Etiology of preterm premature rupture of membranes

The fetal membranes include the amnion, which lines the amniotic cavity, and the chorion, which is attached to the maternal decidua. The amnion and chorion are adherent to one another by an extracellular matrix composed of collagens. These membranes contain the amniotic fluid and provide a physical barrier to ascending infection. PPROM is a pathological condition and has been associated with many factors that overlap with risk factors for preterm birth. Intra‐amniotic infection (IAI) is associated with PPROM, however the cause and effect relationship is not always certain [9]. Additional risk factors associated with PPROM include a history of PPROM, genital tract infection, vaginal bleeding in pregnancy, cigarette smoking, short cervical length, low body mass index, low socioeconomic status, and drug abuse [10–14]. However, the majority of cases of PPROM occur without an identifiable risk factor.

Complications of preterm premature rupture of membranes

PPROM has complications for both the mother and her fetus. The maternal complications include infection, sepsis, preterm labor, and placental abruption. Clinical IAI is diagnosed in 15–25% of patients with PPROM, while post‐partum endometritis complicates 15–20% of PPROM [9, 15, 16]. Placental abruption occurs in 2–5% of women with PPROM [17, 18].

The fetal complications of PPROM include preterm delivery, a non‐reassuring fetal heart rate, umbilical cord prolapse, and intrauterine fetal demise [10]. The risk of stillbirth in women with PPROM is 1–2%, with infection and umbilical cord accidents as contributing factors [19]. PPROM is associated with neonatal complications that vary depending on the gestational age at the time of membrane rupture and delivery, and can include respiratory distress syndrome, neonatal sepsis, intraventricular hemorrhage, necrotizing enterocolitis, and neurodevelopmental impairment [10].

Diagnosis

An accurate diagnosis of PPROM is essential, as failure to diagnose PPROM could result in withholding beneficial treatments for the mother and fetus, while an incorrect diagnosis could lead to unnecessary interventions and a costly hospital admission. The diagnosis of ROMs is generally a clinical diagnosis based on symptoms suggestive of ROM and exam findings.

The symptoms of ROM may include a gush of fluid from the vagina, vaginal bleeding, increased vaginal discharge, or a persistent leakage of a fluid. These symptoms need to be further evaluated as they could also be attributed to causes other than ROM, including urinary incontinence, physiological vaginal discharge, infection, or placental abruption.

A SSE is often the first step to look for pooling of fluid in the posterior cul‐de‐sac of the vagina and to obtain a fluid sample for pH testing and microscopy. The pH of amniotic fluid is between 7.1 and 7.3, which is more alkaline than normal vaginal fluid, which has a pH of 4.5–6.0. Nitrazine paper can be used to test for amniotic fluid, as nitrazine paper will turn blue when exposed to fluid with a pH above 6.0. When amniotic fluid dries on a glass slide, the salt content crystallizes and develops a characteristic appearance of ferning when viewed under a microscope. The presence of pooling, nitrazine paper turning blue, and ferning are suggestive, but not diagnostic, of ROM.

The nitrazine test has a 17% false positive and 10% false negative rate. Contaminants, such as blood, urine, semen, and discharge from certain vaginal and cervical infections, can increase the pH of vaginal fluid above 6.0 and result in a false positive nitrazine test. Ferning has a 6% false positive and 13% false negative rate. False positive ferning can result from the salt content in cervical mucus, semen, and fingerprints on the slide. False negative results for both nitrazine testing and ferning can result when an inadequate sample of amniotic fluid is obtained [20]. The combination of pooling and ferning has a sensitivity of 51–98% and a specificity of 70–88% [21–24]. Because of the low sensitivity of these tests, if the suspicion for ROM is high and the ferning and nitrazine tests are negative, then the exam could be repeated after a period with the patient in the supine position. Additionally, ultrasound may be useful in the evaluation of ROM, as a low amniotic fluid volume supports the diagnosis, while a normal or high amniotic fluid volume may make the diagnosis of ROMs less likely.

The gold standard for the diagnosis of ROM is an amniocentesis with intra‐amniotic instillation of indigo carmine. ROM is diagnosed if blue dye is present on a vaginal tampon 20–30 minutes after the injection of indigo carmine into the amniotic cavity. Because of the risks associated with an amniocentesis, including placental abruption, infection, ROM, and fetal demise, this procedure is used selectively, and is currently limited by a shortage of indigo carmine. Fluorescein instillation into the amniotic cavity followed by a speculum exam and visualization of the cervix with an ultraviolet light 15–45 minutes after the injection has been used as an alternative to indigo carmine. However, the use fluorescein is not routine in clinical practice [25]. Methylene blue and toluidine blue are not appropriate substitutes for indigo carmine because these substances have been implicated in fetal small intestinal atresia, methemoglobinemia, and fetal death [26, 27].

