Are we ready for a new look at the diagnosis of premature rupture ofmembranes?

FEDERICO G. MARIONA1 & LLUIS CABERO2

1Division of Maternal Fetal Medicine, Wayne State University School of Medicine, Michigan Perinatal Associates, Dearborn, Michigan,USA and 2Department of Obstetrics & Gynecology, Hospital Val d’Hebron, Barcelona, Spain

AbstractPremature rupture of membranes is a significant contributor to preterm birth with its associated short- and long-termcomplications. The absence of a standard approach to its management places a burden on the clinicians’ ability to promptly andaccurately diagnose premature rupture of membranes. For the last half century, there have been no significant changes in the waypremature ruptured membranes is diagnosed. With the advent of newer, amniotic fluid-specific, noninvasive, and accuratemarkers, there is an opportunity to update the diagnosis of premature rupture of membranes.

Keywords: Ruptured fetal membranes, update, diagnosis

Premature rupture of membranes (PROM) is defined as thespontaneous rupture of fetal membranes prior to the initiationof labor. It is consistently reported as occurring in approxi-mately 10% of term pregnancies, PROM is associated withover 60% of preterm births. The etiology of PROM ismultifaceted and appears directly related to the gestational ageat which it occurs or may occur in the absence of any of therecognizable risk factors. If PROM has occurred preterm, theaccepted risk of recurrence varies between 15 and 30% [1]. Inthe absence of current accurate and consistent knowledge ofthe etiology of PROM, clinicians are compelled to concentratetheir efforts in the management of the event once it has beenaccurately diagnosed.

The existence of membranes surrounding the fetus inexperimental animals and man was reported by Fabricius inhis notable document, ‘The formed fetus,’ published in 1600[2]. Thomas Denman in 1801 described the surgical PROMjust to condemn it [3]. He added that the PROM whethernatural or artificial ‘has been often mentioned as the cause ofmuch mischief and of many tedious and difficult labors.’Further, he wrote, ‘If the membranes containing the waterswere intended to be the medium by which the os uteri andother tender parts ought to be dilated, some inconveniencemust arise when these are broken and the waters discharged.’To that end, in 1969, some 168 years after Denman’sdescription, Kuznetsov et al. reported in the American Journalof Obstetrics and Gynecology in February of 1960 a 15.4%stillbirth rate after ‘prolonged dry labor.’

In 1948, Knox et al. [4] conducted a study of pregnantwomen with suspected or proven premature labor followed bypreterm birth. Using methodology that would be consideredunsophisticated today, they demonstrated the existence of

acute and chronic, even severe, histological evidence ofinfection in the fetal membranes of the studied population,while absent in the controls. Sixty-two years later, thesefindings have been corroborated in a model of term humanpregnancy, in spontaneous labor with PROM utilizing thetranscriptome of the fetal membranes demonstrating aweakness zone in the area of maximum exposure close tothe cervix with differential expression of genes allowing for thediagnosis of local apoptosis and inflammation [5].

The treatment of PROM is closely associated with the needfor prompt and accurate diagnosis once it is suspected.Management practices continue to present challenges toobstetricians and neonatologists and show substantial varia-tions among practitioners and institutions. The evaluation(diagnosis?) of these patients appears significantly differentbetween practitioners in academic versus nonacademicinstitutions when it comes to performing amniocentesis.Nonacademic practitioners perform amniocentesis in 72% ofthese patients, while academic practitioners do it in 61% ofpatients (p! 0.02) [6].

The critical importance of accurate and prompt diagnosisof PROM at any gestational age to decrease or avoid itsinherent and potential serious complications for mother andfetus have been repeatedly emphasized by investigators for thelast 50 years. The medical and lay literature is overpopulatedwith such works. Yet, neither a single etiology or physio-pathology nor a standardized treatment has yet been agreedupon. Obstetricians and perinatologists still offer a widevariety of approaches to the management of PROM. A recentsurvey aiming at characterizing variations in the managementof pregnant women with PPROM showed that only 30% ofpractitioners in the world had a formal protocol [7].

