A narrative review of estimands in drug development and regulatory evaluation: old wine in new barrels?

BACKGROUND: An estimand defines the target of estimation for a clinical trial through specification of the treatment, target population, variable, population-level summary and of the strategies for intercurrent events. A carefully defined estimand aligns the clinical trial design and analysis with the scientific question of interest and adequately accounts for so-called intercurrent events. The ICH E9(R1) addendum suggests five estimand strategies. We evaluated to what extent current practice in drug development and regulatory assessment fits in the estimand framework. METHODS: We systematically evaluated what estimands, especially what strategies for intercurrent events are advised in European Medicines Agency disease guidelines, used in sponsors' trials and additionally requested by the European Medicines Agency in assessment dossiers. We selected four therapeutic areas: nervous system, oncology, cardiovascular diseases and respiratory diseases. For each, we evaluated all disease guidelines with approved drugs, the dossiers of the most recently approved drugs matching the guidelines and corresponding regulatory questions. RESULTS: Strategies for intercurrent events were present in 18 (53%) of 34 guidelines, in all 34 sponsor documentations and in 15 (44%) of 34 sets of regulatory questions. Treatment policy was advised in 13 (38%) guidelines and was applied in 9 corresponding sponsor documentations. Of these 9, it was the sole strategy in 4 cases and accompanied by another strategy in 5 cases. Hypothetical strategy was not advised in guidelines. However, it was the leading strategy applied in 25 (74%) sponsor documentations. Composite strategy was advised in 3 (9%) guidelines and applied accompanied by another strategy in 2 corresponding sponsor documentations. While on treatment strategy was not advised in guidelines, but was applied in 2 sponsor documentations. Principal stratum strategy was advised in 2 guidelines but not applied in corresponding sponsor documentations. Of the regulatory questions, treatment policy was present in 2 cases (6%), hypothetical in 6 cases (18%), composite in 6 cases (18%) and while on treatment in 1 case (3%). CONCLUSIONS: Estimand attributes are present in guidelines, sponsor documentations and regulatory questions, but not described as estimands. Treatment policy was most often advised in guidelines, but hypothetical was the leading strategy applied in sponsor documentations. Thus, results indicate not a full concordance between the regulatory target of estimation and what is actually estimated. The lack of concordance was mostly due to limitations in collection of intercurrent events data to enable a treatment policy strategy. There is, therefore, a need to better define estimands at the design stage and throughout the applications dossiers and assessment reports.

Comparing induction of labour with oral misoprostol or Foley catheter at term: cost-effectiveness analysis of a randomised controlled multi-centre non-inferiority trial.

OBJECTIVE: To assess the costs of labour induction with oral misoprostol versus Foley catheter. DESIGN: Economic evaluation alongside a randomised controlled trial. SETTING: Obstetric departments of six tertiary and 23 secondary care hospitals in the Netherlands. POPULATION: Women with a viable term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix (Bishop score <6) without a previous caesarean section, were randomised for labour induction with oral misoprostol (n = 924) or Foley catheter (n = 921). METHODS: We performed economic analysis from a hospital perspective. We estimated direct medical costs associated with healthcare utilisation from randomisation until discharge. The robustness of our findings was evaluated in sensitivity analyses. MAIN OUTCOME MEASURES: Mean costs and differences were calculated per women induced with oral misoprostol or Foley catheter. RESULTS: Mean costs per woman in the oral misoprostol group and Foley catheter group were €4470 versus €4158, respectively [mean difference €312, 95% confidence interval (CI) -€508 to €1063]. Multiple sensitivity analyses did not change these conclusions. However, if cervical ripening for low-risk pregnancies in the Foley catheter group was carried out in an outpatient setting, with admittance to labour ward only at start of active labour, the difference would be €4470 versus €3489, respectively (mean difference €981, 95% CI €225-1817). CONCLUSIONS: Oral misoprostol and Foley catheter generate comparable costs. Cervical ripening outside labour ward with a Foley catheter could potentially save almost €1000 per woman. TWEETABLE ABSTRACT: Oral misoprostol or Foley catheter for induction of labour generates comparable costs.

