Publications by authors named "Nick Raine-Fenning"

67 Publications

Suboptimal mid-luteal progesterone concentrations are associated with aberrant endometrial gene expression, potentially resulting in implantation failure.

Reprod Biomed Online 2021 Mar 4;42(3):595-608. Epub 2020 Nov 4.

Division of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, Nottingham, UK. Electronic address:

Research Question: What is the difference in endometrial transcriptomics between women with normal and with low mid-luteal progesterone during the implantation window?

Design: An endometrial biopsy and serum progesterone concentration were taken from participants during the mid-luteal phase (LH+7 to LH+9). A total of 12 participants were recruited and categorized into two groups based on their progesterone concentrations: normal progesterone (>15 ng/ml, n = 6) and low progesterone (<15 ng/ml, n = 6). Global endometrial gene expression between the two groups was compared by microarray techniques. Principal component analysis was used to display the gene's expression pattern. Pathway and gene ontology enrichment analysis were performed to determine the biological mechanism of progesterone on the endometrium.

Results: Several key genes related to endometrial receptivity were found to be regulated by progesterone. With regard to gene ontology and pathway analysis, progesterone was shown to be mainly involved in structure morphogenesis predominantly during a process of decidualization, extracellular matrix-receptor interaction and cell adhesion. Distinct differences were observed in the transcriptomic profiles between the two groups, indicating potential impairment of endometrial receptivity in women with suboptimal progesterone concentrations. There was a relatively similar pattern of gene expression between endometrial samples with progesterone concentrations approximately 10 ng/ml and >15 ng/ml. Thus, a progesterone concentration of between 10 and 15 ng/ml appears to be sufficient to induce endometrial receptivity.

Conclusions: Abnormally low progesterone below the threshold of 10-15 ng/ml during the implantation window results in aberrant endometrial gene expression that may affect implantation potential.
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http://dx.doi.org/10.1016/j.rbmo.2020.10.018DOI Listing
March 2021

The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility.

J Clin Endocrinol Metab 2020 08;105(8)

Nottingham Clinical Trials Unit, University of Nottingham, School of Medicine, Nottingham Health Sciences Partners, Queens Medical Centre, Nottingham, UK.

Objective: To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception.

Design: Observational cohort study.

Setting: A total of 49 hospitals across the United Kingdom between 2011 and 2016.

Participants: Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy.

Methods: Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease.

Intervention: None.

Main Outcome Measure: Rates of thyroid dysfunction.

Results: Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9).

Conclusions: The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.
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http://dx.doi.org/10.1210/clinem/dgaa302DOI Listing
August 2020

Men, chronic illness and healthwork: accounts from male partners of women with endometriosis.

Sociol Health Illn 2020 09 26;42(7):1532-1547. Epub 2020 Jun 26.

School of Medicine, University of Nottingham, Nottingham, UK.

Currently dominant in medical discourse, the concept of self-management sees the responsibility for health and illness shift from the state to the individual. However, while this emphasis on individual responsibility and management has burgeoned, the role and status of partners and other family members in the management of chronic illness remains under-theorised. While self-management privileges individual responsibility for the management of chronic illness, the role of partners remains unclear. This paper utilises data from a study of heterosexual couples' experiences of living with the chronic gynaecological condition endometriosis to explore how male partners engage in its day-to-day management. In all, 22 couples participated in in-depth, semi-structured interviews with each partner interviewed separately (n = 44). Data were analysed thematically and dyadically, informed by an interpretivist relational approach. The paper utilises the concept of healthwork to describe the illness work, everyday life work, biographical work and emotion work men engaged in. The paper demonstrates how the conceptual value of healthwork is enhanced by incorporating an analysis of the emotional effort required in managing chronic illness. The paper illustrates the value of investigating the role of partners in managing chronic illness to provide a fuller account of the distributed and relational nature of healthwork.
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http://dx.doi.org/10.1111/1467-9566.13144DOI Listing
September 2020

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction.

Cochrane Database Syst Rev 2020 02 21;2:CD010167. Epub 2020 Feb 21.

SEMEAR Fertilidade, Reproductive Medicine, Av Aurea Apparecida Braghetto Machado, 220, Ribeirao Preto, Sao Paulo, Brazil, 14021-460.

Background: Subfertility is a condition found in up to 15% of couples of reproductive age. Gamete micromanipulation, such as intracytoplasmic sperm injection (ICSI), is very useful for treating couples with compromised sperm parameters. An alternative method of sperm selection has been described; the spermatozoa are selected under high magnification (over 6000x) and used for ICSI. This technique, named intracytoplasmic morphologically selected sperm injection (IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing assisted reproduction techniques (ART). However, our previous version of this Cochrane Review was unable to find evidence that supported this possible beneficial effect. This is an update of Teixeira 2013.

Objectives: To identify, appraise, and summarise the available evidence regarding efficacy and safety of IMSI compared to ICSI in couples undergoing ART.

Search Methods: We searched for randomised controlled trials (RCTs) in these electronic databases: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and in these trial registers: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We also handsearched the reference lists of included studies and similar reviews. We performed the last electronic search on 18 November 2019.

Selection Criteria: We only considered RCTs that compared ICSI and IMSI; we did not include quasi-randomised trials. We considered studies that permitted the inclusion of the same participant more than once (cross-over or per cycle trials) only if data regarding the first treatment of each participant were available.

Data Collection And Analysis: Two review authors independently performed study selection, data extraction, and assessment of the risk of bias and quality of the evidence; we solved disagreements by consulting a third review author. We corresponded with study investigators to resolve any queries, as required.

Main Results: The updated search retrieved 535 records; we included 13 parallel-designed RCTs comparing IMSI and ICSI (four studies were added since the previous version), comprising 2775 couples (IMSI = 1256; ICSI = 1519). We are uncertain if IMSI improves live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.89 to 1.39; 5 studies, 929 couples; I² = 1%), miscarriage rates per couple (RR 1.07, 95% CI 0.78 to 1.48; 10 studies, 2297 couples; I² = 0%, very-low quality evidence), and miscarriage rate per pregnancy (RR 0.90, 95% CI 0.68 to 1.20; 10 studies, 783 couples; I² = 0%, very-low quality evidence). We are uncertain if IMSI improves clinical pregnancy rates (RR 1.23, 95% CI 1.11 to 1.37; 13 studies, 2775 couples; I² = 47%, very-low quality evidence). None of the included studies reported congenital abnormalities. We judged the evidence for all outcomes to be of very low-quality. We downgraded the quality of the evidence due to limitations of the included studies (risk of bias), inconsistency of results, and a strong indication of publication bias.

Authors' Conclusions: The current evidence from randomised controlled trials does not support or refute the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (IMSI). We are very uncertain of the chances of having a live birth and of the risk of having a miscarriage. We found very low-quality evidence that IMSI may increase chances of a clinical pregnancy, which means that we are still very uncertain about any real difference. We did not find any trials reporting on the risk of congenital abnormalities. Well-designed and sufficiently powered trials are still required.
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http://dx.doi.org/10.1002/14651858.CD010167.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033651PMC
February 2020

Evaluation of progestogen supplementation for luteal phase support in fresh in vitro fertilization cycles.