(Received 18 February 2011; revised 2 April 2011; accepted 5 April 2011)

Correspondence: Federico G. Mariona, Michigan Perinatal Associates, 18181Oakwood Blvd., Suite 302, Dearborn, MI 48124 USA.Tel: "313-593-5957.Fax: "313-593-8919. E-mail: marionaf@oakwood.org

The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(4): 403–407! 2012 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2011.581715

By the middle of the twentieth century, a number ofprocesses, procedures, and physical, as well as chemicalmarkers were used for the diagnosis of PROM (Tables Iand II). All these methods depend on physical propertiesinherent to amniotic fluid, however not specific to amnioticfluid. All methods have been extensively and repeatedlystudied. Either their virtues were extolled or often condemnedas inefficient. False positive and false negative resultscompromised the promptness and accuracy of the diagnosis,creating the scenario for misuse of resources for the treatmentof pregnant women suspected of PROM. Many of the‘markers’ for PROM never passed the stage of a singlepublication, many with no validation studies, most are notavailable for daily clinical use.

By the mid-1970s, a number of clinical investigatorsemphasized the need for an objective method to diagnosePROM. David Charles in Boston wrote:

‘it is axiomatic that a definitive diagnosis of PROM isnecessary before therapy is begun. The importance ofaccurate diagnosis is obvious if the obstetrician is con-versant with the seriousness of the entity. A precisediagnosis may be obtained only by microscopic examinationof the vaginal discharge demonstrating fetal squames andother elements such as hair, vernix caseosa and cells whichstain orange with Nile blue [8].’

In essence, since the middle of the twentieth century, thenoninvasive recommended clinical methods utilized for thediagnosis of PROM have not changed. Recently, anotherindirect, noninvasive, labor intensive, relatively expensive, andhighly variable method – bedside ultrasound – was added todetect the amniotic fluid volume to allow for assumptionsregarding the condition of the fetal membranes.

In 1975, basic investigators described for the first timehuman placenta specific alpha 1 microglobulin (PAMG-1), aprotein with a molecular weight of 20 K/Daltons. Itsconcentration in amniotic fluid (2000–25,000 ng/ml) issubstantially higher than the concentration in cervicovaginalfluid or maternal serum (0.05–2.0 ng/ml) and not found inother tissues of a number of experimental animals, includinghumans [9]. Very little information was reported on itsbiological or physiological importance in pregnancy (Petrunin1977–1980). These findings failed to permeate to the westernworld for a long period of time. No publications related to thepresence of PAMG-1 in amniotic fluid are found in peerreviewed publications involving this marker in the Americanliterature until 2005 [10–13]. PAMG-1 has been observed inthe intervillous fibrin and in the cyto- and syncytiotropho-blastic cells of immature chorion of 8–12 weeks gestation butnot found in maternal blood. No physiologic explanation isfound to describe the mechanism for PAMG-1 migration intothe amniotic cavity.

Some investigators have proposed that the presence ofPAMG-1 in cervicovaginal fluid without ‘clinical’ evidence ofPROM may be associated with microleakage of amniotic fluid[11]. This observation was recently published in associationwith term labor and no ‘clinical’ evidence of PROM. Thedefinition was based on lack of observation of leakage orpooling, negative nitrazine and negative ferning. The authorsexcluded cases of testing discrepancy [14].

In 1992, Salfelder et al. [15] reported the use of fetalfibronectin in vaginal secretions for the detection of PROMusing FDC-6. If positive, it would represent an unequivocalsign of PROM or pre-rupture stretching of the membranes.Soon after this report Putz et al. [16] reported that fetalfibronectin was detected in blood samples of nonpregnantwomen.

In 1993, Rutanen et al. [17] described the insulin-likegrowth factor binding protein-1 (IGFBP-1) as a major proteinin amniotic fluid. They evaluated the measurement of thismarker in cervicovaginal secretions as an indicator of PROM.They compared their results with those obtained by thedetermination of fetal fibronectin in vaginal fluid to diagnosePROM. They reported a positive predictive value of 95% forthe IGFBP-1 and 79% for fetal fibronectin. IGFBP-1 becamethe most commonly used marker for the diagnosis of PROMin Europe. A recent study from Chen et al. compares the useof IGFBP-1 and PAMG-1 for the diagnosis of PROM [18]followed by a comparative study of IGFBP-1, PAMG-1, andnitrazine by Tagore et al. [19] demonstrating that PAMG-1had the highest sensitivity and specificity for the diagnosis ofPROM between 17 and 37 weeks gestation.

