Methods

RCT

Duration of study: May 1991‐30 April 1994

Participants

Setting: Parkland Hospital, Dallas, Texas, USA

Participants: 129 women with confirmed premature rupture of the membranes between 30‐34 weeks' gestation; 1 twin pair in each of early delivery and expectant management group resulting in a total of 131 babies:

• 61 women were randomised to early delivery

• 68 women were randomised to expectant management

Inclusion criteria

• Preterm ruptured membranes at 30‐34 weeks' gestation

• Temperature less than 37.8°C

• No labour

• No maternal or fetal complications necessitating delivery

Exclusion criteria

• Active labour

• Chorioamnionitis defined as a temperature greater than 37.9°C with either uterine tenderness or maternal tachycardia

• Maternal hypertension

Interventions

Intervention: oxytocin labour stimulation if the fetus was cephalic; caesarean section was performed for all other presentations

Control: expectant management

• Maternal observations and fetal heart rate recorded every 8 h

• Electronic fetal heart rate and uterine activity monitoring was performed for 1 h each d until delivery

• Hospitalisation until delivery

• Criteria for delivery included:

  • spontaneous labour;

  • fever;

  • abnormal fetal heart rate

Corticosteroids, tocolysis and antibiotics were not used

Vaginal examinations were not performed in the absence of labour

Outcomes

Maternal

• Admission to delivery interval

• Labour induction

• Caesarean delivery

• Chorioamnionitis

Fetal

• Gestational age at delivery

• Respiratory distress:

  • none

  • halo

  • ventilator

• Intracranial haemorrhage

• Necrotising enterocolitis

• Sepsis: did not specify whether positive culture required

• Duration of time spent in special care nursery

• Stillbirths

• Neonatal deaths

Notes

• Gestational age: determined by menstrual history, timing of first auscultation of fetal heart sounds, fundal height or ultrasound examination.

• Ruptured membranes was diagnosed when amniotic fluid was visualised by sterile speculum examination draining from the cervical os.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table with group allocation pre‐determined

Allocation concealment (selection bias)

Unclear risk

Sequentially numbered sealed envelopes. Not stated if envelopes were opaque or not

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not specified

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up reported
No post‐randomisation exclusions

Selective reporting (reporting bias)

Unclear risk

Outcomes only reported in results. Not pre‐specified

Other bias

Low risk

None noted

Methods

RCT

Duration of study: November 1992‐October 1993

Participants

Setting: Perinatology Department, Centro Medico Nacional, IMSS, Torreon, Coah, Mexico

Participants: 58 women with PROM between 28‐34 weeks of gestation

• 30 women were randomised to early delivery

• 28 women were randomised to expectant management

Inclusion criteria

• Preterm ruptured membranes between 28‐34 weeks' gestation

• Amniotic liquid index > 5 cm

• A negative culture of amniotic liquid obtained by amniocentesis

Exclusion criteria

• Women undergoing labour

• Positive fetal lung maturity tests (tap*, clements* and 650 nm spectrophotometry)

Interventions

Control: managed with short‐term delivery with the application of a fetal lung maturity protocol of 6 doses of 250 mg of intravenous aminophylline every 8 h. Delivered according to obstetric characteristics of each woman

Treatment: managed with the same lung maturity protocol as the controls, but repeating weekly if possible

• All participants had leukocyte counts every 3 d and daily biophysical profile

• Antibiotics not given prophylactically

• Tocolytics used for management of uterine contractions

• Participant delivered if signs of chorioamnionitis

Outcomes

Maternal

• Chorioamnionitis, defined by 15,000 leukocytes in maternal blood at the start of the study or a 50% increase from baseline reading, body temperature > 37.5°C, abdominal pain or a fetal heart rate of > 160 beats/minute without apparent cause

• Caesarean section

• Days between randomisation and delivery

• Causes of caesarean section

• Causes of delivery

Fetal

• Hyaline membrane disease: diagnosed by prematurity, neonatal asphyxia, progressive onset of respiratory insufficiency, thorax X‐rays with the presence of peripheral aerial bronchogram with reticulogranular infiltrates and gasometric respiratory acidosis followed by mixed acidosis

• Neonatal septicaemia diagnosed if the following were present: general poor condition, paleness, jaundice, petechia, equimosis, hypoactivity or irritability, seizure, hepatosplenomegaly, abnormal bleeding, vomit, diarrhoea, gastric residual and hypothermia or fever, leukocytosis (> 25,000), leucopenia (< 5000), total bands (> 500), neutropenia (< 1500), Shilling index of > 0.2 and thrombocytopenia (< 100,000), 1 of 3 lumbar puncture blood culture positive with: > 20 cells, hypoglycorrhaghia (< 40 mg/dL), hyperproteinrhachia (> 280 mg/dL). Sepsis also diagnosed if sepsis protocol started with clinical suspicion without positive culture and clinical improvement after antibiotics