Fertil Steril 2019 09 11;112(3):491-502.e3. Epub 2019 Jun 11.

School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom. Electronic address:

Objective: To evaluate the effectiveness of progestogen supplementation in improving clinical pregnancy rates in women undergoing fresh IVF cycles and to compare different routes, start times, durations, and estrogen coadministration regimen.

Design: Comprehensive systematic review and meta-analysis.

Setting: University.

Patient(s): Women undergoing fresh IVF cycles who did and did not receive progestogen supplementation.

Intervention(s): Summary odds ratios (ORs) were calculated by binomial logistic regression.

Main Outcome Measure(s): Clinical pregnancy rates.

Result(s): Eighty-two articles (26,726 women) were included. Clinical pregnancy rates were increased by IM (OR = 4.57), vaginal (OR = 3.34), SC (OR = 3.36), or oral (OR = 2.57) progestogen supplementation versus no treatment. The greatest benefit was observed when progestogens were supplemented IM versus vaginally (OR = 1.37). The optimal time to commence administration was between oocyte retrieval and ET (OR = 1.31), with oocyte retrieval +1 day being most beneficial. Coadministration of estrogen had no benefit (OR = 1.33), whether progestogens were coadministered vaginally or IM. Clinical pregnancy rates were equivalent when progestogen supplementation was ceased after ≤3 weeks or continued for up to 12 weeks (OR = 1.06).

Conclusion(s): This broad-ranging meta-analysis highlights the need to reevaluate current clinical practice. The use of progestogens in fresh IVF cycles is substantially beneficial to clinical pregnancy. Critically, the use of IM progestogens should not be dismissed, as it yielded the greatest clinical pregnancy rates. Pregnancy success was impacted by initiation of therapy, with 1 day after oocyte retrieval being optimal. There is little evidence to support coadministration of estrogen or prolonging progestogen treatment beyond 3 weeks.
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http://dx.doi.org/10.1016/j.fertnstert.2019.04.021DOI Listing
September 2019

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

Reprod Health 2019 Jun 13;16(1):81. Epub 2019 Jun 13.

Reproductive Health, Manchester, UK.

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.
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http://dx.doi.org/10.1186/s12978-019-0737-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567605PMC
June 2019

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

N Engl J Med 2019 04 23;380(14):1316-1325. Epub 2019 Mar 23.

From the Institute of Metabolism and Systems Research (R.K.D.-S., C.M., M.D.K., K. Boelaert, A.C.), Tommy's National Centre for Miscarriage Research (R.K.D.-S., A.C.), and the Birmingham Clinical Trials Unit, Institute of Applied Health Research (L.J.M., K.K.S., V.C., S.F.-C.), College of Medical and Dental Sciences, University of Birmingham, the Birmingham Women's and Children's NHS Foundation Trust (R.K.D.-S., L.R., M.D.K., A.C.), and University Hospital Birmingham (P.G., R.S.), Birmingham, the Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford (K. Baker), the Miscarriage Association, Wakefield (R.B.-A.), University Hospital Coventry, University Hospitals Coventry and Warwickshire NHS Trust, Coventry (R.A., T.G., S.Q.), Burnley General Teaching Hospital, East Lancashire Hospitals NHS Trust, Lancashire (K. Bhatia), St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester (E.E.-O.), University College Hospital, University College London Hospitals NHS Foundation Trust (D.J.), the Assisted Conception Unit, Guy's and St. Thomas' NHS Foundation Trust (Y.K.), St. Mary's Hospital, Imperial College Healthcare NHS Trust (R.R.), King's College Hospital NHS Foundation Trust (J.R.), and the Barts Research Centre for Women's Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London (A.T., S.T.), London, Ayrshire Maternity Unit, University Hospital Crosshouse, Kilmarnock (M.M.), Royal Bolton Hospital, Bolton NHS Foundation Trust, Bolton (K.M.), West Middlesex University Hospital, Chelsea and Westminster Hospital NHS Foundation Trust, Chelsea (N.N.), St. Michael's Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol (C.O.), Queens Medical Centre, Nottingham University Hospitals NHS Trust (N.R.-F.), and the Nottingham Clinical Trials Unit, University of Nottingham, School of Medicine, Nottingham Health Sciences Partners, Queen's Medical Centre (J.D.), Nottingham, and the Princess Royal Hospital, Shrewsbury and Telford Hospital NHS Trust, Shrewsbury (A.S., M.U.) - all in the United Kingdom; and the Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (S.Y.C.).

Background: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes.

Methods: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation.

Results: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14).

Conclusions: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).
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http://dx.doi.org/10.1056/NEJMoa1812537DOI Listing
April 2019

Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction.

Cochrane Database Syst Rev 2018 10 20;10:CD011537. Epub 2018 Oct 20.

Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK, B15 2TG.

Background: Most women undergoing assisted reproduction treatment will reach the stage of embryo transfer (ET), but the proportion of embryos that can be successfully implanted after ET has remained small since the mid-1990s. Human chorionic gonadotropin (hCG) is a hormone that is synthesised and released by the syncytiotrophoblast and has a fundamental role in embryo implantation and the early stages of pregnancy. Intrauterine administration of hCG via ET catheter during a mock procedure around the time of ET is a novel approach that has been suggested to improve the outcomes of assisted reproduction.

Objectives: To investigate whether intrauterine (intracavity) administration of hCG (IC-hCG) around the time of ET improves clinical outcomes in subfertile women undergoing assisted reproduction.

Search Methods: We performed searches on 9 January 2018 using Cochrane methods.

Selection Criteria: We looked for randomised controlled trials (RCTs) evaluating IC-hCG around the time of ET, irrespective of language and country of origin.

Data Collection And Analysis: Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact study authors when data were missing. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. Primary outcomes were live birth and miscarriage; secondary outcomes were clinical pregnancy rate and complications.

