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1.  The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial 
BMC Women's Health  2013;13:42.
Background
Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI.
Methods/Design
We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.
Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.
Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).
An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm).
Discussion
The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.
Trial registration number
Netherlands Trial register NTR1449
doi:10.1186/1472-6874-13-42
PMCID: PMC3828011  PMID: 24160333
2.  A Comparison of Complications between Open Abdominal Sacrocolpopexy and Laparoscopic Sacrocolpopexy for the Treatment of Vault Prolapse 
Introduction. Sacrocolpopexy is a generally applied treatment for vault prolapse which can be performed laparoscopically or by open laparotomy. Methods. Between October 2007 and December 2012, we performed a multicenter prospective cohort study in 2 university and 4 teaching hospitals in the Netherlands. We included patients with symptomatic posthysterectomy vaginal vault prolapse requiring surgical treatment, who either had abdominal or laparoscopic sacrocolpopexy. We studied surgery related morbidity, which was divided in pre-, peri-, and postoperative characteristics. Results. We studied 85 patients, of whom 42 had open abdominal and 43 laparoscopic sacrocolpopexy. In the laparoscopic sacrocolpopexy group, estimated blood loss was significantly less compared to the abdominal group: 192 mL (±126) versus 77 mL (±182), respectively (P ≤ .001). Furthermore, hospital stay was significantly shorter in the laparoscopic group (4.2 days) as compared to the abdominal group (2.4 days) (P ≤ .001). The overall complication rate was not significantly different (P = .121). However there was a significant difference in favor of the laparoscopic group in peri- and postoperative complications requiring complementary (conservative) treatment and/or extended admittance (RR 0.24 (95%-CI 0.07–0.80), P = .009). Conclusion. Laparoscopic sacrocolpopexy reduces blood loss and hospital stay as compared to abdominal sacrocolpopexy and generates less procedure related morbidity.
doi:10.1155/2013/528636
PMCID: PMC3804373  PMID: 24191158
3.  Treating suspected uterine cavity abnormalities by hysteroscopy to improve reproductive outcome in women with unexplained infertility or prior to IUI, IVF, or ICSI 
Gynecological Surgery  2013;10(3):165-167.
Endometrial polyps, submucous fibroids, uterine septa, and intrauterine adhesions can be found by ultrasound (US), HSG, hysteroscopy, or any combined in 10–15 % of infertile women. Observational studies suggest a better reproductive outcome when these anomalies are removed by operative hysteroscopy. The current Cochrane review assesses the effectiveness of hysteroscopy for treating these suspected anomalies in women with otherwise unexplained infertility or prior to intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection.
doi:10.1007/s10397-013-0798-0
PMCID: PMC3718997  PMID: 23894233
Hysteroscopy; Subfertility; Uterine cavity abnormalities; Randomized controlled trial
4.  Cervical Pessaries for the Prevention of Preterm Birth: A Systematic Review 
Introduction. Reduction of preterm birth is a major goal in obstetric care. We performed a systematic review of randomized controlled trials and cohort studies on the effectiveness of the cervical pessary to prevent preterm birth. Methods. We searched the electronic databases of MEDLINE and Embase from inception until April 2012 to identify studies investigating treatment with a cervical pessary to prevent preterm birth. We constructed two-by-two tables for delivery before 28, 34, and 37 weeks of gestation and calculated relative risks (RRs) with 95% confidence intervals. Results. The search revealed 103 potentially eligible abstracts of which six cohort studies and four randomized controlled trials (RCTs) investigated the effectiveness of the pessary. One RCT (n = 380) demonstrated a lower delivery rate prior to 34 weeks (RR 0.24; 95% CI 0.13–0.43) in the pessary group, while another RCT (n = 108) showed no positive effect of pessary for delivery before 34 weeks (RR 1.73; 95% CI 0.43–6.88). Two older quasi randomized studies and cohort studies indicated potential effect of the pessary. Conclusions. Available randomized and nonrandomized studies indicate potential effectiveness of a cervical pessary in the prevention of preterm birth. More randomized clinical trials are needed before this device can be used in clinical practice.
doi:10.1155/2013/576723
PMCID: PMC3628502  PMID: 23606848
5.  Risk Factors for Cesarean Delivery following Labor Induction in Multiparous Women 
Journal of Pregnancy  2013;2013:820892.