• Birthweight

• Apgar scores at 1 min and 5 min

• Silverman score at 1 min and 5 min

• Perinatal death

• Muscoluskeletal abnormalities

• Amniotic band syndrome

Notes

Gestational age calculated by date of last menstrual period or ultrasound PROM diagnosis performed by Tamiere* procedure (maneuver), cristallography, or the flame test

*The authors are unsure of what this procedure is, although this may be an error in translation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not specified

Incomplete outcome data (attrition bias)
All outcomes

High risk

Results inconsistent with number randomised. Incomplete data not recorded

Selective reporting (reporting bias)

High risk

Outcomes only reported in results. Not pre‐specified. Although inclusion criteria was singleton pregnancy only, results for caesarean section indicate 2 sets of twins in each group. This was not reported.

Other bias

Low risk

None noted

Methods

RCT
Duration of study: May 1977‐July 1980

Participants

Setting: Obstetric services at the University of California Irvine Medical Center and Women's Hospital Memorial Medical Center of Long Beach, Orange County, California, USA

Participants: 160 women; 80 women in early delivery group and 80 women in expectant management group

Inclusion criteria

• Women with preterm premature rupture of the membranes

• 28‐34 weeks' gestation

Exclusion criteria

• Fetal distress

• Chorioamnionitis

• Mature L/S ratio

• Advanced labour

Prior to randomisation all women

• Monitored with an external fetal heart rate monitor for a minimum of 30 min

• Ultrasound examination performed where BPD determined.

• Amniocentesis performed for L/S ratio, gram stain and culture

• Management was delayed until results were known ‐ "usually 3 to 4 hours"

• If the L/S ratio was 1.8:1 or greater or if the gram stain demonstrated bacteria the fetus was not included in the study

Interventions

Intervention: 80 women were randomised to corticosteroids and delivery 48 h after treatment with steroids

• This included betamethasone 12 mg intramuscularly 2 doses 24 h apart

• Tocolysis used when contractions occurred

• Delivery was after 48 h by discontinuing the tocolytic and either induction of labour with oxytocin or caesarean section for obstetric indications

Control: 80 women were randomised to expectant management

• Delivered when labour, chorioamnionitis or fetal distress evident

Criteria for delivery for women in the expectant management group included:

• labour

• chorioamnionitis

• fetal distress

Corticosteroids and tocolysis used in early delivery group. Prophylactic antibiotics not used.

Vaginal examinations were not performed in the absence of labour.

Outcomes

Maternal

• Admission to delivery time

• Caesarean section

• Chorioamnionitis: fever ≥ 100.4°F in the absence of other explanations

• Endometritis

• Wound infection

• Urinary tract infection

• Duration of postpartum hospital stay

Fetal

• Birthweight

• Gestational age

• Respiratory distress

  • made when clinical signs and chest X‐ray film were confirmatory

  • infant required > 24 h/oxygen therapy

  • severe RDS: requiring a ventilator

• Sepsis: not stated as to whether a positive culture required for diagnosis

• Meningitis

• Ophthalmitis

• Pneumonia

• Necrotising enterocolitis

• Fetal death

• Neonatal death

Notes

• Gestational age determined by menstrual history and examination, or by a BPD on presentation

• Rupture of the membranes was documented by sterile speculum examination visualising amniotic fluid pooling in the posterior vaginal vault, alkaline pH by Nitrazine paper and ferning on microscopic examination of fluid from the posterior vaginal fornix.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation schema not defined

Allocation concealment (selection bias)

Unclear risk

Not defined

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Radiologists (for reviewing X‐rays prior to diagnosis of hyaline membrane disease) were blinded as to treatment allocation. However it was not mentioned if all other analysts were blinded to treatment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

No losses to follow‐up reported. However, 1 fetal death in expectant management group removed from denominator of neonatal outcomes

Selective reporting (reporting bias)

Unclear risk

Outcomes only reported in results. Not pre‐specified

Other bias

Low risk

None noted

Methods

RCT

Duration of study: September 1979‐November 1982

Participants

Setting: Ohio State University Hospitals, Ohio, USA

Participants: 73 women; 38 early delivery, 35 expectant management

Inclusion criteria

• Preterm premature rupture of the membranes

• 28‐34 weeks' gestation

Exclusion criteria

• Women with mature L/S ratios (greater than 2:1 or more) were delivered

• Active labour

• Infection

• Twin pregnancy

Interventions

Intervention: corticosteroids, tocolysis and delivery 48‐72 hours after initiation of steroid treatment

• Hydrocortisone 500 mg intravenously every 8 h for 4 doses

• Tocolysis included either magnesium sulphate, terbutaline or ritodrine

• Caesarean section for obstetric indications

Control: expectant management.

• Admission to hospital initially

• Serial observations including vital signs, abdominal examination, WBC counts

• Delivery after labour, chorioamnionitis or fetal distress occurred

• Outpatient management at discretion of managing clinician

Criteria for delivery of women in the expectant management group included

• labour

• chorioamnionitis

• fetal distress

Corticosteroids and tocolysis given to early delivery group. Prophylactic antibiotics not given.