Main Results: Seventeen RCTs investigated the effects of IC-hCG administration for 4751 subfertile women undergoing assisted reproduction. IC-hCG was administered in variable doses at different times before the ET. hCG was obtained from the urine of pregnant women or from cell cultures using recombinant DNA technology.Most studies (12/17) were at high risk of bias in at least one of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations for evidence quality were high risk of bias and serious imprecision.For analyses of live birth and clinical pregnancy, there was considerable heterogeneity (I² > 75%) and therefore we present subgroups for dosage and stage of ET. Exploration for sources of heterogeneity revealed two key prespecified variables as important determinants: stage of ET (cleavage vs blastocyst stage) and dose of IC-hCG (< 500 international units (IU) vs ≥ 500 IU). We performed meta-analyses within subgroups defined by stage of embryo and dose of IC-hCG.Live birth rates among women having cleavage-stage ET with an IC-hCG dose < 500 IU compared to women having cleavage-stage ET without IC-hCG showed no benefit of the intervention and would be consistent with no substantive difference or disadvantage of indeterminate magnitude (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 1.01; one RCT; 280 participants; I² = 0%; very low-quality evidence). In a clinic with a live birth rate of 49% per cycle, use of IC-hCG < 500 IU would be associated with a live birth rate ranging from 28% to 50%.Results show an increase in live birth rate in the subgroup of women undergoing cleavage-stage ET with an IC-hCG dose ≥ 500 IU compared to women having cleavage-stage ET without IC-hCG (RR 1.57, 95% CI 1.32 to 1.87; three RCTs; 914 participants; I² = 0%; moderate-quality evidence). At a clinic with a live birth rate of 27% per cycle, use of IC-hCG ≥ 500 IU would be associated with a live birth rate ranging from 36% to 51%.Results show no substantive differences in live birth among women having blastocyst-stage ET with an IC-hCG dose ≥ 500 IU compared to women having blastocyst-stage ET without IC-hCG (RR 0.92, 95% CI 0.80 to 1.04; two RCTs; 1666 participants; I² = 0%; moderate-quality evidence). At a clinic with a live birth rate of 36% per cycle, use of IC-hCG ≥ 500 IU would be associated with a live birth rate ranging from 29% to 38%.Evidence for clinical pregnancy among women having cleavage-stage ET with an IC-hCG dose < 500 IU showed no benefit of the intervention and would be consistent with no substantive difference or disadvantage of indeterminate magnitude (RR 0.88, 95% CI 0.70 to 1.10; one RCT; 280 participants; I² = 0%; very low-quality evidence).Results show an increase in clinical pregnancy rate in the subgroup of women having cleavage-stage ET with an IC-hCG dose ≥ 500 IU compared to women having cleavage-stage ET without IC-hCG (RR 1.49, 95% CI 1.32 to 1.68; 12 RCTs; 2186 participants; I² = 18%; moderate-quality evidence).Results show no substantive differences in clinical pregnancy among women having blastocyst-stage ET with an IC-hCG dose ≥ 500 IU (RR 0.99, 95% CI 0.85 to 1.15; four RCTs; 2091 participants; I² = 42%; moderate-quality evidence) compared to women having blastocyst-stage ET with no IC-hCG.No RCTs investigated blastocyst-stage ET with an IC-hCG dose < 500 IU.We are uncertain whether miscarriage was influenced by intrauterine hCG administration (RR 1.04, 95% CI 0.81 to 1.35; 11 RCTs; 3927 participants; I² = 0%; very low-quality evidence).Reported complications were ectopic pregnancy (four RCTs; 1073 participants; four events overall), heterotopic pregnancy (one RCT; 495 participants; one event), intrauterine death (three RCTs; 1078 participants; 22 events), and triplets (one RCT; 48 participants; three events). Events were few, and very low-quality evidence was insufficient to permit conclusions to be drawn.

Authors' Conclusions: There is moderate quality evidence that women undergoing cleavage-stage transfer using an IC-hCG dose ≥ 500 IU have an improved live birth rate. There is insufficient evidence for IC-hCG treatment for blastocyst transfer. There should be further trials with live birth as the primary outcome to identify the groups of women who would benefit the most from this intervention. There was no evidence that miscarriage was reduced following IC-hCG administration, irrespective of embryo stage at transfer or dose of IC-hCG. Events were too few to allow conclusions to be drawn with regard to other complications.
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http://dx.doi.org/10.1002/14651858.CD011537.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517300PMC
October 2018

Conducting dyadic, relational research about endometriosis: A reflexive account of methods, ethics and data analysis.

Health (London) 2020 01 6;24(1):79-93. Epub 2018 Jul 6.

Nurture Fertility, East Midlands Fertility Centre, UK; University of Nottingham, UK.

Despite a growing literature on the value of relational data in studies of social phenomena, individuals still commonly constitute the basic unit of analysis in qualitative research. Methodological aspects of interviewing couples, particularly interviewing partners , and of conducting dyadic analysis have received scant attention. This article describes the experience of conducting separate interviews with both partners in 22 heterosexual couples (n = 44) in a study of the impact of the gynaecological condition endometriosis. In order to advance current methodological thinking regarding interviewing couples, we describe the dyadic, relational approach employed in designing the study and our specific method of dyadic analysis. We argue that utilising separate interviews with dyadic analysis rather than conducting joint interviews, while not without its ethical, practical and analytical challenges, offers considerable methodological benefits. Such an approach allows a unique relational insight into the impact of chronic illness on couples and how they navigate chronic illness by illuminating both shared and individual interpretations, experiences, understandings and meanings.
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http://dx.doi.org/10.1177/1363459318786539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873217PMC
January 2020

Serum concentrations of Ang-2 and Flt-1 may be predictive of pregnancy outcome in women with pregnancies of uncertain viability: a phase I exploratory prognostic factor study.

J Obstet Gynaecol 2018 Apr 26;38(3):321-326. Epub 2017 Oct 26.

a Division of Child Health, Obstetrics and Gynaecology , School of Medicine, University of Nottingham , Nottingham , UK.

The aim of this study was to determine whether serum concentrations of Ang-1, Ang-2, Flt-1, IL-15 and/or TRAIL can be used to predict outcome in women with pregnancies of uncertain viability (PUVs). Women presenting to the Early Pregnancy Unit at the Queen's Medical Centre in Nottingham between 17.06.14 and 01.09.15 were prospectively recruited. Serum concentrations of Ang-1, Ang-2, Flt-1, IL-15 and TRAIL were measured in women with PUVs. Women were followed-up according to departmental protocols until viability was determined. Biomarker concentrations were correlated with pregnancy outcome. Ninety-four PUVs were studied, of which 61 (64.9%) were subsequently proven to be viable. There were statistically significant (p < .01), linear (p-value <.01) associations between Ang-2 and Flt-1 concentrations and pregnancy viability such that women with lower concentrations were significantly more likely to have viable pregnancies than women with higher concentrations. In conclusion, Ang-2 and Flt-1 may be useful in predicting outcome in women with PUVs. Impact statement What is already known on this subject: Predicting outcome in women with pregnancies of uncertain viability (PUVs) is challenging. There is currently no accurate and reliable method. All PUVs need to be followed-up until a definitive diagnosis of either a viable or non-viable pregnancy can be made. This takes time, utilises limited resources and generates significant anxiety. Recent studies have demonstrated serum concentrations of Ang-1, Ang-2, Flt-1, IL-15 and TRAIL in viable pregnancies are significantly different to those in non-viable or ectopic pregnancies. What the results of this study add: The results from this prospective study of 94 women with PUVs suggest that serum concentrations of Ang-2 and Flt-1 may be able to predict pregnancy viability in cases of uncertainty. Women with PUVs and low concentrations of Ang-2 or Flt-1 are significantly more likely to have viable pregnancies than women with high concentrations. What the implications are of these findings for clinical practice and/or further research: Evidence from multiple studies is necessary to appreciate the discriminating ability of these prognostic factors. Rapid clinical adoption in the absence of such evidence may lead to wasted resources. If our findings are confirmed, however, these biomarkers, either alone or as part of a prognostic model, may be capable of accurately predicting pregnancy outcome in cases of uncertainty. This would reduce the strain on limited resources and alleviate anxiety for women.
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http://dx.doi.org/10.1080/01443615.2017.1353596DOI Listing
April 2018

Efficacy of Dehydroepiandrosterone (DHEA) to overcome the effect of ovarian ageing (DITTO): A proof of principle double blinded randomized placebo controlled trial.