Objective. To identify potential risk factors for cesarean delivery following labor induction in multiparous women at term. Methods. We conducted a retrospective case-control study. Cases were parous women in whom the induction of labor had resulted in a cesarean delivery. For each case, we used the data of two successful inductions as controls. Successful induction was defined as a vaginal delivery after the induction of labor. The study was limited to term singleton pregnancies with a child in cephalic position. Results. Between 1995 and 2010, labor was induced in 2548 parous women, of whom 80 had a cesarean delivery (3%). These 80 cases were compared to the data of 160 parous women with a successful induction of labor. In the multivariate analysis history of preterm delivery (odds ratio (OR) 5.3 (95% CI 1.1 to 25)), maternal height (OR 0.87 (95% CI 0.80 to 0.95)) and dilatation at the start of induction (OR 0.43 (95% CI 0.19 to 0.98)) were associated with failed induction. Conclusion. In multiparous women, the risk of cesarean delivery following labor induction increases with previous preterm delivery, short maternal height, and limited dilatation at the start of induction.
doi:10.1155/2013/820892
PMCID: PMC3556868  PMID: 23365754
6.  The value of preoperative urodynamics according to gynecologists and urologists with special interest in stress urinary incontinence 
Introduction and hypothesis
The aim of this study is to assess variations in practice in the use of preoperative urodynamics in women with stress urinary incontinence (SUI).
Methods
We performed an E-survey among all Dutch gynecologists and urologists who have SUI as focus in daily practice. The questions concerned the common policy and preferred policy. Descriptive statistics were used.
Results
Of the 260 targeted specialists, 163 (63%) responded. We found that 37% of the respondents performed standard preoperative urodynamics; in the preferred practice, this would reduce to only 18%. Eighty percent indicated they would operate a patient with a positive stress test without urodynamic SUI, whereas 21% would do this also in case the clinical stress test was negative. Only 9% of the respondents indicated they adapted the choice of the type of sling based on urethral pressure profilometry parameters.
Conclusions
Urodynamics are not routinely performed, and outcomes hardly influence the choice of treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s00192-011-1565-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00192-011-1565-2
PMCID: PMC3305873  PMID: 21927939
Urodynamics; Stress urinary incontinence; Surgery; Practice variation
7.  Additional effects of the cervical length measurement in women with preterm contractions: a systematic review 
Purpose
Transvaginal cervical length measurement in women with symptoms of preterm labor has been used to decide if treatment is necessary. Cervical length measurement may also have additional effects on patients, such as providing reassurance, although the evidence to support this is unclear. We explored and summarized to what extent additional effects of cervical length measurement in women with threatened preterm labor have been reported in the clinical literature and what the magnitude of these effects was.
Methods
We performed a systematic review of the literature to identify articles reporting on cervical length measurements in women with symptoms of preterm labor. We assessed whether these articles reported patient outcomes other than preterm delivery.
Results
The electronic and hand search resulted in 764 articles, of which 172 met initial criteria for further eligibility assessment. We found 12 articles that reported additional effects of cervical length measurement in symptomatic women, such as the reassurance or the sensory consequences related to the transvaginal procedure. None of the articles quantified such additional effects.
Conclusions
There appears to be a gap between the presumed effects of cervical length measurement on patient outcomes, such as patients’ reassurance, and the actual assessment of these effects during test evaluations. We suggest that future evaluations of prognostic preterm labor tests include a comprehensive assessment of patient outcomes.
doi:10.1007/s00404-011-1892-z
PMCID: PMC3155022  PMID: 21484403
Cervical length; Preterm labor; Diagnostic test; Methodology; Reassurance; Patient perspective
8.  Maternal health-related quality of life after induction of labor or expectant monitoring in pregnancy complicated by intrauterine growth retardation beyond 36 weeks 
Quality of Life Research  2011;20(9):1427-1436.
