Preterm and Term Prelabor Rupture of Membranes (PPROM and PROM)

Etiology

Pathophysiology of Premature Rupture of Membranes

The fetal membranes play a critical role during gestation, providing mechanical and immunologic protection for the developing fetus. The fetal membranes are made up of 2 layers: the amnion, which is the inner layer, and the chorion, which is the outer membrane connected to the decidual layer of the endometrium. Therefore, the amnion responds to changes within the amniotic cavity, while the chorion plays an important role in immune tolerance at the maternal-fetal interface.[2] The amnion and chorion are connected by the twelfth week of gestation by a strong yet flexible extra-cellular matrix comprised of various collagen types, providing the membranes' structural framework.[2][3] At the end of gestation, significant membrane remodeling occurs due to programmed activation of matrix metalloproteinases and selective apoptosis, leading to significant weakening of the membranes.[4] Interestingly, tumor necrosis factor α or interleukin 1β induces the same biochemical markers of membrane weakening and apoptosis seen at the end of gestation.[4]

Etiology of Premature Rupture of Membranes

PROM or PPROM may occur for various reasons, including normal physiologic weakening of the membranes at term, increased intraamniotic pressure, intraamniotic infection or inflammation, oxidative stress, and membrane remodeling capacity abnormalities.[1][2][5] Inflammation can activate proteases that degrade collagen within the fetal membranes, weakening and predisposing them to rupture. Intrauterine infection is also a common cause of inflammation. However, while intraamniotic infection is seen in a significant proportion of patients with PPROM, it may be either a cause or a result of membrane weakening. For example, while an ascending genital infection from bacterial vaginosis can certainly cause an innate inflammatory response, sterile inflammation from bleeding or tobacco use may also weaken the fetal membranes, allowing for microbial invasion.[2][6]

Oxidative stress generates reactive oxygen species, which can target and degrade collagen. Reactive oxygen species are most commonly produced during cellular respiration and when they are released by immune cells during phagocytosis. Typically, these reactive oxygen species are balanced by antioxidants. However, the reactive oxygen species and antioxidants can become imbalanced due to dietary deficiencies of antioxidants, tobacco use, and high fetoplacental energy demands, including those seen in pregnancies at high altitudes or with concordant intrinsic microvascular disease.[2] Additionally, evidence demonstrates that some single-nucleotide polymorphisms involved in the metabolism of the extracellular matrix can significantly affect the risk of PPROM.[7] However, despite various underlying etiologies, no apparent cause is often identified in patients presenting with PROM and PPROM.

Risk Factors of Premature Rupture of Membranes

Risk factors for PPROM include:

• A history of PPROM
• Short cervical length
• Second- or third-trimester vaginal bleeding
• Amniocentesis and other antenatal intrauterine procedures
• Uterine overdistension
• Connective tissue disorders
• Congenital uterine anomalies
• Nutritional deficiencies of copper and ascorbic acid
• Low body mass index
• Low socioeconomic status
• Cigarette smoking and recreational drug use [1][5][6][8][9]

Epidemiology

PROM complicates approximately 8% of term pregnancies. After PROM at term, spontaneous labor begins within 24 hours in 60% to 70% of patients and within 72 hours in over 95%.[10] In the TERMPROM study, a large prospective randomized controlled trial comparing expectant management to immediate induction of labor, the median time to delivery in the expectant management group was approximately 33 hours.[10] Preterm PROM is less common, complicating only about 1% of deliveries overall. Previable and periviable PPROM occurring before 24 weeks gestation occurs in 0.3% to 0.4% of pregnancies.[11] Black women are twice as likely than White women to experience PPROM and are more than 6 times as likely to experience recurrent PPROM.[12]

History and Physical

Clinical History

Patients with ruptured membranes will classically present with vaginal fluid leakage. Leakage may be significant and continuous or much lighter and intermittent. Some patients may describe their symptoms as an increase in watery discharge. By definition, patients with PROM or PPROM are not in active labor, so regular uterine contractions are absent before membrane rupture.

When obtaining the clinical history, clinicians should inquire about contractions that may indicate the onset of labor, vaginal bleeding (may suggest placental abruption), and fetal movement to assess fetal well-being. Furthermore, additional details regarding ROM should be obtained, including the onset of suspected membrane rupture as prolonged ROM increases risks, the volume of fluid loss observed, and the color and odor of the fluid, which can suggest the presence of meconium or intraamniotic infection. Associated features, including pain, recent sexual encounters, recent trauma, and recent physical activity, are also vital to a thorough history.