Eur J Obstet Gynecol Reprod Biol 2017 Nov 8;218:39-48. Epub 2017 Sep 8.

Division of Obstetrics and Gynaecology, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, Nottinghamshire, NG7 2UH, United Kingdom; Derby Fertility Unit, Royal Derby Hospital, Derby, DE22 3NE, United Kingdom. Electronic address:

Objective: To evaluate the effect of DHEA supplementation on In-Vitro Fertilisation (IVF) outcome as assessed by ovarian response, oocyte developmental competence and live birth rates in women predicted to have poor ovarian reserve (OR). The feasibility of conducting a large trial is also assessed by evaluating the recruitment rates and compliance of the recruited participants with DHEA/placebo intake and follow-up rates.

Study Design: A single centre, double blinded, placebo controlled, randomized trial was performed over two years with 60 women undergoing in-vitro fertilisation (IVF). Subjects were randomized, based on a computer-generated pseudo-random code to receive either DHEA or placebo with both capsules having similar colour, size and appearance. 60 women with poor OR based on antral follicle count or anti-Mullerian hormone thresholds undergoing IVF were recruited. They were randomised to receive DHEA 75mg/day or placebo for at-least 12 weeks before starting ovarian stimulation. They had long protocol using hMG 300 IU/day. Data analysed by "intention to treat". Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups.

Results: The recruitment rate was 39% (60/154). A total of 52 participants (27 versus 25 in the study and placebo groups) were included in the final analysis after excluding eight. While the mean (standard deviation) DHEA levels were similar at recruitment (9.4 (5) versus 7.5 (2.4) ng/ml; P=0.1), the DHEA levels at pre-stimulation were higher in the study group than in the controls (16.3 (5.8) versus 11.1 (4.5) ng/ml; P<0.01). The number (median, range) of oocytes retrieved (4, 0-18 versus 4, 0-15 respectively; P=0.54) and live birth rates (7/27, 26% versus 8/25, 32% respectively; RR (95% CI): 0.74 (0.22-2.48) and mRNA expression of developmental biomarkers in granulosa and cumulus cells were similar between the groups.

Conclusion: Pre-treatment DHEA supplementation, albeit statistical power in this study is low, did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rates during IVF treatment with long protocol in women predicted to have poor OR.
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http://dx.doi.org/10.1016/j.ejogrb.2017.09.006DOI Listing
November 2017

Priorities for research in miscarriage: a priority setting partnership between people affected by miscarriage and professionals following the James Lind Alliance methodology.

BMJ Open 2017 Aug 23;7(8):e016571. Epub 2017 Aug 23.

The James Lind Alliance, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre, Southampton, UK.

Objectives: To identify and prioritise important research questions for miscarriage.

Design: A priority setting partnership using prospective surveys and consensus meetings following methods advocated by the James Lind Alliance.

Setting: UK.

Participants: Women and those affected by miscarriage working alongside healthcare professionals.

Results: In the initial survey, 1093 participants (932 women who have experienced miscarriage, 8 partners, 17 family members, friends or colleagues, 104 healthcare professionals and eight charitable organisations) submitted 3279 questions. A review of existing literature identified a further 64. Non-questions were removed, and the remaining questions were categorised and summarised into 58 questions. In an interim electronic survey, 2122 respondents chose their top 10 priorities from the 58 summary questions. The 25 highest ranked in the survey were prioritised at a final face-to-face workshop. In summary, the top 10 priorities were ranked as follows: research into preventative treatment, emotional aspects in general, investigation, relevance of pre-existing medical conditions, emotional support as a treatment, importance of lifestyle factors, importance of genetic and chromosomal causes, preconception tests, investigation after different numbers of miscarriage and male causal factors.

Conclusions: These results should be the focus of future miscarriage research. Presently, studies are being conducted to address the top priority; however, many other priorities, especially psychological and emotional support, are less well researched areas. We hope our results will encourage both researchers and funders to focus on these priorities.
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http://dx.doi.org/10.1136/bmjopen-2017-016571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629698PMC
August 2017

Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure.

Mol Hum Reprod 2017 07;23(7):478-487

KK Research Centre, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.

Study Question: Is implantation failure following ART associated with a perturbed decidual response in endometrial stromal cells (EnSCs)?

Summary Answer: Dynamic changes in the secretome of decidualizing EnSCs underpin the transition of a hostile to a supportive endometrial microenvironment for embryo implantation; perturbation in this transitional pathway prior to ART is associated with implantation failure.

What Is Known Already: Implantation is the rate-limiting step in ART, although the contribution of an aberrant endometrial microenvironment in IVF failure remains ill defined.

Study Design, Size, Duration: In vitro characterization of the temporal changes in the decidual response of primary EnSCs isolated prior to a successful or failed ART cycle. An analysis of embryo responses to secreted cues from undifferentiated and decidualizing EnSCs was performed. The primary clinical outcome of the study was a positive urinary pregnancy test 14 days after embryo transfer.

Participants/materials, Setting, Methods: Primary EnSCs were isolated from endometrial biopsies obtained prior to IVF treatment and cryopreserved. EnSCs from 10 pregnant and 10 non-pregnant patients were then thawed, expanded in culture, subjected to clonogenic assays, and decidualized for either 2 or 8 days. Transcript levels of decidual marker gene [prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1) and 11β-hydroxysteroid dehydrogenase (HSD11B1)] were analysed using real-time quantitative PCR and temporal secretome changes of 45 cytokines, chemokines and growth factors were measured by multiplex suspension bead immunoassay. The impact of the EnSC secretome on human blastocyst development was scored morphologically; and embryo secretions in response to EnSC cues analyzed by multiplex suspension bead immunoassay.