Silva et al. prospectively compared the use of PAMG-1before and after the injection of indigo carmine viaamniocentesis in women with clinical suspicion of PROMbetween 24 and 42 weeks gestation. They report the PAMG-1results correlated 100% with the dye injection procedure [20].

A recent observation was made by Mittal et al. insymptomatic patients between 16 and 34 weeks gestationwith a sonographic short cervix (525 mm). They reported a32% PAMG-1 positive tests in pregnant women with acervical length of 15 mm associated with rupture ofmembranes (ROM) and preterm labor at 34 weeks gestation.As previously mentioned, these authors also theorized that thepresence of PAMG-1 is due to microperforations in the fetalmembranes [21]. Our experience yet unpublished showedthat women between 19 and 32 weeks gestation with a cervix

Table I. Diagnosis of premature ruptured membranes.

Current traditional approach1. Patient history of sudden gush of clear vaginal discharge2. Sterile vaginal speculum examination visualize leaking fluid from cervix

or pooling3. Nitrazine strip pH indicator turns colors (yellow-blue) in contact with

vaginal discharge4. Microscopic observation of vaginal discharge crystallizing when air dried

for 10 min5. Ultrasound determination of amniotic fluid volume for gestational

age6. Intra-amniotic injection of indigo carmine with dye passing into the

vagina

Table II. The search for markers of PROM.

1974 Diamine oxydase in vaginal fluid.

1975 Placenta alpha microglogulin-1 in amniotic fluid

1978 Intra-amniotic sodium fluorescein1981 Vaginal prolactin

1991 Cervical-vaginal fetal fibronectin

1993 Insulin-like growth factor binding protein1995 Vaginal alpha fetal protein

2003 Vaginal ß-chorionic gonadotrophin

2007 Thyroid hormone in vaginal washings

2009 Proteomic technologies2010 Maternal serum pentraxin 3

404 F. G. Mariona & L. Cabero

#17 mm and fetal membranes at the level of the external os orbulging in the vagina, 8% will be PAMG-1 positive. Thesepatients’ clinical behavior is similar to those on whom PROMhas been diagnosed.

A provocative analogy regarding the delay in the imple-mentation of new technology into clinical obstetric practice isthe evolution of the pregnancy test. In 1928, Ascheim andZondek published their basic research associating pregnantwomen’s urine injected to virgin mice with enlargement andcongestion of their ovaries for the diagnosis of pregnancy, witha 2% error. Their basic experiments were followed by theclinical application of their ‘pregnancy test,’ embraced in theUS in 1929. Agglutination technology for human chorionicgonadotropin (HCG) was developed in 1950s and 1960s,radioimmunoassay in the 1970s, and enzyme immunoassay inthe 1980s. It was not until the full evaluation of theimmunology based serum HCG testing in 1984 – 34 yearslater – that this test became routine in clinical practice and wasevaluated for effectiveness, sensitivity, specificity, technicalrequirements, and costs. Clinical obstetrics has a long recordof protracted acceptance to change, except for electronic fetalmonitoring.

In April of 1988 on its educational bulletin #115, theAmerican College of Obstetricians and Gynecologists addressedPROM for the first time since the inception of its educationalpublications in 1963. The paragraph on ‘diagnosis’ containedthe same indirect methods that had been used for half a century.This bulletin was replaced in June of 1998 by practice bulletin#1 and subsequently by practice bulletin #80 in April of 2007.The bulletins contained the same recommendations for thediagnosis of PROM with the addition of ultrasound. An ‘expertseries’ addressing preterm PROM was published in Obstetricsand Gynecology in January of 2003 containing similarrecommendations. In 2004, the Obstetrical and GynecologicalSurvey volume 59 #9 published a continuing medical education(CME) review article entitled, ‘An evidence based approach tothe evaluation and treatment of PROM, Part 1’ on page 671addresses diagnosis-methods – referencing a 1969 article forbackground. The article includes several chemical markers aspossible methods when the classical approach has been‘equivocal.’ In March of 2005, the British Journal of Obstetricsand Gynecology published ‘preterm premature rupture ofmembranes: diagnosis, evaluation and management strategies,’reported from a US academic source. The paper states: ‘thediagnosis is made by clinical suspicion, patient history andsimple testing. Two tests have withstood the test of time,nitrazine paper and ferning of the vaginal pool. The accuracy ofat least two positive tests will be 93%.’ No further comments orupdates were offered related to diagnosis.