Physical Examination

A sterile speculum exam should be performed to assess the fluid. Direct observation of fluid leakage from the cervical os confirms ROM. Pooling, which refers to the rapid collection of amniotic fluid in the lower blade of the speculum, may also be seen. If leakage of amniotic fluid from the os is not seen, gentle fundal pressure can be applied, or the patient can be asked to Valsalva or cough to provoke fluid leakage. The color and odor of the fluid should be noted. A fluid sample can also be obtained for further evaluation if the diagnosis is in question. 

During the speculum exam, dilation and effacement of the cervix should be visually assessed. Digital examinations increase the risk of intraamniotic infection in patients with ROM; digital examinations to assess cervical dilation, effacement, and station should be avoided unless delivery appears imminent or the patient appears to be in active labor.[13][14][15] Patients should also be inspected for any signs of cervicitis, vaginitis, vaginal bleeding, and umbilical cord or fetal prolapse. One of the most significant potential complications of PROM and PPROM is intrauterine infection. Therefore, all patients presenting with PROM should be assessed for signs and symptoms of intrauterine infection, which include maternal fever, fetal tachycardia, such as a fetal heart rate 160 bpm or more for at least 10 minutes, uterine tenderness, and purulent or foul-smelling discharge.[16][17] 

Evaluation

Confirming the Diagnosis of Rupture of Membranes

Direct visualization of fluid leakage from the cervical os or gross pooling confirms the diagnosis. However, if the diagnosis is still in question after a sterile speculum examination, additional testing can help confirm the diagnosis.

Microscopy

A sample of amniotic fluid can be smeared directly on a slide and allowed to dry. When examined microscopically, dried amniotic fluid forms a crystalized pattern that appears like branches of a fern tree; this is known as arborization or ferning and confirms ROM. Of note, cervical mucus can also produce a crystallized pattern. However, cervical mucus forms fern-like patterns in thick linear bands secondary to its stringlike macroscopic structure (Spinnbarkeit). This crystallized pattern is visually distinct from amniotic fluid, which tends to form a thinner, more delicate pattern across the entire smear.

Vaginal fluid pH testing

A pH test can be performed on vaginal fluid. The pH of amniotic fluid is typically slightly basic, with a range of 7 to 7.4, while normal vaginal secretions in pregnancy have a pH between 3.8 and 4.[18][19] False-positive pH tests, however, are common, as multiple other causes of abnormally high vaginal pH may be present, including the presence of blood or semen, alkaline antiseptics, and bacterial vaginosis. Additionally, false-negative results may occur with prolonged rupture of membranes or minimal amounts of leakage. For these reasons, pH testing is reasonable to include as part of the evaluation for ROM, but it does not definitively confirm or exclude the diagnosis. 

Diagnostic tests for amniotic fluid proteins

Several commercially available tests can detect the presence of amniotic fluid proteins within a sample. The proteins detected in some of the most commonly used tests are placental alpha microglobulin-1 and insulin-like growth factor binding protein-1 (IGFBP-1). One test assesses for the combination of IGFBP-1 and alpha-fetoprotein. The sensitivity of these tests in diagnosing ROM ranges from about 95% to 99% compared to around 85% for conventional methods.[20][21][22]

Dye test

If the diagnosis remains unclear after the initial evaluation, a dye test, often called a "tampon test," can be considered. However, these tests are invasive and rarely used in modern practice. To perform the test, a tampon is placed in the vagina, and dye is injected via a transabdominal needle under ultrasound guidance into the amniotic cavity. ROM is confirmed if the dye appears on the tampon removed 20 minutes later. Indigo carmine was traditionally used for this test but is no longer readily available; fluorescein and phenol-sulfonphthalein are reasonable alternatives.[23]

Additional Diagnostic Studies

Other evaluation studies that may also be conducted to assess maternal-fetal well-being or further narrow the underlying etiology include:

• Evaluation of fetal well-being: Membrane rupture can cause fetal distress, so fetal well-being should always be confirmed. This is typically accomplished with cardiotocographic monitoring and a biophysical profile.[15] 
• Obstetric ultrasound: An obstetric ultrasound is recommended to assess the amniotic fluid volume, as oligohydramnios is often seen. The fetal presentation should also be confirmed, as spontaneous labor frequently follows ROM. 
• Urinalysis: Urinary tract infections predispose patients to urinary incontinence episodes. If the diagnosis of ROM is in doubt, a urine sample can be obtained to rule out urinary tract infections.
• Serum labs: A maternal white blood cell count >15,000/mm³ in the absence of corticosteroid administration is consistent with infection. However, in the absence of clinical findings suggesting intraamniotic infection (eg, fever, uterine tenderness, foul-smelling discharge, fetal tachycardia), an elevated white blood count is nonspecific.

