Christina Cole's research while affiliated with University of Oxford and other places

STUDY QUESTION What are the risk factors and impacts of anxiety in women and men in heterosexual couples undergoing IVF as part of a randomised trial, with a delay in embryo transfer in one arm? SUMMARY ANSWER Duration of infertility, ethnicity and male partner’s anxiety levels were associated with women’s anxiety at the start of treatment, while initial anxiety score, partner’s anxiety score at embryo transfer, ethnicity and clinic location were associated with women’s anxiety levels at embryo transfer; although women undergoing IVF were more anxious than their partners for slightly different reasons, their self-reported state anxiety was not associated with achieving clinical pregnancy, or with switching from delayed frozen embryo transfer to fresh embryo transfer in an IVF trial. WHAT IS KNOWN ALREADY Use of IVF treatment continues to rise and patients undergoing IVF are anxious. Participating in a randomised controlled trial (RCT) with uncertainty of arm randomisation might increase their anxiety, while a delay in treatment may add further to anxiety. STUDY DESIGN, SIZE, DURATION A mixed methods study was conducted using data from the multi-centre E-Freeze RCT cohort conducted across 13 clinics in the UK from 2016 to 2019. A regression analysis on anxiety scores of couples undergoing the IVF trial and a qualitative analysis of participant questionnaires were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS Six hundred and four couples participating in the E-Freeze trial, who had at least one useable State-Trait Anxiety Inventory (STAI) State Anxiety subscale (STAI-S) standardised self-report questionnaire for at least one of the partners, were included in the study. STAI-S scores were measured at consent for trial (T1) and again at embryo transfer (T2). Linear and log binomial regression were used to explore the association between characteristics and STAI-S scores, and the associations between STAI-S scores and non-compliance and clinical pregnancy, respectively. Responses to the open text question were qualitatively analysed inductively using content analysis. MAIN RESULTS AND THE ROLE OF CHANCE Women’s STAI-S scores at T1 (consent) were associated with their ethnicity, duration of infertility and their male partner’s STAI-S score at T1. Women’s STAI-S scores at T2 (embryo transfer) were associated with their ethnicity, location of fertility clinic, their STAI-S score at consent, and their male partner’s STAI-S score at embryo transfer. The adjusted coefficient (95%CI) for women’s STAI-S scores at T2 was -4.75 (-7.29, -2.20, p < 0.001) for ethnic minority versus White, -2.87 (-4.85, -0.89, p = 0.005) for Scotland versus England, 0.47 (0.37, 0.56, p < 0.001) for each point increase in their own score at T1, and 0.30 (0.21, 0.40, p < 0.001) for each point increase in their male partner’s score at T2. On average, women had higher STAI-S scores than men at both time points, and a larger increase of scores between the two time points. However, women’s STAI-S scores were not associated with either non-compliance with trial allocation in the ‘freeze-all’ trial arm, or with chances of pregnancy. Both partners, but particularly women, described feeling anxious about the outcome of IVF, with women carrying the added worry of believing that feeling stressed might itself affect the outcome. Participants highlighted the important role of support from staff in helping them to manage their anxiety. LIMITATIONS, REASONS FOR CAUTION Data were not available on education level or social support, which might influence anxiety scores. Men’s baseline characteristics were not collected. WIDER IMPLICATIONS OF THE FINDINGS Identifying couples at increased risk of emotional distress may be improved by using standardised anxiety measures at the start of the fertility treatment. Women can be reassured that their self-reported state anxiety does not affect their chances of achieving clinical pregnancy through IVF, and this may help to reduce anxiety levels. The psychological wellbeing and experiences of couples undergoing IVF could be supported by patient-centred care: making information about the whole process of treatment and choices available to both partners in accessible formats; ensuring interactions with staff are kind and supportive; and acknowledging and addressing the different concerns of women undergoing IVF and their partners. STUDY FUNDING/COMPETING INTEREST(S) This study was an NIHR HTA (National Institute for Health and Care Research Health Technology Assessment) funded study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER ISRCTN registry: ISRCTN61225414