Main Results And The Role Of Chance: Clonogenicity and induction of decidual marker genes were comparable between EnSC cultures from pregnant and non-pregnant group groups (P > 0.05). Analysis of 23 secreted factors revealed that successful implantation was associated with co-ordinated secretome changes in decidualizing EnSCs, which were most pronounced on Day 2 of differentiation: 17 differentially secreted proteins on Day 2 of decidualization relative to undifferentiated (Day 0) EnSCs (P < 0.05); 11 differentially secreted proteins on Day 8 relative to Day 2 (P < 0.05); and eight differentially secreted proteins on Day 8 relative to Day 0 (P < 0.05). By contrast, failed implantation was associated with a disordered secretome response. Blastocyst development was compromised when cultured for 24 h in medium conditioned by undifferentiated EnSCs when compared to decidualizing EnSCs. Analysis of the embryo microdroplets revealed that human blastocysts mount a secretory cytokine response to soluble decidual factors produced during the early (Day 2) but not late phase (Day 8) of differentiation. The embryo responses to secreted factors from decidualizing EnSCs were comparable between the pregnant and non-pregnant group (P > 0.05).

Large Scale Data: Not applicable.

Limitations, Reasons For Caution: Although this study uses primary EnSCs and human embryos, caution is warranted when extrapolating the results to the in vivo situation because of the correlative nature of the study and limited sample size.

Wider Implications Of The Findings: Our finding raises the prospect that endometrial analysis prior to ART could minimize the risk of treatment failure.

Study Funding And Competing Interest(s): This work was supported by funds from the Biomedical Research Unit in Reproductive Health, a joint initiative of the University Hospitals Coventry & Warwickshire NHS Trust and Warwick Medical School, the University of Nottingham and Nurture Fertility, and the National Medical Research Council, Singapore (NMRC/BNIG14NOV023), the "Instituut voor Innovatie door Wetenschap en Technologie" (IWT, Flanders, Belgium), the "Fonds voor Wetenschappelijk Onderzoek" (FWO, Flanders, Belgium) and the "Wetenschappelijk Fonds Willy Gepts" (WFWG, UZ Brussel). The authors have declared that no conflict of interest exists.
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http://dx.doi.org/10.1093/molehr/gax023DOI Listing
July 2017

Temporal validation of a simplified blastocyst grading system.

Hum Fertil (Camb) 2017 Jun 28;20(2):113-119. Epub 2016 Nov 28.

a Nurture Fertility , The East Midlands Fertility Clinic , Nottingham , UK.

We have recently established the clinical effectiveness and credibility of a simplified blastocyst grading system by demonstrating its prognostic potential and the inter- and intra-observer variability associated with it. To be considered clinically useful, however, the grading system also needs to be accurate (i.e. well calibrated with good discriminative ability). This study prospectively evaluates the performance of the grading system on subsequent patients from the same IVF unit in an attempt to temporally validate the model. All day 5 single embryo transfers between 1st July 2012 and 30th June 2014 were included in the study. The observed implantation, clinical pregnancy and live birth rates according to grade of embryo transferred were compared to the expected rates as predicted by the development data set and the statistical significance of any differences between the two were calculated using the Chi-square test. A total of 435 single embryo transfers were included. For each grade of embryo transferred, there was generally no significant difference between the observed and expected frequencies of implantation, clinical pregnancy and live birth suggesting that the simplified blastocyst grading system is accurate and temporal validation has been satisfactorily demonstrated. It is now necessary to externally validate the grading system to prove generality before further dissemination.
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http://dx.doi.org/10.1080/14647273.2016.1255355DOI Listing
June 2017

Relationship between hair and salivary cortisol and pregnancy in women undergoing IVF.

Psychoneuroendocrinology 2016 12 31;74:397-405. Epub 2016 Aug 31.

Division of Primary Care, School of Medicine, University of Nottingham, UK. Electronic address:

Evidence for an association between cortisol and clinical pregnancy in women undergoing In Vitro Fertilisation (IVF) is mixed with previous studies relying exclusively on short term measures of cortisol in blood, saliva, urine, and/or follicular fluid. Hair sampling allows analysis of systemic levels of cortisol over the preceding 3-6 months. The present study sought to explore the relationship between cortisol and clinical pregnancy outcome in women undergoing IVF utilising multiple indices of cortisol derived from both saliva and hair measured prior to commencing gonadotrophin treatment. A total of 135 women (mean age 34.5 SD+/-4.8) were recruited from an English fertility clinic (December 2012-April 2014) 60% of whom became pregnant (n=81). Salivary cortisol data were obtained over two days: upon awakening, 30min post awakening, and at 22:00. A subsample (n=88) of the women providing salivary samples were approached consecutively to provide hair samples for the measurement of cortisol. Independent Logistic regression analyses revealed that salivary cortisol measures including cortisol awakening response (CAR) (p=0.485), area under the curve with respect to ground (AUCg) (p=0.527), area under the curve with respect to increase (AUCi) (p=0.731) and diurnal slope (p=0.889) did not predict clinical pregnancy. In contrast, hair cortisol concentrations significantly predicted clinical pregnancy (p=0.017). Associations between hair cortisol and clinical pregnancy remained when controlling for accumulations of salivary cortisol (p=0.034) accounting for 26.7% of the variance in pregnancy outcome. These findings provide preliminary evidence that longer term systemic cortisol may influence reproductive outcomes; and in turn suggests that interventions to reduce cortisol prior to commencing IVF could improve treatment outcomes.
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http://dx.doi.org/10.1016/j.psyneuen.2016.08.027DOI Listing
December 2016

Blastocyst culture using single versus sequential media in clinical IVF: a systematic review and meta-analysis of randomized controlled trials.

J Assist Reprod Genet 2016 Oct 5;33(10):1261-1272. Epub 2016 Aug 5.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, 02115, MA, USA.

Purpose: The purpose of this study was to undertake a review of the available evidence comparing the use of a single medium versus sequential media for embryo culture to the blastocyst stage in clinical IVF.

Methods: We searched the Cochrane Central, PubMed, Scopus, ClinicalTrials.gov, Current Controlled Trials and WHO International Clinical Trials Registry Platform to identify randomized controlled trials comparing single versus sequential media for blastocyst culture and ongoing pregnancy rate. Included studies randomized either oocytes/zygotes or women. Eligible oocyte/zygote studies were analyzed to assess the risk difference (RD) and 95 % confidence intervals (CI) between the two media systems; eligible woman-based studies were analyzed to assess the risk ratio (RR) and 95 % CI for clinical pregnancy rate.

Results: No differences were observed between single and sequential media for either ongoing pregnancy per randomized woman (relative risk (RR) = 0.9, 95 % CI = 0.7 to 1.3, two studies including 246 women, I  = 0 %) or clinical pregnancy per randomized woman (RR = 1.0, 95 % CI = 0.7 to 1.4, one study including 100 women); or miscarriage per clinical pregnancy: RR = 1.3, 95 % CI = 0.4 to 4.3, two studies including 246 participants, I  = 0 %). Single media use was associated with an increase blastocyst formation per randomized oocyte/zygote (relative distribution (RD) = +0.06, 95 % CI = +0.01 to +0.12, ten studies including 7455 oocytes/zygotes, I  = 83 %) but not top/high blastocyst formation (RD = +0.05, 95 % CI = -0.01 to +0.11, five studies including 3879 oocytes/zygotes, I  = 93 %). The overall quality of the evidence was very low for all these four outcomes.