Biochemical markers detected in the cervicovaginal fluid have been investigated to identify amniotic fluid in the vagina and aid in the noninvasive diagnosis of ROM. The AmniSure ^® ROM Test (Qiagen, Germantown, Maryland) detects placental alpha macroglobulin‐1 (PAMG‐1), a 34 kDa glycoprotein present in the amniotic fluid in significantly higher concentrations than maternal serum or secretions. AmniSure has been shown to be highly sensitive and specific for ROM when compared to conventional testing with a sensitivity and specificity of 96% and 100%, respectively. AmniSure is more likely to generate a false positive result with labor or advanced cervical dilation [28–31]. Another biochemical marker, Actim PROM (Cooper Surgical, Trumbull, Connecticut), detects insulin‐like growth factor‐binding protein 1 (IGFBP‐1) and has been shown to be 89% sensitive and 83% specific, and superior to both nitrazine and ferning [32]. The diagnostic accuracy of the PAMG‐1 and IGFBP‐1 tests has been studied in a prospective study in women with vaginal bleeding and concern for ROM. PAMG‐1 was less susceptible than IGFBP‐2 to interference by blood, with a sensitivity for the identification of amniotic fluid of 99% versus 91%, and a specificity of 92% versus 75%, respectively [33]. Although comparative studies have shown that AmniSure is superior to Actim PROM for the diagnosis of ROM, a meta‐analysis did not show a difference when the two products were compared in the same clinical scenario [34–36].

Additional biochemical markers that have been evaluated for the diagnosis of ROM include diamine oxidase, alpha‐fetoprotein, soluble intercellular adhesion molecule‐1, fibronectin, prolactin, beta subunit of human chorionic gonadotropin, creatinine, urea, lactate, and Axl receptor tyrosine kinase, however their clinical utility in the diagnosis of ROM is limited at this time [37–54]. There is ongoing research utilizing proteomics and mass spectrometry to identify potential biomarkers of ROM [55].

Management of PPROM

Further maternal and fetal evaluation is necessary after the diagnosis of PPROM. Foremost, an accurate gestational age and fetal viability must be established. In an executive summary by the Eunice Kennedy Schriver National Institute of Child Health and Human Development, Society for Maternal Fetal Medicine, American Academy of Pediatrics and the American Congress of Obstetricians and Gynecologists (ACOG), the fetal periviable period was defined as the gestational age between 20 0/7 weeks and 25 6/7 weeks of gestation [56]. The gestational age at which intervention on behalf of the fetus occurs is generally based on regional and local definitions of viability, as well as a discussion between the patient, obstetrician, and neonatologist. Survival estimates for the baby that take into consideration gestational age, estimated fetal weight, corticosteroid administration, plurality, and fetal sex can aid in this discussion.

Obstetric interventions are not recommended when PPROM occurs at a previable gestational age, and management of previable PPROM will be discussed separately. During the periviable period (20 0/7 weeks to 25 6/7 weeks gestation), certain obstetric interventions are not recommended, while some should be considered, and others are recommended depending on decisions regarding resuscitation and the family’s preferences after appropriate counseling [57]. If a woman’s fetus is of a viable gestational age or periviable and she is a candidate for intervention, then she should be admitted or transferred to a center that can provide both the obstetric and neonatal expertise to care for the mother and a preterm baby.

The initial evaluation of the periviable and viable fetus with suspected PPROM should include confirmation of the diagnosis, as well as an ultrasound determination of the fetal presentation, amniotic fluid volume, and estimated fetal weight. Fetal well‐being should be evaluated by an external fetal heart rate monitor and the presence or absence of uterine contractions should be established by external monitoring. A culture for group B streptococcus (GBS) should be obtained prior to antibiotic administration. Unless the patient is in active labor, a visual assessment of the cervix with a SSE to determine dilation and effacement is preferred over a digital exam, as digital exams have been associated with an increased risk of infection [10].

Evaluation of maternal and fetal status is necessary to determine which patients are candidates for expectant management and those patients for whom delivery is indicated. The diagnoses of cord prolapse and significant placental abruption are obstetric emergencies which necessitate immediate delivery of the viable fetus. Similarly, advanced cervical dilation with fetal malpresentation may be an indication for cesarean delivery. Delivery should also be considered for IAI, labor, and a non‐reassuring fetal heart rate tracing or biophysical profile. In the absence of the above indications for delivery, hospitalization, and expectant management are recommended for pregnancies complicated by PPROM at less than 34 0/7 weeks. During hospital admission, periodic evaluations to exclude IAI, labor, placental abruption, and non‐reassuring fetal status are performed to determine if delivery is indicated. Antenatal testing is suggested to ensure fetal wellbeing, although the frequency and method of evaluation has not been established. At our institution we generally perform daily nonstress tests, weekly biophysical profiles to follow the amniotic fluid volume and fetal presentation, and assess the fetal growth every three to four weeks. More frequent testing may be performed in cases of anhydramnios or fetal growth restriction. Currently, outpatient management is not recommended for PPROM at a viable gestational age [10].

