Birth weight and ovulatory dysfunction.

OBJECTIVE: To explore the association between birthweight and ovulatory dysfunction in adulthood. DESIGN: Case-control study. SETTING: Northeast of Scotland University Hospital, hosting the regional fertility centre and maternity unit. POPULATION: A total of 18,846 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 MEASURES: Daughters' birthweight and standardised birthweight, characteristics of mothers and daughters at delivery and current daughters' characteristics. RESULTS: Cases, Control group 1 and Control group 2 included 466, 548 and 17,832 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 5 minutes. 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.

N-terminal pro-B-type natriuretic peptide concentrations and long-term outcome after cardiac surgery: a prospective cohort study.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict cardiovascular outcome in many settings. There are very few data assessing the utility of NT-proBNP concentrations in the prediction of long-term outcome after cardiac surgery. We assessed the ability of NT-proBNP to predict 3 yr mortality compared with validated clinical risk prediction tools. METHODS: A secondary analysis of a prospectively recruited patient cohort of 1010 patients undergoing cardiac surgery. Baseline clinical details were obtained including EuroSCORE. Multi-variable modelling, area under the receiver operating characteristic curves (AUCs), and net reclassification improvement were utilized. RESULTS: NT-proBNP was a univariable predictor of 3 yr mortality but was no longer a significant predictor in a multivariable model (hazard ratio 1.00 per 250 ng litre(-1), 95% confidence interval 0.98-1.02, P=0.80). The relative and additive predictive values of the preoperative EuroSCORE (both additive and logistic versions) and NT-proBNP concentrations were compared. All were predictive of 3 yr mortality (P<0.001) with almost identical AUCs (0.71 for EuroSCORE, 0.70 for NT-proBNP). When either the EuroSCORE or NT-proBNP concentrations are known, the addition of the other does not improve the ability to predict 3 yr mortality. CONCLUSIONS: Preoperative NT-proBNP concentrations and the EuroSCORE have equivalent, and moderate, predictive accuracy for mortality 3 yr after cardiac surgery. EuroSCORE uses clinical data but is not routinely used for individual clinical risk prediction. NT-proBNP measurement would incur additional costs but can be measured quickly and objectively. With such similar predictive accuracy, factors such as the ease of calculation and cost will likely determine their use in clinical practice.

An exploration of the association between male body mass index and semen quality.

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.

A pragmatic RCT of conventional versus increased concentration sucrose in freezing and thawing solutions for human embryos.

BACKGROUND: 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. METHODS: 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). RESULTS: 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]. CONCLUSIONS: 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.

Minimising twins in in vitro fertilisation: a modelling study assessing the costs, consequences and cost-utility of elective single versus double embryo transfer over a 20-year time horizon.

OBJECTIVES: 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. DESIGN: Microsimulation model. SETTING: Three assisted reproduction centres in Scotland. SAMPLE: A total of 6153 women undergoing treatment at one of three Scottish IVF clinics, between January 1997 and June 2007. METHODS: 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. MAIN OUTCOME MEASURES: Disability-free live births; twin pregnancy rate; women's quality-adjusted life-years (QALYs); health service costs. RESULTS: 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. CONCLUSIONS: 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.

Clomifene citrate and intrauterine insemination as first-line treatments for unexplained infertility: are they cost-effective?

BACKGROUND: First-line treatments for unexplained infertility traditionally include clomifene citrate (CC) or unstimulated intrauterine insemination (IUI). A recently published randomized controlled trial considered the effectiveness of CC and IUI in patients with unexplained infertility and found that neither treatment offered a superior live birth rate when compared with expectant management (EM). This paper reports the economic evaluation conducted alongside this trial in order to assess whether health care providers are gaining value for money in this clinical area. METHODS: Five hundred and eighty women across five Scottish hospitals were randomized to either EM, CC or IUI for 6 months. The primary outcome measure was live births. Resource-use data were collected during the trial and costs were calculated from a UK National Health Service (NHS) perspective. Incremental cost-effectiveness ratios were calculated, expressed as cost per live birth, in order to compare the cost-effectiveness of CC and IUI with that of EM to treat unexplained infertility. RESULTS: Live birth rates in the three randomized groups were: EM = 32/193 (17%), CC = 26/194 (13%) and IUI = 43/193 (22%). The mean (standard deviation) costs per treatment cycle were £0 for EM, £83 (£17) for CC and £98 (£31) for IUI. The mean treatment costs per patient for EM, CC and IUI were £12 (£117), £350 (£220) and £331 (£222), respectively. The cost per live birth for EM, CC and IUI was £72 (95% confidence interval £0-£206), £2611 (£1870-£4166) and £1487 (£1116-£2155), respectively. The incremental cost-effectiveness ratio for IUI versus EM was £5604 (-£12204 to £2227), with CC dominated by IUI. CONCLUSIONS: Despite being more expensive, existing treatments such as empirical CC and unstimulated IUI do not offer superior live birth rates compared with EM of unexplained infertility. They are unlikely to be a cost-effective use of limited NHS resources. The study's main limitation is that it did not consider the psychological effects on couples. ISRCT Number: 71762042.

Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.

OBJECTIVE: To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers. DESIGN: One stage meta-analysis of individual patient data. DATA SOURCES: A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer. Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded. RESULTS: Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18). CONCLUSIONS: Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.

The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial.

OBJECTIVE: To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ). DESIGN: Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ. Setting Grampian, Tayside and Nottingham. Population Women (n = 4439), aged 20-59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002. METHODS: High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy. RESULTS: There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8-81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7-77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5-74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2-51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9-96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years. CONCLUSIONS: We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.

Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial.

OBJECTIVE: To compare the effectiveness of clomifene citrate and unstimulated intrauterine insemination with expectant management for the treatment of unexplained infertility. DESIGN: Three arm parallel group, pragmatic randomised controlled trial. SETTING: Four teaching hospitals and a district general hospital in Scotland. PARTICIPANTS: Couples with infertility for over two years, confirmed ovulation, patent fallopian tubes, and motile sperm. INTERVENTION: Expectant management, oral clomifene citrate, and unstimulated intrauterine insemination. MAIN OUTCOME MEASURES: The primary outcome was live birth. Secondary outcome measures included clinical pregnancy, multiple pregnancy, miscarriage, and acceptability. RESULTS: 580 women were randomised to expectant management (n=193), oral clomifene citrate (n=194), or unstimulated intrauterine insemination (n=193) for six months. The three randomised groups were comparable in terms of age, body mass index, duration of infertility, sperm concentration, and motility. Live birth rates were 32/193 (17%), 26/192 (14%), and 43/191 (23%), respectively. Compared with expectant management, the odds ratio for a live birth was 0.79 (95% confidence interval 0.45 to 1.38) after clomifene citrate and 1.46 (0.88 to 2.43) after unstimulated intrauterine insemination. More women randomised to clomifene citrate (159/170, 94%) and unstimulated intrauterine insemination (155/162, 96%) found the process of treatment acceptable than those randomised to expectant management (123/153, 80%) (P=0.001 and P<0.001, respectively). CONCLUSION: In couples with unexplained infertility existing treatments such as empirical clomifene and unstimulated intrauterine insemination are unlikely to offer superior live birth rates compared with expectant management. TRIAL REGISTRATION: ISRCT No: 71762042.

Comparison of the long-term effects of simple total abdominal hysterectomy with transcervical endometrial resection on urinary incontinence.

OBJECTIVE: To test the hypothesis that the hospital referral rate for urinary incontinence (UI) symptoms, within 10 years of a simple total abdominal hysterectomy (TAH) for dysfunctional uterine bleeding (DUB), would differ to that after a transcervical resection of the endometrium (TCRE). DESIGN: Retrospective case note review. SETTING: Teaching hospital in north east Scotland. POPULATION: All women who had a TAH (316) or a TCRE (229) for DUB, during the period from 1 January 1990 to 31 December 1994, who had never been referred for symptoms of UI prior to their operation. METHODS: Independent t tests, Mann-Whitney U tests and Chi-squared tests were used to compare the two study groups in terms of demographic details and outcome measures. Newcombe's method for the comparison of two unpaired proportions was used to calculate 95% CIs for the differences in outcome measures between the two operations. Logistic regression was conducted to investigate associations with hospital referral for UI. MAIN OUTCOME MEASURES: Hospital referral for UI at 10 years follow up. RESULTS: There were significantly more hospital referrals for UI in the TAH group compared with the TCRE group (46 [15%] versus 16 [7%]; OR 2.27, 95% CI 1.25-4.12). More women were referred for urological investigations after a TAH than after a TCRE (39 [12%] versus 13 [6%], 95% CI for the difference in proportions 2-11%). A higher, but statistically nonsignificant, proportion of women had objectively demonstrated UI after a TAH than after a TCRE (25 [8%] versus 10 [4%], 95% CI for the difference in proportions -1 to 8%). There were a greater number of hospital referrals for treatment of UI in the TAH group (36, 11%) than in the TCRE group (12, 5%), 95% CI for the difference in proportions (1-11%). After adjusting for age, weight, smoking status and mode of delivery, the increased rate of hospital referral for UI after TAH remained, with an odds ratio of 2.31, 95% CI 1.24-4.30. CONCLUSIONS: TAH is associated with a significantly increased incidence of hospital referral for UI, urological investigations and treatment for UI at 10 years of follow up compared with TCRE.

Comparison of sensorineural symptoms between UK orthopaedic surgeons and gynaecologists.