Hysteroscopic resection of a uterine caesarean scar defect (niche) in women with postmenstrual spotting: a randomised controlled trial.

OBJECTIVE: To compare the effectiveness of a hysteroscopic niche resection versus no treatment in women with postmenstrual spotting and a uterine caesarean scar defect. DESIGN: Multicentre randomised controlled trial. SETTING: Eleven hospitals collaborating in a consortium for women's health research in the Netherlands. POPULATION: Women reporting postmenstrual spotting after a caesarean section who had a niche with a residual myometrium of ≥3 mm, measured during sonohysterography. METHODS: Women were randomly allocated to hysteroscopic niche resection or expectant management for 6 months. MAIN OUTCOME MEASURES: The primary outcome was the number of days of postmenstrual spotting 6 months after randomisation. Secondary outcomes were spotting at the end of menstruation, intermenstrual spotting, dysuria, sonographic niche measurements, surgical parameters, quality of life, women's satisfaction, sexual function, and additional therapy. Outcomes were measured at 3 months and, except for niche measurements, also at 6 months after randomisation. RESULTS: We randomised 52 women to hysteroscopic niche resection and 51 women to expectant management. The median number of days of postmenstrual spotting at baseline was 8 days in both groups. At 6 months after randomisation, the median number of days of postmenstrual spotting was 4 days (interquartile range, IQR 2-7 days) in the intervention group and 7 days (IQR 3-10 days) in the control group (P = 0.04); on a scale of 0-10, discomfort as a result of spotting had a median score of 2 (IQR 0-7) in the intervention group, compared with 7 (IQR 0-8) in the control group (P = 0.02). CONCLUSIONS: In women with a niche with a residual myometrium of ≥3 mm, hysteroscopic niche resection reduced postmenstrual spotting and spotting-related discomfort. TWEETABLE ABSTRACT: A hysteroscopic niche resection is an effective treatment to reduce niche-related spotting.

Labour pain with remifentanil patient-controlled analgesia versus epidural analgesia: a randomised equivalence trial.

OBJECTIVE: To distinguish satisfaction with pain relief using remifentanil patient-controlled analgesia (RPCA) compared with epidural analgesia (EA) in low-risk labouring women. DESIGN: Randomised controlled equivalence trial. SETTING: Eighteen midwifery practices and six hospitals in the Netherlands. POPULATION: A total of 408 pregnant women at low risk for obstetric complications initially under the care of primary-care midwives. METHODS: Women randomised before active labour to receive analgesia with RPCA or EA, if requested. MAIN OUTCOME MEASURES: Primary outcome was satisfaction with pain relief measured hourly using a visual analogue scale and summed as area under the curve (AUC). Secondary outcomes were overall satisfaction with pain relief, pain intensity scores during labour, mode of delivery, and maternal and neonatal outcomes. RESULTS: We randomised 418 women, of whom 409 could be followed for the primary endpoint. Analgesia was received by 46% (94/203) in the remifentanil group and 37% (76/206) in the epidural group. The AUC for satisfaction with pain relief was 32 in the remifentanil group and 31 in the epidural group (mean difference -0.50; 95% CI -6.8 to 5.9). Among women who actually received analgesia, these values were 23 and 35, respectively (mean difference -12; 95% CI -22 to -1.5). Secondary outcomes were comparable. CONCLUSIONS: In low-risk labouring women, we could not demonstrate equivalence between a strategy with RPCA to EA with respect to satisfaction with pain relief assessed during the total duration of labour. However, once applied satisfaction was higher in women who received epidural analgesia. TWEETABLE ABSTRACT: Satisfaction with pain relief is higher in women receiving epidural analgesia compared with Remifentanil PCA.

MisoREST: surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: a randomized controlled trial.

