Temporizing management vs immediate delivery in early-onset severe preeclampsia between 28 and 34 weeks of gestation (TOTEM study): An open-label randomized controlled trial.

INTRODUCTION: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management. MATERIAL AND METHODS: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27+5 and 33+5 weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat. RESULTS: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P = .14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes. CONCLUSIONS: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible.

The diagnostic value of fetal fibronectin testing in clinical practice.

AIM: To evaluate the clinical management to withhold treatment for preterm labor in symptomatic women with an intermediate cervical length and negative fetal fibronectin (fFN) testing. METHODS: A retrospective cohort study was performed in a tertiary care teaching hospital in the Netherlands. Pregnant women with a gestational age between 23+5 to 34+0 weeks, with the presence of regular uterine contractions accompanied by a cervical length between 15 and 30 mm and intact membranes, who underwent fFN testing were included to obtain the diagnostic value of fFN testing for preterm delivery within 7 days. RESULTS: Fetal fibronectin testing has an extremely high negative predictive value (100%) and sensitivity (100%) for delivery within 7 days, in singleton and multiple pregnancies. However, specificity (64%) and positive predictive value (10%) of fFN testing in singleton pregnancies are low. Blood present on the fFN sample does not affect the reliability of the fFN test; the negative predictive value remains 100%. CONCLUSION: Women with symptoms of early preterm labor, intact membranes, a cervical length between 15 and 30 mm and negative fFN testing do not deliver within 7 days. Administration of corticosteroids and tocolytics can safely be withhold. Furthermore, blood on the fFN sample does not change the reliability of the fFN test.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Women's Experiences with and Preference for Induction of Labor with Oral Misoprostol or Foley Catheter at Term.

Objective We assessed experience and preferences among term women undergoing induction of labor with oral misoprostol or Foley catheter. Study Design In 18 of the 29 participating hospitals in the PROBAAT-II trial, women were asked to complete a questionnaire within 24 hours after delivery. We adapted a validated questionnaire about expectancy and experience of labor and asked women whether they would prefer the same method again in a future pregnancy. Results The questionnaire was completed by 502 (72%) of 695 eligible women; 273 (54%) had been randomly allocated to oral misoprostol and 229 (46%) to Foley catheter. Experience of the duration of labor, pain during labor, general satisfaction with labor, and feelings of control and fear related to their expectation were comparable between both the groups. In the oral misoprostol group, 6% of the women would prefer the other method if induction is necessary in future pregnancy, versus 12% in the Foley catheter group (risk ratio: 0.70; 95% confidence interval: 0.55-0.90; p = 0.02). Conclusion Women's experiences of labor after induction with oral misoprostol or Foley catheter are comparable. However, women in the Foley catheter group prefer more often to choose a different method for future inductions.

Which Factors Contribute to False-Positive, False-Negative, and Invalid Results in Fetal Fibronectin Testing in Women with Symptoms of Preterm Labor?

Objective We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity.

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial.

BACKGROUND: There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS: We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS: Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred. INTERPRETATION: For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING: ZonMw.

The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women.

