible, it remains unclear to what extent women are aware of the availability of this technique, their attitudes towards its use, or the circumstances under which this technique may be considered. Material and methods An online cross-sectional survey was designed to investigate knowledge and attitudes of women in Denmark and the UK on egg freezing and their potential intentions regarding the procedure. Results Data was collected from September 2012 to September 2013 and the responses of 973 women were analyzed. In total, 83% of women reported having heard of egg freezing, and nearly all considered it acceptable for medical indications, whilst 89% considered it acceptable for social reasons. Overall, 19% expressed active interest in the procedure, and 27% expressed possible interest. Key factors found to positively influence attitudes to accepting the procedure were reassurance that it would not affect future fertility and greater than 50% chance of achieving a live birth. Characteristics significantly associated with intention to freeze eggs were being single, age under 35 years, childlessness, and a history of infertility. In this group, risk and cost were less important considerations. Conclusions This study indicates that there is widespread awareness and support of the availability of eggs freezing for reproductive planning. Reassurance regarding its efficacy appears more important than its potential adverse effects on their health or that of future children, or the costs of the procedure.

Background: Across several European countries family formation is increasingly postponed. The aims of the study were to investigate the desire for family building and fertility awareness in the UK and Denmark.Methods: A population-based internet survey was used among women (n?=?1,000) and men (n?=?237) from the UK (40%) and Denmark (60%). Data covered socio-demographics, family formation, and awareness of female age-related fertility. Data analysis used descriptive statistics and logistic regression analysis for studying associations between low fertility awareness and desired family formation.Results: The majority of all participants desired two or three children. Two-thirds of the childless participants desired a first child at 30+ years, and one-fifth of the women and one-third of the men desired a last child at age 40. Overall, 83% of women and 73% of men were aware that female fertility starts to decline around 25–30 years. Men had significantly lower fertility awareness. Women who underestimated the impact of age on female fertility were significantly more likely to have a desire or attempted their first child at a higher age.Conclusion: Even though the majority were aware of the age-related decrease in female fertility, most desired having children at an age when female fertility has declined. Women who were not sufficiently aware of the impact of advanced age were significantly more likely to have their first child at a higher age. There is a need for developing educational programs for women and men in order to increase the population’s knowledge of fertility and risk factors for infertility.

Background Short and long intervals between pregnancies have been associated with increased risk of adverse birth outcomes including low birth weight and stillbirth. Birthweight is an indicator of the in-utero environment and a key early life risk factor for long-term health outcomes such as obesity and cardiovascular disease. The World Health Organization recommended in 2005 waiting at least 24 months after a live birth before getting pregnant again. There are no UK guidelines on birth spacing. We aimed to investigate the association between duration of the inter-pregnancy interval between successive live birth pregnancies and risk of having a small-for-gestational age (SGA) or large-for-gestational age (LGA) baby. Methods A population-based cohort of prospectively collected routine healthcare data for antenatal care between January 2003 and September 2017 (total n=82 098 pregnancies) at University Hospital Southampton, Hampshire, UK was used. Records of women with their first two singleton live-birth pregnancies were analysed (n=15 922 women). Inter-pregnancy interval was defined as timing between a live birth and the next conception. SGA was defined as 90th percentile weight for gestational age. Logistic regression was used to examine the association between risk of SGA or LGA and inter-pregnancy interval. The models were adjusted for maternal age, ethnicity, highest educational qualification, employment status, baseline maternal BMI, between pregnancy change in maternal BMI, smoking status at second pregnancy booking appointment and conception following infertility treatment. Sensitivity analyses was conducted adjusting for SGA or LGA in previous pregnancies. Results Twelve percent of first pregnancy and 7% of second pregnancy births were SGA. Seven percent of first pregnancy and 13% of second pregnancy births were LGA. Three percent of women each had SGA and LGA babies in both pregnancies. Compared to an interval of 24–35 months, there was a lower risk of SGA birth in second pregnancy with an interval of 12–23 months (adjusted OR 0.82, 95% CI 0.69 to 0.98, p=0.03). The association remained after adjusting for previous outcome of SGA in sensitivity analysis. No association was observed between risk of SGA with intervals of Conclusion An inter-pregnancy interval of 12–23 months was associated with lower risk of SGA, however the duration of the interval was not associated with LGA risk. In high-income countries with relatively healthy pregnant population, further research considering the potential advantages of shorter optimal interval between pregnancies than that recommended by WHO is needed. Acknowledgements David Cable (Electronic Patient Records Implementation and Service Manager) at University Hospital Southampton NHS Foundation Trust for support in accessing the data used in this study.

