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1.  Functional Vascular Changes of the Kidney during Pregnancy in Animals: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(11):e112084.
Renal vascular responses to pregnancy have frequently been studied, by investigating renal vascular resistance (RVR), renal flow, glomerular filtration rate (GFR), and renal artery responses to stimuli. Nonetheless, several questions remain: 1. Which vasodilator pathways are activated and to what extent do they affect RVR, renal flow and GFR across species, strains and gestational ages, 2. Are these changes dependent on renal artery adaptation, 3. At which cellular level does pregnancy affect the involved pathways? In an attempt to answer the questions raised, we performed a systematic review and meta-analysis on animal data. We included 37 studies (116 responses). At mid-gestation, RVR and GFR change to a similar degree across species and strains, accompanied by variable change in renal flow. At least in rats, changes depend on NO activation. At late gestation, changes in RVR, renal flow and GFR vary between species and strains. In rats, these changes are effectuated by sympathetic stimulation. Overall, renal artery responsiveness to stimuli is unaffected by pregnancy, except for Sprague Dawley rats in which pregnancy enhances renal artery vascular compliance and reduces renal artery myogenic reactivity. Our meta-analysis shows that: 1. Pregnancy changes RVR, renal flow and GFR dependent on NO-activation and sympathetic de-activation, but adjustments are different among species, strains and gestational ages; 2. These changes do not depend on adaptation of renal artery responsiveness; 3. It remains unknown at which cellular level pregnancy affects the pathways. Our meta-analysis suggests that renal changes during pregnancy in animals are qualitatively similar, even in comparison to humans, but quantitatively different.
PMCID: PMC4227845  PMID: 25386682
3.  Well being of obstetric patients on minimal blood transfusions (WOMB trial) 
Primary postpartum haemorrhage is an obstetrical emergency often causing acute anaemia that may require immediate red blood cell (RBC) transfusion. This anaemia results in symptoms such as fatigue, which may have major impact on the health-related quality of life. RBC transfusion is generally thought to alleviate these undesirable effects although it may cause transfusion reactions. Moreover, the postpartum haemoglobin level seems to influence fatigue only for a short period of time. At present, there are no strict transfusion criteria for this specific indication, resulting in a wide variation in postpartum policy of RBC transfusion in the Netherlands.
The WOMB trial is a multicentre randomised non-inferiority trial. Women with acute anaemia due to postpartum haemorrhage, 12-24 hours after delivery and not initially treated with RBC transfusion, are eligible for randomisation. Patients with severe physical complaints are excluded. Patients are randomised for either RBC transfusion or expectant management. Health related quality of life (HRQoL) will be assessed at inclusion, at three days and one, three and six weeks postpartum with three validated measures (Multi-dimensional Fatigue Inventory, ShortForm-36, EuroQol-5D). Primary outcome of the study is physical fatigue three days postpartum. Secondary outcome measures are general and mental fatigue scores and generic health related quality of life scores, the number of RBC transfusions, length of hospital stay, complications and health-care costs.
The primary analysis will be by intention-to-treat. The various longitudinal scores will be evaluated using Repeated Measurements ANOVA. A costs benefit analysis will also be performed. The power calculation is based on the exclusion of a difference in means of 1.3 points or greater in favour of RBC transfusion arm regarding physical fatigue subscale. With missing data not exceeding 20%, 250 patients per arm have to be randomised (one-sided alpha = 0.025, power = 80%).
This study will provide evidence for a guideline regarding RBC transfusion in the postpartum patient suffering from acute anaemia. Equivalence in fatigue score, remaining HRQoL scores and physical complications between both groups is assumed, in which case an expectant management would be preferred to minimise transfusion reactions and costs.
Trial registration NCT00335023, Nederlands Trial Register NTR335
PMCID: PMC3022737  PMID: 21162725
4.  Cost-effectiveness of recurrence risk guided care versus care as usual in women who suffered from early-onset preeclampsia including HELLP syndrome in their previous pregnancy (the PreCare study) 
Preeclampsia and HELLP syndrome may have serious consequences for both mother and fetus. Women who have suffered from preeclampsia or the HELLP syndrome, have an increased risk of developing preeclampsia in a subsequent pregnancy. However, most women will develop no or only minor complications. In this study, we intend to determine cost-effectiveness of recurrence risk guided care versus care as usual in pregnant women with a history of early-onset preeclampsia.
