[Show abstract][Hide abstract] ABSTRACT: Infertility is defined as failure to conceive after 1 year of unprotected intercourse. This dichotomization into fertile versus infertile, based on lack of conception over 12-month period, is fundamentally flawed. Time to conception is strongly influenced by factors such as female age and whilst a minority of couples have absolute infertility (sterility), many are able to conceive without intervention but may take longer to do so, reflecting the degree of subfertility. This natural variability in time to conception means that subfertility reflects a prognosis rather than a diagnosis. Current clinical prediction models in fertility only provide individualized estimates of the probability of either treatment-independent pregnancy or treatment-dependent pregnancy, but do not take account of both. Together, prognostic factors which are able to predict natural pregnancy and predictive factors of response to treatment would be required to estimate the absolute increase in pregnancy chances with treatment. This stratified medicine approach would be appropriate for facilitating personalized decision-making concerning whether or not to treat subfertile patients. Published models are thus far of little value for decisions regarding when to initiate treatment in patients who undergo a period of, ultimately unsuccessful, expectant management. We submit that a dynamic prediction approach, which estimates the change in subfertility prognosis over the course of follow-up, would be ideally suited to inform when the commencement of treatment would be most beneficial in those undergoing expectant management. Further research needs to be undertaken to identify treatment predictive factors and to identify or create databases to allow these approaches to be explored. In the interim, the most feasible approach is to use a combination of previously published clinical prediction models.
Human Reproduction 07/2014; 29(9). DOI:10.1093/humrep/deu173 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND
At present, it is unclear which treatment strategy is best for couples with unexplained or mild male subfertility. We hypothesized that the prognostic profile influences the effectiveness of assisted conception. We addressed this issue by analysing individual patient data (IPD) from randomized controlled trials (RCTs).METHODS
We performed an IPD analysis of published RCTs on treatment strategies for subfertile couples. Eligible studies were identified from Cochrane systematic reviews and we also searched Medline and EMBASE. The authors of RCTs that compared expectant management (EM), intracervical insemination (ICI), intrauterine insemination (IUI), all three with or without controlled ovarian stimulation (COS) and IVF in couples with unexplained or male subfertility, and had reported live birth or ongoing pregnancy as an outcome measure, were invited to share their data. For each individual patient the chance of natural conception was calculated with a validated prognostic model. We constructed prognosis-by-treatment curves and tested whether there was a significant interaction between treatment and prognosis.RESULTSWe acquired data from 8 RCTs, including 2550 couples. In three studies (n = 954) the more invasive treatment strategies tended to be less effective in couples with a high chance of natural conception but this difference did not reach statistical significance (P-value for interaction between prognosis and treatment outcome were 0.71, 0.31 and 0.19). In one study (n = 932 couples) the strategies with COS (ICI and IUI) led to higher pregnancy rates than unstimulated strategies (ICI 8% versus 15%, IUI 13% versus 22%), regardless of prognosis (P-value for interaction in all comparisons >0.5), but at the expense of a high twin rate in the COS strategies (ICI 6% versus 23% and IUI 3% versus 30%, respectively). In two studies (n = 373 couples), the more invasive treatment strategies tended to be more effective in couples with a good prognosis but this difference did not reach statistical significance (P-value for interaction: 0.38 and 0.68). In one study (n = 253 couples) the differential effect of prognosis on treatment effect was limited (P-value for interaction 0.52), perhaps because prognosis was incorporated in the inclusion criteria. The only study that compared EM with IVF included 38 couples, too small for a precise estimate.CONCLUSIONS
In this IPD analysis of couples with unexplained or male subfertility, we did not find a large differential effect of prognosis on the effectiveness of fertility treatment with IUI, COS or IVF.