Group B Streptococcus Status

Management of PROM differs depending on the group B streptococcus (GBS) status. After 37 weeks gestation, GBS prophylaxis is only indicated in GBS-positive or other high-risk individuals. In preterm patients, a rectovaginal GBS culture should be obtained if one has not already been obtained in the previous 5 weeks.[1][15][1][24] However, a GBS culture is not indicated if the pregnant individual already has an indication for intrapartum GBS prophylaxis, such as GBS-positive bacteriuria earlier in the pregnancy or a history of a prior neonate with invasive GBS disease.[1][24] 

Treatment / Management

Management of prelabor rupture of membrane cases is determined by gestational age at the time of membrane rupture (see Table. Summary of Management for Patients with Ruptured Membranes Based on Gestational Age). Gestational age guides the decision regarding immediate delivery versus expectant management and the need for corticosteroids with or without proephylactic tocolytics, latency antibiotics, GBS prophylaxis, and magnesium sulfate for neuroprotection. However, regardless of gestational age, immediate delivery is indicated for signs of nonreassuring fetal status, intraamniotic infection, placental abruption, and prolapsed umbilical cord. 

Table. Summary of Management for Patients with Ruptured Membranes Based on Gestational Age

GBS: group B Streptococcus

*Only if GBS is negative.

**Other indications include previous neonate with GBS disease; GBS bacteriuria at any time during the current pregnancy; GBS unknown with at least 1 of the following risk factors: ROM for 18 or more hours, the intrapartum temperature of 38.0 °C (100.4 °F) or higher, GBS positive in a prior pregnancy.[24](B3)

Management Approach in Early Term and Term Patients (37 0/7 Weeks Gestation and Greater)

Immediately moving toward delivery after a diagnosis of PROM at term is associated with better maternal and fetal outcomes compared to expectant management.[25] For example, the TERMPROM trial, which compared expectant management with immediate induction of labor (IOL), showed that despite similar rates of cesarean birth and neonatal infection between the 2 groups, immediate IOL was associated with lower rates of maternal infection.[10] American, British, and Australian/New Zealander guidelines all generally concur and recommend initiating IOL or performing a cesarean delivery if indicated immediately in patients who are GBS-positive or within 24 hours of PROM if GBS-negative or unknown.[1][15] GBS prophylaxis should be administered as indicated.[1][15](A1)

Multiple studies have examined different methods of labor induction in patients with PROM. Notably, evidence suggests that intracervical catheters should be avoided in patients with ruptured membranes, as they have been shown to nearly double the risk of intraamniotic infection compared with pharmacologic induction methods.[26][27] While oxytocin can be used alone for IOL in patients with PROM at term, there is no convincing evidence to support or avoid the use of prostaglandins for cervical ripening in this population. A Cochrane review from 2000 found that there appears to be an increased risk of intraamniotic infection with prostaglandins compared with oxytocin alone.[28] However, a 2005 meta-analysis showed that misoprostol was comparable to oxytocin as initial management for IOL, with similar rates of vaginal birth within 12 and 24 hours and adverse maternal and neonatal outcomes.[29] Additionally, results from several small studies have shown a modest benefit to cervical ripening with prostaglandins in patients with term PROM and an unfavorable cervix.[30] At this time, the choice of whether to use a prostaglandin or oxytocin for cervical ripening in patients with term PROM and an unfavorable cervix can be individualized and based on clinical factors in concert with clinician and patient preference.(A1)

Management Approach in Preterm Patients (36 6/7 or Fewer Weeks Gestation)

Management varies slightly between patients with PPROM before and after the 34-week gestation threshold. However, a single course of corticosteroids is recommended for all pregnant patients with PPROM between viability and 36 6/7 weeks gestation if delivery is anticipated before 37 weeks.[1] Antenatal corticosteroids after PPROM have been shown to reduce neonatal mortality, respiratory distress syndrome, necrotizing enterocolitis, and intraventricular hemorrhage.[31][32][33][34] (A1)