We developed a prediction model to estimate the individual risk of recurrence of early-onset preeclampsia and the HELLP syndrome. In a before-after study, pregnant women with preeclampsia or HELLP syndrome in their previous pregnancy receiving care as usual (before introduction of the prediction model) will be compared with women receiving recurrence risk guided care (after introduction of the prediction model).
Eligible and pregnant women will be recruited at six university hospitals and seven large non-university tertiary referral hospitals in the Netherlands.
The primary outcome measure is the recurrence of early-onset preeclampsia or HELLP syndrome in women allocated to the regular monitoring group.
For the economic evaluation, a modelling approach will be used. Costs and effects of recurrence risk guided care with those of care as usual will be compared by means of a decision model. Two incremental cost-effectiveness ratios will be calculated: 1) cost per Quality Adjusted Life Year (mother unit of analysis) and 2) cost per live born child (child unit of analysis).
This is, to our knowledge, the first study that evaluates prospectively the efficacy of a multivariable prediction rule for recurrent hypertensive disease in pregnancy. Results of this study could either be integrated into the current guideline on Hypertensive Disorders in Pregnancy, or be used to develop a new guideline.
PMCID: PMC2966448  PMID: 20932350
5.  IMproving PArticipation of patients in Clinical Trials - rationale and design of IMPACT 
One of the most commonly reported problems of randomised trials is that recruitment is usually slower than expected. Trials will cost more and take longer, thus delaying the use of the results in clinical practice, and incomplete samples imply decreased statistical power and usefulness of its results. We aim to identify barriers and facilitators for successful patient recruitment at the level of the patient, the doctor and the hospital organization as well as the organization and design of trials over a broad range of studies.
We will perform two cohort studies and a case-control study in the Netherlands. The first cohort study will report on a series of multicenter trials performed in a nationwide network of clinical trials in obstetrics and gynaecology. A questionnaire will be sent to all clinicians recruiting for these trials to identify determinants - aggregated at centre level - for the recruitment rate. In a case control-study nested in this cohort we will interview patients who refused or consented participation to identify factors associated with patients' consent or refusal. In a second cohort study, we will study trials that were prospectively registered in the Netherlands Trial Register. Using a questionnaire survey we will assess whether issues on hospital organization, trial organization, planning and trial design were associated with successful recruitment, i.e. 80% of the predefined number of patients recruited within the planned time.
This study will provide insight in barriers and facilitators for successful patient recruitment in trials. The results will be used to provide recommendations and a checklist for individual trialists to identify potential pitfalls for recruitment and judge the feasibility prior to the start of the study. Identified barriers and motivators coupled to evidence-based interventions can improve recruitment of patients in clinical trials.
PMCID: PMC2955658  PMID: 20875119
6.  Gynaecologists estimate and experience laparoscopic hysterectomy as more difficult compared with abdominal hysterectomy 
Gynecological Surgery  2010;7(4):359-363.
The level of difficulty of various types of hysterectomy differs and may influence the choice of either approach. When surgeons consider one specific approach to hysterectomy as more difficult, they may be reluctant to perform this type of hysterectomy. The main objective of this study was to investigate the potential different levels of difficulty for laparoscopic and abdominal hysterectomy. Furthermore, the accuracy of estimating the level of difficulty was examined. In a randomized controlled trial between laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH), gynaecologists were asked to record the preoperatively estimated and postoperatively experienced level of difficulty on a Visual Analogue Scale (VAS). Differences between LH and AH were examined and the correlation between the estimated uterine weight on bimanual palpation and the actual uterine weight was calculated. A difference on the VAS of three points or more (ΔVAS ≥ 3) was considered clinically relevant. In 72 out of 76 cases, both VAS scores were recorded. LH was estimated and experienced as significantly more difficult as compared with AH. In 13 (18%) cases, ΔVAS was ≥3, equally distributed between LH (n = 6) and AH (n = 7). Eleven of these 13 cases had a positive ΔVAS ≥3, meaning that surgery was experienced as more difficult than it was estimated. Surgeon’s estimation of uterine size correlated well with the actual uterine weight. LH is considered as more difficult than AH, which might be a reason for its slow implementation. In a large proportion of cases, gynaecologists seem to be able to estimate the level of difficulty of hysterectomy accurately.
