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Abstract Background Constipation during pregnancy is a common problem. Nowadays only few effective interventions are published preventing or treating constipation during pregnancy. However, their use is limited due to side-effects. This uncontrolled intervention study was performed to determine if a mixture of probiotics in the treatment of constipation during pregnancy is effective. Methods Women aged ≥ 18 years with functional constipation were included at the Obstetrical outpatient clinic and midwife practices. Patients received during four weeks a daily dose of Ecologic®Relief (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Bifidobacterium longum W108, Lactobacillus casei W79, Lactobacillus plantarum W62 and Lactobacillus rhamnosus W71 (total 4*109 CFU)). For all analyses, the non-parametric paired Wilcoxon test was used. Primary outcome measure was change in defecation frequency. Secondary outcome measures were stool consistency, sensation of incomplete evacuation, sensation of anorectal obstruction, manual manoeuvres to facilitate defecation, abdominal pain, adverse effects, presence of reflux episodes and intake of Bisacodyl. Results 20 women were included. Defecation frequency significantly increased from 3.1 at baseline to 6.7 in week four (p Conclusions Ecologic®Relief is effective in the treatment of constipation during pregnancy. A randomised placebo controlled trial is required to confirm these data.

Abstract Background 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. Methods/Design 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%). Discussion 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 ClinicalTrials.gov NCT00335023, Nederlands Trial Register NTR335

Abstract Background 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. Methods/design 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). Discussion 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.

Abstract Background Cardiovascular disease is the cause of death in 32% of women in the Netherlands. Prediction of an individual's risk for cardiovascular disease is difficult, in particular in younger women due to low sensitive and specific tests for these women. 10% to 15% of all pregnancies are complicated by hypertensive disorders, the vast majority of which develop only after 36 weeks of gestation. Preeclampsia and cardiovascular disease in later life show both features of "the metabolic syndrome" and atherosclerosis. Hypertensive disorders in pregnancy and cardiovascular disease may develop by common pathophysiologic pathways initiated by similar vascular risk factors. Vascular damage occurring during preeclampsia or gestational hypertension may contribute to the development of future cardiovascular disease, or is already present before pregnancy. At present clinicians do not systematically aim at the possible cardiovascular consequences in later life after a hypertensive pregnancy disorder at term. However, screening for risk factors after preeclampsia or gestational hypertension at term may give insight into an individual's cardiovascular risk profile. Methods/Design Women with a history of preeclampsia or gestational hypertension will be invited to participate in a cohort study 2 1/2 years after delivery. Participants will be screened for established modifiable cardiovascular risk indicators. The primary outcome is the 10-year cardiovascular event risk. Secondary outcomes include differences in cardiovascular parameters, SNP's in glucose metabolism, and neonatal outcome. Discussion This study will provide evidence on the potential health gains of a modifiable cardiovascular risk factor screening program for women whose pregnancy was complicated by hypertension or preeclampsia. The calculation of individual 10-year cardiovascular event risks will allow identification of those women who will benefit from primary prevention by tailored interventions, at a relatively young age. Trial registration The HYPITAT trial is registered in the clinical trial register as ISRCTN08132825.

Abstract Background Breech presentation occurs in 3 to 4% of all term pregnancies. External cephalic version (ECV) is proven effective to prevent vaginal breech deliveries and therefore it is recommended by clinical guidelines of the Royal Dutch Organisation for Midwives (KNOV) and the Dutch Society for Obstetrics and Gynaecology (NVOG). Implementation of ECV does not exceed 50 to 60% and probably less. We aim to improve the implementation of ECV to decrease maternal and neonatal morbidity and mortality due to breech presentations. This will be done by defining barriers and facilitators of implementation of ECV in the Netherlands. An innovative implementation strategy will be developed based on improved patient counselling and thorough instructions of health care providers for counselling. Method/design The ultimate purpose of this implementation study is to improve counselling of pregnant women and information of clinicians to realize a better implementation of ECV. The first phase of the project is to detect the barriers and facilitators of ECV. The next step is to develop an implementation strategy to inform and counsel pregnant women with a breech presentation, and to inform and educate care providers. In the third phase, the effectiveness of the developed implementation strategy will be evaluated in a randomised trial. The study population is a random selection of midwives and gynaecologists from 60 to 100 hospitals and practices. Primary endpoints are number of counselled women. Secondary endpoints are process indicators, the amount of fetes in cephalic presentation at birth, complications due to ECV, the number of caesarean sections and perinatal condition of mother and child. Cost effectiveness of the implementation strategy will be measured. Discussion This study will provide evidence for the cost effectiveness of a structural implementation of external cephalic versions to reduce the number of breech presentations at term. Trial Registration Dutch Trial Register (NTR): 1878