Vaginal examinations were not performed in the absence of labour.

Outcomes

Maternal

• Ruptured membranes to delivery time

• Caesarean section

• Chorioamnionitis

• Endometritis: temp > 100.6°F on 2 readings 6 or more h apart > 24 h postpartum

• Duration of hospitalisation

Fetal

• Birthweight

• Duration of admission to delivery

• Apgar score

• Duration of total hospitalisation

• Respiratory distress: required > 24 h oxygen therapy with compatible clinical and chest X‐ray findings

  • duration of time on ventilator

  • duration of time requiring oxygen therapy

• Sepsis: required a positive culture for diagnosis

• Leukopenia

• Jaundice

• Perinatal mortality

Notes

• Gestational age defined by obstetric history and sonography

• Ruptured membranes defined by visualisation of amniotic fluid pooled in the posterior vaginal fornix on sterile speculum examination or positive Nitrazine and ferning tests.

• An L/S ratio is a ratio used to determine fetal pulmonary maturity and therefore, the risk of neonatal RDS if the fetus is delivered prematurely. It is found by testing the amniotic fluid and when the fetal lungs are mature, lecithin exceeds sphingomyelin by 2 to 1.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table

Allocation concealment (selection bias)

Unclear risk

Not defined

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not defined

Incomplete outcome data (attrition bias)
All outcomes

High risk

Losses to follow‐up: 3 women in expectant management group delivered at another hospital and were excluded from analysis.

Post‐randomisation exclusions: 1 neonate with congenital anomalies was excluded post delivery, 1 mother and her baby were excluded for failure to complete steroid therapy.

Selective reporting (reporting bias)

Unclear risk

Outcomes only reported in results. Not pre‐specified

Other bias

Low risk

None noted

Methods

Prospective RCT

Duration of study: March 2008‐October 2011

Participants

Setting: Albania

Participants: 307 pregnant women, 157 in planned early birth group and 150 to expectant management group

Inclusion criteria

• Women with preterm premature rupture of the membranes

• 34‐37 weeks' gestation

Exclusion criteria

• Not defined

Interventions

Planned early birth versus expectant management ‐ not defined

Outcomes

Maternal

• Caesarean section

Fetal

• Neonatal sepsis

• RDS

Notes

Abstract only. Limited data available

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding not possible due to intervention. However the risk was unclear as assessment criteria for outcomes was not mentioned

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not specified

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not specified

Selective reporting (reporting bias)

High risk

Only 3 outcomes as well as secondary unspecified outcomes reported in abstract. Full paper not published

Other bias

Unclear risk

As this is an abstract publication only, cannot determine the overall risk of bias

Methods

RCT

Duration of study: 1 March 1991‐31 July 1992

Participants

Setting: University of Tennessee, Memphis, USA

Participants: 93 women

• 46 women were randomised to induction of labour

• 47 women were randomised to expectant management

Inclusion criteria

• Confirmed premature rupture of the membranes at 32 weeks‐36 weeks 6 days

• Amniotic fluid testing suggestive of fetal pulmonary maturity

Exclusion criteria

• Cervical dilatation greater than 2 cm

• Persistent regular contractions or progressive labour

• Blood or meconium‐stained amniotic fluid

• Suspected chorioamnionitis

• Any maternal or fetal contraindication to expectant management

• Women with fetuses with intrauterine growth restriction

• Women with fetuses with congenital malformations

• A non‐reassuring fetal heart rate tracing (defined as recurrent decelerations, heart rate greater than 160 beats per minute, or the absence of heart rate accelerations)

Interventions

Intervention: intravenous oxytocin infusion

Control: expectant management

• This included 12 h of continuous fetal heart rate monitoring

• Observations performed every 8 h

• Women restricted to bed rest

• Criteria for delivery included

  • progressive labour

  • chorioamnionitis (defined as a temperature > 100.4°F plus any 2 of the following: fetal or maternal tachycardia, uterine contractions or tenderness, foul smelling amniotic fluid in the absence of other identifiable cause)

  • non‐reassuring fetal heart rate pattern including persistent fetal tachycardia or recurrent deceleration and positive cultures for Neisseria gonorrhoeae or GBS

Corticosteroids, tocolysis and prophylactic antibiotics not used

Vaginal examinations not performed in the absence of labour

Outcomes

Maternal

• Latency from randomisation to labour

• Latency from randomisation to delivery

• Duration of maternal hospital stay

• Chorioamnionitis: T > 100.4°F plus 2 of the following:

  • fetal or maternal tachycardia

  • uterine contractions or tenderness

  • foul‐smelling amniotic fluid in the absence of other identifiable cause

• Caesarean delivery

• Postpartum infection requiring antibiotics

Fetal

• Neonatal sepsis: required a positive culture for diagnosis

  • subgrouped into suspected and confirmed sepsis:

    • suspected neonatal sepsis: clinical findings suggestive of neonatal infection or persistent leucopenia with a WBC count < 4000/mm³ or a C‐reactive protein level elevated greater than 0.6;

    • confirmed neonatal sepsis: infants with symptoms of sepsis and positive blood cultures

• Abnormal fetal heart rate pattern

• Birthweight

• Apgar scores

• Respiratory distress:

  • required oxygen therapy (at least 40%) at least 24 h in absence of other identifiable cause

• Pneumonia

• Necrotising enterocolitis

• Intraventricular haemorrhage

• Duration of neonatal hospital stay

• Mortality

Notes

• Gestational age: determined clinically on the basis of menstrual history, earliest ultrasound examination and first clinical assessment

• Ruptured membranes diagnosed by: visualisation of amniotic fluid passing from the cervical os on sterile speculum examination or the presence of a pool of fluid in the posterior vaginal fornix that was positive to both Nitrazine paper and ferning tests

• Fetal pulmonary maturity was determined on pooled vaginal fluid (foam stability index ≥ 47 considered mature), an amniocentesis was performed in the absence of adequate vaginal fluid.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number tables

Allocation concealment (selection bias)

Unclear risk

Not clearly defined. Stated that "blinded" random number tables were used, but no further explanation was given as to what this entailed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Neonatologists were not blinded to the perinatal clinical course. It was not specified whether the assessors of maternal outcomes were blinded to their clinical course.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up or post‐randomisation exclusions

Selective reporting (reporting bias)

Unclear risk

Outcomes only reported in results. Not pre‐specified

Other bias

Low risk

None noted

Methods

Multi‐centre, international RCT

Duration of study: May 2004‐June 2013

Participants

Setting: 65 tertiary hospitals in 11 countries (Australia, Argentina, Brazil, Egypt, New Zealand, Norway, Poland, Romania, South Africa, UK, Uruguay)

Participants: 1835 women

• 923 women were randomised to induction of labour

• 912 women were randomised to expectant management

Inclusion criteria

• Over 16 years of age

• Singleton pregnancy

• Clinically suspected ruptured membranes between 34 weeks‐36 + 6 weeks' gestation

Exclusion criteria

• Established labour

• Chorioamnionitis

• Meconium staining

• Any other contraindications to continuing the pregnancy

Interventions

Intervention

• Delivery scheduled as close to randomisation as possible and preferably within 24 h

• Mode of birth was determined by usual obstetric indications

Control: expectant management

• Inpatient or outpatient management according to local guidelines

Criteria for delivery included

• Spontaneous labour

• At term

• When the attending clinician felt that birth was mandated according to usual indications

Antibiotics were prescribed according to local protocols.

Laboratory testing and other management was per usual hospital practice.

Placental histology was encouraged but not uniformly requested.

Outcomes

Maternal

• Antepartum or intrapartum haemorrhage

• Antepartum or postpartum thrombosis

• Cord prolapse

• Postpartum treatment with antibiotics

• Intrapartum fever (pyrexia ≥ 38.5°C)

• Postpartum haemorrhage (> 1000 mL)

• Mode of delivery

• Onset of labour

• Duration of hospitalisation (total days from randomisation to delivery, and from delivery to discharge or transfer)

• Chorioamnionitis among the women with expectant management

Fetal

• Definite or probable neonatal sepsis

  • Definite:

    • positive culture of a known pathogen from blood or CSF

    • baby treated with antibiotics for 5 or more days (or died before 5 days)

    • presence of clinical signs of infection: respiratory distress (requiring ventilation, continuous positive airway pressure or supplemental oxygen for more than 1 h), apnoea, lethargy, abnormal level of consciousness, circulatory compromise (including hypotension, poor perfusion, need for inotropic support or volume expansion) and/or temperature instability (temperature < 36°C or ≥ 38°C);

    • for organisms of low virulence and/or high likelihood of skin contamination of the blood culture, both a positive blood culture and an abnormal full blood count (WCC < 5 x 10⁹/L or > 30 x 10⁹/L, platelet count < 100,000, neutrophil count < 1.5 x 10⁹/L or raised immature to total neutrophil ratio (I:T ratio > 0.2)) or abnormal C‐reactive protein > 10 mg/L were required

  • Probable:

    • presence of clinical signs where the baby was treated with antibiotics for 5 or more days together with 1 or more of: an abnormal FBC; abnormal C‐reactive protein; positive GBS antigen on bladder tap urine, blood or CSF; elevated CSF WCC⁵ (CSF WCC > 100 x 10⁶/L); growth of a known virulent pathogen (e.g. GBS,E. coli, Listeria) from surface swab; or a histologic diagnosis of pneumonia in an early neonatal death

• Composite neonatal morbidity and mortality indicator (sepsis, mechanical ventilation > 24 h, stillbirth or neonatal death)