STUDY QUESTION: Is curettage more effective than expectant management in case of an incomplete evacuation after misoprostol treatment for first trimester miscarriage? SUMMARY ANSWER: Curettage leads to a higher chance of complete evacuation but expectant management is successful in at least 76% of women with an incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage. WHAT IS KNOWN ALREADY: In 5-50% of the women treated with misoprostol, there is a suspicion of incomplete evacuation of the uterus on sonography. Although these women generally have minor symptoms, such a finding often leads to additional curettage. STUDY DESIGN, SIZE, DURATION: From June 2012 until July 2014, we conducted a nationwide multicenter randomized controlled trial (RCT). Women who had had primary misoprostol treatment for miscarriage with sonographic evidence of incomplete evacuation of the uterus were randomly allocated to either curettage or expectant management (1:1), using a web-based application. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 59 women in 27 hospitals; 30 were allocated to curettage and 29 were allocated to expectant management. A successful outcome was defined as sonographic finding of an empty uterus 6 weeks after randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics of both groups were comparable. Empty uterus on sonography or uneventful clinical follow-up was seen in 29/30 women (97%) allocated to curettage compared with 22/29 women (76%) allocated to expectant management (RR 1.3, 95% CI 1.03-1.6) with complication rates of 10% versus 10%, respectively (RR 0.97, 95% CI 0.21-4.4). In the group allocated to curettage, no woman required re-curettage, while two women (6.7%) underwent hysteroscopy (for other or unknown reasons). In the women allocated to expectant management, curettage was performed in four women (13.8%) and three women (10.3%) underwent hysteroscopy. LIMITATIONS, REASONS FOR CAUTION: Due to a strong patient preference, mainly for expectant management, the targeted sample size could not be included and the trial was stopped prematurely. WIDER IMPLICATIONS OF THE FINDINGS: In women suspected of incomplete evacuation of the uterus after misoprostol, curettage is more effective than expectant management. However, expectant management is equally safe and prevents curettage for most of the women. This finding could further restrain the use of curettage in the treatment of first trimester miscarriage. STUDY FUNDING/COMPETING INTERESTS: This study was funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-82310-97-12066. There were no conflicts of interests. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR3310, http://www.trialregister.nl TRIAL REGISTRATION DATE: 27 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 12 June 2012.

The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial.

BACKGROUND: A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain. However, there are no randomised trials assessing the effectiveness of a hysteroscopic niche resection. METHODS/DESIGN: We planned a multicentre randomised trial comparing hysteroscopic niche resection to no intervention. We study women with postmenstrual spotting after a CS and a niche with a residual myometrium of at least 3 mm during sonohysterography. After informed consent is obtained, eligible women will be randomly allocated to hysteroscopic resection of the niche or expectant management for 6 months. The primary outcome is the number of days with postmenstrual spotting during one menstrual cycle 6 months after randomisation. Secondary outcomes are menstrual characteristics, menstruation related pain and experienced discomfort due to spotting or menstrual pain, quality of life, patient satisfaction, sexual function, urological symptoms, medical consultations, medication use, complications, lost productivity and medical costs. Measurements will be performed at baseline and at 3 and 6 months after randomisation. A cost-effectiveness analysis will be performed from a societal perspective at 6 months after randomisation. DISCUSSION: This trial will provide insight in the (cost)effectiveness of hysteroscopic resection of a niche versus expectant management in women who have postmenstrual spotting and a niche with sufficient residual myometrium to perform a hysteroscopic niche resection. TRIAL REGISTRATION: Dutch Trial Register NTR3269 . Registered 1 February 2012. ZonMw Grant number 80-82305-97-12030.

Transvaginal prolapse repair with or without the addition of a midurethral sling in women with genital prolapse and stress urinary incontinence: a randomised trial.