Late preterm (34 0/7 to 36 6/7 weeks gestation)

Immediate delivery is indicated if the patient is GBS-positive. However, if the patient is GBS negative or unknown, expectant management may be considered until 37 weeks. Study results have shown that immediate delivery is associated with higher rates of neonatal respiratory distress (8% versus 5%) and longer stays in intensive care (4 days versus 2 days). Expectant management is associated with lower rates of cesarean birth but increased rates of intraamniotic infection and antepartum hemorrhage.[35][36] Given these mixed results, thorough counseling, individualized care, and shared decision-making are recommended.[1][15] Corticosteroids are recommended, but latency antibiotics and tocolytics are not. Patients who are GBS unknown should be screened for GBS with a rectovaginal swab and started on GBS prophylaxis, which can be discontinued if the culture returns negative.[24](A1)

Generally, patients with preterm PROM undergoing expectant management should be admitted to the hospital with periodic assessments for fetal well-being, preterm labor, infection, placental abruption, and umbilical cord prolapse. Fetal well-being is typically monitored with regular cardiotocographic monitoring or biophysical profiles and serial growth ultrasounds. Maternal vital signs should be checked regularly, and a rise in temperature should raise suspicion of intraamniotic infection. However, in the absence of clinical signs of infection, monitoring leukocyte counts and inflammatory markers is not indicated; while leukocytosis and elevated inflammatory markers are often seen with intraamniotic infection, these findings are nonspecific and have not been shown to help diagnose intraamniotic infection in the absence of other clinical signs or symptoms.[16] Additionally, corticosteroids will cause transient leukocytosis, making this finding difficult to interpret.

Early preterm (24 0/7 to 33 6/7 weeks gestation)

Expectant management is recommended when no maternal or fetal contraindications exist. Latency antibiotics, a single course of corticosteroids, and GBS prophylaxis (unless known to be GBS-negative) are also all recommended.[1][15][24] To reduce the risk of cerebral palsy, intrapartum magnesium sulfate is recommended between viability and 31 6/7 weeks gestation according to American guidelines and between 24 and 29 6/7 weeks gestation according to British guidelines.[37][38] Like patients in the late preterm with PPROM, patients in the early preterm period are usually monitored in the hospital and regularly assessed for signs of nonreassuring fetal well-being, preterm labor, and infection.(A1)

Latency antibiotics have been shown to prolong pregnancy in patients with PPROM, reduce maternal and neonatal infections, and reduce fetal morbidity. A 7-day course of therapy is recommended in patients with PPROM before 34 weeks gestation. The recommended regimen is intravenous ampicillin 2 g every 6 hours and erythromycin 250 mg every 6 hours for 48 hours, followed by oral amoxicillin 250 mg every 8 hours and erythromycin base 333 mg every 8 hours for 5 additional days.[1][39] Azithromycin can be used as an alternative to erythromycin.[40] Amoxicillin-clavulanic acid is not recommended due to increased rates of necrotizing enterocolitis.[1][41] If the patient is a candidate for GBS prophylaxis, she should receive a regimen that covers GBS.[42](A1)

The use of tocolytics in patients with preterm PROM is controversial but can be considered for up to 48 hours in patients before 34 weeks gestation to allow the fetus to reap the full benefits of a corticosteroid course.[1] Prophylactic tocolytics may be associated with an extended latency period and a lower delivery risk within 48 hours. However, tocolytics are also associated with a higher risk of intrauterine infection before 34 weeks. No significant maternal or neonatal benefit has been shown with tocolytics beyond benefits attributed to a complete course of corticosteroids.[43] 

Previable and periviable (<24 weeks of gestation)

The periviable period is defined as the time between 20 and 25 6/7 weeks gestation.[44] The American Society for Maternal-Fetal Medicine recommends thorough, individualized counseling about the maternal and fetal risks associated with the patient's situation and offering patients with previable and periviable PPROM abortion care.[45] Expectant management can be considered in the absence of contraindications to ongoing pregnancy, which includes intraamniotic infection, placental abruption, cord prolapse, and nonreassuring fetal status. 