PMCID: PMC2974921  PMID: 21124999
Randomized trial; Laparoscopic hysterectomy; Abdominal hysterectomy; Level of difficulty
7.  Pessaries in multiple pregnancy as a prevention of preterm birth: the ProTwin Trial 
Multiple pregnancies are at high risk for preterm birth, and therefore an important cause of infant mortality and morbidity. A pessary is a simple and potentially effective measure for the prevention of preterm birth. Small studies have indicated its effectiveness, but large studies with sufficient power on the subject are lacking. Despite this lack of evidence, the treatment is at present applied by some gynaecologists in The Netherlands.
We aim to investigate the hypothesis that prophylactic use of a cervical pessary will be effective in the prevention of preterm delivery and the neonatal mortality and morbidity resulting from preterm delivery in multiple pregnancy. We will evaluate the costs and effects of this intervention. At study entry, cervical length will be measured. Eligible women will be randomly allocated to receive either a cervical pessary or no intervention. The cervical pessary will be placed in situ at 16 to 20 weeks, and will stay in situ up to 36 weeks gestation or until delivery, whatever comes first.
The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 7.2% without to 3.9% with a cervical pessary, using a two-sided test with an alpha of 0.05 and a power of 0.80.
This trial will provide evidence on whether a cervical pessary will decrease the incidence of early preterm birth and its concomitant bad neonatal outcome in multiple pregnancies.
Trial registration
Current Controlled Trials: NTR 1858
PMCID: PMC2754434  PMID: 19761606
8.  Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial) 
Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours.
The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.
Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, β 0.2 at alpha 0.05).
This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks.
Trial Registration
Clinical trial registration: , NTR 1336, date of registration: June 3rd 2008.
PMCID: PMC2754432  PMID: 19737426
9.  Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial) 
At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective.
We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, β 0.2, α 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin.
This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor.
Trial registration
Nederlands Trial Register (NTR) number 1857, .
PMCID: PMC2752451  PMID: 19723320
10.  Induction of labour versus expectant monitoring in women with pregnancy induced hypertension or mild preeclampsia at term: the HYPITAT trial 
Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates.
Women with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%.
This trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications.
Trial Registration
The protocol is registered in the clinical trial register number ISRCTN08132825.
PMCID: PMC1950708  PMID: 17662114
11.  Rationale and Design of the PRegnancy and Infant DEvelopment (PRIDE) Study 
To optimise the health of pregnant women and their children by evidence-based primary and secondary prevention, more scientific knowledge is needed. To overcome the methodological limitations of many studies on pregnancy and child health, which often use a retrospective design, we established the PRIDE (PRegnancy and Infant DEvelopment) Study.
Methods and Results
The PRIDE Study is a large prospective cohort study that aims at including 150 000–200 000 women in early pregnancy to study a broad range of research questions pertaining to pregnancy complications, maternal and child health, and adverse developmental effects in offspring. Women are invited to participate by their prenatal care provider before or at their first prenatal care visit and are asked to fill out web-based questionnaires in gestational weeks 8–10, 17, and 34, as well as biannually throughout childhood. In addition, a food frequency questionnaire and a paternal questionnaire are administered and medical records are consulted. Multiple validation studies will be conducted and paper-and-pencil questionnaires are available for women who cannot or do not want to participate through the Internet. For subgroups of participants, blood and saliva samples for genetic and biochemical analyses are being collected. The pilot phase, which started in July 2011, showed a response rate of 47%. Recruitment will eventually cover all of the Netherlands.
We expect that this study, which will be the largest birth cohort in the world so far, will provide new insights in the aetiology of disorders and diseases that originate in pregnancy. The PRIDE Study is open for collaboration.
PMCID: PMC3549557  PMID: 23215710
PRIDE Study; life-course; epidemiology; children; attention-deficit/hyperactivity disorder; pregnancy; asthma; autism

Results 1-11 (11)