OBJECTIVE: To compare transvaginal prolapse repair combined with midurethral sling (MUS) versus prolapse repair only. DESIGN: Multi-centre randomised trial. SETTING: Fourteen teaching hospitals in the Netherlands. POPULATION: Women with symptomatic stage two or greater pelvic organ prolapse (POP), and subjective or objective stress urinary incontinence (SUI) without prolapse reduction. METHODS: Women were randomly assigned to undergo vaginal prolapse repair with or without MUS. Analysis was according to intention to treat. MAIN OUTCOME MEASURES: The primary outcome at 12 months' follow-up was the absence of urinary incontinence (UI) assessed with the Urogenital Distress Inventory and treatment for SUI or overactive bladder. Secondary outcomes included complications. RESULTS: One hundred and thirty-four women were analysed at 12 months' follow-up (63 in MUS and 71 in control group). More women in the MUS group reported the absence of UI and SUI; respectively 62% versus 30% UI (relative risk [RR] 2.09; 95% confidence interval [CI] 1.39-3.15) and 78% versus 39% SUI (RR 1.97; 95% CI 1.44-2.71). Fewer women underwent treatment for postoperative SUI in the MUS group (10% versus 37%; RR 0.26; 95% CI 0.11-0.59). In the control group, 12 women (17%) underwent MUS after prolapse surgery versus none in the MUS group. Severe complications were more common in the MUS group, but the difference was not statistically significant (16% versus 6%; RR 2.82; 95% CI 0.93-8.54). CONCLUSIONS: Women with prolapse and co-existing SUI are less likely to have SUI after transvaginal prolapse repair with MUS compared with prolapse repair only. However, only 17% of the women undergoing POP surgery needed additional MUS. A well-informed decision balancing risks and benefits of both strategies should be tailored to individual women.

Prolapse surgery with or without stress incontinence surgery for pelvic organ prolapse: a systematic review and meta-analysis of randomised trials.

OBJECTIVES: The combination of prolapse surgery with an incontinence procedure can reduce the incidence of stress urinary incontinence (SUI) after surgery, but may increase adverse events. We compared the effectiveness and safety of prolapse surgery versus combined prolapse and incontinence surgery in women with pelvic organ prolapse. DESIGN AND SETTING: Pubmed, EMBASE, DARE, the Cochrane Library and the register of Current Controlled Trials were searched for randomised trials (restricted to Burch colposuspension and midurethral sling as incontinence procedure) from 1995 to 2013 limited to the English literature. METHODS: Two reviewers selected eligible articles and extracted the data. Pooling for SUI was based on three patient groups: (1) women with coexisting SUI; (2) women asymptomatic for SUI; and (3) women with occult SUI. For adverse events, pooling was based on incontinence procedure. MAIN OUTCOME MEASURES: The primary outcome was SUI. The secondary outcomes were treatment for SUI, bladder storage symptoms, obstructive voiding and adverse events. RESULTS: Seven trials were included. Pooling for women with coexisting SUI was possible for objective SUI with two studies and showed no difference. Statistical (I(2) = 95%) and clinical heterogeneity was, however, high. The largest study showed a lower incidence of persisting SUI (5% versus 23%) and treatment for this (0% versus 57%) in women who underwent prolapse repair with a midurethral sling. The second study did not find a difference in women undergoing a sacrocolpopexy with or without Burch colposuspension. In asymptomatic women, combination surgery resulted in a lower incidence of de novo subjective SUI (two studies; 24% versus 41%; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3-0.9; I(2) = 36%) and the need for subsequent anti-incontinence surgery (three studies; 2% versus 7%; RR, 0.4; 95% CI, 0.2-0.8; I(2) = 13%). For the outcome objective SUI, pooling was possible for five studies, but statistical heterogeneity was high (I(2) = 82%) and the difference was not statistically significant. In the subgroup of women with occult stress incontinence, we found a lower incidence of objective SUI after combination surgery (two studies; 22% versus 52%; RR, 0.4; 95% CI, 0.3-0.8; I(2) = 32%). There were no differences in bladder storage symptoms, urgency incontinence or long-term obstructive voiding symptoms. Adverse events (two studies; 15% versus 10%; RR, 1.6; 95% CI, 1.0-2.5; I(2) = 0%) and prolonged catheterisation (three studies; 6% versus 1%; RR, 4.5; 95% CI, 1.5-13.3; I(2) = 0%) were more frequent after vaginal prolapse repair with a midurethral sling. CONCLUSIONS: Combination surgery reduces the risk of postoperative stress incontinence, but short-term voiding difficulties and adverse events were more frequent after combination surgery with a midurethral sling.