• Respiratory distress

• Perinatal mortality

• Pneumonia

• Mechanical ventilation (intermittent positive pressure ventilation, continuous positive airway pressure or high frequency ventilation) for greater than 24 h

• Duration of stay in a neonatal intensive or special care unit

• Duration of stay in hospital

• Birthweight

• Apgar score ≤ 7 at 5 min

• Antibiotics in the first 48 h

• Lumbar puncture

• Circulatory compromise requiring arterial line

• Fluid bolus or inotropic support

• Receiving breast milk at discharge (exclusive or mixed feeding)

Notes

• Women who presented with ruptured membranes earlier in pregnancy became eligible on reaching 34 weeks' gestation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐generated randomisation schedule was used in a 1:1 ratio in balanced blocks of variable size, stratified by centre.

Allocation concealment (selection bias)

Low risk

A central telephone service was used for randomisation allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The primary outcome was determined by comprehensive review of the neonatal data by a central adjudication committee masked to the treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All analyses were by intention‐to‐treat. No participants were excluded from the primary intention‐to‐treat analysis due to protocol violations.

Selective reporting (reporting bias)

Low risk

All a‐priori outcomes were reported on.

Other bias

Low risk

None noted

Methods

RCT

Duration of study: 1992‐1994

Participants

Setting: University of Mississippi Medical Center, Jackson, Mississippi, USA

Participants: 120 singleton pregnancies

• 57 women were randomised to early delivery

• 63 women were randomised to expectant management

Inclusion criteria

• Cephalic presentation

• Singleton pregnancy

• 34 weeks' gestation to 36 weeks 6 days gestation

• Preterm premature rupture of the membranes

Exclusion criteria

• Non‐cephalic presentation

• Fetal distress

• Labour on admission

• Chorioamnionitis

• Maternal medical conditions including hypertension, diabetes, active genital herpes, placenta praevia

• Severe fetal anomalies

• Meconium‐stained amniotic fluid

Interventions

Intervention: induction of labour with intravenous oxytocin

Control: expectant management

• Observations and a fetal heart rate assessment every 8 h

• Bed rest and hospitalised until delivery

• Treatment with ampicillin 2 g intravenously was carried out for all participants for GBS prophylaxis

• Criteria for delivery included:

  • non‐reassuring fetal status (recurrent decelerations or persistent tachycardia)

  • initiation of labour

  • signs of clinical chorioamnionitis (defined in the absence of other causes of pyrexia as a temperature > 100.4 °F with either uterine tenderness, leucocytosis, maternal or fetal tachycardia or a foul smelling vaginal discharge)

Corticosteroids and tocolysis not used. Routine antibiotic prophylaxis for all women

Vaginal examinations not performed in the absence of labour

Outcomes

Maternal

• Admission to delivery interval

• Chorioamnionitis: temperature > 100.4 °F with either uterine tenderness (or contractions), leuko‐cytosis, maternal or fetal tachycardia, or a foul‐smelling vaginal discharge

• Postpartum endometritis: temperature > 100.4 °F after the first 24 postpartum hours with associated uterine tenderness

• Duration of hospital stay

• Mode of delivery

Fetal

• Birthweight

• Apgar scores

• Cord pH

• Neonatal nursery admission

• Respiratory distress

• Mechanical ventilation

• Sepsis: positive culture required for diagnosis

• Intraventricular haemorrhage

• Patent ductus arteriosus

• Broncopulmonary dysplasia

• Duration of hospital stay

• Stillbirth

• Neonatal death

Notes

• Gestational age was confirmed by a reliable last menstrual period, early ultrasound or first trimester pelvic examination

  • In the absence of certain dates an ultrasound estimate of fetal weight ≥ 1800 g and ≤ 2500 g was used as an entry criteria.

• Ruptured membranes was confirmed by visualisation of pooling of fluid in the posterior vaginal fornix on sterile speculum examination or ferning under microscopic review in addition to a positive Nitrazine test.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number cards

Allocation concealment (selection bias)

Unclear risk

Opaque sealed envelopes but did not state if envelopes were sequentially numbered

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Neonatologists were not blinded to the perinatal clinical course. It was not specified whether the assessors of maternal outcomes were blinded to their clinical course.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up
No post‐randomisation exclusions

Selective reporting (reporting bias)

Low risk

All a‐priori outcomes were reported on

Other bias

Low risk

None noted

Methods

RCT
Duration of study: not specified

Participants

Setting: Wake Forest University Medical Center, North Carolina, USA

Participants: 68 women

• 22 women randomised to steroid and early delivery group

• 22 women randomised to no‐steroid and early delivery group

• 24 women randomised to no‐steroid and expectant group

Inclusion criteria

• Women with preterm premature rupture of the membranes

• 28‐34 weeks' gestation

Exclusion criteria

• Evidence of fetal distress

• Active labour

• Cervix > 3 cm dilated

• Sensitivity to tocolysis

• History of preterm premature rupture of the membranes > 24 h

• Existing infection

Interventions

Intervention: included 2 groups

Group 1. Steroid group who received intramuscular betamethasone 6 mg or 12 mg on admission and another dose 12 h later