Objective
Pregnancies complicated by intrauterine growth retardation (IUGR) beyond 36 weeks of gestation are at increased risk of neonatal morbidity and mortality. Optimal treatment in IUGR at term is highly debated. Results from the multicenter DIGITAT (Disproportionate Intrauterine Growth Intervention Trial At Term) trial show that induction of labor and expectant monitoring result in equal neonatal and maternal outcomes for comparable cesarean section rates. We report the maternal health-related quality of life (HR-QoL) that was measured alongside the trial at several points in time.
Methods
Both randomized and non-randomized women were asked to participate in the HR-QoL study. Women were asked to fill out written validated questionnaires, covering background characteristics, condition-specific issues and the Short Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression scale (HADS), and Symptom Check List (SCL-90) at baseline, 6 weeks postpartum and 6 months postpartum. We compared the difference scores of all summary measures between the two management strategies by ANOVA. A repeated measures multivariate mixed model was defined to assess the effect of the management strategies on the physical (PCS) and mental (MCS) components of the SF-36. Analysis was by intention to treat.
Results
We analyzed data of 361 randomized and 198 non-randomized patients. There were no clinically relevant differences between the treatments at 6 weeks or 6 months postpartum on any summary measures; e.g., on the SF-36 (PCS: P = .09; MCS: P = .48). The PCS and the MCS were below norm values at inclusion. The PCS improved over time but stayed below norm values at 6 months, while the MCS did not improve.
Conclusion
In pregnancies complicated by IUGR beyond 36 weeks, induction of labor does not affect the long-term maternal quality of life.
doi:10.1007/s11136-011-9891-x
PMCID: PMC3195683  PMID: 21468753
Intrauterine growth retardation; Small for gestational age; Quality of life; Induction of labor; Expectant management
9.  Long-term health-related and economic consequences of short-term outcomes in evaluation of perinatal interventions 
Background
Many perinatal interventions are performed to improve long-term neonatal outcome. To evaluate the long-term effect of a perinatal intervention follow-up of the child after discharge from the hospital is necessary because serious sequelae from perinatal complications frequently manifest themselves only after several years. However, long-term follow-up is time-consuming, is not in the awareness of obstetricians, is expensive and falls outside the funding-period of most obstetric studies. Consequently, short-term outcomes are often reported instead of the primary long-term end-point. With this project, we will assess the current state of affairs concerning follow-up after obstetric RCTs and we will develop multivariable prediction models for different long-term health outcomes. Furthermore, we would like to encourage other researchers participating in follow-up studies after large obstetric trials (> 350 women) to inform us about their studies so that we can include their follow-up study in our systematic review. We would invite these researchers also to join our effort and to collaborate with us on the external validation of our prediction models.
Methods/Design
A systematic review of neonatal follow-up after obstetric studies will be performed. All reviews of the Cochrane Pregnancy and Childbirth group will be assessed for reviews on interventions that aimed to improve neonatal outcome. Reviews on interventions primary looking at other aspects than neonatal outcome such as labour progress will also be included when these interventions can change the outcome of the neonate on the short or long-term. Our review will be limited to RCTs with more than 350 women. Information that will be extracted from these RCTs will address whether, how and for how long follow-up has been performed. However, in many cases long-term follow-up of the infants will not be feasible. An alternative solution to limited follow-up could be to develop prediction models to estimate long-term health outcomes of the newborn based on specific perinatal outcomes and other covariates. For the development of multivariable prediction models for several health outcomes, we will use data available from a Dutch cohort study of preterm (< 32 weeks) and/or small for gestational age infants (< 1500 g). These infants were born in The Netherlands in 1983 and followed until they reached the age of 19.