Prognostic profiles and the effectiveness of assisted conception: secondary analyses of individual patient data.

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. RESULTS: We 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.

Relationship of isolated single umbilical artery to fetal growth, aneuploidy and perinatal mortality: systematic review and meta-analysis.

OBJECTIVE: To review the available literature on outcome of pregnancy when an isolated single umbilical artery (iSUA) is diagnosed at the time of the mid-trimester anomaly scan. METHODS: We searched MEDLINE (1948-2012), EMBASE (1980-2012) and the Cochrane Library (until 2012) for relevant citations reporting on outcome of pregnancy with iSUA seen on ultrasound. Data were extracted by two reviewers. Where appropriate, we pooled odds ratios (ORs) for the dichotomous outcome measures: small for gestational age (SGA), perinatal mortality and aneuploidy. For birth weight we determined the mean difference with 95% CI. RESULTS: We identified three cohort studies and four case-control studies reporting on 928 pregnancies with iSUA. There was significant heterogeneity between cohort and case-control studies. Compared to fetuses with a three-vessel cord, fetuses with an iSUA were more likely to be SGA (OR 1.6 (95% CI, 0.97-2.6); n = 489) or suffer perinatal mortality (OR 2.0 (95% CI, 0.9-4.2); n = 686), although for neither of the outcomes was statistical significance reached. The difference in mean birth weight was 51 g (95% CI, -154.7 to 52.6 g): n = 407), but again this difference was not statistically significant. We found no evidence that fetuses with iSUA have an increased risk for aneuploidy. CONCLUSION: In view of the non-significant association between iSUA and fetal growth and perinatal mortality, and in view of the heterogeneity in studies on aneuploidy, we feel that large-scale, prospective cohort studies are needed to reach definitive conclusions on the appropriate work-up in iSUA pregnancies. At present, targeted growth assessment after diagnosis of iSUA should not be routine practice.

Cost-effectiveness of induction of labour at term with a Foley catheter compared to vaginal prostaglandin E2 gel (PROBAAT trial).

OBJECTIVE: To assess the economic consequences of labour induction with Foley catheter compared to prostaglandin E2 gel. DESIGN: Economic evaluation alongside a randomised controlled trial. SETTING: Obstetric departments of one university and 11 teaching hospitals in the Netherlands. POPULATION: Women scheduled for labour induction with a singleton pregnancy in cephalic presentation at term, intact membranes and an unfavourable cervix; and without previous caesarean section. METHODS: Cost-effectiveness analysis from a hospital perspective. MAIN OUTCOME MEASURES: We estimated direct medical costs associated with healthcare utilisation from randomisation to 6 weeks postpartum. For caesarean section rate, and maternal and neonatal morbidity we calculated the incremental cost-effectiveness ratios, which represent the costs to prevent one of these adverse outcomes. RESULTS: Mean costs per woman in the Foley catheter group (n = 411) and in the prostaglandin E2 gel group (n = 408), were €3297 versus €3075, respectively, with an average difference of €222 (95% confidence interval -€157 to €633). In the Foley catheter group we observed higher costs due to longer labour ward occupation and less cost related to induction material and neonatal admissions. Foley catheter induction showed a comparable caesarean section rate compared with prostaglandin induction, therefore the incremental cost-effectiveness ratio was not informative. Foley induction resulted in fewer neonatal admissions (incremental cost-effectiveness ratio €2708) and asphyxia/postpartum haemorrhage (incremental cost-effectiveness ratios €5257) compared with prostaglandin induction. CONCLUSIONS: Foley catheter and prostaglandin E2 labour induction generate comparable costs.