• Ritodrine or terbutaline tocolysis used for a minimum of 24 h after the first steroid dose

• Delivery between 24‐48 h after initial PROM and after 24 h of steroid therapy

• Caesarean section performed for obstetric indications

Group 2. No‐steroid group who received similar treatment to group 1 except no steroids were given

Control: expectant management

• 24 women randomised to expectant group

• Received no tocolytics or steroids

• Caesarean section for usual obstetric indications

Criteria for delivery in the expectant group not specified

Corticosteroids and tocolysis used for early delivery group. Prophylactic antibiotics not used.

Not specified as to whether digital vaginal examinations were performed

Outcomes

Maternal

• Duration of latency period

• Maximum temperature

• Maternal sepsis: T > 37.7°C on 2 occasions at least 6 h apart, uterine tenderness and a rising WBC

• Use of tocolysis

• Mode of delivery

Fetal

• Birthweight

• Duration of hospitalisation

• Respiratory distress:

  • none

  • mild

  • moderate

  • severe

• Neonatal sepsis: positive culture required for diagnosis

• Neonatal deaths

Notes

• Gestational age confirmed by ultrasound on admission

• Ruptured membranes diagnosed by ferning under microscopy, Nitrazine test and/or visualisation of pooling of amniotic fluid in the posterior fornix or the vagina at the time of sterile speculum examination

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised cards were used. Participants were randomly assigned by drawing a sealed envelope from a group of randomised cards, it did not state how the randomisation sequence was generated.

Allocation concealment (selection bias)

Unclear risk

Sealed envelopes but did not state if opaque or sequentially numbered

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not specified

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up
No post‐randomisation exclusions

Selective reporting (reporting bias)

Low risk

All a‐priori outcomes were reported on

Other bias

Low risk

None noted

Methods

RCT
Duration of study: 1 June 1983‐15 November 1984

Participants

Setting: E.H. Crump Women's Hospital and Perinatal Center, Memphis, Tennessee, USA

Participants: 47 women

• 26 women randomised to early delivery

• 21 women randomised to expectant management

Inclusion criteria

• 25‐36 weeks' gestation

• Preterm premature rupture of the membranes

• Fetal pulmonary maturity demonstrated on amniotic fluid (an L/S ratio of 2 or more or a Foam stability index of 47 or more)

Exclusion criteria

• Spontaneous labour at presentation

• Chorioamnionitis

Interventions

Intervention: early delivery either by induction of labour with oxytocin or caesarean section for all non‐vertex presentations

Control: expectant management

• External electronic fetal monitoring performed for 8‐12 h

• Bed rest for as long as amniotic fluid leakage continued

• Hospital discharge permitted at the discretion of the attending physician

• Monitored with serial temperature, pulse, fetal heart rate, WBC and differential counts

Criteria for delivery in the expectant group of women

• Labour

• Fetal distress

• Chorioamnionitis

Corticosteroids, tocolysis and prophylactic antibiotics not used

Vaginal examinations not performed in the absence of labour

Outcomes

Maternal

• Time from rupture of membranes to labour

• Time from rupture of membranes to delivery

• Duration of labour

• Delivery by caesarean section

• Chorioamnionitis: maternal fever (38°C on 2 occasions or a single reading on 38.3°C) with foul‐smelling vaginal discharge and uterine tenderness, or when no other source for maternal fever could be identified

• Endometritis: fever (excluding during 1st 24 h postpartum) plus uterine tenderness or foul‐smelling lochia

Fetal

• Birthweight

• Apgar score < 7 at 5 min

• Neonatal duration of hospitalisation

• Hyaline membrane disease

• Transient pulmonary insufficiency (includes respiratory insufficiency of prematurity, RDS, and transient tachypnoea of the newborn)

• Need for mechanical ventilation > 24 h

• Need for oxygen therapy > 3 d

• Infection

• Sepsis: not specified if positive culture required for diagnosis

• Pneumonia

• Meningitis

• Necrotising enterocolitis

• Intracranial haemorrhage

• Seizures

• Perinatal death

Notes

• Gestational age determined by "best clinical estimate" including ultrasound examination on admission

• Ruptured membranes diagnosed by speculum examination demonstrating pooled amniotic fluid in the vaginal vault or alkaline pH by Nitrazine paper and microscopic ferning of air dried vaginal vault fluid

• Fetal pulmonary maturity required

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequential sealed envelope odd‐even random numbers

Allocation concealment (selection bias)

Unclear risk

Sealed envelopes, did not specify if opaque or sequentially numbered

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

• Obstetricians not blinded to maternal allocation group

• Neonatologists blinded to perinatal clinical course

However, did not mention if outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Losses to follow‐up: no losses to follow‐up