Discussion
The systematic review will provide insight in the extent and methods used for follow-up assessments after obstetric RCTs in the past. The prediction models can be used by future studies to extrapolate short-term outcomes to a long-term horizon or to indicate for which neonates long-term follow-up is required, as their outcomes (either absence or presence of sequelae) cannot be adequately predicted from short-term outcomes and clinical background characteristics.
doi:10.1186/1471-2393-10-42
PMCID: PMC2928175  PMID: 20698963
11.  Protocol for the value of urodynamics prior to stress incontinence surgery (VUSIS) study: a multicenter randomized controlled trial to assess the cost effectiveness of urodynamics in women with symptoms of stress urinary incontinence in whom surgical treatment is considered 
BMC Women's Health  2009;9:22.
Background
Stress urinary incontinence (SUI) is a common problem. In the Netherlands, yearly 64.000 new patients, of whom 96% are women, consult their general practitioner because of urinary incontinence. Approximately 7500 urodynamic evaluations and approximately 5000 operations for SUI are performed every year. In all major national and international guidelines from both gynaecological and urological scientific societies, it is advised to perform urodynamics prior to invasive treatment for SUI, but neither its effectiveness nor its cost-effectiveness has been assessed in a randomized setting.
The Value of Urodynamics prior to Stress Incontinence Surgery (VUSIS) study evaluates the positive and negative effects with regard to outcome, as well as the costs of urodynamics, in women with symptoms of SUI in whom surgical treatment is considered.
Methods/design
A multicentre diagnostic cohort study will be performed with an embedded randomized controlled trial among women presenting with symptoms of (predominant) SUI.
Urinary incontinence has to be demonstrated on clinical examination and/or voiding diary. Physiotherapy must have failed and surgical treatment needs to be under consideration.
Patients will be excluded in case of previous incontinence surgery, in case of pelvic organ prolapse more than 1 centimeter beyond the hymen and/or in case of residual bladder volume of more than 150 milliliter on ultrasound or catheterisation.
Patients with discordant findings between the diagnosis based on urodynamic investigation and the diagnosis based on their history, clinical examination and/or micturition diary will be randomized to operative therapy or individually tailored therapy based on all available information.
Patients will be followed for two years after treatment by their attending urologist or gynaecologist, in combination with the completion of questionnaires.
Six hundred female patients will be recruited for registration from approximately twenty-seven hospitals in the Netherlands. We aspect that one hundred and two women with discordant findings will be randomized.
The primary outcome of this study is clinical improvement of incontinence as measured with the validated Dutch version of the Urinary Distress Inventory (UDI). Secondary outcomes of this study include costs, cure of incontinence as measured by voiding diary parameters, complications related to the intervention, re-interventions, and generic quality of life changes.
Trial registration
Clinical Trials NCT00814749.
doi:10.1186/1472-6874-9-22
PMCID: PMC2722584  PMID: 19622153
12.  Induction of labour versus expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks (the PPROMEXIL-trial) 
Background
Preterm prelabour rupture of the membranes (PPROM) is an important clinical problem and a dilemma for the gynaecologist. On the one hand, awaiting spontaneous labour increases the probability of infectious disease for both mother and child, whereas on the other hand induction of labour leads to preterm birth with an increase in neonatal morbidity (e.g., respiratory distress syndrome (RDS)) and a possible rise in the number of instrumental deliveries.
Methods/Design
We aim to determine the effectiveness and cost-effectiveness of immediate delivery after PPROM in near term gestation compared to expectant management. Pregnant women with preterm prelabour rupture of the membranes at a gestational age from 34+0 weeks until 37+0 weeks will be included in a multicentre prospective randomised controlled trial. We will compare early delivery with expectant monitoring.
