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Diagnosis of Premature Rupture of Membranes:Inspiration From the Past and Insights for theFutureAmira El-Messidi, MD, FRCSC, RDMS, 1 Alan Cameron, MD, FRCOG, FRCP (Glas) 21Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Royal Victoria Hospital, McGill University, Montreal QC

2Fetal Medicine, Department of Obstetrics and Gynaecology, The Queen Mothers Hospital, Glasgow, Scotland

Abstract

Objective: To review the diagnostic methods described to confirmpremature rupture of membranes during pregnancy, and to assesstheir effectiveness in establishing the diagnosis.

Data Sources and Extraction: The medical literature was searchedto identify all relevant studies and reviews on methods for diagnosisof membrane rupture published in English up to January 31, 2009.Medline and the Cochrane databases were searched, andreference lists in identified articles were also examined. Articlesnot available through journals online editions were retrieved bymanual search.

Study Selection: We identified 71 original studies and reviews ondiagnostic methods of chorioamniotic membrane rupture publishedin English. These articles were reviewed and results weresummarized based on the diagnostic test assessed.

Conclusion: Recognition of the importance of and difficulties inconfirmation of rupture of the chorioamniotic membranes pervadespast and present obstetric publications. The subjectivity and poor sensitivity of early diagnostic techniques for confirmation of ruptured membranes sparked technical advancements usingbiochemical markers. None of these biochemical tests havegained popularity, although novel techniques involving placentalmarkers such as placental alpha microglobulin-1 may provide afuture solution to the problem of diagnosing chorioamnioticmembrane rupture.

Rsum

Objectif : Analyser les mthodes diagnostiques dcrites pour confirmer la rupture prmature des membranes pendant la

grossesse, ainsi quafin den valuer lefficacit pour ce qui estde ltablissement du diagnostic.

Sources et extraction des donnes : Des recherches ont tmenes dans la littrature mdicale en vue didentifier toutesles tudes et analyses pertinentes portant sur les mthodes deprocder au diagnostic de la rupture des membranes qui ont tpublies en anglais jusquau 31 janvier 2009. Des recherchesont aussi t menes dans Medline et les bases de donnesCochrane, et les listes de rfrences des articles identifis ontgalement t examines. Les articles ntant pas disponiblespar lintermdiaire des ditions lectroniques des revuesspcialises ont t rcuprs par recherche manuelle.

Slection des tudes : Nous avons identifi 71 tudes et analysesoriginales portant sur les mthodes permettant de diagnostiquer la rupture des membranes chorioamniotiques qui ont t publies

en anglais. Ces articles ont t analyss et les rsultats ont trsums en fonction du test diagnostic valu.

Conclusion : La reconnaissance de limportance de la confirmationde la rupture des membranes chorioamniotiques et de sesdifficults est omniprsente dans les publications passs etprsentes du domaine de lobsttrique. La subjectivit, la faiblesensibilit et les premires techniques diagnostiques visant laconfirmation de la rupture des membranes ont donn lieu desperces techniques faisant appel des marqueurs biochimiques. Aucun de ces tests biochimiques ne sest dmarqu, et ce, malgrle fait que des techniques novatrices faisant appel desmarqueurs placentaires (comme lalpha-microglobuline-1placentaire) puissent fournir une future solution au problmeque pose le diagnostic de la rupture des membraneschorioamniotique.

J Obstet Gynaecol Can 2010;32(6):561569

INTRODUCTION

Premature rupture of membranes may occur at term orimmediately preceding labour, or it may be an unex-pected complication during the preterm period, when it isreferred to as preterm premature rupture of membranes.

Chorioamniotic membrane rupture may have severalunderlying causes, although in many cases PROM andPPROM will not have recognized etiologies. Thepathophysiology leading to PROM at term has been shownto be different from the pathophysiology leading to PPROM. At term, weakening of the membranes may result fromphysiologic changes combined with shearing forces inducedby contractions.14 Generalized weakness of the membraneshas been more difficult to identify with prematurely rupturedmembranes.5 PPROM may result from a focal deficit ratherthan a generalized weakness of the membranes.6

Term PROM complicates approximately 8% of pregnancies.7 Among these, approximately 50% of affected women willbegin labour spontaneously within 12 hours, 70% within 24hours, 85% within 48 hours, and 95% within 72 hours.79Fetal morbidities associated with term PROM include

JUNE JOGC JUIN 2010 l 561

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ascending infection and in utero cord compression.7 Mater-nal risks of term PROM include chorioamnionitis andpostpartum febrile morbidity.7,9Preterm PROM, a complication of 2% to 20% of alldeliveries,10 is a known important contributor to maternaland perinatal morbidity and perinatal mortality. Latency in

PPROM, defined as the interval between PROM and birth,7

is known to be inversely related to gestational age at rupture,and is also related to a multitude of other factors, including number of fetuses,11 severity of oligohydramnios,12myometrial thickness,13 and the existence of maternal orobstetrical complications. The major cause of perinatalmorbidity and mortality associated with PPROM isprematurity.7 Morbidities related to prematurity includerespiratory distress syndrome, necrotizing enterocolitis,interventricular hemorrhage, cerebral palsy, and sepsis.7Other complications include in utero umbilical cord com-pression, cord prolapse and fetal distress, fetalmalpresentation, placental abruption, chorioamnionitis with subsequent endometritis, and risk of operative delivery from this multitude of factors.7 Maternal sepsis is a rare butlife-threatening complication reported in nearly 1% of cases.7