The latency period

In the absence of indications for delivery, expectant management is recommended to decrease the risks to the baby associated with prematurity. The latency period is defined as the time between ROMs and delivery, either spontaneous or indicated. At least 50% of women with ROM who undergo expectant management deliver within a week [58]. Factors associated with a shorter latency period include a later gestational age at the time of ROM, oligohydramnios, cervical dilation >1 cm, cervical length < 2 cm, fetal growth restriction, and nulliparity [19, 59, 60]. Re‐accumulation of the amniotic fluid after PPROM has been associated with an increased latency and decreased perinatal morbidity and mortality [61]. Certain interventions, such as antenatal corticosteroids, magnesium sulfate for neuroprotection, and delivery at 34 0/7 weeks have been shown to improve neonatal outcomes, while latency antibiotics have been shown to prolong latency in women with PPROM.

Corticosteroids for prematurity

Antenatal corticosteroids have been shown to decrease neonatal mortality, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis in infants born to women with PPROM [62, 63]. A single course of corticosteroids is recommended in cases of PPROM between 24 0/7 and 34 0/7 weeks of gestation, and may be considered as early as 23 0/7 weeks of gestation. Antenatal corticosteroids are not recommended prior to 23 0/7 weeks of gestation, as they have not been shown to decrease the risk of complications in infants born prior to 23 0/7 weeks of gestation [10, 57]. Betamethasone, 12 mg intramuscularly 24 hours apart times 2 doses, or alternatively dexamethasone, 6 mg intramuscularly every 6 hours times 4 doses, have been shown to provide benefits for infants born preterm without increasing the risk of infection in the mother or neonate [64]. While a repeat course of antenatal corticosteroids has not been shown to increase the rate of neonatal sepsis or maternal chorioamnionitis in PPROM compared to a single course, a clear benefit has not been demonstrated. Therefore, there is currently insufficient evidence to recommend for or against a repeat course of corticosteroids in the setting of PPROM [10, 65, 66].

Magnesium sulfate for fetal neuroprotection

Randomized control trials and meta‐analyses have shown that magnesium sulfate given to women at risk for preterm delivery reduces the risk of a diagnosis of cerebral palsy in the infants [67–69]. In the largest randomized control trial evaluating the neuroprotective benefits of magnesium sulfate, 86% of the subjects were diagnosed with PPROM. In this trial composed primarily of patients with PPROM, magnesium sulfate was administered between 24 0/7 weeks and 31 6/7 weeks to women at risk for imminent delivery and decreased the risk of cerebral palsy in the infants [70]. Magnesium sulfate has been found to be both cost effective ($1462.60 vs $1607.50) and result in improved outcomes (56.7022 vs. 56.6972 quality‐adjusted life years) when administered to women at risk for preterm birth due to PPROM less than 32 0/7 weeks of gestation [71]. The use of magnesium sulfate for fetal neuroprotection has not been shown to prolong latency in women with PPROM without labor between 24 0/7 and 32 0/7 weeks gestation [72]. The optimal dose and duration of magnesium sulfate has not been determined. At our institution we administer a 6 g intravenous bolus of magnesium sulfate, over 30 minutes, followed by a 2 g h⁻¹ maintenance infusion if delivery is felt to be imminent.

Magnesium sulfate for fetal neuroprotection should be considered for women with PPROM at risk of imminent delivery after 23 0/7 weeks, and is recommended between 24 0/7 weeks and 32 0/7 weeks [12, 68, 70].

Prophylactic antibiotics in PPROM

Prophylactic antibiotics in the setting of PPROM under 34 0/7 weeks of gestation has been shown to increase the latency period, reduce infectious morbidity, and reduce gestational age‐dependent morbidity [16, 73–75]. A retrospective study evaluated 17 877 pregnancies at a single institution in which PPROM occurred in 1.7% of patients. In the absence of any medical interventions, including prophylactic antibiotics and corticosteroids, greater than 90% of women entered spontaneous labor within 48 hours [76]. In contrast, another retrospective study with 66 775 patients, in which the rate of PPROM was 1.4%, patients were administered prophylactic antibiotics and corticosteroids, and only 26% of women delivered within 48 hours of ROM [60]. Similarly, a randomized trial by the National Institute of Child Health and Human Development Maternal Fetal Medicine Unit showed a significant prolongation in pregnancy in women with PPROM who were administered prophylactic antibiotics (6.1 versus 2.9 days, p < 0.01) [74].

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