Significant maternal risks of expectant management include potentially severe infection, hemorrhage, and death. Results from a 2022 retrospective cohort of patients with PPROM between 14 and 24 weeks gestation by Sklar et al showed composite maternal morbidity rates of 60% in the expectant management group compared with only 33% in the abortion care group (see Table. Maternal Morbidity After Preterm Premature Rupture of Membranes at <24 Weeks' Gestation).[11] 

Table. Maternal Morbidity After Preterm Premature Rupture of Membranes at <24 Weeks' Gestation 

Clinicians should note that maternal sepsis can progress rapidly to death. For example, a study on maternal mortality in France provided results that found the median interval from PPROM to the first signs of infection was 5 days; the median time from infection diagnosis to death was only 18 hours.[46] A delay in uterine evacuation was determined to have contributed to at least some of the deaths in that series. 

Notably, expectant management in previable and periviable situations is generally not associated with positive neonatal outcomes. In a European series of patients known as the PPROMEXIL-III cohort, 52 of 86 (60%) patients with previable PROM were delivered before 24 weeks, and only 23 neonates survived until discharge. Long-term data showed that 13 of these children (15% of the original 86) had normal neurodevelopment at 2 and 5 years.[47] This is similar to the results reported by Sklar et al, who found only 15.7% of women in the expectant management group avoided morbidity and had a neonate who survived until discharge.[11]

Given these risks, the decision to proceed with abortion care versus expectant management should consider the ability of the clinicians to care for the pregnant person and their neonate, the fetal prognosis, the "views of risk" as determined by both the healthcare team and the patient, and patient preference.[45] In patients who chose abortion care, dilation and evacuation are associated with substantially lower risks of hemorrhage, infection, and retained tissue than induction of labor.[48] In patients who undergo expectant management, latency antibiotics can be considered as early as 20 0/7 weeks gestation, while GBS prophylaxis, corticosteroids, tocolysis, and magnesium sulfate are not recommended until the time when neonatal resuscitation would be considered, which is typically between 22 and 24 weeks gestation, depending on local resources.[45]

Differential Diagnosis

The differential diagnosis of fluid leaking from the vagina includes:

• Vaginitis
• Lower urinary tract infection
• Urinary incontinence
• Fluids from recent intercourse
• Vesicovaginal fistula
• Trauma to the urogenital tract

These alternative diagnoses can be ruled out with a proper history, physical examination, and basic diagnostic tests, such as a urinalysis and microscopic evaluation of vaginal secretions using potassium hydroxide and wet mount preparations.

Prognosis

Prognosis is largely dependent on the gestational age at which membrane rupture occurs. After PROM at term, outcomes are generally favorable. Birth within 7 days of membrane rupture occurs in at least 50% of patients with PPROM. Although rare, cessation of fluid leakage with restoration of normal amniotic fluid volume and favorable outcomes is possible.[49][50][51] The risk of complications in PPROM is relatively high. As the latency period lengthens, the risk of maternal infection increases, but neonatal complications associated with extreme prematurity decrease.

Regarding periviable PPROM, neonatal survival rates are much higher when PPROM occurs after 22 weeks (58%) than when PPROM occurs before 22 weeks gestation (14% to 22%).[52][53] In a European series of patients known as the PPROMEXIL-III cohort, 52 of 86 (60%) patients with previable PROM delivered before 24 weeks gestation, and only 23 neonates survived until discharge. Long-term data showed that 13 of these children (15% of the original 86) had normal neurodevelopment at 2 and 5 years.[47] Women with a history of PPROM have a higher risk of recurrent PPROM and preterm birth. Progesterone supplementation should be offered in future pregnancies to reduce the risk of spontaneous preterm birth.[54]

Complications

Maternal Risks

Maternal complications associated with PROM include:

• Intrauterine infection
• Sepsis
• Placental abruption
• Antenatal, intrapartum, and postpartum hemorrhage
• Death

Fetal and Neonatal Risks

Fetal and neonatal complications associated with PROM include:

• Neonatal sepsis
• Complications of prematurity
  • Respiratory distress syndrome
  • Intraventricular hemorrhage
  • Necrotizing enterocolitis
  • Retinopathy of prematurity
  • Hypothermia
  • Glucose and electrolyte abnormalities
  • Failure to thrive
  • Death
• Complications of prolonged oligohydramnios
  • Pulmonary hypoplasia
  • Limb contractures and skeletal deformities [1][52]