Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis

INTRODUCTION — Prelabor rupture of membranes (PROM) refers to fetal membrane rupture before the onset of uterine contractions. Preterm PROM (PPROM) refers to PROM before 37+0 weeks of gestation. It is responsible for, or associated with, approximately one-third of preterm births and is the single most common identifiable factor associated with preterm birth.

The epidemiology, pathogenesis, clinical manifestations, diagnosis, and clinical course of PROM at approximately 23 to 37 weeks of gestation will be discussed here. Management of PROM at 23 to 37 weeks, as well as PROM before and after this gestational age range, are reviewed separately:

●(See "Preterm prelabor rupture of membranes: Management and outcome".)

●(See "Prelabor rupture of membranes before and at the limit of viability".)

●(See "Prelabor rupture of membranes at term: Management".)

PREVALENCE — Approximately 3 percent of pregnancies <37 weeks are complicated by PPROM. By gestational age, approximately 0.5 percent of PROM occurs at <27 weeks, 1 percent occurs at 27 to 34 weeks, and 1 percent occurs at 34 to 37 weeks [1-3].

PATHOGENESIS — The pathogenesis of spontaneous membrane rupture is not completely understood. The strength and integrity of fetal membranes derive from extracellular membrane proteins, including collagens, fibronectin, and laminin, whereas matrix metalloproteases (MMPs) decrease membrane strength by increasing collagen degradation [4]. A variety of pathologic events (eg, subclinical or overt infection, inflammation, mechanical stress, bleeding) can disrupt these and other homeostatic processes and initiate a cascade of biochemical changes that culminate in PROM [5]. Although the pathway varies depending on the initiating event (which is not always identifiable), it is likely that all pathways lead to a final common pathway ending in membrane rupture. (See "Spontaneous preterm birth: Pathogenesis".)

RISK FACTORS — A variety of risk factors predispose to development of PPROM. These risk factors are similar to those for preterm labor (table 1) (see "Spontaneous preterm birth: Overview of risk factors and prognosis"). However, many patients have no obvious identifiable risk factor.

A history of PPROM in a previous pregnancy, genital tract infection, antepartum bleeding, and cigarette smoking have a particularly strong association with PPROM and are discussed below [6].

●Genital tract infection – Genital tract infection is the single most common identifiable risk factor for PPROM. Three lines of epidemiologic evidence strongly support this association: (1) patients with PPROM are significantly more likely than those with intact membranes to have pathogenic microorganisms in the amniotic fluid, (2) patients with PPROM have a significantly higher rate of histologic chorioamnionitis than those who deliver preterm without PPROM, and (3) the frequency of PPROM is significantly higher in patients with certain lower genital tract infections (particularly bacterial vaginosis) than in uninfected patients [7]. (See "Bacterial vaginosis: Clinical manifestations and diagnosis".)

The association between bacterial colonization of the lower genital tract and PPROM is not surprising. Many of the microorganisms that colonize the lower genital tract have the capacity to produce phospholipases, which can stimulate the production of prostaglandins and thereby lead to the onset of uterine contractions. In addition, the host's immune response to bacterial invasion of the endocervix and/or fetal membranes leads to the production of multiple inflammatory mediators that can cause localized weakening of the fetal membranes and result in PPROM [7]. Genetic regulation of the host's immune and inflammatory responses appears to play a role in susceptibility and response to infections associated with PPROM. (See "Spontaneous preterm birth: Pathogenesis" and "Spontaneous preterm birth: Overview of risk factors and prognosis".)

●Previous PPROM – Studies have consistently reported that a history of PPROM is a strong risk factor for recurrence. As an example, the Preterm Prediction Study, a large prospective study conducted by the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network, observed that patients with a history of PPROM leading to preterm birth had a threefold higher frequency of PPROM in a subsequent pregnancy compared with those with no such history (13.5 versus 4.1 percent, relative risk [RR] 3.3, 95% CI 2.1-5.2) [8]. Moreover, in the subsequent pregnancy, patients with a history of PPROM leading to preterm birth were at high risk of PPROM and preterm birth before 28 weeks (1.8 versus 0.13 percent in patients with no history of preterm birth due to PPROM, RR 13.5, 95% CI 23.0-80.3). Others have reported recurrence rates as high as 32 percent [9].

●Antepartum bleeding – First trimester vaginal bleeding is associated with a small but statistically significant increase in the risk of PPROM [10]. Antepartum bleeding in more than one trimester increases the risk of PPROM three- to sevenfold [6,11,12].