For over 70 years, there has been controversy among healthcare professionals about the optimal approach to clinicalassessment and diagnosisof prematurely ruptured membranes.In most cases, membrane rupture can be confirmed by doc-umenting amniotic fluid leakage from the cervical os with visualization of pooling in the posterior vaginal fornix.14However, the diagnosis of PROM is difficult if there is aslowfluid leakorany bleeding, orwhenthe classic gush offluiddoes not occur.15 In addition, the relatively small amount of amniotic fluid present early in gestation further challengesthe diagnosis of ruptured membranes.16 Ladfors et al.17showed that even later in pregnancy (after 34 weeks), speculumexamination for visualization of amniotic fluid carries a12% false negative rate when no fluid is seen. In 1951,Schumann18 described the two sac theory of membranerupture: he stated that amniotic fluid can dissect betweenthe two layers of membranes and produce a bulge that rupturesinto the vagina, leaving one intact layer with remaining fluid

enclosed and appearing to rupture at a later time. In suchcases, women give a history of fluid leakage, and tests forleakage should be positive, although membranes appear clin-ically to be intact at delivery. Occasionally, women present with a history suspicious for membrane rupture, but clinical

examination is negative or inconclusive; they subsequently return with clearly identifiable rupture of the membranes. Whether these cases represent preliminary minimaltransudation of fluid across weakened membranes or minimalleakage around a firmly applied fetal presenting part cannotbe determined. In approximately 20% to 25% of cases,

rupture of membranes is not grossly apparent.10,19

A patientshistory may suggest membrane rupture, but test results arenon-confirmatory, creating an obstetrical dilemma. Early and accurate diagnosis of membrane rupture would allow forgestational age-specific interventions to optimize perinataloutcome and minimize serious complications.20 Therefore,the search for an ideal test to diagnose membrane rupturedefinitively with no delay continues.

Although initial studies may be encouraging, diagnostictechniques are usually found subsequently to be limited by inaccuracies from false positives and false negatives withpoorer sensitivities and specificities than originally anticipated. The ideal test should be simple, rapid, inexpensive, andnon-invasive. Optimally, the accuracy of the test should notbe hampered by the presence of blood, semen, infectedurine, or othercontaminants. An accurate biochemical markerfor membrane rupture should have a high concentration inthe amniotic fluid, a low concentration in maternal blood,and an extremely low background concentration incervicovaginal discharge with intact membranes.10

We sought to review the diagnostic methods currently usedto confirm premature rupture of membranes and to assesstheir effectiveness in establishing the diagnosis.

METHODS

We searched Medline and the Cochrane databases for allrelevant studies and reviews published in English onaccuracies of diagnostic methods for the diagnosis of ruptureof the membranes up to January 31, 2009. Key words usedfor the Medline searchwere premature rupture of membranes,amniotic fluid, diagnosis, and tests. Articles notavailable online were retrieved by manual search. We foundno Cochrane reviews of diagnostic methods of PROM, asdiscussed in this report. The studies identified showed evidencefrom levels II-2, II-3, and III, according to ranking of TheCanadian Task Force on Preventive Health Care.21,22

MICROSCOPIC FETAL CELL IDENTIFICATION

A literature review by Friedman et al.23 described the firstmicroscopic technique for identification of fetal particles inamniotic fluid, developed by Philipp et al in 1929 andpublished in the German literature. In this technique, fetallanugo hairs were identified in amniotic fluid. This was presumedto be incontrovertible evidence of membrane rupture whenidentified in vaginal secretions. However, because of the

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562 l JUNE JOGC JUIN 2010

ABBREVIATIONS

AFI amniotic fluid index

PAMG-1 placental alpha-microglobulin-1

PROM premature rupture of membranes

PPROM preterm premature rupture of membranes

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scant amounts of fetal lanugo hair in amniotic fluid and thefact that such hair was present in amniotic fluid only later inpregnancy, this method never gained popularity. As thisstudy was not published in the English language, statisticaldata are not shown in the Table.

Subsequent diagnostic tests were based on cytologicinspection for fetal squamous cells in the vagina. Interest incytologic diagnosis was based on the noted absence of stain within the cytoplasm and nucleus of vernix caseosa cellscompared with vaginal squamous cells.24 Investigatorssearched for fetal cells in vaginal fluid using diverse stainsincluding Masson stain,24 Sudan III to demonstrate fetal fatparticles,2527 Papanicolaou stain,28,29 pinacyanole stain,30,31acridene orange stain,32 and Nile blue sulphate stain.33

Recognizing the challenge to diagnose PROM in clinically equivocal cases, Averette et al.30 studied 100 patients in

whom the integrity of the chorioamniotic membrane couldnot be determined by visualization of fluid on speculumexamination. Fetal cell staining with pinacyanole to identify vernix caseosa cells in such cases showed high accuracy rates (97%), similar to those in earlier studies among

patients with clinically confirmed membrane rupture.

