Marc Spaanderman

Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT)

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.

Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial

BACKGROUNDnInduction of labour is a common obstetric procedure. Both mechanical (eg, Foley catheters) and pharmacological methods (eg, prostaglandins) are used for induction of labour in women with an unfavourable cervix. We aimed to compare the effectiveness and safety of induction of labour with a Foley catheter with induction with vaginal prostaglandin E2 gel.nnnMETHODSnWe did an open-label, randomised controlled trial in 12 hospitals in the Netherlands between Feb 10, 2009, and May 17, 2010. We enrolled women with a term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix, an indication for induction of labour, and no prior caesarean section. Participants were randomly allocated by an online randomisation system to induction of labour with a 30 mL Foley catheter or vaginal prostaglandin E2 gel (1:1 ratio). Because of the nature of the intervention this study was not blinded. The primary outcome was caesarean section rate. Secondary outcomes were maternal and neonatal morbidity and time from intervention to birth. All analyses were done on an intention-to-treat basis. We also did a meta-analysis that included our trial. The trial was registered with the Dutch trial registry, number NTR 1646.nnnFINDINGSn824 women were allocated to induction of labour with a Foley catheter (n=412) or vaginal prostaglandin E2 gel (n=412). Caesarean section rates were much the same between the two groups (23%vs 20%, risk ratio [RR] 1·13, 95% CI 0·87-1·47). A meta-analysis including our trial data confirmed that a Foley catheter did not reduce caesarean section rates. We recorded two serious maternal adverse events, both in the prostaglandin group: one uterine perforation and one uterine rupture.nnnINTERPRETATIONnIn women with an unfavourable cervix at term, induction of labour with a Foley catheter is similar to induction of labour with prostaglandin E2 gel, with fewer maternal and neonatal side-effects.nnnFUNDINGnNone.

Effect of Maintenance Tocolysis With Nifedipine in Threatened Preterm Labor on Perinatal Outcomes A Randomized Controlled Trial

IMPORTANCEnIn threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome.nnnOBJECTIVEnTo determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth.nnnDESIGN, SETTING, AND PARTICIPANTSnAPOSTEL-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).nnnINTERVENTIONnRandomization 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.nnnMAIN OUTCOME MEASURESnPrimary 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.nnnRESULTSnMean (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).nnnCONCLUSIONS AND RELEVANCEnIn 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.nnnTRIAL REGISTRATIONntrialregister.nl Identifier: NTR1336.

Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors

The objectives of our study were to examine 1) the proportion of responders and nonresponders to exercise training in terms of vascular function; 2) a priori factors related to exercise training-induced changes in conduit artery function, and 3) the contribution of traditional cardiovascular risk factors to exercise-induced changes in artery function. We pooled data from our laboratories involving 182 subjects who underwent supervised, large-muscle group, endurance-type exercise training interventions with pre-/posttraining measures of flow-mediated dilation (FMD%) to assess artery function. All studies adopted an identical FMD protocol (5-min ischemia, distal cuff inflation), contemporary echo-Doppler methodology, and observer-independent automated analysis. Linear regression analysis was used to identify factors contributing to changes in FMD%. We found that cardiopulmonary fitness improved, and weight, body mass index (BMI), cholesterol, and mean arterial pressure (MAP) decreased after training, while FMD% increased in 76% of subjects (P < 0.001). Training-induced increase in FMD% was predicted by lower body weight (β = -0.212), lower baseline FMD% (β = -0.469), lower training frequency (β = -0.256), and longer training duration (β = 0.367) (combined: P < 0.001, r = 0.63). With the exception of a modest correlation with total cholesterol (r = -0.243, P < 0.01), changes in traditional cardiovascular risk factors were not significantly related to changes in FMD% (P > 0.05). In conclusion, we found that, while some subjects do not demonstrate increases following exercise training, improvement in FMD% is present in those with lower pretraining body weight and endothelial function. Moreover, exercise training-induced change in FMD% did not correlate with changes in traditional cardiovascular risk factors, indicating that some cardioprotective effects of exercise training are independent of improvement in risk factors.