The development of PPROM in the setting of bleeding from abruption may be related to the high decidual concentration of tissue thromboplastin factor (also known as tissue factor III). In addition to its hemostatic properties, thrombin binds to decidual protease-activated receptors (PAR1 and 3) that up-regulate the expression of proteases such as matrix metalloproteases, which, in turn, degrade membranes. (See 'Pathogenesis' above and "Spontaneous preterm birth: Pathogenesis", section on '#3 Decidual hemorrhage'.)

●Cigarette smoking – The risk of PPROM among smokers is increased two- to fourfold compared with nonsmokers. The risk persists even after adjustment for known confounders. The mechanism for the association is unclear. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate".)

In addition, polyhydramnios, acute abdominal trauma (eg, from a motor vehicle collision, accidental fall, or domestic violence), and several polymorphisms of genes related to infection, inflammation, and collagen degradation have been identified as risk factors for PPROM.

CLINICAL FINDINGS

Patient presentation — The classic clinical presentation of PPROM is a sudden "gush" of clear or pale yellow fluid from the vagina that soaks through clothes. However, many patients describe only leaking small amounts of fluid either continuously or intermittently, and some just report a sensation of abnormal wetness of the vagina or perineum.

Physical examination — For patients who are not in active labor, examination of the cervix and vagina should be performed using a sterile speculum. Digital examination should be avoided because it may increase the risk of intrauterine infection and thus decrease the latency period (ie, time from PPROM to delivery) [13-15].

Direct observation of amniotic fluid leaking from the cervical os and pooling in the vaginal vault is diagnostic of PPROM. If amniotic fluid is not immediately visible, the patient can be asked to push on their fundus, Valsalva, or cough to provoke leakage of amniotic fluid from the cervical os.

The cervix may appear dilated and/or effaced, and rarely, prolapse of a fetal part or the umbilical cord may be observed.

Ultrasonography — Many, if not most, patients have amniotic fluid volume that is less than expected for gestational age. Criteria for oligohydramnios vary slightly among sonographers but can be defined as a maximum vertical pocket (MVP, also called single deepest pocket [SDP]) of amniotic fluid <2 cm or an amniotic fluid index (AFI) ≤5 cm (some use ≤2 cm and <5 cm, respectively). (See "Assessment of amniotic fluid volume", section on 'Semiquantitative techniques'.)

In a prospective study of 290 singleton pregnancies with PPROM at 24 to 34 weeks of gestation, 67 percent had an AFI <5 cm, and 47 percent had an MVP <2 cm [16].

Laboratory — Hematology and chemistry tests are normal in the absence of infection or other complications of pregnancy. Laboratory tests to identify amniotic fluid are described below. (See 'Laboratory tests' below.)

DIAGNOSTIC EVALUATION AND DIAGNOSIS

Our approach — We base the diagnosis of PPROM primarily on characteristic findings on both history and physical examination: a pregnant patient presents with a history of leaking fluid, and on sterile speculum examination, pooling of amniotic fluid in the posterior vaginal vault is observed. Pooling is the gold standard for diagnosis. If pooling is not observed, asking the patient to press on their fundus, cough, and bear down can enhance flow of amniotic fluid from the cervical os and confirm the diagnosis.

If pooling is still not seen, the author performs an ultrasound examination to assess amniotic fluid volume. In the author's practice, in a patient with a characteristic history of leaking fluid:

●Oligohydramnios (defined by an amniotic fluid index [AFI] ≤5 cm, maximum vertical pocket [MVP] <2 cm, or subjective impression) is presumptive evidence of PROM, so no additional diagnostic testing is performed.

●If the amniotic fluid volume is low normal (defined as an AFI 6 or 7 cm or by subjective impression) or normal (eg, by an AFI >7 cm or subjective impression), the author orders one of the commercial tests for detecting amniotic fluid (see 'Commercial tests' below) and uses the result to confirm or exclude the diagnosis of PROM.

●If the amniotic fluid volume is high (defined by an AFI >24 cm, MVP ≥8 cm, or subjective impression), this finding almost always excludes the diagnosis of PPROM. The patient is discharged home if not in labor and given instructions to call if leaking recurs. (See "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations".)

Access to ultrasound is readily available to most clinicians and the examination also provides information about fetal status. The author no longer performs nitrazine paper or fern tests, primarily because of the possibility of false-positive results that could lead to inappropriate clinical decisions. Moreover, some facilities no longer permit clinicians to perform these tests because of quality assurance and compliance issues. (See 'Nitrazine and fern tests' below.)

