A large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of ...miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome.
Randomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone.
pregnant women of less than 7 weeks' gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both.
multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate.
LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone. Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations. Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions.
After an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study. The study website can be accessed via www.ALIFE2study.org.
The ALIFE2 study was registered on 19 March 2012 under registration number NTR3361.
Objective
To evaluate long‐term effects of maintenance tocolysis with nifedipine on neurodevelopmental outcome of the infant.
Design, Setting and Population
Follow up of infants of women who ...participated in a multicentre randomised controlled trial on maintenance tocolysis with nifedipine versus placebo.
Methods
Two years after the APOSTEL II trial on maintenance tocolysis with nifedipine versus placebo, we asked participants to complete the Ages and Stages Questionnaire.
Main outcome measures
Infant development was measured in five domains. Developmental delay was defined as a score of ≤1 SD in one or more developmental domains. We performed exploratory subgroup analysis in women with preterm prolonged rupture of the membranes, and in women with a cervical length <10 mm at study entry.
Results
Of the 276 women eligible for follow up, 135 (52.5%) returned the questionnaire, encompassing data of 170 infants. At 2 years of age, infants of women with nifedipine maintenance tocolysis compared with placebo had a higher overall incidence of fine motor problems (22.2 versus 7.6%, OR 3.43, 95% CI 1.29–9.14, P = 0.01), and a lower incidence of poor problem‐solving (21.1 versus 29.1%, OR 0.27, 95% CI 0.08‐0.95, P = 0.04).
Conclusions
This follow‐up study revealed no clear benefit of nifedipine maintenance tocolysis at 2 years of age. As short‐term adverse perinatal outcome was not reduced in the original APOSTEL II trial, we conclude that maintenance tocolysis does not appear to be beneficial at this time.
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No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2‐year infant outcome.
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No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2‐year infant outcome.
Objective
To assess the costs of labour induction with oral misoprostol versus Foley catheter.
Design
Economic evaluation alongside a randomised controlled trial.
Setting
Obstetric departments of six ...tertiary and 23 secondary care hospitals in the Netherlands.
Population
Women with a viable term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix (Bishop score <6) without a previous caesarean section, were randomised for labour induction with oral misoprostol (n = 924) or Foley catheter (n = 921).
Methods
We performed economic analysis from a hospital perspective. We estimated direct medical costs associated with healthcare utilisation from randomisation until discharge. The robustness of our findings was evaluated in sensitivity analyses.
Main outcome measures
Mean costs and differences were calculated per women induced with oral misoprostol or Foley catheter.
Results
Mean costs per woman in the oral misoprostol group and Foley catheter group were €4470 versus €4158, respectively mean difference €312, 95% confidence interval (CI) –€508 to €1063. Multiple sensitivity analyses did not change these conclusions. However, if cervical ripening for low‐risk pregnancies in the Foley catheter group was carried out in an outpatient setting, with admittance to labour ward only at start of active labour, the difference would be €4470 versus €3489, respectively (mean difference €981, 95% CI €225–1817).
Conclusions
Oral misoprostol and Foley catheter generate comparable costs. Cervical ripening outside labour ward with a Foley catheter could potentially save almost €1000 per woman.
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Oral misoprostol or Foley catheter for induction of labour generates comparable costs.
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Oral misoprostol or Foley catheter for induction of labour generates comparable costs.
Objective
To evaluate whether in symptomatic women, the combination of quantitative fetal fibronectin (fFN) testing and cervical length (CL) improves the prediction of preterm delivery (PTD) within ...7 days compared with qualitative fFN and CL.
Design
Post hoc analysis of frozen fFN samples of a nationwide cohort study.
Setting
Ten perinatal centres in the Netherlands.
Population
Symptomatic women between 24 and 34 weeks of gestation.
Methods
The risk of PTD <7 days was estimated in predefined CL and fFN strata. We used logistic regression to develop a model including quantitative fFN and CL, and one including qualitative fFN (threshold 50 ng/ml) and CL. We compared the models’ capacity to identify women at low risk (<5%) for delivery within 7 days using a reclassification table.
Main outcome measures
Spontaneous delivery within 7 days after study entry.
Results
We studied 350 women, of whom 69 (20%) delivered within 7 days. The risk of PTD in <7 days ranged from 2% in the lowest fFN group (<10 ng/ml) to 71% in the highest group (>500 ng/ml). Multivariable logistic regression showed an increasing risk of PTD in <7 days with rising fFN concentration 10–49 ng/ml: odds ratio (OR) 1.3, 95% confidence interval (95% CI) 0.23–7.0; 50–199 ng/ml: OR 3.2, 95% CI 0.79–13; 200–499 ng/ml: OR 9.0, 95% CI 2.3–35; >500 ng/ml: OR 39, 95% CI 9.4–164 and shortening of the CL (OR 0.86 per mm, 95% CI 0.82–0.90). Use of quantitative fFN instead of qualitative fFN resulted in reclassification of 18 (5%) women from high to low risk, of whom one (6%) woman delivered within 7 days.