Techniques for wound closure at caesarean section: a randomized clinical trial.

OBJECTIVE: It is unclear which technique for skin closure should be used at caesarean section (CS) in order to get the best cosmetic result. STUDY DESIGN: We conducted a randomized controlled trial to assess the cosmetic result of different techniques for skin closure after CS. A two-center single-blind randomized controlled trial was performed in The Netherlands. Women undergoing their first CS were eligible for the trial. In a factorial design, women were randomly allocated to (1) closure of the fat layer versus non-closure and (2) staples or intracutaneous stitches for skin closure. The cosmetic result was assessed using the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: We included 124 women. In the stitches group 63% [39/62] women judged the scar as satisfactory, versus 63% [38/60] in the staples group (RR 1.01; 95% CI 0.64-1.6). When the subcutaneous fat layer was closed, 52% [33/63] of the women scored the scar as satisfactory, versus 75% [44/59] of the women in whom the fat layer was not separately closed (RR 0.53; 95% CI 0.32-0.89). This effect was independent of the subcutaneous thickness (p-value for interaction 0.64). Of the secondary outcomes, subcutaneous closure of the fat layer was associated with a longer admission time (median 4 days; IQR 3-5 versus 3 days; IQR 3-5, p-value 0.023). CONCLUSIONS: The choice of staples or stitches does not affect the cosmetic result after a caesarean section. Closing of the subcutaneous fat layer, however, negatively affects the cosmetic result and is associated with a longer admission time.

Tailored expectant management: risk factors for non-adherence.

INTRODUCTION: Prediction models for spontaneous pregnancy are useful tools to prevent overtreatment, complications and costs in subfertile couples with a good prognosis. The use of such models and subsequent expectant management in couples with a good prognosis are recommended in the Dutch fertility guidelines, but not fully implemented. In this study, we assess risk factors for non-adherence to tailored expectant management. METHODS: Couples with mild male, unexplained and cervical subfertility were included in this multicentre prospective cohort study. If the probability of spontaneous pregnancy within 12 months was ≥40%, expectant management for 6-12 months was advised. Multivariable logistic regression was used to identify patient and clinical characteristics associated with non-adherence to tailored expectant management. RESULTS: We included 3021 couples of whom 1130 (38%) had a ≥40% probability of a spontaneous pregnancy. Follow-up was available for 1020 (90%) couples of whom 214 (21%) had started treatment between 6 and 12 months and 153 (15%) within 6 months. A higher female age and a longer duration of subfertility were associated with treatment within 6 months (OR: 1.06, 95% CI: 1.01-1.1; OR: 1.4; 95% CI: 1.1-1.8). A fertility doctor in a clinical team reduced the risk of treatment within 6 months (OR: 0.62; 95% CI: 0.39-0.99). CONCLUSIONS: In couples with a favorable prognosis for spontaneous pregnancy, there is considerable overtreatment, especially if the woman is older and duration of the subfertility is longer. The presence of a fertility doctor in a clinic may prevent early treatment.

Implementation of evidence-based practice: outside the box, throughout the hospital.