The primary outcome of this study is neonatal sepsis. Secondary outcome measures are maternal morbidity (chorioamnionitis, puerperal sepsis) and neonatal disease, instrumental delivery rate, maternal quality of life, maternal preferences and costs. We anticipate that a reduction of neonatal infection from 7.5% to 2.5% after induction will outweigh an increase in RDS and additional costs due to admission of the child due to prematurity. Under these assumptions, we aim to randomly allocate 520 women to two groups of 260 women each. Analysis will be by intention to treat. Additionally a cost-effectiveness analysis will be performed to evaluate if the cost related to early delivery will outweigh those of expectant management. Long term outcomes will be evaluated using modelling.
Discussion
This trial will provide evidence as to whether induction of labour after preterm prelabour rupture of membranes is an effective and cost-effective strategy to reduce the risk of neonatal sepsis.
Controlled clinical trial register
ISRCTN29313500
doi:10.1186/1471-2393-7-11
PMCID: PMC1934382  PMID: 17617892
13.  Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial) 
Background
Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects.
Methods/Design
The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 – 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, β 0.2 at alpha 0.05).
Discussion
This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour.
Trial registration
Clinical trial registration: NTR2947, date of registration: June 20th 2011.
doi:10.1186/1471-2393-14-93
PMCID: PMC3944539  PMID: 24589124
Preterm birth; Tocolytics; Nifedipine; Atosiban; Outcome; Drug safety
15.  The influence of medical testing on patients’ health: an overview from the gynecologists’ perspective 
Background
A medical tests may influence the health of patients by guiding clinical decisions, such as treatment in case of a positive test result. However, a medical test can influence the health of patients through other mechanisms as well, like giving reassurance. To make a clinical recommendation about a medical test, we should be aware of the full range of effects of that test on patients. This requires an understanding of the range of effects that medical testing can have on patients. This study evaluates the mechanisms through which medical testing can influence patients’ health, other than the effect on clinical management, from a gynecologist’s perspective.
Methods
A qualitative study in which explorative focus groups were conducted with gynecologists, gynecological residents and gynecological M.D. researchers (n = 43). Discussions were transcribed verbatim. Transcriptions were coded inductively and analyzed by three researchers.
Results
All participants contributed various clinical examples in which medical testing had influenced patients’ health. Clinical examples illustrated that testing, in itself or in interaction with contextual factors, may provoke a wide range of effects on patients. Our data showed that testing can influence the doctor’s perceptions of the patients’ appraisal of their illness, their perceived control, or the doctor-patient relationship. This may lead to changes in psychological, behavioral, and/or medical outcomes, both favorably or unfavorably. The data were used to construct a conceptual framework of effects of medical testing on patients.
Conclusions
Besides supporting clinical decision making, medical testing may have favorable or unfavorable effects on patients’ health though several mechanisms.
doi:10.1186/1472-6947-13-117
PMCID: PMC3842635  PMID: 24106969
Test evaluation; Patient outcomes; Diagnostic test; Methodology; Qualitative research
16.  Subsequent Pregnancy after Preterm Prelabor Rupture of Membranes before 27 Weeks' Gestation 
AJP Reports  2013;3(2):113-118.
Objective Midtrimester preterm prelabor rupture of membranes (PPROM) has a high rate of neonatal mortality and morbidity. The aim of this study was to study outcomes of subsequent pregnancies after a pregnancy with PPROM before 27 weeks' gestation.
Study Design Retrospective study of subsequent pregnancies of women who suffered PPROM before 27 weeks' gestation from 1994 to 2009. The main outcome measure was the risk of recurrence of PPROM before 27 weeks' gestation. The authors also studied preterm birth and pregnancy outcome in the subsequent pregnancy. Finally, they assessed associative factors for subsequent premature delivery.
Results They identified 307 patients, of whom 118 women had a subsequent pregnancy. Of 99 women with complete outcome data, 9 women (9%) had PPROM before 27 weeks' gestation in a subsequent pregnancy and 35 women (35%) had a preterm delivery. In 58 (59%) of pregnancies no major complications occurred. They found three associative factors for premature delivery in a subsequent pregnancy: negative vaginal culture for Group B streptococcus, increasing maternal age and early gestational age at PPROM in the index pregnancy.