Post‐randomisation exclusions: 7 women for preterm labour, 4 women for "protocol violations", and 4 other women with unspecified reason

Selective reporting (reporting bias)

Unclear risk

Outcomes only reported in results. Not pre‐specified

Other bias

Low risk

None noted

Methods

Multi‐centre, parallel, open‐label RCT
Duration of study: January 2007‐September 2009

Participants

Setting: 8 academic and 52 non‐academic hospitals in the Netherlands

Participants: 532 women

• 266 women randomised to early birth (included 268 babies)

• 266 women randomised to expectant management (included 270 babies)

Inclusion criteria

• Singleton or twin pregnancy with PPROM between 34 and 36 + 6 weeks' gestation who were not in labour within 24 h of PPROM

• PPROM had to be diagnosed after 26 + 0 weeks

Exclusion criteria

• Monochorionic multiple pregnancy

• Abnormal (non‐reassuring) cardiotocogram

• Meconium‐stained amniotic fluid

• Signs of intrauterine infection

• Major fetal anomalies

• Haemolysis, elevated liver enzymes, and low platelets (HELLP syndrome)

• Severe pre‐eclampsia

Interventions

Intervention: induction of labour within 24 h after randomisation. Induction performed according to national guidelines. After vaginal examination, labour induced with either prostaglandin or oxytocin, or caesarean section performed as soon as feasible in case of planned caesarean

Control: expectant management

• Monitored according to local protocol until spontaneous birth, which could be outpatient or inpatient

• Daily maternal temperature, monitoring and twice‐weekly blood sampling for maternal leukocyte count and C‐reactive protein measurement

Criteria for delivery in the expectant group of women

• Induced at 37 weeks according to national guidelines

• If planned caesarean section, caesarean section performed as soon as labour commenced

• Induction of labour < 37 weeks if clinical signs of infection or other fetal or maternal indication for birth

Tocolysis and prophylactic antibiotics used according to local protocols

Corticosteroids given in PPROM < 34 weeks' gestation

Vaginal examinations not performed in the absence of labour

Outcomes

Maternal

• Antepartum haemorrhage

• Uterine rupture

• Umbilical cord prolapse

• Signs of chorioamnionitis (defined as fever before or during labour and a temperature < 37.5°C on 2 occasions more than 1 h apart before or during labour, or a temperature > 38.0°C on 1 occasion with uterine tenderness)

• Leukocytosis

• Maternal or fetal tachycardia (or a foul‐smelling vaginal discharge in absence of any other cause of hyperpyrexia)

• Maternal sepsis (defined as a temperature > 38.5°C and a positive blood culture or circulatory instability requiring intensive care monitoring)

• Thromboembolic complications

• Urinary tract infection treated with antibiotics

• Endometritis (defined as a temperature > 38.0°C on 2 occasions at least 1 h apart after the 1st 24 h postpartum with associated uterine tenderness)

• Pneumonia

• Anaphylactic shock

• HELLP syndrome

• Maternal death

• Other complications

• Total length of hospital stay

• Admission to the ICU

• Mode of birth

• Need for anaesthesia

Fetal

• Neonatal sepsis:

  • positive blood culture at birth (excluding Staph epidermidis)

  • 2 or more symptoms of infection (apnoea, temperature instability, lethargy, feeding intolerance, respiratory distress, haemodynamic instability) within 72 h after birth plus 1 of the following: positive blood culture, C‐reactive protein > 20 mmol/L, positive surface cultures of a known virulent pathogen

• RDS

• Wet lung

• Meconium aspiration syndrome

• Pneumothorax/pneumomediastinum

• Asphyxia

• Late onset neonatal sepsis

• Hypoglycaemia

• Necrotizing enterocolitis

• Hyperbilirubinaemia

• Intraventricular haemorrhage

• Periventricular leucomalacia

• Convulsions

• Other neurological abnormalities

• Other complications

• Intrapartum death

• Total length of hospital stay and admission

• Length of stay on NICU

Notes

• Rupture of membranes was diagnosed based on history and clinical findings such as gross vaginal fluid loss in combination with other available diagnostic test methods.

• Gestational age was based either on first trimester ultrasound scan or, in women with a regular cycle, on the first day of the last menstrual cycle if the expected date of birth differed less than 7 days from that estimated by ultrasound. In women with unknown EDD, gestational age was estimated by 2nd trimester ultrasound measurements.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐generated randomisation schedule was used in a 1:1 ratio using a block size of 4, stratified for centre and parity.

Allocation concealment (selection bias)

Low risk

Randomisation allocation was performed on a central password‐protected web‐based application.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Criteria for sepsis were entered in the database and the case was judged by an independent panel of paediatricians who were unaware of the allocation of randomisation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data analysed on intention‐to‐treat basis. 2 participants were excluded post randomisation from the primary intention‐to‐treat analysis due to ineligibility.