Although fetal cell staining techniques were consideredrapid, simple, and durable, concerns about inaccuraciesemerged. Contamination from the powder on examinationgloves gave false positive results as anuclear granulesmimicked fetal cells,31 and hypercornified vaginal cells alsosimulated anucleate fetal cells.32 False negatives resultedfrom the subjectivity of inspection, having insufficientcellular material,32 or after a prolonged time interval frommembrane rupture. Accuracy rates appear to diminish withincreased duration between presumed membrane rupture

Diagnosis of Premature Rupture of Membranes: Inspiration From the Past and Insights for the Future


Accuracy of diagnostic tests for PROM

Test used for diagnosis

DiscriminatoryconcentrationMean (range)

Samplingsite

Patients, nMean(range)

SN, %Mean(range)

SP, %Mean(range)

FN, %Mean(range)

FP, %Mean(range)

Fetal cells (bromthymol

blue)34,36

N/A Vagina 239

(176239)

90.2

(85.794.7)

98.4

(97.499.3)

7.5

(0.614.3)

1.7

(0.72.6)pH 19,23,31,39,40,46,54,55,57,59,62 6.5

(6.07.0) 35,36,55,57,59Vagina 125

(46250)90.2

(81.3100.0)79.3

(16.0100.0)12.4

(033.3)28.2

(0100.0)

Fetal cells (Masson stains) 24 N/A Vagina 275 94.2 99.0 5.8 1.0

Fetal cells (Papanicolaoustain) 23,28

N/A Vagina 75(50100)

92.8(92.0 - 93.5)

92.7(91.394.0)

4.3(2.06.5)

7.4(6.08.7)

Fetal cells (Pinacyanolstain) 23,30,31

N/A Vagina 150(100250)

88.3(71.098.7)

95.4(91.798.8)

11.7(1.329)

3.7(1.28.3)

Fetal cells (Acrideneorange stain) 23,32

N/A Vagina 200(100300)

75.5(61.289.7)

90(87.392.7)

24.6(10.338.8)

10.0(7.312.7)

Fetal cells (Nileblue sulphate) 23,33

N/A Vagina 106(100111)

89.5(80.798.2)

98.6(97.1100.0)

10.6(1.819.3)

1.5(02.9)

Crystallization 23,37,38-40,43,54,74 N/A Vagina 198(51509)

90.8(62.0 - 98.5)

95.3(88.2100.0)

4.4(1.212.9)

4.7(0.011.8)

History alone 23 N/A N/A 100 90.3 88.4 9.7 11.6

History + pH + crystalization 23 N/A Vagina 100 90.8 95.6 9.2 4.4

History + pH + Nile Blue stain 23 N/A Vagina 100 87.1 92.7 12.9 7.3

History + Crystallization + NileBlue stain 23

N/A Vagina 100 87.1 95.6 12.9 4.4

History + ultrasound +crytallization 74

N/A N/A 83 85.1 78.6 11.1 21.4

pH + Crystallization + NileBlue stain 23

N/A Vagina 100 90.8 95.6 9.2 4.4

AmnioInjection Evans blueT1824 47

N/A Amnio-centesis

18 100.0 100.0 0.0 0

DAO 19,58,67 22.5 U/L 19, 67 Vagina 168(100272)

88.9(83.0100.0)

98.3(95.0100.0)

8.5(017.0)

1.7(05.0)

3.32 log glucose + log fructose 49 17.7279 N/A 215 98.9 96.0 7.7 2.6

continued

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and diagnostic testing. Early authors including King 34 and

Bourgeois24

reported 57% and 81.8% accuracy ratesrespectively, beyond the initial 24-hour period of membranerupture. This was later confirmed by others, and shorterintervals to testing were shown to affect rates of diagnosticaccuracy.23

As novel methods were developed, older cytologic techniquesbegan losing popularity, because they were time-consuming,required trained cytologists, were ineffective before 32 weeksgestation, and provided an uncertain diagnosis of membranerupture.29

LITMUS PAPER AND pH TESTING

Litmus paper testing began development at approximately the same time as fetal cell staining methods. Because of thedifference in pH of vaginal secretions (4.5 to 5.5) andamniotic fluid (7.0 to 7.5), it was rightly assumed that thepH of vaginal secretions would rise when contaminated by escaping amniotic fluid.35 This assumption prompted pre-liminary experiments with bromthymol blue dye and, later,nitrazine applicators. Although similar in principle tobromthymol blue, a reported advantage of nitrazine is thecomplete change in colour of the applicator when exposedto amniotic fluid in vaginal secretions.36 Impregnated with

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Table continued

Test used for diagnosis

Discriminatoryconcentration

Mean(range)

Samplingsite

Patients, nMean(range)

SN, %Mean(range)

SP, %Mean(range)

FN, %Mean(range)

FP, %Mean(range)

Prolactin RIA 50,51,52 3mU/mL,592ng/mL,51

20.2IU/mL52

Vagina 57(20100)

88.0(76.0100.0) 51,52

85.0(70.0100.0) 51,52

68.0 15.0(030.0) 51,52

AFP (RIA) 60,67,76,77,80 53.3 g/L(2-125)

Vagina 122(52312)

80.6(17.6100.0),

NR 60

91.9(80.097.4),

NR 60

5.4(0.016.0),

NR 60

8.1(2.620.0),

NR 60

AFP (RIA) 57,58,59 77.5 g/L(30-125)

Cervix 89(46131)

92.0(84.0100.0)

86.9(85.788.0)

8.0(016.0)