Background Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur during the sensitive periconceptional window of development, it has recently become a matter of urgency to investigate risk in ART-conceived children. Methods We have conducted the first large-scale, national cohort study of early growth in ART children from birth to school age, linking the register of ART, held by the UK’s Human Fertilisation and Embryology Authority, to Scottish maternity and child health databases. Results In this study of 5200 ART and 20,800 naturally conceived (NC) control children, linear regression analysis revealed the birthweight of babies born from fresh embryo transfer cycles is 93.7 g [95% CI (76.6, 110.6)g] less than NC controls, whereas babies born from frozen embryo transfer (FET) cycles are 57.5 g [95% CI (30.7, 86.5)g] heavier. Fresh ART babies grew faster from birth (by 7.2 g/week) but remained lighter (by 171 g), at 6–8 weeks, than NC babies and 133 g smaller than FET babies; FET and NC babies were similar. Length and occipital-frontal circumference followed the same pattern. By school entry (4–7 years), weight, length and BMI in boys and girls conceived by fresh ART and FET were similar to those in NC children. Conclusions ART babies born from fresh embryo transfer grow more slowly in utero and in the first few weeks of life, but then show postnatal catch up growth by school age, compared to NC and FET babies. As low birth weight and postnatal catch-up are independent risk factors for cardiometabolic disease over the life-course, we suggest that further studies in this area are now warranted. Electronic supplementary material The online version of this article (10.1186/s12916-018-1203-7) contains supplementary material, which is available to authorized users.

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

An automated chip-based electrospray platform was used to develop a high-throughput nanoelectrospray high resolution mass spectrometry (nESI-HRMS) method for multiplexed parallel untargeted and targeted quantitative metabolic analysis of urine samples. The method was demonstrated to be suitable for metabolic analysis of large sample numbers and can be applied to large-scale epidemiological and stratified medicine studies. The method requires a small amount of sample (5 μL of injectable volume containing 250 nL of original sample), and the analysis time for each sample is three minutes per sample to acquire data in both negative and positive ion modes. Identification of metabolites was based on the high resolution accurate mass and tandem mass spectrometry using authentic standards. The method was validated for 8 targeted metabolites and was shown to be precise and accurate. The mean accuracy of individual measurements being 106% and the intra- and inter-day precision (expressed as relative standard deviations) were 9% and 14%, respectively. Selected metabolites were quantified by standard addition calibration using the stable isotope labelled internal standards in a pooled urine sample, to account for any matrix effect. The multiple point standard addition calibration curves yielded correlation coefficients greater than 0.99, and the linear dynamic range was more than three orders of magnitude. As a proof-of-concept the developed method was applied for targeted quantitative analysis of a set of 101 urine samples obtained from female participants with different pregnancy outcomes. In addition to the specifically targeted metabolites, several other metabolites were quantified relative to the internal standards. Based on the calculated concentrations, some metabolites showed significant differences according to different pregnancy outcomes. The acquired high resolution full-scan data were used for further untargeted fingerprinting and improved the differentiation of urine samples based on pregnancy outcome.

Recurrent implantation failure (RIF) is a source of distress and frustration to both patients and their clinicians. In the absence of clinically useful tests, the therapeutic approach has been largely empirical, with limited efficacy. In recent years, new insights into the role of the endometrium in implantation have emerged, and a number of dysfunctions that may underlie implantation failure have been characterized. These point to the presence, in some patients, of an underlying endometrial pathology. In this article, the case is made that constitutive (rather than maturation) defects underlying RIF can be identified. Evidence is presented of a specific transcriptomic signature that is highly predictive of RIF.