BACKGROUND: Evidence-based practice (EBP) is a generally accepted means to improve healthcare quality. However, not all healthcare professionals and managers apply EBP in daily practice. We investigated EBP attitudes, knowledge and the perceived barriers and facilitators to practising EBP , to define tailor-made interventions for improving evidence-based behaviour. METHODS: In this cross-sectional survey, doctors and nurses from five major specialities of a university hospital were invited to complete the McColl and Barriers questionnaires. RESULTS: Response rates were 70% (305÷435) for doctors and 74% (396÷537) for nurses. They were welcoming towards EBP, but considered time constraints, knowledge gaps and poor availability of evidence as major barriers to implement EBP . They also mentioned contradicting results (75%) and flawed methodology (69%), while nurses frequently mentioned unawareness of (75%), or difficulty in reading and interpreting research papers (70%). Regarding EBP knowledge, 6/8 common EBP terms could be explained by 54% of doctors but by only 15% of nurses. Facilitating factors among doctors concerned the availability and accessibility of high-level evidence and communication of evidence during various clinical meetings and handovers for clinical decision making. Among nurses, promoting factors involved more teaching and instances to incorporate EBP in clinical practice. Both groups desired more managerial support in terms of motivation and opportunities. CONCLUSIONS: Doctors and nurses have embraced the EBP paradigm as an important means to improve quality of clinical patient care, but its application is still cumbersome. This paper offers a tailored programme for implementation and managerial role-models.sustainment of EBP, corroborated by professional and managerial role-models.

Is fetal cardiac function gender dependent?

INTRODUCTION: An increased nuchal translucency (NT) is more common in males. A delayed diastolic cardiac function maturation has been proposed to explain this and the reported gender-related differences in ductus venosus (DV) flow. OBJECTIVE: To investigate gender-related differences in fetal cardiac function. METHODS: One hundred and ninety karyotypically/phenotypically normal fetuses with structurally normal hearts and known NT measurement, (104 > 95th percentile), were prospectively included between 1 October 2003 and 1 April 2009. They had been referred for fetal echocardiography. Three hundred and nine echocardiograms were performed between 11 and 35 weeks' gestation. The atrioventricular valve E- and A-wave peak velocity, E/A-velocity ratio and E/TVI ratio, myocardial performance index, semilunar valves acceleration time (AT) and peak velocity, stroke volume and cardiac output as well as DV pulsatility index for veins at 11-14 weeks' gestation, were measured. A multilevel analysis was performed using the NT (multiples of the median) as a continuous variable. RESULTS: The male : female ratio was 1.56:1. The tricuspid valve E/TVI was significantly higher and pulmonary valve AT significantly lower in females compared to males. No other significant differences in cardiac function were found. CONCLUSIONS: Our findings suggest better right ventricular (RV) relaxation and increased RV afterload in female fetuses, independent of NT thickness, between 11 and 35 weeks' gestation.

Cardiac function in trisomy 21 fetuses.

OBJECTIVES: Trisomy 21 is associated with an increased nuchal translucency thickness (NT), abnormal ductus venosus (DV) flow at 11-14 weeks' gestation and congenital heart defects (CHD), and cardiac dysfunction has been hypothesized as the link between them. We therefore aimed to investigate whether cardiac function is altered in trisomy 21 fetuses. METHODS: Between December 2003 and June 2009, we performed echocardiography on 46 trisomy 21 fetuses (28 with structurally normal heart and 18 with CHD) and on 191 chromosomally/phenotypically normal fetuses with a confirmed normal heart (87 with normal NT and 104 with NT ≥ 95(th) percentile), between 11 and 35 weeks' gestation. Measurements included: E- and A-wave peak velocity, E/A velocity ratio and E/time velocity integral (TVI) ratio over atrioventricular valves; myocardial performance index (MPI); semilunar valve peak velocity and acceleration time; stroke volume (SV); cardiac output; and DV pulsatility index for veins (PIV) at 11-14 weeks' gestation. Data were categorized into three different age groups for analysis (11 to 13 + 6, 14 to 21 + 6 and 22 to 35 weeks' gestation). RESULTS: The tricuspid valve (TV) A-wave velocity and aortic valve peak velocity were significantly reduced in trisomy 21 compared with normal fetuses. Other highly significant differences found in trisomy 21 fetuses at 11-14 weeks' were increased TV-E/A ratio and DV-PIV, and decreased pulmonary valve peak velocity. We also observed evidence of left ventricular (LV) systolic dysfunction, reduced SV and increased MPI. After 14 weeks' gestation, the mitral valve A-wave peak velocity and E/TVI ratio were significantly reduced in the trisomy 21 fetuses with normal hearts compared with the controls with increased NT. CONCLUSIONS: In comparison with controls with normal or increased NT, cardiac function in trisomy 21 fetuses is abnormal irrespective of the presence of CHD. Evidence for cardiac loading (increased preload and afterload) and LV systolic (in the first trimester) and later diastolic dysfunction was observed.

