Preterm prelabour rupture of membranes (PPROM) is a complication that occurs in 3 per cent of live pregnancies between 22+0 and 36+6 weeks gestation, with the majority of these pregnancies delivering within one week of membrane rupture.¹ Prematurity-related morbidity varies with gestational age and the three main causes of neonatal death associated with PPROM are prematurity, sepsis and pulmonary hypoplasia.²

The purpose of this article is to present a snapshot of the current evidence-based guidance for specifically the diagnosis, relevance of laboratory test monitoring for chorioamnionitis, prophylactic antibiotic management and timing of delivery for women with PPROM. Our aims of care should be to use an evidence-based approach to managing patient care to maximise the benefits of increasing in utero fetal maturity, while minimising both maternal and neonatal morbidity and mortality.

Diagnostic aids

The diagnosis of PPROM is primarily clinical and is made via visualisation of amniotic fluid from the cervix on sterile speculum examination. In cases of uncertainty, laboratory and point-of-care tests can be used to aid in the diagnosis of amniorrhexis.

• Nitrazine paper can be used to detect pH changes in vaginal secretions. This test is affected by alkaline fluids such as semen, blood and soap.³
• Placental alpha microblobulin-1 protein assay (PAMG-1 [Amnisure]) is a rapid slide test that uses immunochromatography methods to detect trace amounts of placental alpha micoglobulin-1 protein in vaginal fluid. It is a point-of-care test that provides results within 5–10 minutes of collection. This test is not affected by semen or trace amounts of blood.⁴
• Insulin-like growth factor binding protein 1 (IGFBP-1 [Actim PROM]) is secreted by decidual and placental cells and has a very high concentration in amniotic fluid. This test is not affected by the presence of infected vaginal secretions, urine, semen or small amounts of blood. It, too, is a point-of-care test providing results in 5–10 minutes.⁵

A 2013 meta-analysis of prospective observational or cohort studies investigating IGFBP-1 (Actim PROM) and PAMG-1 (Amnisure) for diagnosis of ruptured membranes concluded that PAMG-1 was more accurate than IGFBP-1 for diagnosis in all patient populations.⁶ A subsequent randomised trial of 120 pregnant women with signs and symptoms of membrane rupture were evaluated with the PAMG-1, IGFBP-1 and nitrazine tests. Results identified sensitivity, specificity, positive predictive value and negative predictive value of PAMG-1 (100%, 100%, 100% and 100%) IGFBP-1 (93.33%, 98.89%, 96.55% and 97.80%) and nitrazine test (93.33%, 94.44%, 84.85% and 97.7%).⁷

Point-of-care tests are both highly sensitive and specific while being a practical aid in the diagnosis of PPROM.

Antenatal monitoring for chorioamnionitis

The RCOG Green-top Guideline 44 defines the diagnostic criteria of clinical chorioamnionitis as maternal pyrexia, tachycardia, leucocytosis, uterine tenderness, offensive vaginal discharge and fetal tachycardia. There is conflicting evidence in the literature regarding the accuracy or usefulness of laboratory tests indicating leucocytosis and raised C-reactive protein in the prediction of chorioamnionitis. It has a low sensitivity (less than 20 per cent) and high specificity (greater than 90 per cent) for chorioamnionitis and, as such, may only be useful in excluding infection.^{8 9}

Routine antibiotics

Prophylactic antibiotics are known to prolong latency and reduce maternal and fetal infection following PPROM.¹⁰ Prolonged rupture of membranes increases the risk of intrauterine infection, which carries adverse consequences affecting both the woman and her infant. Streptococcus agalactiae, or GBS, is the most frequent cause of early onset neonatal sepsis.¹¹

There is a range of published data demonstrating erythromycin resistance in GBS isolates and, as such, 48 hours of intravenous ampicillin is the recommendation from Centers for Disease Control and the American College of Obstetricians and Gynaecologists for coverage until a rectovaginal swab has excluded GBS colonisation.¹²

Twenty-two trials involving more than 6000 women with PPROM before 37 weeks were included in a meta-analysis.¹³ The use of antibiotics following PPROM was associated with a statistically significant reduction in chorioamnionitis (RR 0.57, 95% CI 0.37-0.86). Ultimately, the data were insufficient to determine whether any antibiotic regimen (drug, dose, duration) was better than another, but amoxicillin-clavulanate was associated with an increased risk of neonatal necrotising enterocolitis (RR 4.72, 95% CI 1.57–14.23)¹³

There are two large randomised controlled trials investigating prophylactic antibiotic regimens in the setting of PPROM; the ORACLE 1 trial and the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Trial (NICHD MFMU).

