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Carolien Roos,
Marc E A Spaanderman,
Ewoud Schuit,
Kitty W M Bloemenkamp,
Antoinette C Bolte,
Jérôme Cornette,
Johannes J J Duvekot, Jim van Eyck,
Maureen T M Franssen,
Christianne J de Groot, [......],
Dimitri N M Papatsonis,
Martina M Porath,
Hubertina C J Scheepers,
Sicco A Scherjon,
Krystyna M Sollie,
Sylvia M C Vijgen,
Christine Willekes,
Ben Willem J Mol,
Joris A M van der Post,
Fred K Lotgering
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ABSTRACT: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome.
To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth.
APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010).
Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses.
Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis.
Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45).
In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time.
trialregister.nl Identifier: NTR1336.
JAMA The Journal of the American Medical Association 01/2013; 309(1):41-7. · 30.03 Impact Factor
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Sophie Ms Liem,
Dick J Bekedam,
Kitty Wm Bloemenkamp,
Anneke Kwee,
Dimitri Nm Papatsonis,
Joris Am van der Post,
Arianne C Lim,
Hubertina Cj Scheepers,
Christine Willekes,
Johannes J Duvekot,
Marc Spaanderman,
Martina Porath, Jim van Eyck,
Monique C Haak,
Marielle G van Pampus,
Hein W Bruinse,
Ben Willem J Mol,
Maud A Hegeman
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ABSTRACT: ABSTRACT: The initial sample size calculation in our protocol (Hegeman et al, BMC Pregnancy Childbirth, 2009, 9:44) was based on the expected proportion of 'bad neonatal outcome' in the intervention group (3.9%) and control group (7.2%) and accounts for the fact that the outcomes in children form multiple pregnancies are non-independent using an intra class correlation of 0.6. As the intervention is performed on the mother, analysis should be done on the maternal level. This adjustment was made during recruitment and approved by the medical ethics committee of the Academic Medical Centre in Amsterdam (ref. No. MEC 09/107). The sample size is calculated based on the primary outcome 'bad neonatal outcome'.
BMC Pregnancy and Childbirth 05/2012; 12:37. · 2.83 Impact Factor
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Arianne C Lim,
Ewoud Schuit,
Kitty Bloemenkamp,
Rob E Bernardus,
Johannes J Duvekot,
Jan Jaap H M Erwich, Jim van Eyck,
Rolf H H Groenwold,
Tom H M Hasaart,
Piet Hummel, [......],
Anneke Kwee,
Charlotte M van Oirschot,
Mariëlle G van Pampus,
Dimitri Papatsonis,
Martina M Porath,
Marc E Spaanderman,
Christine Willekes,
Janine Wilpshaar,
Ben W J Mol,
Hein W Bruinse
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ABSTRACT: To estimate whether administration of 17α-hydroxyprogesterone caproate can prevent neonatal morbidity in multiple pregnancies by reducing the preterm birth rate.
We conducted a multicenter, double-blind, placebo-controlled randomized trial in 55 obstetric clinics in the Netherlands. Women with a multiple pregnancy were randomized to weekly injections of either 250 mg 17α-hydroxyprogesterone caproate or placebo, starting between 16 and 20 weeks of gestation and continuing until 36 weeks of gestation. The main outcome measure was adverse neonatal outcome. Secondary outcome measures were gestational age at delivery and delivery before 28, 32, and 37 weeks of gestation.
We randomized 671 women. A composite measure of adverse neonatal outcome was present in 110 children (16%) born to mothers in the 17α-hydroxyprogesterone caproate group, and in 80 children (12%) of mothers in the placebo group (relative risk [RR] 1.34; 95% confidence interval [CI] 0.95-1.89). The mean gestational age at delivery was 35.4 weeks for the 17α-hydroxyprogesterone caproate group and 35.7 weeks for the placebo group (P=.32). Treatment with 17α-hydroxyprogesterone caproate did not reduce the delivery rate before 28 weeks (6% in the 17α-hydroxyprogesterone caproate group compared with 5% in the placebo group, RR 1.04; 95% CI 0.56-1.94), 32 weeks (14% compared with 10%, RR 1.37; 95% CI 0.91-2.05), or 37 weeks of gestation (55% compared with 50%, RR 1.11; 95% CI 0.97-1.28).