BACKGROUND: The combination of the qualitative fetal fibronectin test and cervical length measurement has a high negative predictive value for preterm birth within 7 days; however, positive prediction is poor. A new bedside quantitative fetal fibronectin test showed potential additional value over the conventional qualitative test, but there is limited evidence on the combination with cervical length measurement. OBJECTIVE: The purpose of this study was to compare quantitative fetal fibronectin and qualitative fetal fibronectin testing in the prediction of spontaneous preterm birth within 7 days in symptomatic women who undergo cervical length measurement. STUDY DESIGN: We performed a European multicenter cohort study in 10 perinatal centers in 5 countries. Women between 24 and 34 weeks of gestation with signs of active labor and intact membranes underwent quantitative fibronectin testing and cervical length measurement. We assessed the risk of preterm birth within 7 days in predefined strata based on fibronectin concentration and cervical length. RESULTS: Of 455 women who were included in the study, 48 women (11%) delivered within 7 days. A combination of cervical length and qualitative fibronectin resulted in the identification of 246 women who were at low risk: 164 women with a cervix between 15 and 30 mm and a negative fibronectin test (<50 ng/mL; preterm birth rate, 2%) and 82 women with a cervix at >30 mm (preterm birth rate, 2%). Use of quantitative fibronectin alone resulted in a predicted risk of preterm birth within 7 days that ranged from 2% in the group with the lowest fibronectin level (<10 ng/mL) to 38% in the group with the highest fibronectin level (>500 ng/mL), with similar accuracy as that of the combination of cervical length and qualitative fibronectin. Combining cervical length and quantitative fibronectin resulted in the identification of an additional 19 women at low risk (preterm birth rate, 5%), using a threshold of 10 ng/mL in women with a cervix at <15 mm, and 6 women at high risk (preterm birth rate, 33%) using a threshold of >500 ng/mL in women with a cervix at >30 mm. CONCLUSION: In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.

Early nasogastric tube feeding in optimising treatment for hyperemesis gravidarum: the MOTHER randomised controlled trial (Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding).

BACKGROUND: Hyperemesis gravidarum (HG), or intractable vomiting during pregnancy, is the single most frequent cause of hospital admission in early pregnancy. HG has a major impact on maternal quality of life and has repeatedly been associated with poor pregnancy outcome such as low birth weight. Currently, women with HG are admitted to hospital for intravenous fluid replacement, without receiving specific nutritional attention. Nasogastric tube feeding is sometimes used as last resort treatment. At present no randomised trials on dietary or rehydration interventions have been performed. Small observational studies indicate that enteral tube feeding may have the ability to effectively treat dehydration and malnutrition and alleviate nausea and vomiting symptoms. We aim to evaluate the effectiveness of early enteral tube feeding in addition to standard care on nausea and vomiting symptoms and pregnancy outcomes in HG patients. METHODS/DESIGN: The MOTHER trial is a multicentre open label randomised controlled trial ( www.studies-obsgyn.nl/mother ). Women ≥ 18 years hospitalised for HG between 5 + 0 and 19 + 6 weeks gestation are eligible for participation. After informed consent participants are randomly allocated to standard care with intravenous rehydration or early enteral tube feeding in addition to standard care. All women keep a weekly diary to record symptoms and dietary intake until 20 weeks gestation. The primary outcome will be neonatal birth weight. Secondary outcomes will be the 24-h Pregnancy Unique Quantification of Emesis and nausea score (PUQE-24), maternal weight gain, dietary intake, duration of hospital stay, number of readmissions, quality of life and side-effects. Also gestational age at birth, placental weight, umbilical cord plasma lipid concentration and neonatal morbidity will be evaluated. Analysis will be according to the intention to treat principle. DISCUSSION: With this trial we aim to clarify whether early enteral tube feeding is more effective in treating HG than intravenous rehydration alone and improves pregnancy outcome. TRIAL REGISTRATION NUMBER: NTR4197 . Date of registration: October 2(nd) 2013.

Risk stratification with cervical length and fetal fibronectin in women with threatened preterm labor before 34 weeks and not delivering within 7 days.