The ORACLE 1 trial enrolled 4826 women with diagnosed PPROM and investigated the use of a combination of oral antibiotics versus placebo and concluded that erythromycin alone was associated with prolongation of the pregnancy and was safe and effective in improving rates of adverse perinatal outcomes.¹⁴ A seven year follow-up study, the ORACLE Children Study, revealed that early improved outcomes for neonates did not make a substantial difference to the children’s health and development long term.¹⁵

NICHD MFMU randomised 614 women with diagnosed PPROM to receive placebo versus 48 hours of intravenous ampicillin (2 g every six hours) and then five days of oral amoxicillin (250 mg every eight hours) and erythromycin (333 mg every eight hours). Therapy did prolong pregnancy and reduce neonatal morbidity.¹⁶

UpToDate prefers the single use of azithromycin 1 g orally on admission, in addition to ampicillin 2 g intravenously every six hours for 48 hours, followed by amoxicillin 500 mg orally three times daily for an additional five days. The rationale behind the use of azithromycin is its specific targeting of Ureaplasmas, an important cause of chorioamnionitis in this setting.¹⁷ This is a similar regimen to that shown to be effective in the NICHD MFMU trial; however, azithromycin is given in lieu of a five-day course of erythromycin because of its ease of administration, improved gastrointestinal tolerance, favourable cost profile and similar efficacy. A retrospective study of prophylactic antibiotic regimes in women with PPROM concluded similar pregnancy and neonatal outcomes with ampicillin plus erythromycin or ampicillin plus azithromycin.¹⁸

In the setting of unknown GBS status, it is reasonable to administer 48 hours of IV ampicillin followed by a course of oral erythromycin and amoxicillin. The use of azithromycin is not currently supported by the RCOG or RANZCOG guidelines for management of PPROM and higher powered studies into its use in this setting are required.

Given the continual changes in bacterial sensitivities, it is important to recognise that we will require ongoing studies to determine optimal prophylactic antibiotic regimen required in the setting of PPROM.

Timing of birth

Expediting delivery of women with PPROM is indicated if evidence of intrauterine infection, placental abruption, non-reassuring fetal status or high risk of cord prolapse is suspected. In the absence of these risk factors and optimal dating, expectant management can be considered beyond 34 weeks of gestation. Patients should be counselled regarding the increased risk of chorioamnionitis compared with decreased risk of serious neonatal respiratory issues and admission to neonatal care units.

The point at which to augment labour following PPROM is dependent on the evaluation of potential benefits of advanced gestational age at delivery and the risks associated with prolonged rupture of membranes. A retrospective series examining neonatal outcomes following cases with PPROM between 32 and 36 weeks demonstrated that the optimal gestation for reduced morbidity was 34 weeks.¹⁹

The PPROMT multicentre and the PPROMEXIL-2 randomised controlled trials compared immediate delivery with expectant management of women with a singleton pregnancy and PPROM between 34 and 36+6 weeks gestation. ²⁰ Comparison of neonatal outcomes between the groups demonstrated a similar risk of neonatal sepsis between the women who had been induced and those who had expectant management: PPROMT 2% vs 3% and PPROMEXIL-2 3% vs 4%.²¹ Both trials concluded that induction of labour (IOL) did not reduce the risk of neonatal sepsis, and the PPROMT trial found that IOL increased the risk of respiratory morbidity.

Summary

• Point-of-care tests are highly specific and sensitive in aiding diagnosis
• Maternal CRP testing is not necessary as the sensitivity in detection of intrauterine infection is low
  Management with 48 hours of intravenous ampicillin (in addition to oral erythromycin) can be considered in the setting of PPROM to broaden the antibiotic coverage
• Expectant management should be favoured beyond 34 weeks gestation in the absence of signs or symptoms of chorioamnionitis

Further research, into not only these specific talking points but also the broader management of PPROM, will aid in standardising patient care on an evidence-based approach. A willingness to remain up to date with this evidence and adjust our management accordingly is essential in maintaining optimal care of our patients.

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