13.2(12.014.3)

human placental lactogen(hPL) RIA 51

31 ng/mL Vagina 52 NR NR NR NR

fFN monoclonal assay(ROM check) 58,59,63,64,65

50 ng/mL Vagina 160(54406)

93.6(90.098.2)

65.7(26.897.0)

13.1(3.025.0)

17.0(6.028.0)

fFN monoclonal assay(ROM check) 59

25 ng/mL Vagina 46 87.5 92.9 11.9 7.1

IGFBP-1 immunoenzyme(PromTest) 19, 46, 65,71,72,73,74

35 g/L(3-100)

Vagina,cervix72

130(54174)

84.9(74.4100.0)

92.8(71.498.2)

14.7(039.2)

7.3(1.828.6)

IGFBP-1 dipstick(ActimPROM) 10

400 g/L Amniocentesis 20 NR NR NR NR

Lactate 68 4.5 mmol/L Vagina 200 86 92 92 87

b hCG (ELCIA) 52,60,61,62 46.4 mIU/mL Vagina 137(100188)

83.9(68.0100.0)

89.5(84.295.0)

9.1(0.025.0)

10.5(5.016.0)

Ultrasound amnioticfluid index 46

< 80 mm N/A 151 94.0 91.0 6.2 9.0

Creatinine concentrationassay 69,70

0.36 mg/dL Vagina 114(88139)

100.0 100.0 0.0 0.0

Urea concentration 70 12 mg/dL Vagina 139 100.0 100.0 0.0 0

PAMG-1(AmniSure) 76,77

5 ng/mL Vagina 194(184203) 98.8(98.798.9) 93.8(87.5100.0) 1.2(1.11.3) 6.3(0.012.5)

PAMG-1 (AmniSure) 10 5 ng/mL Amniocentesis 20 NR NR NR NR

AmnioSenseabsorbent pad 15,78

pH> 5.2 N/A 69(34103)

99.2(98.3100.0)

70.0(65.075.0)

0.85(01.7)

30.0(25.035.0)

Legend: SN: sensitivity; SP: specificity; FN: false negative; FP: false positive; DAO: diamine oxidase; IGFBP-1: insulin growth factor binding protein-1;PAMG-1: placental alpha microglobulin-1; bhCG: beta subunit human chorionic gonadotropin; fFN: fetal fibronectin; AFP: alpha fetoprotein; RIA: radioimmunoassay;NR: not reported; N/A: not applicable

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sodium-dinitro-phenylozonapthol-disulphonate, nitrazinepaper showed promising early results in detecting membranerupture, with accuracies of 100%35 and 98.9%36 in clinically ruptured cases, and similarly high rates of accuracy among intact cases. This preliminary high optimism regarding nitrazine testing decreased by the1960s,31,37 because of false

positive results from vaginal infections, blood, semen, alka-line urine or alkaline antiseptics, and false negatives in casesof minimal leakage from chronic membrane rupture orhigh leak of the membranes.15

AMNIOTIC FLUID CRYSTALLIZATION

Amniotic fluid crystallization, created primarily by thesodium chloride and protein content, began to dominatecytologic stains, with reported accuracies in clinically ruptured cases ranging from 73.0% to 98.5%.26,27,32,3740Screening for arborization provided an accuracy of 97.8%

compared with 87.3% for litmus paper testing.37

Interest-ingly, Tricomi et al.37 suggested that fluid for examinationshould be aspirated from the vagina no further than 3 cmfrom the introitus to avoid contamination and false positiveferning results from cervical mucus lying in the posteriorfornix. Initial optimism with low false negative rateschanged as missed diagnoses in the presence of blood,meconium, or heavy leukorrhea became recognized.23 Falsepositive results were subsequently attributed to fingerprints,semen, or cervical mucus.23,41,42

In most ferning specimens tested in early studies,23,26,3740

sensitivity and specificity analyses were performed on women in labour, in whom there was certainty about thediagnosis of membrane rupture.43 In most clinical situa-tions, however, the test is intended for patients who haveequivocal rupture. De Haan et al.43 showed that the modestdiagnostic reliability of the fern test compared with earlierpublished data is at least partly due to differences in study populations (i.e., whether the women were in labour ornot). These authors showed false positive and false negativerates of 11.8% and 2.0%, respectively, in labouring womentested for amniotic fluid crystallization, compared withrates of 21.2.% and 40.6%, respectively, in women not inlabour.43 Thus, the result of the fern test became viewed assupportive rather than conclusive for non-labouring women with non-specific vaginal fluid loss.

COMBINATION OF DIAGNOSTIC TESTS

Many early studies either tested one method for diagnosisof membrane rupture or compared two methods. Friedmanet al.23 were the first to test individual methods as well as dif-ferent combinations of tests, which more commonly reflects true clinical practice. They also attempted to corre-late the time of testing with the time of presumed rupture.