Abstract Background 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. Methods/Design 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). Discussion 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: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.

Abstract Background 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. Methods/Design 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 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. Discussion 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, http://www.trialregister.nl.

Abstract Background 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. Methods/Design 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. Discussion 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

Abstract Background Reliable antenatal identification of pre-eclampsia and small for gestational age is crucial to judicious allocation of monitoring resources and use of preventative treatment with the prospect of improving maternal/perinatal outcome. The purpose of this systematic review was to determine the accuracy of five serum analytes used in Down's serum screening for prediction of pre-eclampsia and/or small for gestational age. Methods The data sources included Medline, Embase, Cochrane library, Medion (inception to February 2007), hand searching of relevant journals, reference list checking of included articles, contact with experts. Two reviewers independently selected the articles in which the accuracy of an analyte used in Downs's serum screening before the 25th gestational week was associated with the occurrence of pre-eclampsia and/or small for gestational age without language restrictions. Two authors independently extracted data on study characteristics, quality and results. Results Five serum screening markers were evaluated. 44 studies, testing 169,637 pregnant women (4376 pre-eclampsia cases) and 86 studies, testing 382,005 women (20,339 fetal growth restriction cases) met the selection criteria. The results showed low predictive accuracy overall. For pre-eclampsia the best predictor was inhibin A>2.79MoM positive likelihood ratio 19.52 (8.33,45.79) and negative likelihood ratio 0.30 (0.13,0.68) (single study). For small for gestational age it was AFP>2.0MoM to predict birth weight < 10th centile with birth < 37 weeks positive likelihood ratio 27.96 (8.02,97.48) and negative likelihood ratio 0.78 (0.55,1.11) (single study). A potential clinical application using aspirin as a treatment is given as an example. There were methodological and reporting limitations in the included studies thus studies were heterogeneous giving pooled results with wide confidence intervals. Conclusion Down's serum screening analytes have low predictive accuracy for pre-eclampsia and small for gestational age. They may be a useful means of risk assessment or of use in prediction when combined with other tests.

Abstract Background Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term. Methods/design The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm. Discussion This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term. Trial registration Dutch Trial Register and ISRCTN-Register: ISRCTN10363217.

Abstract Background 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. Methods/Design 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%. Discussion 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.

Abstract Background Pre-eclampsia, a syndrome of hypertension and proteinuria, is a major cause of maternal and perinatal morbidity and mortality. Accurate prediction of pre-eclampsia is important, since high risk women could benefit from intensive monitoring and preventive treatment. However, decision making is currently hampered due to lack of precise and up to date comprehensive evidence summaries on estimates of risk of developing pre-eclampsia. Methods/Design A series of systematic reviews and meta-analyses will be undertaken to determine, among women in early pregnancy, the accuracy of various tests (history, examinations and investigations) for predicting pre-eclampsia. We will search Medline, Embase, Cochrane Library, MEDION, citation lists of review articles and eligible primary articles and will contact experts in the field. Reviewers working independently will select studies, extract data, and assess study validity according to established criteria. Language restrictions will not be applied. Bivariate meta-analysis of sensitivity and specificity will be considered for tests whose studies allow generation of 2 × 2 tables. Discussion The results of the test accuracy reviews will be integrated with results of effectiveness reviews of preventive interventions to assess the impact of test-intervention combinations for prevention of pre-eclampsia.