While advances in assisted reproductive techniques have been substantial, failure of the apparently viable embryo to implant remains a source of distress and frustration to patients and specialists alike. The unique maternal immunological response to the embryo and the notion that defects in early placentation underlie the great complications of pregnancy have focused attention on the therapeutic potential of peri-implantation immunomodulation. On the face of it, the rationale for this approach is very attractive. However, as will be argued in this review, the clinical evidence base supporting the use of immunosuppressive treatments is weak and difficult to apply in practice and fails the needs of both doctors and their patients. This evidence gap is filled by justifications that are based largely on meeting patient expectations and commercial imperatives. However, this does not mean that immunomodulation treatments should be written off as ineffective. The literature in this field, while suffering the same challenges of heterogeneity, small studies, and publication bias as other areas of medicine, does hint at the way forward. Recurrent implantation failure and pregnancy loss are not diagnoses but clinical presentations that require appropriate phenotyping and etiological investigation. We are increasingly gaining the tools to make an "endometrial diagnosis," and these will allow us to design clinical studies of interventions that treat the underlying cause rather than the symptoms of implantation failure. The current evidence base does not support the clinical use of immunomodulation therapies in patients undergoing IVF. However, more discerning phenotyping may identify groups who could benefit.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: We aim to assess the clinical effectiveness and safety profile of currently applied controlled ovarian stimulation (COS) protocols, and to generate a clinically-useful ranking of these protocols.

STUDY QUESTION What is the effect of the positive reappraisal coping intervention (PRCI) on anxiety in women awaiting the outcome of an IVF/ICSI cycle? SUMMARY ANSWER Women reported significantly more anxiety during the waiting period than before treatment, but the use of the PRCI did not significantly reduce anxiety during the waiting period. WHAT IS KNOWN ALREADY Waiting for the outcome of IVF/ICSI treatment after embryo transfer is one of the most stressful periods of fertility treatments. At present, no evidence-based coping interventions are available to assist women though this waiting period. The PRCI has been designed to address this unmet need by promoting positive reappraisal coping. STUDY DESIGN, SIZE, DURATION A three-armed randomized controlled trail (RCT) was designed to evaluate the PRCI in women undergoing IVF/ICSI. Data were collected between October 2010 and June 2012. A total of 377 participants were randomized to receive either the PRCI and emotional monitoring, emotional monitoring only, or routine care. Only the PRCI-monitoring group received the coping intervention, comprising an explanatory leaflet and ten statements to be read at least once in the morning and once in the evening. PARTICIPANT, MATERIALS, SETTING, METHODS To capture the general impact of the PRCI, all three groups completed questionnaires at three time points: just before the waiting period (time 1: stimulation phase), on Day 10 of the 14-day waiting period (time 2: waiting period) and 6 weeks after the start of the waiting period (time 3: 6-week follow-up). In addition, to capture the specific impacts of the PRCI on the days of the waiting period, the PRCI-monitoring group and the monitoring-control group also rated their emotions and reactions daily, for the 14-day waiting period. MAIN RESULTS AND THE ROLE OF CHANCE Of the women who agreed to participate and who met eligibility criteria, 377 were randomized. All study participants reported significantly more anxiety and depression during the waiting period than before treatment (P < 0.001). The mean difference in anxiety between time 1 versus time 2 was 1.465 (95% CI 1.098–1.832). The mean difference in depression between time 1 versus time 2 was 0.514 (95% CI 0.215–0.813). Use of the PRCI did not significantly reduce anxiety or depression, or daily negative emotions during the waiting period. However, patients randomized to the PRCI reported significantly more positive emotions during the waiting period (P < 0.001) than the monitoring-control group, and reported the intervention to be easy to use, and as having a positive psychological effect. No significant differences were found between the groups in treatment outcome. LIMITATIONS, REASONS FOR CAUTION The lack of difference observed in the present study for anxiety levels between the PRCI and the monitoring-control group could have been due to the effects of monitoring itself or its ability to attenuate or obscure the effects of the PRCI intervention in unknown ways. A randomized group of women who used only the PRCI without daily monitoring would provide more insight. WIDER IMPLICATIONS OF THE FINDINGS The PRCI was shown to help women reinterpret the demands of the waiting period in a more positive way. These results are consistent with previous studies showing that positive reappraisal coping is a useful strategy for unpredictable and uncontrollable situations represented by a medical waiting period. This simple low cost self-help coping intervention increases positive affect during the waiting period in an IVF/ICSI treatment.

