A Pilot Randomized Controlled Trial On Complete Bed Rest Versus Activity Restriction After Preterm Premature Rupture of the Membranes
Phase: NA
Conditions: Preterm Premature Rupture of Membrane
Sponsor: Centro Hospitalar Lisboa Norte

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STUDY PROTOCOL 
 
TITLE 
A Pilot Randomized Controlled Trial On Complete Bed Rest Versus Activity Restriction After 
Preterm Premature Rupture of the Membranes 
AUTHORS AND AFFILIATION 
Inês Martins, Inês Pereira, Nuno Clode 
Department of Obstetrics, Gynecology and Reproductive Medicine, CHLN - Hospital 
Universitário de Santa Maria, Lisboa, Portugal 
BACKGROUND 
Preterm premature rupture of the membranes (PPROM) is defined as spontaneous rupture of 
the membranes before labor at less than 37 weeks of gestation. It complicates 3 percent of 
pregnancies but is responsible for one third of cases of preterm birth, which is the leading cause 
of perinatal morbidity and mortality in developed countries. PPROM etiology is still unclear but 
underlying infectious process, increased inflammatory pathway activation and genetic 
predisposition are probably involved. Latency time from PPROM to delivery is usually brief and 
inversely proportional to gestational age (GA) at rupture. During this time, intrauterine infection, 
placental abruption, umbilical cord compression or prolapse, and fetal compression and hypoxia 
are possible consequences. Chorioamnionitis is the major maternal consequence of PPROM. 
Neonatal morbidity is also higher when PPROM is complicated by chorioamnionitis but 
prematurity remains the major neonatal consequence after PPROM. Several studies support 
that prolonged latency improves fetal maturation and does not worsen neonatal prognosis, for 
a given GA at birth. In order to increase GA at birth, expectant management of viable 
pregnancies with prophylactic antibiotic administration is recommended. Antepartum bed rest 
is also widely prescribed, although its effectiveness to prevent preterm birth has not been 
demonstrated.  
OBJETIVE 
We aimed to access the impact of bed rest in latency time to delivery, chorioamnionitis 
incidence and other maternal and neonatal outcomes in pregnancies complicated by PPROM, 
thus enabling proper sample size calculation for future powered randomized controlled trial. 
STUDY DESIGN 
Pilot unblinded randomized controlled trial (1:1 allocation ratio). 
Simple random allocation sequence generated by the investigators and implemented by 
sequentially numbered sealed envelopes. 
CENTER 
Department of Obstetrics, Gynecology and Reproductive Medicine, CHLN - Hospital 
Universitário de Santa Maria, Lisboa, Portugal. 

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POPULATION 
Eligible patients include those with single pregnancies with PPROM at 24+0-33+6 weeks of 
gestation admitted to our tertiary center. 
PPROM diagnosis on the basis of patient’s history and sterile speculum examination with 
visualization of amniotic fluid pooling in the vagina and/or leaking from the cervical canal. 
Exclusion criteria: indication for immediate delivery on admission (chorioamnionitis, placenta 
abruption, cord prolapse, signs of fetal hypoxia/distress), fetal malformations, multiple 
gestation, and maternal immunosuppressive disease. 
SAMPLE SIZE 
Considering future sample size calculation based upon assumed differences between groups 
regarding latency and infection, we aim a sample of 30 participants. 
ENROLLEMENT 
Participants enrolled by physicians after hospital admission and after written informed consent 
is obtained. 
INTERVENTION 
Bed rest vs activity: Activity restriction group with motion limited to bathroom privileges and 
walks to the ward canteen four times per day. Participants on complete bed rest group keep 
antepartum confinement to bed with toileting restricted to bedpan use. Participants in this 
group receive prophylactic subcutaneous enoxaparin (40mg/day). 
All patients receive standard care for PPROM according to the institution protocol, including 
hospital admission, antibiotic prophylaxis (ampicillin IV 2mg/4id plus erythromycin IV 500m/4id 
for 48h, followed by amoxicillin PO 500 mg/3id plus erythromycin PO 500 mg/3id for 5 days), 
fetal lung maturation (betamethasone IM 12mg/d for 48h), leucogram and C reactive protein 
(CRP) analysis (daily for 1 week and thrice weekly after), nonstress tests daily, and weekly 
ultrasound assessment (biophysical profile and flowmetry). 
Delivery is planned for 34th week. In case of spontaneous labor or adverse occurrence 
(chorioamnionitis, abruptio placentae, signs of fetal hipoxia/distress) it can occur earlier. Mode 
of delivery respected obstetrical indications. 
OUTCOMES 
Maternal outcomes: latency to delivery after PPROM, clinical chorioamnionitis (defined as 
maternal fever plus leukocytosis and CRP elevation, or as maternal fever plus any two of the 
following: fetal tachycardia; maternal tachycardia; uterine tenderness; purulent amniotic fluid), 
cause of pregnancy termination (spontaneous labor, 34th week, adverse occurrence), mode of 
delivery, placenta abruption, cord prolapse, and thromboembolic events. 
Neonatal outcomes: included GA at delivery, birth weight, APGAR score at fifth minute, length 
of hospitalization, neonatal sepsis, composite adverse pulmonary outcome (need for ventilatory 
support, respiratory distress syndrome, bronchopulmonary dysplasia), and neonatal death.  

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STATISTICAL ANALYSES 
Intention-to-treat analysis; significance level of 5%. 
Statistical analysis performed by IBM® SPSS® Statistics version 24. 
Categorical variables compared by Chi-square or Fisher exact test as appropriate. Medians of 
quantitative variables compared by Mann-Whitney U test. Latency from PPROM to delivery 
compared by univariate analysis using Mann-Whitney U test and by survival analysis using 
Kaplan–Meier curve with group stratification. 
Sample size for future RCT calculated based on difference between the means of latency time. 
APPROVAL BY THE ETHICS COMMITTEE 
Approved. 
INFORMED CONSENT 
Written informed consent required for all participant. 
FINACING 
None.