Background Tongue-tie can be diagnosed in 3–11% of babies, with some studies reporting almost universal breastfeeding difficulties, and others reporting very few feeding difficulties that relate to the tongue-tie itself, instead noting that incorrect positioning and attachment are the primary reasons behind the observed breastfeeding difficulties and not the tongue-tie itself. The only existing trials of frenotomy are small and underpowered and/or include only very short-term or subjective outcomes. Objective To investigate whether frenotomy is clinically and cost-effective to promote continuation of breastfeeding at 3 months in infants with breastfeeding difficulties diagnosed with tongue-tie. Design A multicentre, unblinded, randomised, parallel group controlled trial. Setting Twelve infant feeding services in the UK. Participants Infants aged up to 10 weeks referred to an infant feeding service (by a parent, midwife or other breastfeeding support service) with breastfeeding difficulties and judged to have tongue-tie. Interventions Infants were randomly allocated to frenotomy with standard breastfeeding support or standard breastfeeding support without frenotomy. Main outcome measures Primary outcome was any breastmilk feeding at 3 months according to maternal self-report. Secondary outcomes included mother’s pain, exclusive breastmilk feeding, exclusive direct breastfeeding, frenotomy, adverse events, maternal anxiety and depression, maternal and infant NHS health-care resource use, cost-effectiveness, and any breastmilk feeding at 6 months of age. Results Between March 2019 and November 2020, 169 infants were randomised, 80 to the frenotomy with breastfeeding support arm and 89 to the breastfeeding support arm from a planned sample size of 870 infants. The trial was stopped in the context of the COVID-19 pandemic due to withdrawal of breastfeeding support services, slow recruitment and crossover between arms. In the frenotomy with breastfeeding support arm 74/80 infants (93%) received their allocated intervention, compared to 23/89 (26%) in the breastfeeding support arm. Primary outcome data were available for 163/169 infants (96%). There was no evidence of a difference between the arms in the rate of breastmilk feeding at 3 months, which was high in both groups (67/76, 88% vs. 75/87, 86%; adjusted risk ratio 1.02, 95% confidence interval 0.90 to 1.16). Adverse events were reported for three infants after surgery [bleeding ( n = 1), salivary duct damage ( n = 1), accidental cut to the tongue and salivary duct damage ( n = 1)]. Cost-effectiveness could not be determined with the information available. Limitations The statistical power of the analysis was extremely limited due to not achieving the target sample size and the high proportion of infants in the breastfeeding support arm who underwent frenotomy. Conclusions This trial does not provide sufficient information to assess whether frenotomy in addition to breastfeeding support improves breastfeeding rates in infants diagnosed with tongue-tie. Future work There is a clear lack of equipoise in the UK concerning the use of frenotomy, however, the effectiveness and cost-effectiveness of the procedure still need to be established. Other study designs will need to be considered to address this objective. Trial registration This trial is registered as ISRCTN 10268851. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (project number 16/143/01) and will be published in full in Health Technology Assessment ; Vol. 27, No. 11. See the NIHR Journals Library website for further project information. The funder had no role in study design or data collection, analysis and interpretation. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Objectives: This mixed-methods feasibility study aimed to explore parents' and medical practitioners' views on the acceptability and design of a clinical trial to determine whether routine prophylactic proton pump inhibitors (PPI) reduce the incidence of anastomotic stricture in infants with oesophageal atresia (OA). Design: Semi-structured interviews with UK parents of an infant with OA and an online survey, telephone interviews and focus groups with clinicians. Data were analysed using reflexive thematic analysis and descriptive statistics. Participants and setting: We interviewed 18 parents of infants with OA. Fifty-one clinicians (49 surgeons, 2 neonatologists) from 20/25 (80%) units involved in OA repair completed an online survey and 10 took part in 1 of 2 focus groups. Interviews were conducted with two clinicians whose survey responses indicated they had concerns about the trial. Outcome measures: Parents and clinicians ranked the same top four outcomes ('Severity of anastomotic stricture', 'Incidence of anastomotic stricture', 'Need for treatment of reflux' and 'Presence of symptoms of reflux') as important to measure for the proposed trial. Results: All parents and most clinicians found the use, dose and duration of omeprazole as the intervention medication, and the placebo control, as acceptable. Parents stated they would hypothetically consent to their child's participation in the trial. Concerns of a few parents and clinicians about infants suffering with symptomatic reflux, and the impact of this for study retention, appeared to be alleviated through the symptomatic reflux treatment pathway. Hesitant clinician views appeared to change through discussion of parental support for the study and by highlighting existing research that questions current practice of PPI treatment. Conclusions: Our findings indicate that parents and most clinicians view the proposed Treating Oesophageal Atresia with prophylactic proton pump inhibitors to prevent STricture (TOAST) trial to be feasible and acceptable so long as infants can be given PPI if clinicians deem it clinically necessary. This insight into parent and clinician views and concerns will inform pilot phase trial monitoring, staff training and the development of the trial protocol.