Indeed, these authors showed a precipitous increase in errorrate when the time interval between membrane rupture andsampling exceeded two hours.23 False negative tests weremore commonly associated with prolonged rupture. Noneof the traditional procedures proved entirely satisfactory inisolation, but combinations of any three of the following

produced a diagnostic accuracy of 93.1%23

:1. a positive history,

2. a positive nitrazine test,

3. fluid crystallization, or

4. Nile blue sulphate staining.

ULTRASOUND ASSESSMENT OFAMNIOTIC FLUID VOLUME

In the late 20th century, it was theorized that thesonographic identification of oligohydramnios woulddevelop after membrane rupture,44 thereby facilitating diag-nosis and subsequent management. Manning et al.45 initially described a technique for measuring by ultrasound thedeepest vertical pool of amniotic fluid in patients withintrauterine growth restriction. This method was later usedto assess membrane rupture; it was shown that ultrasoundquantification of the deepest amniotic fluid pocket is of poor quality in confirming membrane rupture.44 No signifi-cant difference was found in the mean depth of amnioticfluid pocket between 100 patients with confirmed termPROM and 51 patients with intact membranes.44

Oligohydramnios may not be detected in patients withconfirmed PROM, possibly because drainage may becomeintermittent or even stop once the presenting part descendsand acts as a plug, preventing further drainage.44 Robson etal. suggested that a significant amount of amniotic fluidneeds to drain rapidly and continuously foroligohydramnios to occur, especially because the fluid isreplaced to varying degrees by the fetus.44 Erdemoglu etal.46 showed that a reduction in the four-quadrant AFIbelow 80 mm did not reliably identify cases of suspectedmembrane rupture by history with negative visualization of fluid by speculum examination. The measurement of AFIoffers no advantage over measurement of a single verticalpocket of fluid in cases where ultrasound is used to evaluatepossible membrane rupture.

INTRA-AMNIOTIC DYE INJECTION

By 1970, amniocentesis with injection of dye to confirmamniotic membrane rupture had become a commonplaceprocedure; it was thought to be safe and had high patientacceptability rates.47 Prior to amniocentesis, intravenousinjection of radioisotope was performed for placental local-ization, and the amnio-injection was performed under local



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anaesthesia. Interestingly, the two reported disadvantagesof the procedure at that time were related to difficulty indiagnosis in the presence of meconium-stained fluid andthe possibility of neonatal skin staining for 48 hours afterdye injection.47 Several types of stains have been used foramnio-injections, with safety hazards reported only for

methylene blue (see below). Although ultrasonographically guided transabdominalinstillation of indigo carmine dye (1 mL of dye in 9 mL of sterile normal saline) and observation for fluid passagetransvaginally is designated an unequivocal diagnosticmethod for confirmation of membrane rupture, 14 this inva-sive test carries increased maternal and fetal risk. Inherentrisks of intra-amniotic dye injection include trauma, bleeding,infection, and preterm labour.48 While strengthening diagnostic certainty, a negative dye test may occur if themembranes seal after previous amniotic fluid leakage.

GLUCOSE AND FRUCTOSE MEASUREMENTS

Gorodeski et al.49 examined the difference betweenamniotic fluid and cervicovaginal mucus in their concentra-tions of solutes. During pregnancy, glucose and fructose arepresent in high concentrations in cervical mucus, withreported means of 240 mg/100 mL and 30.4 mg/100 mL,respectively.49 Amniotic fluid concentrations are noticeably lower, with mean concentrations of 39 mg/100 mL and3.3mg/100 mL, respectively. Gorodeski et al.49 showed thatlow values of glucose and fructose are found in amniotic

fluid aspirated in a true case of membrane rupture. Bestresults are obtained with a calculated linear sum of the values(3.32 log glucose + log fructose). These authors reported noconfounding by meconium or vaginal discharge.

This technique is fairly impractical in testing for membranerupture, and further studies have not expanded upondiffer-ential carbohydrate gradients.

MODERN METHODS

Because of the limitations of available testing methods,

investigators have sought alternative markers in vaginalamniotic fluid, such as prolactin5052, alpha-fetoprotein,5159b-subunit of human chorionic gonadotropin,52,6062 fetalfibronectin,58,59,6366 diamine oxidase,19,58,67 lactate,68creatinine,69,70 urea,70 and insulin growth factor binding protein-1, previously called placental protein12.10,19,46,65,66,7174 Interest in assessment of these markersstems from their high concentrations in amniotic fluid com-pared with normal vaginal secretions, but all require speciallaboratory equipment and training.14 Although these markersare useful for patients with intact membranes or unequivocalmembrane rupture, they remain unpopular due to cost,

testing complexity, and low test sensitivities in cases of equivocal rupture.

PLACENTAL ALPHA-MICROGLOBULIN-1

Initially isolated in Moscow in 1975,75 PAMG-1 has under-gone recent evaluation for diagnostic testing in PPROM. This 34kDa placental glycoprotein is abundant in amnioticfluid (200025 000 ng/mL), with much lower concentra-tions in maternal blood (525 ng/mL).20 The protein ispresent in negligible amounts in cervicovaginal secretions with intact membranes (0.050.2ng/mL).76 The 1000- to10 000-fold difference in concentration between amnioticfluid and cervicovaginal secretions stimulated interest in aPAMG-1 immunoassay. Marketed as AmniSure (AmniSureInternational, Cambridge, MA), the assaysminimumdetec-tion threshold for PAMG-1 is 5 ng/mL, sufficient for 99%accuracy with minimal false negatives. PAMG-1 can be

detected with as little as 0.25 L of amniotic fluid in 1 mL of vaginal secretions.76 In the presence of blood or vaginitis,the background level of PAMG-1 can occasionally reach amaximum of 3 ng/mL.76 False-positive results with use of the AmniSure assay seem very unlikely, although these may appear with increased use.77 Further, assay of PAMG-1appears to be reliable over a wide range of gestational ages(11 to 42 weeks), and proved superior to conventional com-bined clinical tests involving visualization of fluid pooling inthe posterior fornix, arborization, and nitrazine testing.77

This test is currently available in Europe and was recently approved by the Food and Drug Administration for use inthe United States. AmniSure is a novel rapid, non-invasivebedside test that may be very helpful in diagnosis of difficultcases without visible leakage. Further studies are needed toassess the reliability of the test according to the time frommembrane rupture.