Conclusions: Although using a single medium for extended culture has some practical advantages and blastocyst formation rates appear to be higher, there is insufficient evidence to recommend either sequential or single-step media as being superior for the culture of embryos to days 5/6. Future studies comparing these two media systems in well-designed trials should be performed.
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http://dx.doi.org/10.1007/s10815-016-0774-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065552PMC
October 2016

Endometrial spatio-temporal image correlation (STIC) and prediction of outcome following assisted reproductive treatment.

Eur J Obstet Gynecol Reprod Biol 2016 Aug 29;203:320-5. Epub 2016 Jun 29.

School of Medicine, University of Nottingham, Nottingham, United Kingdom; Nurture Fertility, The East Midlands Fertility Centre, The Fertility Partnership, United Kingdom. Electronic address:

Objective: The aim of this study was to correlate manual and spherical endometrial spatio-temporal image correlation (STIC) vascularity indices with assisted reproductive treatment (ART) outcomes.

Study Design: STIC ultrasound assessments of the endometrium were carried out at three time-points in 127 women in a prospective observational study.

Results: Biochemical pregnancy rate was 69% (88/127), with a biochemical and clinical pregnancy loss of 17%. Endometrial STIC vascularity indices in the assessed time-points did not differ between subjects who achieved a clinical pregnancy and those who did not (P>0.05). For first trimester miscarriage, minimal manual vascularization index (VI) at oocyte collection (cut-off value ≥0.7; sensitivity 80.0% and specificity 68.1%) demonstrated the highest area under the curve (AUC) of 0.8.

Conclusion: In summary, STIC modality is not a useful tool to predict ART outcome, however manual STIC analysis of endometrial vascularity seems to be more accurate in predicting first trimester pregnancy loss.
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http://dx.doi.org/10.1016/j.ejogrb.2016.06.015DOI Listing
August 2016

Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction.

Cochrane Database Syst Rev 2016 May 20(5):CD011537. Epub 2016 May 20.

Obstetrics and Gynaecology, Newcastle University, Newcastle upon Tyne, UK, NE1 7RU.

Background: Subfertility affects 15% of couples and represents the inability to conceive naturally following 12 months of regular unprotected sexual intercourse. Assisted reproduction refers to procedures involving the in vitro handling of both human gametes and represents a key option for many subfertile couples. Most women undergoing assisted reproduction treatment will reach the stage of embryo transfer (ET) but the proportion of embryos that successfully implant following ET has remained small since the mid-1990s. Human chorionic gonadotropin (hCG) is a hormone synthesised and released by the syncytiotrophoblast and has a fundamental role in embryo implantation and the early stages of pregnancy. Intrauterine administration of synthetic or natural hCG via an ET catheter during a mock procedure around the time of ET is a novel approach that has recently been suggested to improve the outcomes of assisted reproduction.

Objectives: To investigate whether the intrauterine administration of hCG around the time of ET improves the clinical outcomes in subfertile women undergoing assisted reproduction.

Search Methods: We performed a comprehensive literature search of the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, registers of ongoing trials andreference lists of all included studies and relevant reviews (from inception to 10 November 2015), in consultation with the Cochrane Gynaecology and Fertility Group Trials Search Co-ordinator.

Selection Criteria: We included all randomised controlled trials (RCTs) evaluating intrauterine administration of hCG around the time of ET in this review irrespective of language and country of origin.

Data Collection And Analysis: Two authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We performed statistical analysis using Review Manager 5 in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We assessed evidence quality using GRADE methods.

Main Results: Twelve RCTs investigated the effect of intrauterine administration of hCG for 4038 subfertile women undergoing assisted reproduction. The intra-cavity hCG (IC-hCG) was administered in variable doses at different timings before the ET. The source of hCG was from the urine of pregnant women or from cell cultures using recombinant DNA technology.Most of the studies (9/12) were at high risk of bias in at least one of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.For the analyses of live birth and clinical pregnancy, there was considerable heterogeneity (I(2) greater than 75%) and we did not undertake a meta-analysis. Exploration for the sources of heterogeneity identified two key pre-specified variables as important determinants: stage of ET (cleavage versus blastocyst stage) and dose of IC-hCG (less than 500 international units (IU) versus 500 IU or greater). We then performed meta-analysis for these analyses within the subgroups defined by stage of embryo and dose of IC-hCG.There was an increase in live birth rate in the subgroup of women having cleavage-stage ETs with an IC-hCG dose of 500 IU or greater compared to women having cleavage-stage ETs with no IC-hCG (risk ratio (RR) 1.57, 95% confidence interval (CI) 1.32 to 1.87, three RCTs, n = 914, I(2) = 0%, moderate quality evidence). In a clinic with a live birth rate of 25% per cycle then the use of IC-hCG -500 IU or greater would be associated with a live birth rate that varies from 33% to 46%. We did not observe a significant effect on live birth in any of the other subgroups.The was an increase in clinical pregnancy rate in the subgroup of women having cleavage-stage ETs with an IC-hCG dose of 500 IU or greater compared to women having cleavage-stage ETs with no IC-hCG (RR 1.41, 95% CI 1.25 to 1.58, seven RCTs, n = 1414, I(2) = 0%, moderate quality evidence). We did not observe a significant effect on clinical pregnancy in either of the other subgroups.There was no evidence that miscarriage was influenced by intrauterine hCG administration (RR 1.09, 95% CI 0.83 to 1.43, seven RCTs, n = 3395, I(2) = 0%, very low quality evidence).Other complications reported in the included studies were ectopic pregnancy (three RCTs, n = 915, three events overall), heterotopic pregnancy (one RCT, n = 495, one event), intrauterine death (two RCTs, n = 978, 21 events) and triplets (one RCT, n = 48, three events). There was no evidence of a difference between the groups, but there were too few events to allow any conclusions to be drawn and the evidence was very low quality.

Authors' Conclusions: The pregnancy outcome for cleavage-stage ETs using an IC-hCG dose of 500 IU or greater is promising. However, given the small size and the variable quality of the trials and the fact that the positive finding was from a subgroup analysis, the current evidence for IC-hCG treatment does not support its use in assisted reproduction cycles. A definitive large clinical trial with live birth as the primary outcome is recommended. There was no evidence that miscarriage was influenced by intrauterine hCG administration, irrespective of embryo stage at transfer or dose of IC-hCG. There were too few events to allow any conclusions to be drawn with regard to other complications.
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http://dx.doi.org/10.1002/14651858.CD011537.pub2DOI Listing
May 2016

'We needed to change the mission statement of the marriage': biographical disruptions, appraisals and revisions among couples living with endometriosis.

Sociol Health Illn 2016 06 17;38(5):721-35. Epub 2015 Dec 17.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, UK.