Human Reproduction Update 10/2013; 20(1). DOI:10.1093/humupd/dmt035 · 8.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To explore the association between birthweight and ovulatory dysfunction in adulthood. DesignCase-control study. SettingNortheast of Scotland University Hospital, hosting the regional fertility centre and maternity unit. PopulationA total of 18846 mother-daughter record pairs from the Aberdeen Fertility Centre Data Set and the Aberdeen Maternity and Neonatal Databank (AMND). Cases were the daughters with ovulatory dysfunction attending the Aberdeen Fertility Centre between 1992 and 2007, Control group 1 included the daughters attending the fertility centre with confirmed ovulation, and Control group 2 included all women naturally fertile who gave birth in Aberdeen during the same period. Methods
The electronic maternity records of the mothers of women in the three groups were retrieved from AMND and compared. Main outcome measuresDaughters' birthweight and standardised birthweight, characteristics of mothers and daughters at delivery and current daughters' characteristics. ResultsCases, Control group 1 and Control group 2 included 466, 548 and 17832 daughters, respectively. The mean birthweight (standard deviation) in grams was comparable between Cases 3203 (522), Control group 1, 3235 (482) P=0.30, and Control group 2, 3226 (495) P=0.31. The proportions of daughters born small for gestational age, large for gestational age, or preterm were comparable between the Cases group and each Control group, as was the mode of delivery and Apgar scores at 1 and 5minutes. The age at delivery, body mass index, social class or pregnancy complications were comparable in the mothers of the Cases and each Control group. Conclusions
Ovulatory dysfunction does not appear to be related to birthweight or perinatal events.
BJOG An International Journal of Obstetrics & Gynaecology 05/2013; 121(3). DOI:10.1111/1471-0528.12262 · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conventionally, most in vitro fertilization (IVF) embryos are transferred in fresh treatment cycles with freezing reserved for spare ones. Improvement in cryopreservation facilities over time has encouraged the greater use of this technology with the success rate of frozen replacement cycles approaching that associated with fresh embryo transfer. Data from observational studies suggest that obstetric and perinatal outcomes are better in pregnancies resulting from frozen replacement cycles. In the interests of promoting feto-maternal safety is it therefore time to avoid fresh embryo transfers in IVF, freeze all available embryos and replace them in subsequent cycles? In this article we explore the biological plausibility of this concept, appraise the evidence underpinning it and consider the implications of adopting such a strategy in routine clinical practice. The outcomes of existing randomized trials appear to favour a strategy of frozen embryo transfer, but larger trials are needed before a major change in clinical practice can be considered.
Human Reproduction 11/2012; 28(1). DOI:10.1093/humrep/des386 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To increase our understanding of factors underlying the decision to store gametes after the diagnosis of cancer.
Qualitative interview study.
Andrology, Haematology, and Oncology Departments of a Scottish teaching hospital, and patients' own homes.
Sixteen men and 18 women aged 17-49 years recently diagnosed with cancer; 15 health professionals concerned in cancer care.
Audio-recorded semi-structured interviews were transcribed verbatim and analysed thematically. Topics included perceptions of diagnosis; prognosis; future reproductive choices; priorities; quality of information received; communication and decisions made about future reproductive choices; and the role of partners, family, friends and healthcare professionals. Professional interviews examined their role in decision making and that of protocols and guidelines, together with information emerging from patient interview analysis.
Themes identified following analysis of interview transcripts.
The primary barriers to pursuing fertility preservation were the way in which information was provided and the 'urgent need for treatment' conveyed by staff. Survival was always viewed as paramount, with future fertility secondary. Sperm banking was viewed as 'part and parcel' of oncology care, and the majority of men quickly stored sperm as 'insurance' against future infertility. Few women were afforded the opportunity to discuss their options, reflecting clinicians' reservations about the experimental nature of egg and ovarian tissue cryopreservation, and the need for partner involvement in embryo storage.
Significant gaps in the information provided to young women diagnosed with cancer suggest the need for an early appointment with a fertility expert.
BJOG An International Journal of Obstetrics & Gynaecology 05/2012; 119(9):1049-57. DOI:10.1111/j.1471-0528.2012.03368.x · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current evidence concerning the best treatment option for couples with unexplained and male subfertility is inconclusive. Most studies that have evaluated the effectiveness of treatment options, such as expectant management (EM), intrauterine insemination (IUI), with or without controlled ovarian stimulation (COS), and in vitro fertilisation (IVF), have not taken the couples' prognosis into account. It is very likely that the individual prognosis of the couple influences the effect of treatment. Individual patient data analyses allow us to take these prognostic factors into account, and to evaluate their effect on treatment outcome. This study aims to use anonymised data from relevant published trials to perform an individual patient data meta-analysis, evaluating the effect of couples' prognosis on the effectiveness of EM, IUI, with or without COS, and IVF.