NON-INVASIVE ABSORBENT PAD

Efforts to be able to confirm chorioamniotic membranerupture with minute amounts of amniotic fluid have

recently led to the development of the absorbent pad, AmnioSense. This 12 4 cm pad has a central strip thatchanges colour on contact with fluid with a pH > 5.2.15,78 After contact with urine, the strip reverts to its original col-our when dry. This is due to the detachment of conju-gate-based nitrazine molecules by the urine ammoniumions.15 AmnioSense has undergone cytotoxicity and skinirritation and sensitization testing, and it complies with theUS Pharmacopoeia Guidelines.15 In a study of 34 womenpresenting with suspected membrane rupture, the AmnioSense pad initially showed 100% sensitivity; overallspecificity was 75%, but when women with bacterial

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11. Myles TD, Espinoza R, Meyer W, Bieniarz A. Preterm premature ruptureof membranes: comparison between twin and singleton gestations. J MaternFetal Neonat Med 1997;6:15963.

12. Park JS, Yoon BH, Romero R, Moon JB, Oh SY, Kim JC, et al. Therelationship between oligohydramnios and the onset of preterm laborin preterm premature rupture of membranes. Am J Obstet Gynecol2001;184:45962.

13. Buhimschi CS, Buhimschi IA, Norwitz ER, Sfakianaki AK, Hamar B,Copel JA, et al. Sonographic myometrial thickness predicts the latency interval of women with preterm premature rupture of the membranesand oligohydramnios. Am J Obstet Gynecol 2005;193:76270.

14. Mercer BM. Preterm rupture of the membranes: diagnosis and management.Clin Perinatol 2004;31:76582.

15. Bornstein J, Geva A, Solt I, Fait V, Schoenfeld A, Shoham HK, et al.Nonintrusive diagnosis of premature ruptured amniotic membranes using a novel polymer. Am J Perinatol 2006;23:3514.

16. Brace RA. Physiology of amniotic fluid volume regulation.Clin Obstet Gynecol 1997;40:2809.

17. Ladfors L, Mattsson LA, Eriksson M, Fall O. Is a speculum examinationsufficient for excluding the diagnosis of ruptured fetal membranes?

Acta Obstet Gynecol Scand 1997;76:73942.18. Schuman W. Double sac with secondary rupture of the bag of waters during

labor; a clinical entity, and its explanation from examination of themembranes. Am J Obstet Gynecol 1951;62:6338.

19. Gaucherand P, Salle B, Sergeant P, Guibaud S, Brun J, Bizollon CA, et al.Comparative study of three vaginal markers of the premature rupture of membranesinsulin like growth factor binding protein 1, diamine-oxidase,pH. Acta Obstet Gynecol Scand 1997;76:53640.

20. Park JS, Lee SE, Norwitz ER. Non-invasive testing for rupture of thefetal membranes. Touch Briefings: US Obstetrics and Gynecology 2007;Issue 1: 136.

21. Woolf SH, Battista RN, Anderson GM, Logan AG, Wang E. Assessing theclinical effectiveness of preventative maneuvers: analytic principles andsystemic methods in reviewing evidence and developing clinical practicerecommendations. A report by the Canadian Task Force on the PeriodicHealth Examination. J Clin Epidemiol 1990;43: 891905.

22. Canadian Task Force on the Preventive Health Care. New grades forrecommendations from the Canadian Task Force on Preventive HealthCare. CMAJ 2003;169:2078.

23. Friedman ML, McElin TW. Diagnosis of ruptured fetal membranes. Clinicalstudy and review of the literature. Am J Obstet Gynecol 1969;104:54450.

24. Bourgeois GA. The identification of fetal squames and the diagnosis of ruptured membranes by vaginal smear. Am J Obstet Gynecol 1942;44:807.

25. Von Numers C. A new method of diagnosis of rupture of the membranes. Acta Obstet Gynecol Scand 1936;16:24960.

26. Paavola A. Methods based on the study of crystals and fat staining: use indiagnosing rupture of membranes. Ann Chir Gynaecol Fenn 1958;47:228.

27. Volet B, Morier-Genoud J. The crystallization test in amniotic fluid.Gynaecologia 1960;149:15161.

28. Goldfine S. The detection of ruptured membranes by vaginal smear. Am J Obstet Gynecol 1955;70:10914.

29. Hopman BC, Wargo JD, Werch SC. Cytology of vernix caseosa cells.Obstet Gynecol 1957;10:6569.

30. Averette HE, Hopman BC, Ferguson JH. Cytodiagnosis of ruptured fetalmembranes. Am J Obstet Gynecol 1963;87:22630.

31. Gall SA, Spellacy WN. Cyologic diagnosis of ruptured membranes.Obstet Gynecol 1964;24:7325.

32. Kushner DH, Chang IW, Vercruysse JM. Fluorescence microscopy fordetermination of ruptured fetal membranes by vaginal smear. ObstetGynecol 1964;23:1969.