Conclusion
In symptomatic women, quantitative fFN testing does not improve the prediction of PTD within 7 days compared with qualitative fFN testing in combination with CL measurement in terms of reclassification from high to low (<5%) risk, but it adds value across the risk range.
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Quantitative fFN testing adds value to qualitative fFN testing with CL measurement in the prediction of PTD.
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Quantitative fFN testing adds value to qualitative fFN testing with CL measurement in the prediction of PTD.
•Women with recurrent miscarriage had higher HSCRP and lower albumin and vitamin D levels.•This suggests a proinflammatory state in women who experienced recurrent miscarriage.•Results were ...independent of classic cardiovascular risk factors.•No differences were found in more specific cardiovascular biomarkers.•More research (observational and intervention) is warranted to investigate the association with vitamin D insufficiency.
A history of recurrent miscarriage is associated with future cardiovascular disease. The aim of this study was to determine novel cardiovascular biomarkers in women with a history of recurrent miscarriage as this might lead to a better understanding of the association.
Women who visited the recurrent miscarriage clinic at Leiden University Medical Centre (between 2000 and 2010), and had three consecutive miscarriages ≤30 years were invited to participate in this follow-up study (between 2012 and 2014). The reference group consisted of women with at least one uncomplicated pregnancy and a history of no miscarriage, matched on zip code, age, and date of pregnancy.
Cardiovascular biomarkers were determined, classified into; inflammation (HsCRP, lipoprotein-associated phospholipase A2), thrombosis (homocysteine, folate, anti-cardiolipin antibodies and anti-ß-2-glycoprotein antibodies), lipid metabolism (lipoprotein(a)), renal function (creatinine, microalbuminuria), myocardial damage (N-terminal pro-brain natriuretic peptide, high sensitive TroponineT) and multiple mechanisms (albumin, vitamin D).
In both groups, 36 women were included. Women with recurrent miscarriage had a significantly higher median HsCRP (1.49 mg/L) compared to women with no miscarriage (1.01 mg/L, p = 0.03) and a significantly lower mean albumin (46.0 vs 47.6g/L, p = 0.004) and vitamin D (55.6 vs 75.4nmol/L, p = 0.007), respectively. Differences remained after adjustments for classic cardiovascular risk factors (BMI, smoking, diabetes mellitus, and hypertension).
Our findings suggest a proinflammatory state in women with a history of recurrent miscarriage, which suggests a less optimal health, compared to women with no miscarriage. More research (observational and intervention) is warranted to investigate the association with vitamin D.
Some clinicians advise prophylactic administration of antenatal steroids for fetal lung maturation in women with a triplet pregnancy. However, the effect of corticosteroids is limited to 10 to 14 ...days after administration. The aim of this study was to assess the natural course of triplet pregnancies to allow a better anticipation for administration of corticosteroids.
We collected data on all triplet pregnancies in the Netherlands from 1999 to 2007 from the Netherlands Perinatal Registration. We calculated time to delivery, the risk of delivery in 2-week intervals at different gestational ages, and the time frame between hospital admission and delivery of the first child.
Median gestational age at delivery of 494 women with a triplet pregnancy was 33
weeks (interquartile range of 31-35
weeks). Twenty-one women (4.3%) delivered between 22 and 24 weeks and 146 women (29.6%) delivered before 32 weeks. At a gestational age of 24 weeks, the chance to deliver within the next week was 0.6%. For 26, 28, 30, 31, and 32 weeks, these risks were 2.4, 2.5, 8.1, 7, and 16.7%, respectively.
Before 32 weeks of gestation, prophylactic administration of steroids is not indicated as the risk to deliver within 7 days is < 10%.
Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term.Design Multicentre randomised equivalence trial (the ...Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)).Setting Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008.Participants Pregnant women who had a singleton pregnancy beyond 36+0 weeks’ gestation with suspected intrauterine growth restriction.Interventions Induction of labour or expectant monitoring.Main outcome measures The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means.Results 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference −9.9 days, 95% CI −11.3 to −8.6) and weighed 130 g less (mean difference −130 g, 95% CI −188 g to −71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference −0.8%, 95% CI −4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI −5.0% to 5.6%).Conclusions In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth.Trial registration International Standard Randomised Controlled Trial number ISRCTN10363217.
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