Based on earlier systematic reviews and an updated search, randomised controlled trials will be considered for inclusion. Untreated subfertile couples with unexplained or male subfertility included in trials comparing EM, IUI, with or without COS, and IVF are included. Authors of the included studies will be invited to share their original anonymised data. The data will be assessed on validity, quality and completeness. The prognosis of the individual couple will be calculated with existing prognostic models. The effect of the prognosis on treatment outcome will be analysed with marker-by-treatment predictiveness curves, illustrating the effect of prognosis on treatment outcome. This study is registered in PROSPERO (registration number CRD42011001832).
Ultimately, this study may help to select the appropriate fertility treatment, tailored to the needs of an individual couple.
BJOG An International Journal of Obstetrics & Gynaecology 05/2012; 119(8):953-7. DOI:10.1111/j.1471-0528.2012.03343.x · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding.
Network meta-analysis on the primary outcome measures of amenorrhoea, heavy bleeding, and patients' dissatisfaction with treatment.
Nineteen randomised controlled trials (involving 3287 women) were identified through electronic searches of the Cochrane Library, Medline, Embase and PsycINFO databases from inception to April 2011. The reference lists of known relevant articles were searched for further articles. Two reviewers independently selected articles without language restrictions. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials involving second generation endometrial destruction techniques for women with heavy menstrual bleeding unresponsive to medical treatment.
Of the three most commonly used techniques, network meta-analysis showed that bipolar radiofrequency and microwave ablation resulted in higher rates of amenorrhoea than thermal balloon ablation at around 12 months (odds ratio 2.51, 95% confidence interval 1.53 to 4.12, P<0.001; and 1.66, 1.01 to 2.71, P=0.05, respectively), but there was no evidence of a convincing difference between the three techniques in the number of women dissatisfied with treatment or still experiencing heavy bleeding. Compared with bipolar radio frequency and microwave devices, an increased number of women still experienced heavy bleeding after free fluid ablation (2.19, 1.07 to 4.50, P=0.03; and 2.91, 1.23 to 6.88, P=0.02, respectively). Compared with radio frequency ablation, free fluid ablation was associated with reduced rates of amenorrhoea (0.36, 0.19 to 0.67, P=0.004) and increased rates of dissatisfaction (4.79, 1.07 to 21.5, P=0.04). Of the less commonly used devices, endometrial laser intrauterine thermotherapy was associated with increased rates of amenorrhoea compared with all the other devices, while cryoablation led to a reduced rate compared with bipolar radio frequency and microwave.
Bipolar radio frequency and microwave ablative devices are more effective than thermal balloon and free fluid ablation in the treatment of heavy menstrual bleeding with second generation endometrial ablation devices.
[Show abstract][Hide abstract] ABSTRACT: To describe the risk of maternal sepsis associated with obesity and other understudied risk factors such as operative vaginal delivery.
Population-based, case-control study.
North NHS region of Scotland.
All cases of pregnant, intrapartum and postpartum women with International Classification of Disease-9 codes for sepsis or severe sepsis recorded in the Aberdeen Maternal and Neonatal Databank (AMND) from 1986 to 2009. Four controls per case selected from the AMND were frequency matched on year-of-delivery.
Cases and controls were compared; significant variables from univariable regression were adjusted in a multivariable logistic regression model.
Dependent variables were uncomplicated sepsis or severe ('near-miss') sepsis. Independent variables were demographic, medical and clinical delivery characteristics. Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) are reported.
Controlling for mode of delivery and demographic and clinical factors, obese women had twice the odds of uncomplicated sepsis (OR 2.12; 95% CI 1.14-3.89) compared with women of normal weight. Age <25 years (OR 5.15; 95% CI 2.43-10.90) and operative vaginal delivery (OR 2.20; 95% CI 1.02-4.87) were also significant predictors of sepsis. Known risk factors for maternal sepsis were also significant in this study (OR for uncomplicated and severe sepsis respectively): multiparity (OR 6.29, 12.04), anaemia (OR 3.43, 18.49), labour induction (OR 3.92 severe only), caesarean section (OR 3.23, 13.35), and preterm birth (OR 2.46 uncomplicated only).