33. Brosens I, Gordon H. The cytological diagnosis of ruptured membranesusing Nile Blue Sulphate staining. J Obstet Gynaecol Br Commonw 1965;72:3426.

34. King AG. The determination of rupture of membranes. Am J ObstetGynecol 1935;30:8602.

35. Baptisti A. Chemical test for determination of ruptured membranes. Am J Obstet Gynecol 1938;35:68890.

36. Abe T. Detection of rupture of fetal membranes with Nitrazine indicator. Am J Obstet Gynecol 1940;39:4004.

37. Tricomi V, Hall JE, Bittar A, Chambers D. Arborization test for thedetection of ruptured fetal membranesclinical evaluation.Obstet Gynecol 1966;27:2759.

38. Smith RW, Callagen DA. Amniotic fluid crystallization test for rupturedmembranes. Obstet Gynecol 1962;20:65560.

39. Kovacs D. Crystallization test for the diagnosis of ruptured membranes. Am J Obstet Gynecol 1962;83:1257.

40. Ferron M, Bilodeau R. Amniotic fluid crystallization test for rupturedmembranes. Can Med Assoc J 1963;89:10647.

41. Lodeiro JG, Hsieh KA, Byers JH, Feinstein SJ. The fingerprint, afalse-positive fern test. Obstet Gynecol 1989;73:8734.

42. McGregor JA. Johnson S. Fig-leaf ferning and positive nitrazine testing:semen, a cause of misdiagnosis of premature rupture of membranes[letter to the editor]. Am J Obstet Gynecol 1985;151:11423.

43. de Haan HH, Offermans JPM, Smits F, Schouten HJA, Peeters LL. Valueof the fern test to confirm or reject the diagnosis of ruptured membranesis modest in nonlaboring women presenting with non-specific vaginal fluidloss. Am J Perinatol 1994;11:4650.

44. Robson MS, Turner MJ, Stronge JM, OHerlihy CO. Is amniotic fluidquantitation of value in the diagnosis and conservative management of prelabour membrane rupture at term? Br J Obstet Gynaecol 1990;97:3248.

45. Manning FA, Hill FM, Platt LD. Qualitative amniotic fluid volumedetermination by ultrasound. Antepartum detection of intrauterine growthretardation. Am J Obstet Gynecol 1981;139:2548.

46. Erdemoglu E, Mungan T. Significance of detecting insulin-like growthfactor binding protein-1 in cervicovaginal secretions: comparison withnitrazine test and amniotic fluid volume assessment. Acta Obstet GynecolScan 2004;83:6226.

47. Atlay RD, Sutherst JR. Premature rupture of the fetal membranes confirmedby intra-amniotic injection of dye (Evans blue T-1824). Am J ObstetGynecol 1970;108:9934.

48. Gibbs RS, Blanco JD. Premature Rupture of the membranes. ObstetGynecol 1982;60:6719.

49. Gorodeski I, Paz M, Insler V, Fishel J. Diagnosis of rupture of the fetalmembranes by glucose and fructose measurements. Obstet Gynecol1979;53:6116.

50. Koninckx PR, Trappeniers H, Van Assche FA. Prolactin concentrationin vaginal fluid: a new method for diagnosing ruptured membranes.Br J Obstet Gynaecol 1981;88:60710.

51. Huber JF, Bischof P, Extermann P, Beguin F, Herrmann WL. Are vaginalfluid concentrations of prolactin, a -fetoprotein and human placentallactogen useful for diagnosing ruptured membranes? Br J Obstet Gynaecol1983;90:11835.

52. Shahin M, Raslan H. Comparative study of three amniotic fluid markersin premature rupture of membranes: prolactin, beta subunit of humanchorionic gonadotropin, and alpha-fetoprotein. Gynecol Obstet Invest2007;63:1959.

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53. Rochelson BL, Richardson DA, Macri JN. Rapid assay-possible applicationin the diagnosis of premature rupture of the membranes. Obstet Gynecol1983;62:4148.

54. Rochelson BL, Rodke G, White R, Bracero L, Baker DA. A rapidcalorimetric AFP monoclonal antibody test for the diagnosis of pretermrupture of the membranes. Obstet Gynecol 1987;69:1635.

55. Hjertberg R, Belfrage P, Eneroth P. Latex agglutination test for

a -fetoprotein in the diagnosis of premature rupture of the amnioticmembranes (PROM). Acta Obstet Gynecol Scand 1987;66:4379.

56. Gaucherand P, Guibaud S, Rudigoz RC, Wong A. Diagnosis of prematurerupture of the membranes by the identification of alpha-feto-protein in vaginal secretions. Acta Obstet Gynecol Scand 1994;73:4569.

57. Kishida T, Yamada H, Negishi H, Sagawa T, Makinoda S, Fujimoto S.Diagnosis of preterm rupture of the membranes using a newly developed AFP monoclonal antibody test kit. Eur J Obstet Gynecol Reprod Biol1995;58:6772.