Conclusions Women with PPROM before 27 weeks have a 9% recurrence risk of early PPROM and a risk of 35% of having a preterm delivery in a subsequent pregnancy.
doi:10.1055/s-0033-1353389
PMCID: PMC3799705  PMID: 24147248
preterm rupture of membranes; recurrence; preterm birth
17.  Improving the implementation of tailored expectant management in subfertile couples: protocol for a cluster randomized trial 
Background
Prognostic models in reproductive medicine can help to identify subfertile couples who would benefit from fertility treatment. Expectant management in couples with a good chance of natural conception, i.e., tailored expectant management (TEM), prevents unnecessary treatment and is therefore recommended in international fertility guidelines. However, current implementation is not optimal, leaving room for improvement. Based on barriers and facilitators for TEM that were recently identified among professionals and subfertile couples, we have developed a multifaceted implementation strategy. The goal of this study is to assess the effects of this implementation strategy on the guideline adherence on TEM.
Methods/design
In a cluster randomized trial, 25 clinics and their allied practitioners units will be randomized between the multifaceted implementation strategy and care as usual. Randomization will be stratified for in vitro fertilization (IVF) facilities (full licensed, intermediate/no IVF facilities). The effect of the implementation strategy, i.e., the percentage guideline adherence on TEM, will be evaluated by pre- and post-randomization data collection. Furthermore, there will be a process and cost evaluation of the strategy. The implementation strategy will focus on subfertile couples and their care providers i.e., general practitioners (GPs), fertility doctors, and gynecologists. The implementation strategy addresses three levels: patient level: education materials in the form of a patient information leaflet and a website; professional level: audit and feedback, educational outreach visit, communication training, and access to a digital version of the prognostic model of Hunault on a website; organizational level: providing a protocol based on the guideline. The primary outcome will be the percentage guideline adherence on TEM. Additional outcome measures will be treatment-, patient-, and process-related outcome measures.
Discussion
This study will provide evidence about the effectiveness and costs of a multifaceted implementation strategy to improve guideline adherence on TEM.
Trial registration
http://www.trialregister.nlNTR3405. This study is sponsored by ZonMW.
doi:10.1186/1748-5908-8-53
PMCID: PMC3680105  PMID: 23688282
18.  Induction of labour with a Foley catheter or oral misoprostol at term: the PROBAAT-II study, a multicentre randomised controlled trial 
Background
Induction of labour is a common obstetric procedure. At present, different methods are used for induction of labour in women with an unfavourable cervix. Recently, we showed that in term women with an unfavorable cervix the use of a Foley catheter in comparison with vaginal Prostaglandin E2 gel, results in a comparable vaginal delivery rate. A meta-analysis on the subject indicated lower rates of hyperstimulation, and probably as a sequel fewer cases of postpartum haemorrhage. Misoprostol (PgE1) is another type of prostaglandin frequently used for labour induction, recommended by the international federation of gynaecology and obstetrics (FIGO). Misoprostol can be administered by vaginal, rectal and oral route. There is evidence that oral administration results in less asphyxia and hyperstimulation than vaginal administration. At present, valid comparisons between oral misoprostol and Foley catheter are lacking. Therefore, we propose a randomised controlled trial comparing Foley catheter to oral misoprostol in order to assess safety and cost-effectiveness.
Methods/Design
We plan a multicentre, randomised, controlled, open-label clinical trial among term pregnant women with a vital singleton in cephalic presentation, unfavorable cervix, intact membranes and an indication for induction of labour. After informed consent, women will be randomly allocated by a webbased randomisation system to transcervical Foley catheter or oral misoprostol (50 mcg every 4 hours). The primary outcome will be a composite of complications of uterine hyperstimulation, i.e. post partum haemorrhage and asphyxia. Secondary outcomes are mode of delivery, maternal and neonatal morbidity, costs and women’s preference. Serious adverse events such as severe maternal or neonatal morbitity or mortality will be monitored and reported to an independent data safety monitory board. With a sample size of 1860 women we will be able to demonstrate a 5% non-inferiority of the Foley catheter as compared to misoprostol for the composite outcome.