OBJECTIVE: To stratify the risk of spontaneous preterm delivery using cervical length (CL) and fetal fibronectin (fFN) in women with threatened preterm labor who remained pregnant after 7 days. DESIGN: Prospective observational study. SETTING: Nationwide cohort of women with threatened preterm labor from the Netherlands. POPULATION: Women with threatened preterm labor between 24 and 34 weeks with a valid CL and fFN measurement and remaining pregnant 7 days after admission. METHODS: Kaplan-Meier and Cox proportional hazards models were used to estimate cumulative percentages and hazard ratios (HR) for spontaneous delivery. MAIN OUTCOME MEASURES: Spontaneous delivery between 7 and 14 days after initial presentation and spontaneous preterm delivery before 34 weeks. RESULTS: The risk of delivery between 7 and 14 days was significantly increased for women with a CL < 15 mm or a CL ≥15 to <30 mm and a positive fFN, compared with women with a CL ≥30 mm: HR 22.3 [95% confidence interval (CI) 2.6-191] and 14 (95% CI 1.8-118), respectively. For spontaneous preterm delivery before 34 weeks the risk was increased for women with a CL < 15 mm [HR 6.3 (95% CI 2.6-15)] or with a CL ≥15 to <30 mm with either positive fFN [HR 3.6 (95% CI 1.5-8.7)] or negative fFN [HR 3.0 (95% CI 1.2-7.1)] compared with women with a CL ≥ 30 mm. CONCLUSIONS: In women remaining pregnant 7 days after threatened preterm labor, CL and fFN results can be used in risk stratification for spontaneous delivery.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

What is the risk of preterm delivery after arrested preterm labor?

OBJECTIVE: The aim of this study is to assess if women with arrested preterm labor (PTL) have an increased risk of preterm delivery (PTD) compared with healthy pregnant women, and if digital examination, fetal fibronectin (fFn) and cervical length (CL) are prognostic markers for PTD after arrested PTL. STUDY DESIGN: Prospective-matched cohort study among women with arrested PTL (cases) and healthy pregnant women (controls). RESULTS: We included 74 index cases and 74 controls. PTD occurred in 20 (27%) index cases and in 5 (7%) controls (hazard ratio [HR], 4.5; 95% confidence interval [CI], 1.7-12). A dilatation of the cervix ≥ 1 cm (HR, 9.1 [95% CI, 3.3-25], an fFn positive status (HR, 13 [95% CI, 4.3-40]), and a CL < 15 mm (HR, 11 [95% CI, 3.1-38]) increased this risk in cases compared with controls. Knowledge of the fFn result had additional value over the cervical dilatation or CL in the prediction of persistent PTD, with an increased risk in case of a positive fFn test. CONCLUSION: Women stay at increased risk for PTD after arrested PTL. This risk further increased in case of ≥ 1 cm cervical dilatation, CL < 15 mm and/or a positive fFn status.

Randomized comparison of nifedipine and placebo in fibronectin-negative women with symptoms of preterm labor and a short cervix (APOSTEL-I Trial).

OBJECTIVE: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test. STUDY DESIGN: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women. RESULTS: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women. CONCLUSION: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine.

Prediction of postpartum hemorrhage in women with gestational hypertension or mild preeclampsia at term.

OBJECTIVE: To assess whether postpartum hemorrhage can be predicted in women with gestational hypertension or mild preeclampsia at term. DESIGN: A cohort study in which we used data from our multicentre randomized controlled trial (HYPITAT trial). SETTING: The study was conducted in 38 hospitals in the Netherlands between 2005 and 2008. POPULATION: Women with gestational hypertension or mild preeclampsia at term (n = 1132). METHODS: An antepartum model (model A) and an antepartum/intrapartum model (model B) were created using logistic regression. The predictive capacity of the models was assessed with receiver operating characteristic analysis and calibration. MAIN OUTCOME MEASURE: Postpartum hemorrhage, defined as blood loss >1000 mL within 24 h after delivery. RESULTS: Postpartum hemorrhage occurred in 118 (10.4%) women. Maternal age (odds ratio 1.03), prepregnancy body mass index (odds ratio 0.96), and women with preeclampsia (odds ratio 1.5) were independent antepartum prognostic variables of postpartum hemorrhage. Intrapartum variables incorporated in the model were gestational age at delivery (odds ratio 1.2), duration of dilatation stage (odds ratio 1.1), and episiotomy (odds ratio 1.5). Model A and model B showed moderate discrimination, with areas under the receiver operating characteristic curve of 0.59 (95% confidence interval 0.53-0.64) and 0.64 (95% confidence interval 0.59-0.70), respectively. Calibration was moderate for model A (Hosmer-Lemeshow p = 0.26) but better for model B (Hosmer-Lemeshow p = 0.36). The rates of postpartum hemorrhage ranged from 4% (lowest 10%) to 22% (highest 10%). CONCLUSION: In the assessment of performance of a prediction model, calibration is more important than discriminative capacity. Our prediction model shows that for women with gestational hypertension or mild preeclampsia at term, distinction between low and high risk of developing postpartum hemorrhage is possible when antepartum and intrapartum variables are combined.

Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial).

BACKGROUND: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects. METHODS/DESIGN: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, ß 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour. CLINICAL TRIAL REGISTRATION: NTR2947, date of registration: June 20th 2011.

Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL - III trial).

BACKGROUND: Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome. METHODS/DESIGN: Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. INTERVENTION: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, ß-error 0.2 and α-error 0.05). DISCUSSION: This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure. TRIAL REGISTRATION: NTR3492 Dutch Trial Register (http://www.trialregister.nl).

Prediction of preterm birth in multiple pregnancies: development of a multivariable model including cervical length measurement at 16 to 21 weeks' gestation.

OBJECTIVE: To develop a multivariable prognostic model for the risk of preterm delivery in women with multiple pregnancy that includes cervical length measurement at 16 to 21 weeks' gestation and other variables. METHODS: We used data from a previous randomized trial. We assessed the association between maternal and pregnancy characteristics including cervical length measurement at 16 to 21 weeks' gestation and time to delivery using multivariable Cox regression modelling. Performance of the final model was assessed for the outcomes of preterm and very preterm delivery using calibration and discrimination measures. RESULTS: We studied 507 women, of whom 270 (53%) delivered < 37 weeks (preterm) and 66 (13%) < 32 weeks (very preterm). Women with cervical length < 30 mm delivered more often preterm (hazard ratio 1.9; 95% CI 0.7 to 4.8). Other independently contributing predictors were previous preterm delivery, monochorionicity, smoking, educational level, and triplet pregnancy. Prediction models for preterm and very preterm delivery had a c-index of 0.68 (95% CI 0.63 to 0.72) and 0.68 (95% CI 0.62 to 0.75), respectively, and showed good calibration. CONCLUSION: In women with a multiple pregnancy, the risk of preterm delivery can be assessed with a multivariable model incorporating cervical length and other predictors.

Objectif : Élaborer un modèle pronostique multivarié (comportant la mesure de la longueur cervicale à 16 - 21 semaines de gestation et d'autres variables) pour ce qui est du risque d'accouchement préterme chez les femmes connaissant une grossesse multiple. Méthodes : Nous avons utilisé les données issues d'un essai randomisé précédent. Nous avons évalué l'association entre les caractéristiques maternelles et de grossesse (dont la mesure de la longueur cervicale à 16 - 21 semaines de gestation et le délai avant l'accouchement) au moyen du modèle de régression multivariée de Cox. Le rendement du modèle final a été évalué en fonction de critères d'évaluation traitant du moment de l'accouchement (préterme et très préterme) au moyen de mesures d'étalonnage et de discrimination. Résultats : Nous avons étudié 507 femmes, dont 270 (53 %) ont accouché < 37 semaines (préterme) et 66 (13 %) < 32 semaines (très préterme). Les femmes qui présentaient une longueur cervicale < 30 mm ont plus souvent connu un accouchement préterme (densité de l'incidence, 1,9; IC à 95 %, 0,7 - 4,8). Parmi les autres facteurs prédictifs indépendants, on trouvait les antécédents d'accouchement préterme, la monochorionicité, le tabagisme, le niveau de scolarité et la présence d'une grossesse triple. Les modèles prédictifs pour ce qui est des accouchements préterme et très préterme comptaient un indice C de 0,68 (IC à 95 %, 0,63 - 0,72) et de 0,68 (IC à 95 %, 0,62 - 0,75), respectivement, et présentaient un bon étalonnage. Conclusion : Chez les femmes qui connaissent une grossesse multiple, le risque d'accouchement préterme peut être évalué au moyen d'un modèle multivarié comportant la mesure de la longueur cervicale et d'autres facteurs prédictifs. 

