Assessment of Perinatal Outcome by uSe of Tocolysis in Early Labour APOSTEL IV Assessment of Perinatal Outcome by uSe of Tocolysis in Early Labour Nifedipine versus placebo in the treatment of preterm premature rupture of membranes September 2012 apostel4@studies-obsgyn.nl

Background Preterm birth 75% of neonatal deaths1 40% of childhood neurological morbidities High immediate and long-term costs2 Neonatal outcome is strongly related to gestational age at delivery3 1 Ananth et al. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006 2 Gilbert et al. The cost of prematurity: quantification by gestational age and birth weight. Obstet Gynecol 2003 3 Landelijke Neonatale Registratie 2003. Dutch Neonatal Database 2002. Prismant 2002

APOSTEL II Study Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor Objective: To evaluate the effectiveness of tocolytic maintenance therapy for postponing delivery after initial 48-hour tocolytic therapy in women with threatened preterm birth from 26-32 weeks gestational age.

APOSTEL I Study Alleviation of Pregnancy Outcome by Suspending of Tocolysis in Early Labour: Costs and effects of fibronectin as a triage in women with threatened preterm labour. Objective: To assess whether testing for fibronectin is a cost-effective strategy that prevents unnecessary treatment in women with threatened preterm labour.

APOSTEL III Study Assessment of Perinatal Outcome by use of Specific Tocolytics in Early Labour: Nifedipine versus Atosiban in the treatment of threatened preterm labour. Objective: To compare the effectiveness of the tocolytic agents Nifedipine (a calcium channel blocking agent) versus Atosiban (an oxytocin receptor antagonist) in the improvement of neonatal outcome in women with threatened preterm labour (25-34 weeks gestation).

Assessment of Perinatal Outcome by uSe of Tocolysis in Early Labour APOSTEL IV Study Assessment of Perinatal Outcome by uSe of Tocolysis in Early Labour Nifedipine versus placebo in the treatment of preterm premature rupture of membranes Preterm Premature Rupture of Membranes Incidence of all pregnancies: 3-5%1 Incidence of preterm birth: 25-40% 1Lee T, Silver H. Etiology and epidemiology of preterm premature rupture of the membranes. Clinics in Perinatology: Prelabor Rupture of Membranes. 2001;28(4):721–734.

PPROM Delivery after PPROM Kenyon (2004)1: Partus <48 hours after PPROM (20-37 wk): 39.9% (717/1799) Partus < 7 days after PPROM (20-37 wk): 67.5% (1189/1762) Pasquier (2008)2 Partus < 7 days after PPROM (24-34 wk): 60% 1Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2003; CD001058. 2Pasquier JC, Rabilloud M, Picaud JC et al. Modeling the duration of the latency period after preterm premature rupture of the membranes according to maternal and pregnancy characteristics: DOMINOS study. European Journal of Obstetrics, Gynecology, & Reproductive Biology 2008; 139: 157-63.

PPROM PPROMEXIL Trial: Induction of labour versus expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks

PPROM Current situation Effectiveness of tocolysis has not been proven No uniform guideline No uniform treatment

APOSTEL IV Study Multicenter randomised placebo-controlled clinical trial in all ten perinatal centers in the Netherlands . Intervention: Random allocation to nifedipine (intervention) or placebo (control) during the period until the start of signs of active labour (≥ 3 contractions per 10 minutes) (with a maximum of 18 days). Objective: To assess whether in women with early PPROM tocolytics improve perinatal outcome. N= 120 patients 

Inclusion criteria Women with PPROM between 24+0/7 and 33+6/7 weeks gestational age Exclusion criteria ≥ 3 contractions per 10 minutes Previous treatment with tocolysis (Tocolysis for less than 6 hours for transportation is allowed) Ruptured membranes longer than 72 hour Signs of chorioamnionitis Placenta praevia Severe maternal disease (hypertension, HELLP syndrome, preeclampsia or other) Women with any contraindication for the use of nifedipine Major congenital anomaly Signs of fetal distress (abnormal CTG, abnormal biophysical profile) Signs of intra uterine infection

Flowchart APOSTEL IV Study: Multicenter randomised placebo-controlled clinical trial in all ten perinatal centers in the Netherlands Women with a gestational age between 24+0/7 and 33+6/7 weeks with ruptured membranes without other signs of active labour. Inclusion APOSTEL IV ≥ 3 contractions per 10 minutes Previous treatment with tocolysis Ruptured membranes longer than 72 hour Signs of chorioamnionitis Placenta praevia Severe maternal disease Women with any contraindication for the use of nifedipine Major congenital anomaly Signs of fetal distress Signs of intra uterine infection R Exclusion Nifedipine 4dd20 mg orally during the period until the start of signs of active labour (≥ 3 contractions per 10 minutes) with a maximum of 18 days. Placebo 4dd20 mg orally during the period until the start of signs of active labour (≥ 3 contractions per 10 minutes) with a maximum of 18 days

Endpoints Main study parameter/endpoint Neonatal mortality Composite neonatal morbidity Chronic Lung disease Periventricular leucomalacia > grade 1 Severe intraventricular haemorrhage > grade 2 Necrotising enterocolitis Proven sepsis Secondary study parameters/endpoints Gestational age at delivery Birth weight Number of days on additional oxygen Number of days on supported ventilation Number of days in intensive care Total days in hospital Costs

Contact Website: www.studies-obsgyn.nl/apostel4 Email: apostel4@studies-obsgyn.nl

APOSTEL IV