Laboratory tests

Commercial tests — The author bases the choice of commercial test on cost and the ease of performance in an individual hospital laboratory. Several tests for diagnosis of PROM are now commercially available. A 2013 meta-analysis of prospective observational or cohort studies investigating insulin-like growth factor binding protein 1 (IGFBP-1 [Actim PROM]) and placental alpha microglobulin-1 protein assay (PAMG-1 [AmniSure]) for diagnosis of rupture of membranes concluded PAMG-1 (AmniSure) was more accurate than IGFBP-1 (Actim PROM) for diagnosis of rupture of membranes in all patient populations (eg, known rupture status, uncertain rupture status) [17]. A subsequent randomized trial reported similar findings [18].

Health care providers using these tests should be aware of their limitations, which are listed in the manufacturer's instructions, and use them as one component of the overall clinical assessment for PPROM (eg, history, speculum examination, ultrasound findings) [19]. There are no data to indicate that the performance of these tests varies across pregnancy.

PAMG-1 (AmniSure) — AmniSure is a rapid slide test that uses immunochromatography to detect trace amounts of placental alpha microglobulin-1 protein in vaginal fluid. Placental alpha microglobulin-1 is released from decidual cells. The test is not affected by semen or trace amounts of blood.

The test is designed to be performed by the provider at the point of care using a commercially available kit but can be performed in the hospital laboratory if clinician credentialing is a concern. A sterile swab is inserted into the vagina for one minute, then placed into a vial containing a solvent for one minute, and then an AmniSure test strip is dipped into the vial. The test result is revealed by the presence of one or two lines within the next 5 to 10 minutes (one visible line means a negative result for amniotic fluid, two visible lines is a positive result, and no visible lines is an invalid result).

In large studies, sensitivity ranged from 94.4 to 98.9 percent, and specificity ranged from 87.5 to 100 percent [20-24]. In one study, the authors hypothesized that false-positive results in three patients might have been due to a small leak that sealed over [21].

IGFBP-1 (Actim PROM) — IGFBP-1, also called placental protein 12 (PP12), is secreted by decidual and placental cells and has a very high concentration in amniotic fluid compared with other bodily fluids. An easy-to-use immunochromatography dipstick method (eg, Actim PROM) is available in some countries for use at the bedside to detect IGFBP-1 in vaginal secretions but can be performed in the hospital laboratory if clinician credentialing is a concern. A positive test is denoted by the presence of two blue lines on the dipstick. The test is not affected by the presence of bacteria in vaginal secretions, urine, semen, or small amounts of blood.

Sensitivity ranges from 95 to 100 percent, specificity ranges from 93 to 98 percent, and positive predictive value approaches 98 percent [23,25-28]. The test is most accurate when performed as soon as possible after PROM.

Placental protein 12 and alpha-fetoprotein (ROM Plus) — A combination monoclonal/polyclonal antibody test for diagnosis of PPROM detects two protein markers found in amniotic fluid: PP12 (also called IGFBP-1) and alpha-fetoprotein (AFP). The test is performed by placing the ROM Plus test swab in the vagina for 15 seconds, placing the swab in a diluent, and then placing a sample of the diluent on a special test strip, which develops a line if the proteins are present. Trace amounts of blood do not affect the test.

A multicenter prospective observational study that compared the accuracy of this point-of-care test with conventional clinical assessment (speculum examination plus both fern and nitrazine tests) for diagnosis of rupture of membranes in 285 patients at 15 to 42 weeks of gestation found that the immunoassay had higher sensitivity (99 versus 85 percent) and lower specificity (91 versus 98 percent) [29]. A limitation of this study was that confirmation of PROM was based on review of the medical records following delivery.

Nitrazine and fern tests

●Nitrazine – Nitrazine paper is used to test the pH of vaginal fluid. Nitrazine (or phenaphthazine) is a pH indicator dye that indicates pH in the 4.5 to 7.5 range. Amniotic fluid usually has a pH range of 7.0 to 7.3, which is different from the normal vaginal pH of 3.8 to 4.2 and usually different from the pH of urine, which is typically <6.0 but may be higher (picture 1) [30].

False-negative and false-positive nitrazine test results occur in up to 5 percent of cases [31,32]. False-negative test results can occur when leaking is intermittent or the amniotic fluid is diluted by other vaginal fluids. False-positive results can be due to the presence of alkaline fluids in the vagina, such as blood, seminal fluid, or soap. In addition, the pH of urine can be elevated to near 8 if infected with Proteus species.

●Fern – Dried amniotic fluid shows an arborization (ferning) pattern when viewed under a microscope. Fluid from the posterior vaginal fornix is swabbed onto a glass slide and allowed to dry for at least 10 minutes. Amniotic fluid produces a delicate ferning pattern, in contrast to the thick and wide arborization pattern of dried cervical mucus (picture 2 and picture 3).