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: 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). INTERVENTION: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.

Predictive value of the baseline T-QRS ratio of the fetal electrocardiogram in intrapartum fetal monitoring: a prospective cohort study.

OBJECTIVE: To evaluate the added value of the baseline T/QRS ratio to other known risk factors in predicting adverse outcome and interventions for suspected fetal distress. DESIGN: Prospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Laboring women with a high-risk cephalic singleton pregnancy beyond 36 weeks of gestation. METHODS: We obtained STAN(®) recordings (ST-analysis, Neoventa, Sweden) from two previous studies. Three patient groups were defined: cases with adverse outcome, cases with emergency delivery because of suspected fetal distress without adverse outcome, and a reference group of uncomplicated cases. Baseline T/QRS ratios among the adverse outcome and intervention for suspected fetal distress cases were compared to those of the uncomplicated cases. The ability of baseline T/QRS to predict adverse outcome and suspected fetal distress was determined using a multivariable logistic model. MAIN OUTCOME MEASURES: The added value of the baseline T/QRS to other known risk factors in the prediction of adverse outcome and interventions for suspected fetal distress. RESULTS: From 3462 recordings, 2459 were available for analysis. Median baseline T/QRS for uncomplicated cases, adverse outcome and interventions for suspected fetal distress were 0.12 (range 0.00-0.52), 0.12 (0.00-0.42) and 0.13 (0.00-0.39), respectively. There was no statistical difference between these groups. Multivariable analysis showed no added value of baseline T/QRS in the prediction of either adverse outcome or interventions for suspected fetal distress. CONCLUSION: Baseline T/QRS has no added value in the prediction of adverse neonatal outcome or interventions for suspected fetal distress.

Identification of cases with adverse neonatal outcome monitored by cardiotocography versus ST analysis: secondary analysis of a randomized trial.

OBJECTIVE: To evaluate whether correct adherence to clinical guidelines might have led to prevention of cases with adverse neonatal outcome. DESIGN: Secondary analysis of cases with adverse outcome in a multicenter randomized clinical trial. SETTING: Nine Dutch hospitals. POPULATION: Pregnant women with a term singleton fetus in cephalic position. METHODS: Data were obtained from a randomized trial that compared monitoring by STAN® (index group) with cardiotocography (control group). In both trial arms, three observers independently assessed the fetal surveillance results in all cases with adverse neonatal outcome, to determine whether an indication for intervention was present, based on current clinical guidelines. MAIN OUTCOME MEASURES: Adverse neonatal outcome cases fulfilled one or more of the following criteria: (i) metabolic acidosis in umbilical cord artery (pH < 7.05 and base deficit in extracellular fluid >12 mmol/L); (ii) umbilical cord artery pH < 7.00; (iii) perinatal death; and/or (iv) signs of moderate or severe hypoxic ischemic encephalopathy. RESULTS: We studied 5681 women, of whom 61 (1.1%) had an adverse outcome (26 index; 35 control). In these women, the number of performed operative deliveries for fetal distress was 18 (69.2%) and 16 (45.7%), respectively. Reassessment of all 61 cases showed that there was a fetal indication to intervene in 23 (88.5%) and 19 (57.6%) cases, respectively. In 13 (50.0%) vs. 11 (33.3%) cases, respectively, this indication occurred more than 20 min before the time of delivery, meaning that these adverse outcomes could possibly have been prevented. CONCLUSIONS: In our trial, more strict adherence to clinical guidelines could have led to additional identification and prevention of adverse outcome.

Remifentanil patient controlled analgesia versus epidural analgesia in labour. A multicentre randomized controlled trial.

BACKGROUND: Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments. METHODS/DESIGN: The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia.Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief.Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects.The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared. DISCUSSION: This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR2551, http://www.trialregister.nl.