17α-hydroxyprogesterone caproate does not prevent neonatal morbidity or preterm birth in multiple pregnancies.
ISRCTN Register, www.isrctn.org, ISRCTN40512715.
Obstetrics and Gynecology 09/2011; 118(3):513-20. · 4.73 Impact Factor
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Denise H J Delahaije,
Sander M J van Kuijk,
Carmen D Dirksen,
Simone J S Sep,
Louis L Peeters,
Marc E Spaanderman,
Hein W Bruinse,
Laura D de Wit-Zuurendonk,
Joris A M van der Post,
Johannes J Duvekot, Jim van Eyck,
Mariëlle G van Pampus,
Mark A B H M van der Hoeven,
Luc J Smits
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ABSTRACT: 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.
BMC Pregnancy and Childbirth 10/2010; 10:60. · 2.83 Impact Factor
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Katrien Oude Rengerink,
Brent C Opmeer,
Sabine L M Logtenberg,
Lotty Hooft,
Kitty W M Bloemenkamp,
Monique C Haak,
Martijn A Oudijk,
Marc E Spaanderman,
Johannes J Duvekot,
Christine Willekes,
Maria G van Pampus,
Martina M Porath, Jim van Eyck,
Marko J Sikkema,
Ben Willem J Mol
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ABSTRACT: 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.
BMC Medical Research Methodology 01/2010; 10:85. · 2.67 Impact Factor
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Carolien Roos,
Liesbeth Hcj Scheepers,
Kitty Wm Bloemenkamp,
Annemiek Bolte,
Jerome Cornette,
Jan B Derks,
Hans Jj Duvekot, Jim van Eyck,
Joke H Kok,
Anneke Kwee, [......],
Dimitri Nm Papatsonis,
Martina M Porath,
Joris Am van der Post,
Sicco A Scherjon,
Krystyne Sollie,
Marc Ea Spaanderman,
Sylvia Mc Vijgen,
Christine Willekes,
Ben Willem J Mol,
Fred K Lotgering
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ABSTRACT: 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, beta 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.
Clinical trial registration: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.
BMC Pregnancy and Childbirth 10/2009; 9:42. · 2.83 Impact Factor
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Maud A Hegeman,
Dick J Bekedam,
Kitty Wm Bloemenkamp,
Anneke Kwee,
Dimitri Nm Papatsonis,
Joris Am van der Post,
Arianne C Lim,
Hubertina Cj Scheepers,
Christine Willekes,
Johannes J Duvekot,
Marc Spaanderman,
Martina Porath, Jim van Eyck,
Monique C Haak,
Marielle G van Pampus,
Hein W Bruinse,
Ben Willem J Mol
[show abstract]
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ABSTRACT: 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.
Current Controlled Trials: NTR 1858.
BMC Pregnancy and Childbirth 09/2009; 9:44. · 2.83 Impact Factor
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Jolande Y Vis,
Femke F Wilms,
Martijn A Oudijk,
Martina M Porath,
Hubertina C J Scheepers,
Kitty W M Bloemenkamp,
Annemiek C Bolte,
Jérôme Cornette,
Jan B Derks,
Johannes J Duvekot, [......],
Anneke Kwee,
Brent C Opmeer,
Maria G van Pampus,
Fred K Lotgering,
Sicco A Scherjon,
Krystyna M Sollie,
Marc E A Spaanderman,
Christine Willekes,
Joris A M van der Post,
Ben Willem J Mol
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ABSTRACT: 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, beta 0.2, alpha 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.
Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl.
BMC Pregnancy and Childbirth 09/2009; 9:38. · 2.83 Impact Factor
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ABSTRACT: Preeclampsia and maladaptation to pregnancy: A role for atrial natriuretic peptide?Background The majority of women with a history of preeclampsia have either an underlying thrombophilic disorder or a vascular disorder. In this study, we tested the hypothesis that only the latter condition predisposes for abnormal hemodynamic adaptation to pregnancy.
Kidney International 09/2001; 60(4):1397-1406. · 6.61 Impact Factor
