1. 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

2. 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 Dutch Neonatal Database Prismant 2002

3. 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 weeks gestational age.

4. 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.

5. 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).

6. 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.

7. 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; CD
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:

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

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

10. 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 

11. 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

12. 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

13. 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

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

16. APOSTEL IV