Well-estrogenized cervical mucus or a fingerprint on the microscope slide may cause a false-positive fern test; false negatives can be due to inadequate amniotic fluid on the swab or heavy contamination with vaginal discharge or blood.

Home tests — In the United Kingdom, an absorbent pad (AmnioSense) that changes color at pH >5.2 is used as a panty liner and marketed to pregnant people. Vaginal flora (eg, Candida albicans) may cause false-positive results [33].

The manufacturer cites sensitivity and specificity of 95.8 and 87 percent, respectively, compared with standard clinical diagnosis [34]. In a study of 139 pregnant people, the sensitivity and specificity of this device for diagnosis of membrane rupture were 98 and 65 percent, respectively (95% CI 91-100 and 54-75, respectively) [33].

Other

●Instillation of dye (tampon test) – This invasive test has been replaced by commercial noninvasive tests. It can be challenging to perform when amniotic fluid volume is severely reduced, and can cause rupture of membranes if the membranes are intact. (See 'Commercial tests' above.)

In the past, clinicians performed the "tampon test" in problematic cases. Under ultrasound guidance, 1 mL of indigo carmine dye in 9 mL of sterile saline was injected transabdominally into the amniotic fluid, and a tampon was placed in the vagina. Twenty minutes later, the tampon was removed and examined for blue staining, which indicated leakage of amniotic fluid. It should be noted that maternal urine will also stain blue and should not be mistaken for amniotic fluid.

Indigo carmine dye is no longer readily available in the United States. Possible alternatives to indigo carmine include sodium fluorescein and phenolsulfonphthalein (where available) [35].

DIFFERENTIAL DIAGNOSIS — Other causes of vaginal/perineal wetness include urinary incontinence, excessive vaginal discharge (normal or related to infection), cervical mucus, and perspiration. These entities can be distinguished by differences in their characteristics.

●Characteristics of amniotic fluid:

•The appearance of amniotic fluid (clear or pale yellow) can be similar to that of urine, but amniotic fluid is odorless (in the absence of infection).

•Amniotic fluid leakage is continuous or intermittent, whereas bladder leakage should cease after the bladder is emptied and kept at low volume.

•Amniotic fluid usually has a pH range of 7.0 to 7.3, which is different from the normal vaginal pH of 3.8 to 4.2 and usually different from the pH of urine, which is typically <6.0 but may be higher (picture 1) [30].

•Amniotic fluid and urine have different chemical compositions (urine has higher creatinine and urea levels [36]), but such testing is rarely indicated.

●Characteristics of vaginal discharge:

•Vaginal discharge may be clear or yellow, similar to amniotic fluid and urine, but it is generally thick, not watery, and has distinct findings (table 2) that distinguish it from these other substances.

●Perspiration may result in perineal wetness, but it is not accompanied by pooling in the vagina.

●Cervical mucus is clear and has a high pH (7) like amniotic fluid, but no more than a small amount pools in the vagina and leakage is self-limited. It has a thick and wide arborization pattern (picture 2 and picture 3) in contrast to the delicate ferning pattern of amniotic fluid. (See 'Nitrazine and fern tests' above.)

●A reduction of amniotic fluid volume on ultrasound is a nonspecific finding related to many etiologies, including PPROM, but these etiologies (eg, abnormality of the fetal kidney/urinary tract, fetal growth restriction) are not associated with leaking and have other fetal findings. (See "Assessment of amniotic fluid volume".)

CLINICAL COURSE — Cessation of fluid leakage is rare, except in patients with PPROM related to amniocentesis. Sealing of membranes is associated with a more favorable prognosis [37]. (See "Diagnostic amniocentesis", section on 'Leakage of amniotic fluid'.)

The duration of the latency period (ie, time from PROM to delivery) inversely correlates with gestational age at membrane rupture and is shorter in cases with residual oligohydramnios [38]. Nevertheless, the majority of pregnancies with PPROM deliver within one week of membrane rupture. In a randomized trial of 239 group B streptococcus-negative patients with PPROM at 24 to 32 weeks managed expectantly with prophylactic antibiotics, the median time to delivery was 6.1 days; the cumulative delivery rate was 27 percent within 48 hours, 56 percent within 7 days, 76 percent within 14 days, and 86 percent within 21 days [39,40]. Among the minority of patients who did not deliver within this timeframe, one had a latency period of 59 days.