58. Gaucherand P. Guibaus S, Awada A, Rudigoz RC. Comparative study of three amniotic fluid markers in premature rupture of membranes:fetal fibronectin, alpha-fetoprotein, diamino-oxydase. Acta Obstet

Gynecol Scand 1995;74:11821.59. Kishida T, Yamada H, Negishi H, Sagawa T, Makinoda S, Fujimoto S.

Diagnosis of premature rupture of the membranes in preterm patients,using an improved AFP kit: comparison with ROM-check and/or nitrazinetest. Eur J Obstet Gynecol Reprod Biol 1996;69:7782.

60. Kim YH, Park YW, Kwon HS, Kwon JA, Kim BJ. Vaginal fluidb -humanchorionic gonadotropin level in the diagnosis of premature rupture of membranes. Acta Obstet Gynecol Scand 2005;84:8025.

61. Anai T, Tanaka Y, Hirota Y, Miyakawa I.Vaginal fluid hCG levels fordetecting premature rupture of membranes. Obstet Gynecol 1997;89:2614.

62. Esim, E, Turan C, Unal O, Dansuk R, Cengizglu B. Diagnosis of prematurerupture of membranes by identification of b-HCG in vaginal washing fluid.Eur J Obstet Gynecol Reprod Biol 2003;107:3740.

63. Hellemans P, Verdonk P, Baekelandt M, Joostens M, Franx M. Gerris J.Preliminary results with the use of the ROM-check immunoassay in theearly detection of rupture of the amniotic membranes. Eur J ObstetGynecol Reprod Biol 1992;43:1739.

64. Eriksen NL, Parisi VM, Daoust S, Flamm B, Garite TJ, Cox SM. Fetalfibronectin: a method for detecting the presence of amniotic fluid.Obstet Gynecol 1992;80:4514.

65. Rutanen EM, Pekonen F, Karkkainen T. Measurement of insulin-likegrowth factor binding protein-1 in cervical/vaginal secretions: comparison with the ROM-check Membrane Immunoassay in the diagnosis of rupturedfetal membranes. Clinic Chimica Acta 1993;214:7381.

66. Guibourdenche J, Luton D, Andre E, Noel M, Pourquet D. Rapid detectionof insulin-like growth factor-binding protein-1 and foetal fibronectin incervico-vaginal secretions to diagnose premature membrane rupture. AnnClin Biochem 1999;36:3889.

67. Elmfors B, Tryding N. The diagnosis of ruptured fetal membranes by measurement of the diamine oxidase (DAO) activity in vaginal fluid. J Obstet Gynaecol Br Commonw 1974;81:3612.

68. Wiberg-Itzel E, Cnattingius S, Nordstrom L. Lactate determination in vaginal fluids: a new method in the diagnosis of prelabour rupture of membranes. Br J Obstet Gynecol 2005;112:7548.

69. Gurbuz A, Karateke A, Kabaca C. Vaginal fluid creatinine in prematurerupture of membranes. Int J Gynaecol Obstet 2004;85:2701.

70. Kafali H, Oksuzler. Vaginal fluid urea and creatinine in diagnosis of premature rupture of membranes. Arch Gynecol Obstet 2007;275:15760.

71. Lockwood CJ, Wein, R, Chien D, Ghidini A, Alvarez M, Berkowitz RL.Fetal membrane rupture is associated with the presence of insulin-likegrowth factor-binding protein-1 in vaginal secretions. Am J Obstet Gynecol1994;171:14650.

72. Rutanen EM, Karkkainen TH, Lehtovirta J, Uotila JT, Hinkula MK,Hartikainem AL. Evaluation of a rapid strip test for insulin-like growth

factor binding protein-1 in the diagnosis of ruptured fetal membranes.Clinic Chimica Acta 1996;253:91101.

73. Darj E, Lyrenas S. Insulin-like growth factor binding protein-1, a quick way to detect amniotic fluid. Acta Obstet Gynecol Scand 1998;77:2957.

74. Jeurgens-Borst AJCM, Bekkers RLM, Sporken JMJ, van den Berg PP.Use of insulin like growth factor binding protein-1 in the diagnosis of ruptured fetal membranes. Eur J Obstet Gynecol Reprod Biol2002;102:114.

75. Petrunin DD, Griaznova IM, Petrunina IuA, Tatarinov IuS.Immunochemical identification of organ specific human placentalalpha-microglubulin and its concentration in amniotic fluid [article inRussian]. Akush Ginekol (Mosk) 1977;1:645.

76. Cousins LM, Smok D, Lovett SM, Poeltler DM. AmniSure placental alpha

microglobulin-1 rapid immunoassay versus standard diagnostic methodsfor detection of rupture of membranes. Am J Perinatol 2005;22:14.

77. Lee SE, Park JS, Norwitz ER, Kim KW, Park HS, Jun JK. Measurementof placental alpha-microglobulin-1 in cervicovaginal discharge to diagnosisrupture of membranes. Obstet Gynecol 2007;109:63440.

78. Mulhair L, Carter J, Poston L, Seed P, Briley A. Prospective cohort study investigating the reliability of the AmnioSens method for detection of spontaneous rupture of membranes. BJOG 2009;116:3138.

79. Cowett RM, Hakanson DO, Kocon RW, Oh W. Untoward neonatal effectof intraamniotic administration of methylene blue. Obstet Gynecol1976;48(Suppl):74s-75s.

80. Plunkett GD. Neonatal complications [letter to the editor]. Obstet Gynecol1973;41:4767.



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