Obesity, operative vaginal delivery and age <25 years are significant risk factors for sepsis and should be considered in clinical obstetric care.
BJOG An International Journal of Obstetrics & Gynaecology 03/2012; 119(4):474-83. DOI:10.1111/j.1471-0528.2011.03239.x · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is becoming a serious problem, especially in industrialized societies. This study was designed to explore the association between body mass index (BMI) and semen quality. Semen analysis and demographic data were collected from male partners of couples undergoing fertility investigations in a referral fertility centre. Men were classified into groups according to their BMI (A, <18.5; B, 18.5-24.99; C, 25-29.99; D, ≥30 kg/m(2)). Data from 2035 men were analysed using logistic regression. There were 18, 839, 909 and 269 men in groups A, B, C and D, respectively. Taking group B as the reference, adjusted odds ratios (95% CI) for groups A, C and D for semen volume <2 ml were 1.57 (0.49-5.01), 1.06 (0.82-1.38) and 1.69 (1.20-2.38), respectively; for sperm morphology <15%, 1.44 (0.45-4.61), 1.07 (0.86-1.33) and 1.50 (1.06-2.09); for sperm concentration <20 million/ml, 0.46 (0.10-2.07), 1.03 (0.82-1.31) and 1.00 (0.72-1.41); and for motility <50%, 2.62 (0.73-9.45), 0.96 (0.78-1.18) and 0.75 (0.56-1.01). In conclusion, obese men are more likely to have lower semen volume and fewer morphologically normal spermatozoa than men with normal BMI.
[Show abstract][Hide abstract] ABSTRACT: European guidelines on fertility care emphasize that subfertile couples should receive information about their chances of a natural conception and should not be exposed to unnecessary treatments and risks. Prognostic models can help to estimate their chances and select couples with a good prognosis for tailored expectant management (TEM). Nevertheless, TEM is not always practiced. The aim of this study was to identify any barriers or facilitators for TEM among professionals and subfertile couples.
A qualitative study was performed with semi-structured in-depth interviews of 21 subfertile patients who were counselled for TEM and three focus-group interviews of 21 professionals in the field of reproductive medicine. Two theoretical models were used to guide the interviews and the analyses. The primary outcome was the set of identified barriers and facilitators which influence implementation of TEM.
Among the subfertile couples, main barriers were a lack of confidence in natural conception, a perception that expectant management is a waste of time, inappropriate expectations prior to the first consultation, misunderstanding the reason for expectant management and overestimation of the success rates of treatment. Both couples and professionals saw the lack of patient information materials as a barrier. Among professionals, limited knowledge about prognostic models leading to a decision in favour of treatment was recognized as a main barrier. A main facilitator mentioned by the professionals was better management of patients' expectations.
We identified several barriers and facilitators which can be addressed to improve the implementation of TEM. These should be taken into account when designing future implementation strategies.
Human Reproduction 06/2011; 26(8):2122-8. DOI:10.1093/humrep/der175 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intact frozen-thawed embryos have a greater potential than damaged embryos to establish successful pregnancies. This study aimed to determine whether elevated concentrations of sucrose during freezing would increase the proportion of patients with ≥ 50% of embryos intact after thawing (primary outcome), and improve clinical outcome.
In a two arm, parallel group, pragmatic trial, IVF/ICSI couples were randomized prospectively to have their supernumerary embryos frozen in a medium containing 0.1 M sucrose (control; n = 99) or 0.3 M sucrose (intervention; n = 102).