A traditional source of obstetrical education, WilliamsObstetrics, XXII edition, chapter 17, page 425 addresses thedetection of PROM emphasizing three significant reasons for

the importance of proper diagnosis: 1. PROM greatlyincreases the possibility of prolapsed or compression of theumbilical cord, 2. Labor ensues soon if the pregnancy is atnear term, and 3. A delay of 24 h or more after PROM is morelikely to be accompanied by infection. The textbook states that‘of several recommended diagnostic tests for PROM, none iscompletely reliable and unequivocal.’ Identification of PROMcomes ‘from the injection of various dyes via amniocentesis’(Table I).

Recently, the European Association of Perinatal Medicinehas submitted an update to their guidelines for the manage-ment of spontaneous preterm labor, which includes thediagnosis of PROM [22].

It is widely recognized in the practice of clinical obstetricsthat the only objective noninvasive method to diagnose PROMis the direct observation of leakage of amniotic fluid through theuterine cervix at the time of a sterile speculum examination. Thediagnosis of PROM is accomplished in over 90% of the‘suspected’ cases by a combination of an appropriately obtainedpatient history, the observation of leakage through the uterinecervix, and the use of a spectrum of indirect 70-year-oldmethods, neither one of which is specifically related to thepresence of amniotic fluid. All of the sanctioned methods(Table I) use physical characteristics of the vaginal contents(‘pooling’, local pH, crystallization on a vaginal discharge driedsmear), bedside ultrasound frequently repeated as an ‘officialultrasound’ hours later, and in less than 1% of the population‘suspected of PROM’ by amniocentesis and injection of indigocarmine with observation of stained vaginal discharge.

Practitioners who provide maternity care are deluged by‘new technology’ described as providing evidence for the useof recently discovered (not necessarily available for daily use)and superior methods to improve medical care, properlyutilize increasingly scarcer resources, improve clinical out-comes, and decrease the cost of health care. A number ofthese markers are not Federal Drug Administration (FDA)approved, are unavailable in the United States, are notavailable for daily patient care outside of limited researchprotocols, have an unduly prolonged turn around time forreport, and are considered ‘experimental and investigational’by third party payers and therefore of very limited daily use bythe practicing clinicians (Table II).

If we recognized the frequency of false positive and falsenegative results provided by the traditional indirect tests todiagnose PROM that we have utilized for more than half acentury, patients and physicians will benefit from consideringthe use of certain newer technologies (Table III).

After its first description in 1975, PAMG-1 is nowcommercially available (AmnisureTM), approved by theFDA and European Union for the diagnosis of PROM.Cervicovaginal fluid testing via PAMG-1 with a diagnosticthreshold set at 5.0 ng/ml, properly performed and

Table III. Clinical performance of traditional techniques to diagnose PROM.

Technique Sensitivity (%) Specificity (%) PPV (%) NPV (%) FN (%)

Vaginal speculum 12Vaginal pH 90–97 16–70 63–75 80–93 12.9

Fern test in labor 98 88.2 92 96 12.9

Fern test not in labor 51.4 70.8 40US AFV 56 97

Amniocentesis " dye injection and observation of vaginal tampon staining. Invasive, considered by some as the gold standard.

US AFV, amniotic fluid volume by ultrasound; PPV, positive predictive value; NPV, negative predictive value; FN, false negative.

New look at the premature rupture 405

interpreted, has a metric performance of 98.9% sensitivity,100% specificity, a positive predictive value of 100% for theFDA approved testing objective, and a negative predictivevalue of 99.1% [10,13,18,19; Table IV].