Background Premature birth is the leading cause of neonatal death and can cause major morbidity. Maximising the amount of maternal breastmilk given to very premature infants is important to improve outcomes, but this can be challenging for parents. Parents of infants receiving neonatal care also have high rates of anxiety and distress. There is growing evidence for the impact of maternal relaxation interventions on lactation, as well as mental health. The trial will assess whether a brief self-directed relaxation and visualisation intervention, recommended for use several times a day during expression of milk, improves lactation and mental health outcomes for mothers of very premature infants. Methods Multi-centre, randomised, controlled, unmasked, parallel-group trial with planned 132 participants who have experienced premature birth between 23 weeks and 31 weeks and 6 days of gestation and plan to express milk for at least 14 days. The primary outcome is the highest 24-h expressed milk yield recorded on any of day 4, day 14 or day 21 after birth. Secondary outcomes include exclusive breastmilk feeding at 36 weeks post-menstrual age and at 4 months after the estimated date of delivery, Spielberger State Trait Anxiety Index at day 21 and Post-traumatic stress Check List (for DSM 5) at day 21. Discussion Breastmilk feeding for premature infants is an important research priority, but there are few randomised controlled trials assessing interventions to help parents reach lactation goals in this challenging context. This trial will assess whether a no cost, easily scalable relaxation tool has a role in this setting. Given the lack of harm and potential for immediate dissemination, even a small benefit could have an important global impact. Trial registration ISRCTN16356650. Date assigned: 19/04/2021.

Background Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. Objective We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. Design This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. Setting Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. Participants Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years. Interventions If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). Outcomes The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State–Trait Anxiety Inventory scores. Results A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos ( n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval –2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval –2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. Limitations We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. Conclusion When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. Trial registration This trial is registered as ISRCTN61225414. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

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

Background: More effective recruitment strategies like alternative approaches to consent are needed to facilitate adequately powered trials. Witholding Enteral feeds Around Transfusion was a multicentre, randomised, pilot trial that compared withholding and continuing feeds around transfusion. The primary clinical outcome was necrotising enterocolitis. The trial used simplified opt-out consent with concise parent information and no consent form. Objective: To explore the views and experiences of parents and health professionals on the acceptability and feasibility of opt-out consent in randomised comparative effectiveness trials. Methods: A qualitative, descriptive interview-based study nested within a randomised trial. Semistructured interview transcripts were analysed using inductive thematic analysis. Setting: Eleven neonatal units in England. Participants: Eleven parents and ten health professionals with experience of simplified consent. Results: Five themes emerged: 'opt-out consent operationalised as verbal opt-in consent', 'opt-out consent normalises participation while preserving parental choice', 'opt-out consent as an ongoing process of informed choice', 'consent without a consent form' and 'choosing to opt out of a comparative effectiveness trial', with two subthemes: 'wanting "normal care"' and 'a belief that feeding is better'. Conclusion: Introducing a novel form of consent proved challenging in practice. The principle of a simplified, opt-out approach to consent was generally considered feasible and acceptable by health professionals for a neonatal comparative effectiveness trial. The priority for parents was having the right to decide about trial participation, and they did not see opt-out consent as undermining this. Describing a study as 'opt-out' can help to normalise participation and emphasise that parents can withdraw consent.

Background: The E-Freeze trial is a multi-centre randomised controlled trial of fresh versus frozen embryo transfer for women undergoing in vitro fertilisation. This paper describes the statistical analysis plan for the E-Freeze trial. Methods and design: E-Freeze is a two-arm parallel-group, multi-centre, individually randomised controlled trial to determine if a policy of freezing embryos, followed by thawed frozen embryo transfer, results in a higher healthy baby rate when compared with the current policy of transferring fresh embryos. Couples undergoing their first, second or third cycle of in vitro fertilisation at fertility centres in the UK were randomised to either fresh or frozen embryo transfer. The primary outcome is a healthy baby, defined as a live singleton baby born at term with an appropriate weight for gestation. This paper describes the statistical analysis plan for the trial, including the analysis principles, definitions of outcomes, methods for primary analysis, pre-specified subgroup analysis and sensitivity analysis. This plan was finalised prior to completion of recruitment to the trial. Trial registration: ISRCTN registry: ISRCTN61225414 . Registered on 29 December 2015.

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