More control (74/99) than intervention (63/102) couples had at least one embryo thawed (P = 0.07). Significantly more (P = 0.005) intervention (53/63) than control (45/74) couples had ≥ 50% of embryos intact. Freezing in a medium containing 0.3 M sucrose increased by 3.4-fold [95% confidence interval (CI) (1.45, 7.82)] the likelihood of a couple having ≥ 50% of their embryos intact. In the fresh cycle, live birth rate per transfer was similar in the control (35/95) and intervention (36/93) groups (P = 0.91). More control (19/63) than intervention (9/59) couples had a live birth after frozen embryo transfer (P = 0.08). When fresh and frozen cycles were combined, fewer intervention (n = 102) than control (n = 99) couples had at least one live birth (42 versus 53%). The difference in cumulative live birth rate was not significant [hazard ratio = 0.75, 95% CI (0.49, 1.13); P = 0.17].
Increasing the concentration of sucrose in the freezing medium improves embryo survival, but this is not reflected by increased cumulative birth rates. Clinical Trials Registration number: ISRCTN93314892.
Human Reproduction 05/2011; 26(8):1987-96. DOI:10.1093/humrep/der147 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays.
We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction.
We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology.
In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice.
Human Reproduction Update 05/2011; 17(3):301-10. DOI:10.1093/humupd/dmq060 · 8.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To undertake a cost effectiveness analysis comparing first and second generation endometrial ablative techniques, hysterectomy, and the levonorgestrel releasing intrauterine system (Mirena) for treating heavy menstrual bleeding.
Model based economic evaluation with data from an individual patient data meta-analysis supplemented with cost and outcome data from published sources taking an NHS (National Health Service) perspective. A state transition (Markov) model was developed, the structure being informed by the reviews of the trials and clinical input. A subgroup analysis, one way sensitivity analysis, and probabilistic sensitivity analysis were also carried out.
Four hypothetical cohorts of women with heavy menstrual bleeding.
One of four alternative strategies: Mirena, first or second generation endometrial ablation techniques, or hysterectomy.
Cost effectiveness based on incremental cost per quality adjusted life year (QALY).
Hysterectomy is the preferred strategy for the first intervention for heavy menstrual bleeding. Although hysterectomy is more expensive, it produces more QALYs relative to other remaining strategies and is likely to be considered cost effective. The incremental cost effectiveness ratio for hysterectomy compared with Mirena is £1440 (€1633, $2350) per additional QALY. The incremental cost effectiveness ratio for hysterectomy compared with second generation ablation is £970 per additional QALY.
In light of the acceptable thresholds used by the National Institute for Health and Clinical Excellence, hysterectomy would be considered the preferred strategy for the treatment of heavy menstrual bleeding. The results concur with those of other studies but are highly sensitive to utility values used in the analysis.
[Show abstract][Hide abstract] ABSTRACT: To assess the cumulative costs and consequences of double embryo transfer (DET) or elective single embryo transfer (eSET) in women commencing in vitro fertilisation (IVF) treatment aged 32, 36 and 39 years.
Three assisted reproduction centres in Scotland.
A total of 6153 women undergoing treatment at one of three Scottish IVF clinics, between January 1997 and June 2007.
A microsimulation model, populated using data inputs derived from a large clinical data set and published literature, was developed to compare the costs and consequences of using eSET or DET over multiple treatment cycles.
Disability-free live births; twin pregnancy rate; women's quality-adjusted life-years (QALYs); health service costs.
Not only did DET produce a higher cumulative live birth rate compared with eSET for women of all three ages, but also a higher twin pregnancy rate. Compared with eSET, DET ranged from costing an additional £ 27,356 per extra live birth in women commencing treatment aged 32 years, to costing £ 15,539 per extra live birth in 39-year-old women. DET cost ∼ £ 28,300 and ∼ £ 20,300 per additional QALY in women commencing treatment aged 32 and 39 years, respectively.
Considering the high twin pregnancy rate associated with DET, coupled with uncertainty surrounding QALY gains, eSET is likely to be the preferred option for most women aged ≤ 36 years. The cost-effectiveness of DET improves with age, and may be considered cost-effective in some groups of older women. The decision may best be considered on a case-by-case basis for women aged 37-39 years.
BJOG An International Journal of Obstetrics & Gynaecology 04/2011; 118(9):1073-83. DOI:10.1111/j.1471-0528.2011.02966.x · 3.86 Impact Factor