study question: How do the expression patterns of neuronal markers differ in the endometrium of women with and without endometriosis? summary answer: The neuronal markers, PGP9.5, NGFp75 and VR1, are expressed in the endometrium at levels that do not differ between women with and without endometriosis. what is known already: Aberrant neuronal growth within the uterus may contribute to abnormal fertility and uterine dysfunction. However, controversy still exists as to whether aberrant innervation in the endometrium is associated with gynaecological pathology such as endometriosis. This may reflect the use of subjective methods such as histology to assess the innervation of the endometrium. We, therefore, employed a quantitative method, western blotting, to study markers of endometrial innervation in the presence and absence of endometriosis. study design, size, duration: This study included 45 women undergoing laparoscopic examination for the diagnosis of endometriosis. Endometrial samples were analysed by western blot for the expression of neuronal and neurotrophic markers, PGP9.5, VR1 and NGFp75. participants/materials,settings,methods: Endometrial pipelle biopsies were obtained from patients with (n ¼ 20, study group) and without (n ¼ 25, control group) endometriosis. Tissue was analysed by immunohistochemistry and western blot analysis for the expression of pan-neuronal marker, PGP9.5, sensory nociceptive marker, TPVR1, and low-affinity neurotrophic growth factor receptor, NGFRp75. mainresultsandtheroleofchance: PGP9.5, NGFp75 and VR1 were expressed in the endometrium of women, independent of the presence of endometriosis. Furthermore, the expression level of PGP9.5, VR1 and NGFp75 did not alter between the two cohorts of women. limitations,reasonsforcaution: Studies of this nature are subject to the heterogeneous nature of patient population and tissue samples despite attempts to standardize these parameters. Hence, further studies using similar methodology will be required to confirm our results. widerimplicationsofthefindings: Our results highlight that sensory neuronal markers are present in women with and without endometriosis. Future work will assess what the targets of the endometrial nerves are and investigate their function, their impact on endometrial biology and, in particular, whether aberrant neuronal function, rather than the mere presence of neuronal function, could be the root cause of subfertility and/or pain affecting many endometriosis sufferers. Our results do not, however, confirm the previous paradigm of increased innervation in the endometrium of women with endometriosis, nor the use of nerve cell detection from pipelle biopsies to diagnose endometriosis. study funding/competing interest(s): This work was funded by the Infertility Research Trust (IRT) and the University of Malaya. There are no competing interests.

BACKGROUND Frozen-thawed embryo transfer (FET) enables surplus embryos derived from IVF or IVF-ICSI treatment to be stored and transferred at a later date. In recent years the number of FET cycles performed has increased due to transferring fewer embryos per transfer and improved laboratory techniques. Currently, there is little consensus on the most effective method of endometrium preparation prior to FET. METHODS Using both MEDLINE and EMBASE database a systematic review and meta-analysis of literature was performed. Case-series, case-control studies and articles in languages other than English, Dutch or Spanish were excluded. Those studies comparing clinical and ongoing pregnancy rates as well as live birth rates in (i) true natural cycle FET (NC-FET) versus modified NC-FET, (ii) NC-FET versus artificial cycle FET (AC-FET), (iii) AC-FET versus artificial with GnRH agonist cycle FET and (iv) NC-FET versus artificial with GnRH agonist cycle FET were included. Forest plots were constructed and relative risks or odds ratios were calculated. RESULTS A total of 43 publications were selected for critical appraisal and 20 articles were included in the final review. For all comparisons, no differences in the clinical pregnancy rate, ongoing pregnancy rate or live birth rate could be found. Based on information provided in the articles no conclusions could be drawn with regard to cancellation rates. CONCLUSIONS Based on the current literature it is not possible to identify one method of endometrium preparation in FET as being more effective than another. Therefore, all of the current methods of endometrial preparation appear to be equally successful in terms of ongoing pregnancy rate. However, in some comparisons predominantly retrospective studies were included leaving these comparisons subject to selection and publication bias. Also patients' preferences as well as cost-efficiency were not addressed in any of the included studies. Therefore, prospective randomized studies addressing these issues are needed.

The analysis of endometrial secretions offers a window on human peri-implantation events that have hitherto been difficult to study noninvasively. Uterine secretomic analysis provides a sensitive means of interrogating the contents of secretions, which have been shown to play a key role in determining endometrial receptivity and embryo-endometrial signaling, and in providing a nourishing environment to the preimplantation embryo. Compared with other means of assessing the endometrium with genomics or proteomics, secretomics offers a nondisruptive approach, allowing analysis during conception cycles. It also provides information on the downstream molecular profile directly encountered by the embryo, offering an integrated review of the complete endometrial surface rather than information representative of only a discrete biopsy site. In this article, recent data derived from uterine secretomics are reviewed. In addition to in vivo studies, recent data from in vitro studies that are changing our understanding of the role of the endometrium in embryo selection are reviewed. Finally, the role of uterine secretions in nutrition and early development programming of the embryo is considered.