IMproving PArticipation of patients in Clinical Trials - rationale and design of IMPACT

BackgroundOne 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.Methods/designWe 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.DiscussionThis 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.

A new method for plasma volume measurements with unlabeled dextran-70 instead of 125I-labeled albumin as an indicator.

A method has been developed to determine plasma volume with dextran-70 without the use of a fluorescent label. The results obtained are compared to those found using the 125I-labeled albumin method, which is taken as the gold standard. The CV of the method is about 5%, compared to 3% with the gold standard. It is shown to be of use for the determination of an increase in plasma volume during pregnancy.

Clinical differences between early-onset HELLP syndrome and early-onset preeclampsia during pregnancy and at least 6 months postpartum

OBJECTIVEnWe sought to evaluate whether clinical and laboratory variables differ between former patients who had HELLP syndrome and former patients who had preeclampsia (PE) without HELLP.nnnSTUDY DESIGNnWe compared early-onset HELLP (n = 75) with early-onset PE (n = 40) with respect to clinical features during the hypertensive complication and to metabolic, hemodynamic, and hemostatic variables determined at least 6 months postpartum.nnnRESULTSnHELLP differed from PE by a borderline higher frequency of eclampsia (13% vs 3%) during the complication, and by a lower prevalence of hypertension (19% vs 33%), proteinuria (2% vs 23%), thrombophilia (6% vs 27%), obesity (9% vs 33%), hypertriglyceridemia (1% vs 15%), hyperglycemia (0% vs 11%), and elevated levels of fasting homocysteine (6% vs 21%) at least 6 months postpartum.nnnCONCLUSIONnWomen with HELLP had fewer signs of abnormalities consistent with the metabolic syndrome and a 4-fold lower prevalence of thrombophilia as compared with PE women without HELLP.

Venous adjustments in healthy and hypertensive pregnancy

Gestational hypertensive (GH) disease is generally preceded by a poor first trimester circulatory adaptation. However, the initial arterial response (i.e., drop in peripheral vascular resistance and rise in renin–angiotensin–aldosterone system activity) seems largely comparable. We reviewed the venous adjustments in healthy and GH pregnancy. Changes in plasma volume (PV), venous compliance (VC), α-atrial natriuretic peptide (α-ANP) levels, inferior vena cava diameter and left atrial diameter were compared with the nonpregnant state. All showed an increase during healthy pregnancy. By contrast, GH pregnancy is characterized by an attenuated or even absent rise in PV and VC with an exaggerated rise in α-ANP. We propose that a blunted venous adaptation in GH disease originates from an inadequate venous reserve capacity. The venous compartment is unable to accommodate the increasing PV and becomes relatively overfilled. Subsequently, α-ANP levels increase, hampering further PV expansion. With increasing arter...

Reduced renal function after preeclampsia does not result from accelerated age-dependent renal function loss

Preeclampsia is associated with later kidney disease. This study tested the hypothesis that the normal decline in renal function with age is more rapid in formerly preeclamptic women than in controls. Four groups were compared cross‐sectionally: young women with a history of preeclampsia (n = 34), young controls (n = 12), middle‐aged women with a history of preeclampsia (n = 22) and middle‐aged controls (n = 29). We measured blood pressure (semi‐automatic device), effective renal plasma flow (ERPF, para‐aminohippurate clearance), glomerular filtration rate (GFR, creatinine clearance) and cardiac output (Doppler echocardiography). ERPF was lower in both young and middle‐aged women with a history of preeclampsia relative to controls. The decrease in both GFR and ERPF with age was comparable in both groups. In conclusion, the lower renal function in middle‐aged formerly preeclamptic women does not result from accelerated age‐dependent renal function loss, but from an already reduced renal function relative to parous controls at young age.

Differentiating between gestational and chronic hypertension; an explorative study

Guidelines define hypertension diagnosed before 20 weeks gestation as chronic hypertension (CH) and thereafter as gestational hypertension (GH). We tested whether hypertension diagnosed before 20 weeks is preceded by CH and whether pregnancy outcome depends on the time of onset of hypertension.