The concept of biographical disruption has been widely applied in sociological explorations of chronic illness and has been subject to much theoretical scrutiny, reflection and development. However, little attention has been given to the impact of biographical disruption beyond the individual level. This article explores the concept from a dyadic perspective, utilising data from an exploratory, qualitative study (ENDOPART) that investigated the impact of endometriosis on women and their male partners. In total, 22 couples participated in in-depth, semi-structured, face-to-face interviews. The women and their partners were interviewed separately and, in most cases, simultaneously, by different interviewers. Data analysis was informed by an interpretivist relational approach, foregrounding the meanings participants applied to their experiences, treating interviews as accounts, and exploring partners' accounts in relation to one another. Two analytic approaches generated several themes for exploration in the context of the concept of biographical disruption: sex and intimacy; planning for and having children; working lives and social lives. The article argues that biographical disruptions are social and inter-relational processes and discusses how couples living with endometriosis negotiated these disruptions, how they were appraised and how lives and expectations were revised as a result.
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http://dx.doi.org/10.1111/1467-9566.12392DOI Listing
June 2016

A clinically useful simplified blastocyst grading system.

Reprod Biomed Online 2015 Oct 8;31(4):523-30. Epub 2015 Jul 8.

Nurture Fertility, The East Midlands Fertility Clinic, Nottingham NG10 5QG, UK; Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK.

The aim of this study was to investigate whether a new simplified blastocyst grading system (A: fully expanded, clear inner cell mass, cohesive trophectoderm; B: not yet expanded, clear inner cell mass, cohesive trophectoderm; C: small inner cell mass ± irregular trophectoderm ± excluded/degenerate cells) was clinically useful. All day-5 single embryo transfers between 15 June 2009 and 29 June 2012 were reviewed. Implantation, clinical pregnancy and live birth rates were related to embryo quality. Five embryologists were asked to grade and decide the clinical fate of 80 images of day-5 embryos on two occasions 4-6 weeks apart. Implantation, clinical pregnancy and live birth rates decreased with deteriorating embryo quality. A highly significant (P < 0.01) difference was observed between the groups. Inter-observer agreement was substantial for grade allocation (K = 0.63) and clinical decision-making (K = 0.66). Intra-observer agreement ranged from substantial (K = 0.71) to almost perfect (K = 0.88) for grade allocation, and was almost perfect for clinical fate determination (K ≥ 0.84). This grading system is quick and easy to use, effectively predicts IVF outcome and has levels of agreement similar to, if not better than, those associated with more complex grading systems.
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http://dx.doi.org/10.1016/j.rbmo.2015.06.017DOI Listing
October 2015

4-D Assessment of Endometrial Vascularity Using Spatiotemporal Image Correlation: A Study Comparing Spherical Sampling and Whole-Tissue Analysis.

Ultrasound Med Biol 2015 Nov 14;41(11):2798-805. Epub 2015 Aug 14.

Nurture Fertility, East Midlands Fertility Clinic, Nottingham, UK. Electronic address:

Our aim in the study described here was to assess the feasibility of spatiotemporal image correlation power Doppler quantification of the endometrium with two techniques: spherical samples and whole tissue. We scanned 51 women in the midluteal phase of the menstrual cycle: STIC assessment of the whole endometrium was not possible in 10% of cases, whereas spherical analysis was possible in all. The time taken for data set analysis was much longer for the whole endometrium compared with spherical analysis (1478.9 ± 291 s vs. 266.8 ± 39.3 s, p < 0.05). Intra-class correlation coefficients for the vascularization flow index (VFI) were similar for both methods. Volumetric vascularity indices were higher when spherical sampling was conducted. Significant cycle-to-cycle variability in the vascularity indices was present, with coefficients of variation exceeding 20% for both techniques. We found that STIC power Doppler quantification of the whole endometrium is possible in the majority of cases, however, it is time consuming and limited by significant cycle-to-cycle variability.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2015.06.002DOI Listing
November 2015

Artificial oocyte activation to improve reproductive outcomes in women with previous fertilization failure: a systematic review and meta-analysis of RCTs.

Hum Reprod 2015 Aug 16;30(8):1831-41. Epub 2015 Jun 16.

Ribeirao Preto Medical School, University of Sao Paulo (FMRP-USP), Ribeirao Preto, Brazil

Study Question: In couples with previous fertilization failure, are reproductive outcomes improved using ICSI followed by artificial oocyte activation (ICSI-AOA) compared with conventional ICSI?

Summary Answer: There is insufficient evidence available from RCTs to judge the efficacy and safety of ICSI-AOA for couples with previous fertilization failure.

What Is Known Already: In cases with previous low fertilization rates or total fertilization failure using ICSI due to sperm-related, oocyte activation deficiency, several methods of AOA have been described, which employ mechanical, electrical or chemical stimuli. Reported fertilization and pregnancy rates appear to be improved after ICSI-AOA compared with conventional ICSI; however, the small studies performed to date make it difficult to assess the clinical efficacy or safety of AOA.

Study Design, Size, And Duration: The present systematic review and meta-analysis identified RCTs that compared ICSI-AOA and conventional ICSI. The last electronic search was conducted in August 2014 and there was no limitation regarding language, publication date, or publication status. We included studies that randomized either oocytes or women and included them in two different parts of this review: a women-based review and an oocyte-based review. For the women-based review, the primary outcome of effectiveness was live birth per randomized woman and the primary outcome for safety was congenital anomalies per clinical pregnancy. For the oocyte-based review, the primary outcome was embryo formation per oocyte randomized.

Participants/materials, Setting, And Methods: Record screening and data extraction were performed independently by two authors and risk of bias was assessed by three authors. The effects of ICSI-AOA compared with conventional ICSI were summarized as risk ratio (RR) and the precision of the estimates was evaluated by the 95% confidence interval (CI).

Main Results And The Role Of Chance: A total of 14 articles were assessed for eligibility and 9 included in the meta-analysis: 2 studies comprised the woman-based review (n = 168 women) and 7 studies the oocyte-based review (n = 4234 oocytes). Only four studies evaluated AOA due to fertilization failure after conventional ICSI: these were included in the quantitative analysis. In two studies evaluating couples with a history of fertilization failure in a previous cycle, ICSI-AOA was associated with an increase in the proportion of cleavage stage embryos (RR 5.44, 95% CI 2.98-9.91) and top/high quality cleavage stage embryos (RR 10.02, 95% CI 2.45-40.95). There was no evidence of effect on fertilization rate (RR 2.97, 95% CI 0.84-10.48). In the two studies that evaluated ICSI-AOA as a rescue method for unfertilized oocytes after conventional ICSI, ICSI-AOA was associated with an increase in fertilization (RR 8.26, 95% CI 1.28-53.32, P = 0.03) and cleavage rates (RR 8.65, 95% CI 2.28-32.77) although there was no significant effect on the likelihood of blastocyst formation (RR 1.97, 95% CI 0.11-34.99). The remaining five studies evaluated ICSI-AOA for reasons other than fertilization failure and were excluded.