Fetal cardiac function between 11 and 35 weeks' gestation and nuchal translucency thickness.

OBJECTIVES: The pathophysiological background of an increased nuchal translucency (NT) is still poorly understood. Cardiac dysfunction has been proposed as a cause. The aim of this study was to determine if, in fetuses with normal hearts, the NT thickness is related to cardiac function throughout gestation. METHODS: The NT was measured in 191 karyotypically/phenotypically normal fetuses with structurally normal hearts and was increased (≥ 95(th) centile) in 104. All fetuses had been referred for fetal echocardiography and were prospectively included between October 1 2003 and April 1 2009. Three-hundred and ten echocardiograms were performed between 11 and 35 weeks' gestation. The E- and A-wave velocity, E/A velocity ratio, E/time velocity integral (TVI) ratio over the atrioventricular (AV) valves, myocardial performance index, acceleration time (AT) and peak velocity over the semilunar valves, stroke volume (SV) and cardiac output (CO) as well as the ductus venosus pulsatility index for veins at 11-14 weeks' gestation (DV-PIV), were measured. A multilevel analysis was performed using the NT multiples of the median (MoM) as a continuous variable. RESULTS: AV-E- and A-wave velocities, E/A velocity ratios, semilunar valve peak velocity, SV, CO and aortic valve (AoV) AT increased significantly with advancing gestation. At 11-14 weeks' gestation, the AoV-AT, tricuspid valve (TV)-E/A, TV-E/TVI ratios and DV-PIV increased, and the pulmonary valve (PV) AT decreased, with increasing NT-MoMs. After midgestation, the PV-AT increased and the AoV-AT, TV-E/A and TV-E/TVI ratios decreased with increasing NT-MoMs. CONCLUSIONS: NT thickness is related to right ventricular diastolic function and semilunar valve AT. Our findings suggest improved first-trimester, but later reduced, right ventricular relaxation and discordant ventricular afterload in fetuses with an increased NT.

Ductus venosus pulsatility index measurement reduces the false-positive rate in first-trimester screening.

OBJECTIVE: To investigate if ductus venosus (DV) pulsatility index for veins (PIV) and a-wave measurements can increase the accuracy of first-trimester Down syndrome screening in a high-risk population. METHODS: The database of our fetal medicine unit was searched for all cases at increased first-trimester Down syndrome risk. Multivariable logistic regression was used to construct a prediction rule for chromosomal anomalies at any given maternal age, nuchal translucency multiples of the median (NT-MoM) and DV-PIV MoM. The discriminative ability of the model was assessed by using receiver-operating characteristics (ROC) analysis. RESULTS: The study population included 445 fetuses. DV-PIV was increased (≥ 95(th) percentile) in 239 (54%) and DV a-wave was abnormal in 187 fetuses (42%). In this cohort, 80% of all chromosomal anomalies were identified by an increased DV-PIV and 68% by an abnormal a-wave. The odds of chromosomal anomalies increased by a factor of 4.2 per MoM increase in DV-PIV, adjusted for NT and maternal age. The area under the ROC curve for the prediction of chromosomal anomalies was 0.79. After correction for DV-PIV, DV a-wave did not significantly add to the prediction of chromosomal anomalies. CONCLUSION: In a population of fetuses at increased first-trimester risk for Down syndrome, the combination in a logistic regression model of NT, DV-PIV and maternal age can improve the accuracy of screening for trisomy 21 and other chromosomal anomalies. This is the first study that models the additional value of DV-PIV as a continuous variable to NT measurement alone in a high-risk first-trimester population.