Selective reporting (reporting bias)

Low risk

All a‐priori outcomes were reported on.

Other bias

Low risk

None noted

Methods

Multi‐centre, parallel, open‐label RCT
Duration of study: December 2009‐January 2011

Participants

Setting: 8 academic and 52 non‐academic hospitals in the Netherlands

Participants: 195 women

• 100 women randomised to early birth (included 100 babies)

• 95 women randomised to expectant management (included 98 babies)

Inclusion criteria

• Singleton or twin pregnancy with PPROM between 34 and 36 + 6 weeks' gestation who were not in labour within 24 h of PPROM

• PPROM had to be diagnosed after 26 + 0 weeks

Exclusion criteria

• Monochorionic multiple pregnancy

• Abnormal (non‐reassuring) cardiotocogram

• Meconium‐stained amniotic fluid

• Signs of intrauterine infection

• Major fetal anomalies

• HELLP syndrome

• Severe pre‐eclampsia

Interventions

Intervention: induction of labour with 24 h after randomisation. Induction performed according to national guidelines. After vaginal examination, labour induced with either prostaglandin or oxytocin, or caesarean section performed as soon as feasible in case of planned caesarean.

Control: expectant management

• Monitored according to local protocol until spontaneous birth which could be outpatient or inpatient

• Daily maternal temperature, monitoring and twice‐weekly blood sampling for maternal leukocyte count and C‐reactive protein measurement

Criteria for birth in the expectant group of women

• Induced at 37 weeks according to national guidelines

• If planned caesarean section, caesarean section performed as soon as labour commenced

• Induction of labour < 37 weeks if clinical signs of infection or other fetal or maternal indication for birth

Tocolysis and prophylactic antibiotics used according to local protocols

Corticosteroids given in PPROM < 34 weeks' gestation

Vaginal examinations not performed in the absence of labour

Outcomes

Maternal

• Antepartum haemorrhage

• Uterine rupture

• Umbilical cord prolapse

• Signs of chorioamnionitis (defined as fever before or during labour and a temperature < 37.5°C on 2 occasions more than 1 h apart before or during labour, or a temperature > 38.0°C on 1 occasion with uterine tenderness)

• Leukocytosis

• Maternal or fetal tachycardia (or a foul‐smelling vaginal discharge in absence of any other cause of hyperpyrexia)

• Maternal sepsis (defined as a temperature > 38.5°C and a positive blood culture or circulatory instability requiring intensive care monitoring)

• Thromboembolic complications

• Urinary tract infection treated with antibiotics

• Endometritis (defined as a temperature > 38.0°C on 2 occasions at least 1 h apart after the 1st 24 h postpartum with associated uterine tenderness)

• Pneumonia

• Anaphylactic shock

• HELLP syndrome

• Maternal death

• Other complications

• Total length of hospital stay

• Admission to the ICU

• Mode of birth

• Need for anaesthesia

Fetal

• Neonatal sepsis:

  • positive blood culture at birth (excluding Staph epidermidis);

  • 2 or more symptoms of infection (apneas, temperature instability, lethargy, feeding intolerance, respiratory distress, haemodynamic instability) within 72 h after birth plus 1 of the following: positive blood culture, C‐reactive protein > 20 mmol/L, positive surface cultures of a known virulent pathogen

• RDS

• Wet lung

• Meconium aspiration syndrome

• Pneumothorax/pneumomediastinum

• Asphyxia

• Late onset neonatal sepsis

• Hypoglycaemia

• Necrotizing enterocolitis

• Hyperbilirubinaemia

• Intraventricular haemorrhage

• Periventricular leucomalacia

• Convulsions

• Other neurological abnormalities

• Other complications

• Intrapartum death

• Total length of hospital stay and admission

• Length of stay on NICU

Notes

• Rupture of membranes was diagnosed based on history and clinical findings such as gross vaginal fluid loss in combination with other available diagnostic test methods.

• Gestational age was based either on first trimester ultrasound scan or, in women with a regular cycle, on the first day of the last menstrual cycle if the expected date of birth differed less than 7 days from the estimated by ultrasound. in women with unknown EDD, gestational age was estimated by 2nd trimester ultrasound measurements.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐generated randomisation schedule was used in a 1:1 ratio using a block size of 4, stratified for centre and parity.

Allocation concealment (selection bias)

Low risk

Randomisation allocation was performed on a central password‐protected web‐based application.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding not possible due to intervention. However this was likely low risk of bias due to objective and specific assessment criteria for outcomes, where lack of blinding did not affect treatment decisions or other aspects of care.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Criteria for sepsis were entered in the database and the case was judged by an independent panel of paediatricians who were unaware of the allocation of randomisation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data analysed on intention‐to‐treat basis. No participants were excluded.

Selective reporting (reporting bias)

Low risk

All a‐priori outcomes were reported on.

Other bias

Low risk

None noted