Recently, an in vitro study was conducted on an additional41 patients. Amniotic fluid was obtained and processed at thetime of a cesarean delivery at term qnd processed utilizingIGFBP-1 and PAMG-1 in tandem. Sensitivity, response time,and reproducibility of both tests were compared. PAMG-1showed a superior performance [23].

There is an important balance between evidence ofeffectiveness, clinical practice, and cost when planning toincorporate this test into maternity care. The test may beused to completely replace the current diagnostic steps. Inthat case, the purchase and environmental protection(temperature, humidity) of Nitrazine strips will no longerbe necessary, as well as the purchase and maintenance of amicroscope and glass slides and container for discarding ofused slides. The need to purchase, ultrasound equipment,cost of the maintenance and replacement of damagedtransducers, and update of the equipment will not benecessary. There will be no need to have a trainedtechnologist to provide the US examination 24/7 in level Iinstitutions where the number of obstetrical patients peryear does not warrant the implementation of a fullyequipped obstetrical triage unit. Experienced obstetricalnursing personnel or certified nurse midwives can providethe test at the bedside. Periodic quality control and updatesof personnel skills are done according to policies establishedin each institution or obstetrical department.

A number of ‘imponderables’ must enter into this clinicalequation. A pregnant woman who complaints of abnormalvaginal discharge and whose diagnosis is ambiguous willgreatly benefit from the use of a simple, rapid, accurate,noninvasive, non-labor intensive test, administered andreported at the point of care, and rapidly communicated toher physician, allowing for swift and appropriate disposition.If appropriate and based on evidence, the test can completelyreplace all the other tests currently in use, or conversely beutilized in ‘ambiguous’ cases.

A number of steps will be simplified if such a test is madeavailable for the diagnosis of PROM. Maternal ambulancetransfers to level II or III institutions will decrease, as well ashospital admissions for ‘observation,’ repeated exams, and useof additional therapies (antibiotics, tocolytics, steroids, non-stress testing, repeated amniotic fluid volume determinations,cervical status evaluation via ultrasound, continuous monitor-ing, biophysical profiles, pregnancy interruption, or formalinduction of labor). To the above, we may add possibledisruption of family life and employee–employer relationshipsif the diagnosis falsely documents PROM. A prompt andaccurate diagnosis will avoid the woman’s and family’s workschedule being disrupted; absenteeism and need for areplacement worker will decrease. Conversely, when the testis positive, all appropriate management policies will be

instituted in preparation for the possible prolonged hospita-lization, delivery planning, and preterm birth, includingneonatal consultation and social worker intervention whenindicated. In this era of medical practice, even the possibilityof litigation due to failure to diagnose PROM promptly andaccurately will be avoided. Long-term personal and familyside effects due to the loss of an extreme premature baby orcomplications from sepsis or long-term systemic failures maydecrease.

The above discussion brings us to the question that was theimpetus for this writing: are we ready for a serious new look atthe way we diagnose PROM? Is it time to rethink theprocesses and procedures of the last 70 years? Is it time toreplace the old indirect technology with an up-to-date specificmarker to detect the presence of amniotic fluid in the vaginaldischarge in those pregnant women between 16 and 41 weeksof gestation that present with abnormal leakage? Weencourage extending the clinical database to provide solidevidence for the updating of the traditional diagnostictechniques.

Clinical obstetrics has been charged frequently for lackingadequate applicable basic research that can be translated intocare to provide optimal outcomes to our patients. The use ofPAMG-1 to promptly, accurately, and inexpensively diagnosePROM may be a relevant change in our practice.

Timely and accurate testing is an important step in medicalcare. The discovery of new markers and the development ofnew technologies require that we clinicians remain attentive toremarkable advances to deal with pregnancy complications.Scientists must be able to provide translational research forpractitioners to incorporate into clinical practice at thebedside.

Obstetricians carry the extraordinary responsibility to carefor a pregnant woman and her fetus, often considered as aunique situation in clinical medicine, the duty to respond tothe needs of two patients. As such we must remain alert andresponsive to useful changes and innovations in our field ofpractice.

Declaration of interest: The authors report no conflicts ofinterest. The authors alone are responsible for the content andwriting of the paper.

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