Limitations And Reasons For Caution: The majority of the studies were not considered to be similar enough for meta-analysis due to different AOA methods and patient inclusion criteria, thus limiting the possibility of pooling studies and achieving a more robust conclusion. Only two studies examined ICSI-AOA in couples with previous fertilization failure, and only one of these included couples with proven male-related, oocyte activation deficiency, which is the primary indication for AOA. The resulting evidence was considered to be of very low quality and should be interpreted with caution.

Wider Implications Of The Findings: There is insufficient evidence available from the currently available RCTs to judge the efficacy or safety of ICSI-AOA on key reproductive outcomes in couples with previous fertilization failure. Such interventions should be further examined by well-designed RCTs before the introduction of ICSI-AOA as a standard treatment.

Study Funding/competing Interests: No funding was obtained. No competing interests to declare.

Registration Number: PROSPERO CRD42014007445.
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http://dx.doi.org/10.1093/humrep/dev136DOI Listing
August 2015

Lipidomic analysis of plasma samples from women with polycystic ovary syndrome.

Metabolomics 2015;11(3):657-666. Epub 2014 Aug 17.

School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH UK.

Polycystic ovary syndrome (PCOS) is a common disorder affecting between 5 and 18 % of females of reproductive age and can be diagnosed based on a combination of clinical, ultrasound and biochemical features, none of which on its own is diagnostic. A lipidomic approach using liquid chromatography coupled with accurate mass high-resolution mass-spectrometry (LC-HRMS) was used to investigate if there were any differences in plasma lipidomic profiles in women with PCOS compared with control women at different stages of menstrual cycle. Plasma samples from 40 women with PCOS and 40 controls aged between 18 and 40 years were analysed in combination with multivariate statistical analyses. Multivariate data analysis (LASSO regression and OPLS-DA) of the sample lipidomics datasets showed a weak prediction model for PCOS versus control samples from the follicular and mid-cycle phases of the menstrual cycle, but a stronger model (specificity 85 % and sensitivity 95 %) for PCOS versus the luteal phase menstrual cycle controls. The PCOS vs luteal phase model showed increased levels of plasma triglycerides and sphingomyelins and decreased levels of lysophosphatidylcholines and phosphatidylethanolamines in PCOS women compared with controls. Lipid biomarkers of PCOS were tentatively identified which may be useful in distinguishing PCOS from controls especially when performed during the menstrual cycle luteal phase.
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http://dx.doi.org/10.1007/s11306-014-0726-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419155PMC
August 2014

Endometrial injury in women undergoing assisted reproductive techniques.

Cochrane Database Syst Rev 2015 Mar 22(3):CD009517. Epub 2015 Mar 22.

Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clinicas da FMRP-USP, 8 andar, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, Brazil, 14048-900.

Background: Implantation of an embryo within the endometrial cavity is a critical step in assisted reproductive techniques (ART). Previous research has suggested that endometrial injury - intentional damage to the endometrium - can increase the probability of pregnancy in women undergoing ART.

Objectives: To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing ART.

Search Methods: We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American Caribbean Health Sciences Literature (LILACS) and ClinicalTrials.gov. The original search was performed in November 2011, and further searches were done in March 2014 and January 2015.

Selection Criteria: Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing ART, versus no intervention or a sham procedure.

Data Collection And Analysis: Two independent review authors screened studies and extracted data which were checked by a third review author. Two review authors independently assessed risk of bias. We contacted and corresponded with study investigators as required and analysed data using risk ratio (RR) and a random-effects model. We assessed the quality of the evidence by using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria.

Main Results: We included 14 trials that included 1063 women in the intervention groups and 1065 women in the control groups. Thirteen studies compared endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle versus no injury, and one study compared endometrial injury on the day of oocyte retrieval versus no injury. Overall, eight of the 14 included studies were deemed to be at high risk of bias in at least one domain.In studies comparing endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle versus no intervention or a sham procedure, endometrial injury was associated with an increase in live birth or ongoing pregnancy rate: RR 1.42, 95% confidence interval (CI) 1.08 to 1.85; P value 0.01; nine RCTs; 1496 women; I² = 53%; moderate-quality evidence. In other words, moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with endometrial injury. A sensitivity analysis removing the studies at high risk of bias showed no difference in effect.There was no evidence of an effect on miscarriage, however the evidence is of low-quality: RR 0.99, 95% CI 0.63 to 1.53; P value 0.06; eight RCTs; 500 clinical pregnancies; I² = 10%; low-quality evidence.Endometrial injury was also associated with an increased clinical pregnancy rate: RR 1.34, 95% CI 1.21 to 1.61; P value 0.002; 13 RCTs; 1972 women; I² = 45%; moderate-quality evidence. This suggests that if 30% of women achieve clinical pregnancy without endometrial injury, between 33% and 48% will achieve clinical pregnancy with this intervention.Endometrial injury was associated with increased pain, however the evidence was of very low quality. One study reported pain on a VAS scale: MD 4.60, 95% CI 3.98 to 5.22; P value < 0.00001; one RCT; 158 women. Two studies reported the number of pain complaints after the procedure; one recorded no events in either group, and the other reported that endometrial injury increased pain complaints: OR 8.65, 95% CI 2.49 to 30.10; P value 0.0007; one RCT; 101 women.Results from the only randomised controlled trial (RCT) comparing endometrial injury on the day of oocyte retrieval versus no injury, reported that this endometrial injury markedly decreased live birth (RR 0.31, 95% CI 0.14 to 0.69; P value 0.004; 156 women; low-quality evidence) and clinical pregnancy (RR 0.36, 95% CI 0.18 to 0.71; P value 0.003; one RCT; 156 women; low-quality evidence).

Authors' Conclusions: Moderate-quality evidence indicates that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle is associated with an improvement in live birth and clinical pregnancy rates in women with more than two previous embryo transfers. There is no evidence of an effect on miscarriage, multiple pregnancy or bleeding. The procedure is mildly painful. Endometrial injury on the day of oocyte retrieval is associated with a reduction of clinical and ongoing pregnancy rates.Although current evidence suggests some benefit of endometrial injury, we need evidence from well-designed trials that avoid instrumentation of the uterus in the preceding three months, do not cause endometrial damage in the control group, stratify the results for women with and without recurrent implantation failure (RIF) and report live birth.
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March 2015

Endometrial injury and reproductive outcomes: there's more to this story than meets the horse's blind eye.

Hum Reprod 2015 Mar 20;30(3):749. Epub 2015 Jan 20.

Department of Obstetrics and Gynecology, Ribeirao Preto Medical School, University of Sao Paulo (FMRP-USP), Ribeirao Preto, Brazil

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http://dx.doi.org/10.1093/humrep/deu365DOI Listing
March 2015

Endometrial scratching for women with repeated implantation failure.

Hum Reprod 2014 Dec 14;29(12):2855-6. Epub 2014 Oct 14.

Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo (DGO-FMRP-USP), Ribeirao Preto, Brazil

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http://dx.doi.org/10.1093/humrep/deu257DOI Listing
December 2014