Discussion
Worldwide, various methods are being used for labour induction. Results of the proposed trial will contribute to the answer which method of induction of labour is most safe, cost-effective, and patient friendly and will help to construct evidence based guidelines.
Trial registration
The Netherlands Trial Register NTR3466
doi:10.1186/1471-2393-13-67
PMCID: PMC3610263  PMID: 23506128
Induction of labour; Oral misoprostol; Foley catheter; Asphyxia; Post partum haemorrhage; Hyperstimulation; Bishop score; Unfavourable cervix
19.  SIMPLE: implementation of recommendations from international evidence-based guidelines on caesarean sections in the Netherlands. Protocol for a controlled before and after study 
Background
Caesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently.
Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives).
Methods
An independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs.
Discussion
This study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child.
Trial registration
http://www.clinicaltrials.gov: NCT01261676
doi:10.1186/1748-5908-8-3
PMCID: PMC3547819  PMID: 23281646
20.  The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial 
BMC Women's Health  2012;12:29.
Background
Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime.
Methods/Design
Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT.
Discussion
The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines.
Trial registration
NTR2657
doi:10.1186/1472-6874-12-29
PMCID: PMC3460731  PMID: 22989359
Ovarian reserve; Antral follicle count; IVF; Individualised FSH stimulation dosages; Live birth rate
21.  Remifentanil patient controlled analgesia versus epidural analgesia in labour. A multicentre randomized controlled trial 
Background
Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments.
Methods/design
The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia.
Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief.
Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects.
The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared.
Discussion
This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day.
Trial registration number
Dutch Trial Register NTR2551, http://www.trialregister.nl
doi:10.1186/1471-2393-12-63
PMCID: PMC3464937  PMID: 22748068
Analgesia; Labour; Remifentanil; Patient controlled analgesia; Epidural
22.  Costs and effects of screening and treating low risk women with a singleton pregnancy for asymptomatic bacteriuria, the ASB study 
Background
The prevalence of asymptomatic bacteriuria (ASB) in pregnancy is 2-10% and is associated with both maternal and neonatal adverse outcomes as pyelonephritis and preterm delivery. Antibiotic treatment is reported to decrease these adverse outcomes although the existing evidence is of poor quality.
Methods/Design
We plan a combined screen and treat study in women with a singleton pregnancy. We will screen women between 16 and 22 weeks of gestation for ASB using the urine dipslide technique. The dipslide is considered positive when colony concentration ≥105 colony forming units (CFU)/mL of a single microorganism or two different colonies but one ≥105 CFU/mL is found, or when Group B Streptococcus bacteriuria is found in any colony concentration. Women with a positive dipslide will be randomly allocated to receive nitrofurantoin or placebo 100 mg twice a day for 5 consecutive days (double blind). Primary outcomes of this trial are maternal pyelonephritis and/or preterm delivery before 34 weeks. Secondary outcomes are neonatal and maternal morbidity, neonatal weight, time to delivery, preterm delivery rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal admission days and costs.
Discussion
This trial will provide evidence for the benefit and cost-effectiveness of dipslide screening for ASB among low risk women at 16–22 weeks of pregnancy and subsequent nitrofurantoin treatment.
Trial registration
Dutch trial registry: NTR-3068
doi:10.1186/1471-2393-12-52
PMCID: PMC3433391  PMID: 22892110
24.  Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials 
Background
Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.
Methods/design
We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.
Discussion
Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.
doi:10.1186/1471-2393-12-13
PMCID: PMC3315727  PMID: 22420582
25.  Laparoscopy to predict the result of primary cytoreductive surgery in advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study 
BMC Cancer  2012;12:31.
Background
Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer.
Methods
Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat.
Discussion
Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients.
Trial registration
Netherlands Trial Register number NTR2644
doi:10.1186/1471-2407-12-31
PMCID: PMC3292486  PMID: 22264278

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