Introduction: The associations of epidural analgesia and low Apgar score found in the Swedish Registry might be a result of confounding by indication. The objective of this study was to assess the possible effect of intrapartum epidural analgesia on low Apgar score and neonatal intensive care unit (NICU) admission in term born singletons with propensity score matching.Material and Methods: This was a propensity score matched study (n = 257 872) conducted in a national cohort of 715 449 term live born singletons without congenital anomalies in the Netherlands. Mothers with prelabor cesarean section were excluded. Main outcome measures were 5-minute Apgar score <7, 5-minute Apgar score <4 and admission to a NICU for at least 24 hours. First, an analysis of the underlying risk factors for low Apgar score <7 was performed. Multivariable analyses were applied to assess the effect of the main risk factor, intrapartum epidural analgesia, on low Apgar score to adjust the results for confounding factors. Second, a propensity score matched analysis on the main risk factors for epidural analgesia was applied. By propensity score matching the (confounding) characteristics of the women who received epidural analgesia with the characteristics of the control women without epidural analgesia, the effect of possible confounding by indication is minimized.Results: Intrapartum epidural analgesia was performed in 128 936 women (18%). Apgar score <7 was present in 1.0%, Apgar score <4 in .2% and NICU admission in .4% of the deliveries. The strongest risk factor for Apgar score <7 was epidural analgesia (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.8-2.0). The propensity score matched adjusted analysis of women with epidural analgesia showed significant adverse neonatal outcomes: aOR 1.8 (95% CI 1.7-1.9) for AS <7, aOR 1.6 (95% CI 1.4-1.9) for AS <4 and aOR 1.7 (95% CI 1.6-1.9) for NICU admission. The results of epidural analgesia on AS <7 were also significantly increased for spontaneous start of labor (aOR 2.0, 95% CI 1.8-2.1) and for spontaneous delivery.Conclusions: Intrapartum epidural analgesia at term is strongly associated with low Apgar score and more NICU admissions, especially in spontaneous deliveries. This association needs further research and awareness. [ABSTRACT FROM AUTHOR]

Introduction: Midwife-led models of care have been the subject of debate for many years. We conducted a study to compare intrapartum and neonatal mortality rates in midwife-led (primary) vs obstetrician-led (secondary) care at the onset of labor in low-risk term women.Material and Methods: We performed an unmatched and a propensity score matched cohort study using data from the national perinatal audit registry (PAN) and from the national perinatal registry (PERINED) of the Netherlands. We included women with singleton pregnancies (without congenital anomalies or antepartum fetal death) who gave birth at term between 2010 and 2012. We excluded the following major risk factors: non-vertex position of the fetus, previous cesarean birth, hypertension, diabetes mellitus, prolonged rupture of membranes (≥24 hours), vaginal bleeding in the second half of pregnancy, nonspontaneous start of labor and post-term pregnancy (≥42 weeks). The primary outcome was intrapartum or neonatal mortality up to 28 days after birth. Secondary outcome measures were mode of delivery and a 5-minute Apgar score <7.Results: We included 259 211 women. There were 100/206 642 (0.48‰) intrapartum and neonatal deaths in the midwife group and 23/52 569 (0.44‰) in the obstetrician group (odds ratio [OR] 1.11, 95% CI 0.70-1.74). Propensity score matched analysis showed mortality rates of 0.49‰ (26/52 569) among women in midwife-led care and 0.44‰ (23/52 569) for women in obstetrician-led care (OR 1.13, 95% CI 0.65-1.98). In the midwife group there were significantly lower rates of vaginal instrumental deliveries (8.4% vs 13.0%; matched OR 0.65, 95% CI 0.62-0.67) and intrapartum cesarean sections (2.6% vs 8.2%; matched OR 0.32, 95% CI 0.30-0.34), and fewer neonates with low Apgar scores (<7 after 5 minutes) (0.69% vs 1.11%; matched OR 0.61, 95% CI 0.53-0.69).Conclusions: Among low-risk term women, there were comparable intrapartum and neonatal mortality rates for women starting labor in midwife-led vs obstetrician-led care, with lower intervention rates and fewer low Apgar scores in the midwife group. [ABSTRACT FROM AUTHOR]