In the absence of spontaneous labor, delivery timing depends on occurrence of complications that would prompt delivery or gestational age ≥34 weeks. Antepartum management and timing of delivery are discussed in detail separately. (See "Preterm prelabor rupture of membranes: Management and outcome", section on 'Timing of delivery'.)

COMPLICATIONS — The fetus and neonate are at greater risk of PPROM-related morbidity and mortality than the mother (table 3).

●Chorioamnionitis – Chorioamnionitis has been reported in up to 60 percent of cases and is a common reason for induction or initiation of spontaneous labor [41]. Clinical chorioamnionitis is increased twofold in cases with residual oligohydramnios [38]. (See "Clinical chorioamnionitis".)

●Abruption – Placental abruption occurs in 2 to 5 percent of pregnancies complicated by PPROM [42-45]. The risk is increased seven- to ninefold in PPROM pregnancies complicated by intrauterine infection or oligohydramnios [43,44]. Placental abruption may be the precipitating event for, or a consequence of, PPROM. (See "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences", section on 'Pathophysiology'.)

●Other – Fetal malpresentation is common, given the preterm gestational age and the frequent occurrence of reduced amniotic fluid volume. Noncephalic presentation may increase the risk of cord prolapse, abruption, infection, and fetal demise [46].

The risk of cord prolapse is especially high (11 percent in one study [47]) in the setting of both noncephalic fetal presentation and PPROM. (See "Umbilical cord prolapse" and "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prelabor rupture of membranes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Preterm prelabor rupture of membranes (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Terminology and epidemiology – Preterm prelabor rupture of membranes (PPROM) refers to rupture of fetal membranes prior to onset of labor in pregnancies <37+0 weeks. It occurs in 3 percent of pregnancies. PPROM is the most common identifiable cause of preterm birth and responsible for one-third of such births. (See 'Introduction' above and 'Prevalence' above.)

●Risk factors – Genital tract infection, a history of PPROM in a previous pregnancy, antepartum bleeding, and cigarette smoking have a particularly strong association with PPROM. PPROM in a previous pregnancy is associated with at least a threefold increase in risk of PPROM in the subsequent pregnancy. Other important risk factors include polyhydramnios and abdominal trauma. (See 'Risk factors' above.)

●Diagnosis – The diagnosis of PPROM is clinical, based on visualization of amniotic fluid coming out of the cervical canal/pooling in the posterior vaginal fornix of a patient who presents with a history of leaking fluid. In the absence of pooling, we suggest an ultrasound examination as the next step in the diagnostic evaluation (algorithm 1). In a patient with a characteristic history of leaking fluid (see 'Our approach' above):

•In the absence of another obvious cause such as fetal urinary tract obstruction, oligohydramnios is presumptive evidence of PROM, so no additional diagnostic testing is performed.

•If the amniotic fluid index (AFI) is low normal or normal, the author orders one of the commercial tests for detecting amniotic fluid in the vagina and uses the result to confirm or exclude the diagnosis of PROM. (See 'Commercial tests' above.)

Checking pH and arborization ("nitrazine and fern") on a sample from the posterior vaginal fornix is an acceptable alternative. However, these tests can be misleading in the setting of bleeding, highly estrogenized cervical mucus, and a urinary tract infection due to Proteus species. (See 'Nitrazine and fern tests' above.)

•If the AFI is high (polyhydramnios), this finding almost always excludes the diagnosis of PPROM. The patient is discharged home if not in labor and given instructions to call if leaking recurs.

●Differential diagnosis – Other causes of vaginal/perineal wetness include urinary incontinence, excessive vaginal discharge (normal or related to infection), cervical mucus, and perspiration. These diagnoses can be excluded by history, physical examination, sonography, and laboratory testing for amniotic fluid. (See 'Differential diagnosis' above.)

●Clinical course

•Cessation of fluid leakage is rare, except in patients with PPROM related to amniocentesis. Sealing of membranes is associated with a more favorable prognosis. (See 'Clinical course' above.)

•The duration of the latency period (ie, time from PROM to delivery) inversely correlates with gestational age at membrane rupture; however, the majority of pregnancies with PPROM deliver within one week of membrane rupture. In the absence of spontaneous labor, delivery timing depends on occurrence of complications that would prompt delivery or gestational age ≥34 weeks. (See 'Clinical course' above.)

•The fetus and neonate are at greater risk of PPROM-related morbidity and mortality than the mother (table 3). In the absence of spontaneous labor, complications that should prompt delivery include chorioamnionitis, placental abruption, and fetal heart rate abnormalities suggesting cord prolapse or compromise. (See 'Complications' above.)