BACKGROUND: We have previously described significant differences in self-reported neurological symptoms of orthopaedic surgeons when compared to a group of gynaecologists. We suggested that this may be secondary to occupational sources of hand-transmitted vibration. The original study was intentionally brief and failed to address potential confounders. AIMS: To compare the prevalence of sensorineural symptoms between UK orthopaedic surgeons and gynaecologists and adjust for potential confounding factors. METHODS: Postal questionnaires were sent to 2040 members of the British Orthopaedic Association and 1797 members of the Royal College of Gynaecologists requesting information about demographics and self-reported neurological symptoms. Demographics of the orthopaedic surgeons and gynaecologists were compared using chi-squared tests and independent t-tests. Multiple logistic regressions were carried out to compare the prevalence of symptoms while adjusting for potential confounding factors. RESULTS: Differences in the demographic profile of the orthopaedic surgeons and gynaecologists were identified: orthopaedic surgeons were predominantly male, were more junior in grade, were younger, used double gloving more often, had larger glove size, were more likely to be ambidextrous, to use vibrating tools outside of work and to consume greater amounts of alcohol. Orthopaedic surgeons reported a higher prevalence of tingling and numbness of fingers while at work and at other times. These differences were significant even after adjusting for potential confounding factors. CONCLUSION: Observed differences could be related to exposure to hand-transmitted vibration at work. Further assessment of risk to orthopaedic surgeons from hand-held power tools used in the course of their work is recommended.

Absence of conception after caesarean section: voluntary or involuntary?

BACKGROUND: Women who deliver by caesarean section have been shown to be less likely to have a subsequent pregnancy. It is not clear whether this is due to a direct effect of the procedure on future fertility or due to deliberate avoidance of a future pregnancy. OBJECTIVE: To investigate whether absence of conception following caesarean section is voluntary or involuntary. DESIGN: Follow up of a population-based retrospective cohort. SETTING: Grampian region, Scotland. POPULATION: Women who had no further viable pregnancies within 5 years of an initial delivery. METHODS: Cases included women who delivered their first child by caesarean section between 1980 and 1995 but had no further viable pregnancies by December 2000. Controls included women who delivered their first child during the same period, by means of either spontaneous vaginal delivery (SVD) or instrumental vaginal delivery (IVD), and who had no further viable pregnancies by December 2000. Eligible women were identified from the Aberdeen Maternity and Neonatal Databank (AMND) and sent postal questionnaires to determine the extent to which not conceiving after first delivery was voluntary and the reasons for avoiding further pregnancies. Characteristics of the different mode of delivery groups were compared using univariate techniques. MAIN OUTCOME MEASURES: Extent to which absence of conception following an initial delivery by caesarean section is voluntary. RESULTS: Questionnaires were returned by 3204 (60%) of 5300 women identified from the AMND. Of these, 1675 women had not conceived at all during the follow-up period (median duration = 13 years). Absence of conception was voluntary in 488 (69%; 95% CI 66-73%) women following caesarean section, 340 (71%; 95% CI 67-76%) following SVD and 354 (72%; 95% CI 68-76%) following IVD. Few women considered seeking fertility treatment (caesarean section = 72 [10%], SVD = 50 [11%], IVD = 39 [8%]). Of the women who decided to delay or avoid a further pregnancy, fewer women who delivered by SVD reported that the birth experience influenced their decision (caesarean section = 163 [32%], SVD = 67 [18%], IVD = 136 [35%]; P < 0.001). CONCLUSIONS: Irrespective of mode of delivery, not conceiving following the birth of the first child is mainly voluntary. The experience of the previous birth is one of several factors affecting women's decisions to avoid a subsequent pregnancy.

Risk stratification in acute coronary syndromes--does the TIMI risk score work in unselected cases?

BACKGROUND: Management of patients with an acute coronary syndrome (ACS) requires accurate risk stratification to guide appropriate therapy. AIM: To assess the utility of the TIMI risk score in stratifying patients with possible ACS in routine clinical practice. DESIGN: Prospective observational study. METHODS: We recruited 869 consecutive patients with a diagnosis of possible ACS attending the acute medical receiving unit of a district general hospital. The main outcome measures were recurrent myocardial infarction, urgent revascularization, and all-cause mortality. TIMI risk score was calculated for each patient, and each was also assigned a risk group based on electrocardiogram (ECG) changes and troponin levels only. After follow-up, Cox univariate and multivariate regression was used to evaluate the influence of potential risk factors on duration of event-free survival, and likelihood ratio tests to assess the fit of the models. RESULTS: Increasing TIMI risk score was associated with increased risk of events (p<0.001), as was higher risk group from ECG plus troponin stratification (p<0.001). The likelihood ratio comparison favoured the TIMI risk score (difference 13.910, 5 degrees of freedom, p = 0.016). DISCUSSION: The TIMI risk score is a valid tool for risk stratification in unselected cases with possible acute coronary syndrome. It is superior to ECG changes and troponin alone, although this simpler method also achieves good risk stratification.