Making the Diagnosis with Dr. Sina Haeri

Learning Objectives: Upon completion of this activity, participants should be better able to

• Discuss the important components of PROM evaluation with limitations of each element
• Formulate an evidence-based and practical approach to PROM evaluation in practice

The Case

• 24 year old G1P0, at 26w2d presents to triage for evaluation for prelabor rupture of membranes (PROM)
• Entered prenatal care at 11w5d gestation and has otherwise had an uncomplicated course

Chief Complaint

• Post-coital large gush of fluid from the vagina 3 hours prior to arrival to hospital
• Reports some intermittent leaking

Synopsis

Prelabor rupture of membranes (PROM) refers to membrane rupture prior to onset of labor, and its management remains one of the most controversial issues in obstetrics. Preterm PROM (PPROM) prior to 37 week gestation is associated with over 1/3 of all preterm births, and poses a management dilemma when occurring prior to 22-23 weeks gestation. False positive or negative PROM diagnosis may lead to unnecessary interventions or less than ideal monitoring, respectively, which can lead to adverse perinatal outcomes. Below are key points to consider to evaluate and help make the diagnosis of PROM.

History

Presentation

• Patient will report leaking of fluid
  • Main differential is usually that of urine leakage, associated with full bladder
  • Other considerations include copious vaginal discharge

Questions are Guided to Sort Out the Differential Diagnosis

• Intermittent vs continuous leakage
  • Urine leakage usually associated with coughing or overextended bladder and usually not intermittent or continuous flow
• Odor
  • Urine or infection will have a smell | amniotic fluid will not
• Color
  • Urine vs amniotic fluid is usually not easy to distinguish based on color
  • Darker or yellow color more suggestive of vaginal discharge especially if more viscous
  • Patients will usually report if they see bleeding, but still important to ask and document
• Timing of event
  • May be associated with trauma, although usually PROM is a spontaneous event
• Pain
  • May be associated with UTI or chorioamnionitis (infected amniotic fluid)

Physical Examination

Step 1: Sterile Speculum Exam

• If the following findings are observed, patient has PROM and manage accordingly
  • Amniotic fluid leaking through the cervix or
  • Pooling of amniotic fluid in the posterior vaginal vault

Step 2: Ultrasound Assessment of Amniotic Fluid Volume (AFV)

• Normal amniotic fluid volume values
  • Deepest vertical pocket >2 cm and/or
  • Amniotic fluid index >5 cm
• Next steps based on AVF
  • Normal AFV: Unlikely to have PROM
  • Oligohydramnios: Proceed to step 3

Step 3: Biochemical Tests

PAMG-1 (AmniSure®): placental alpha microglobulin-1 protein

• Rapid, noninstrumental, point of care immunochromatographic assay
• PAMG-1 is present in the blood, amniotic fluid and cervico-vaginal discharge of pregnant women
• Gestational age range: 11-42 weeks
• Sensitivity 98.9% | Specificity 98.1%

IGFBP-1 (Actim® Prom): Insulin like growth factor binding protein 1

• Immunoassay rapid test
• IGFBP-1 is present in the amniotic fluid of pregnant women
• Gestational age range: ≥29 weeks
• Sensitivity of 90.1% | Specificity of 91.0%

PP12/AFP (ROM Plus®): IGFBP-1 (also known as PP12 [placental protein 12]) and AFP (alpha-fetoprotein)

• Rapid immunochromatographic test
• Maternal and fetal AFP levels can be elevated for other reasons such as NTDs
  • Test has not been evaluated for potential interference in these clinical scenarios
• Gestational age range: 23-37 weeks
• Sensitivity 99% | Specificity 75%

Comparative Studies

• Ramsauer et al (2013): PAMG-1 had superior accuracy over IGFBP-1 when PROM diagnosis was equivocal
  • PAMG-1: Sensitivity 96.0% | Specificity 98.9%
  • IGFBP-1: Sensitivity 73.9% | Specificity 77.8%
• Liang et al (2014): PAMG-1 demonstrated better performance characteristics compared to IGFBP-1 and Nitrazine
  • PAMG-1: Sensitivity 100% | Specificity 100% | PPV 100% | NPV 100%
  • IGFBP-1: Sensitivity 93.33% | Specificity 98.89% | PPV 96.55% |97.80%
  • Nitrazine: Sensitivity 93.33% | Specificity 94.44% | PPV 84.85% |97.70%

Note: Biochemical tests are screening tests | Always place test results in the context of the clinical scenario, including patient history and findings | The pregnancy should never be managed based on biochemical testing alone

Additional Considerations

Other Clinical Tests

Nitrazine Paper

• Standard pH values
  • Amniotic fluid pH: 7.1 to 7.3
  • Normal Vaginal pH: 4.5 to 6.0
  • Urine pH: <6
• Sensitivity: 93% (at 1 hour of PROM) to 76% (at ≥24 hours of PROM)
  • Potential FN causes: Dilution from other vaginal fluids
• specificity: 92%
  • Potential FP causes: Other alkaline fluids such as blood, seminal fluid, soap, or infections (e.g., BV)

Arborization (ferning)

• Different patterns observed on glass slide once fluid obtained from posterior vaginal fornix is allowed to dry (minimum 10 minutes)
  • Delicate ferning pattern: Amniotic fluid
  • Thick, wide arborization pattern: Dried cervical mucus
• In women who are in labor
  • Sensitivity 98.0% | Specificity 88.2%
• In women who are not in labor
  • Sensitivity 51.4% | Specificity 70.8%
• False positive: Well-estrogenized cervical mucus
• False negative: Inadequate amniotic fluid | Contamination with vaginal discharge or blood

Note: ACOG includes nitrazine and ferning as diagnostic screening tests | UK NICE guideline and Royal College of Obstetricians and Gynaecologists (RCOG) recommend against the use of nitrazine and support the option of biochemical testing | The International Federation of Gynecology and Obstetrics (FIGO) likewise states that “biochemical markers are better than traditional methods … the rapid strip test based on PAMG-1 seems to be a more sensitive bedside test than other tests”

Invasive Dye Tests

• Indication: Definitive approach when PROM diagnosis remains unclear
• Indigo carmine has been traditional dye of choice but limited availability in the US
  • Other suggested options include sodium fluorescein and phenol red (see below)
• Procedure
  • Instillation into the amniotic sac: Difficult when AFV is low
  • 1 mL indigo carmine in 9 mL of sterile saline injected transabdominally
  • Tampon in vagina for 20 minutes to check for leak
• Alternative to indigo carmine
  • Sodium Fluorescein: 1-4 mL 5% (50-200 mg) | Followed by speculum exam of cervix at 15 and 45 minutes post injection using long-wave UV light to look for yellow-green fluorescent fluid leaking from cervix
  • Phenol-sulfonphthalein (phenol red): Sufficient dose is 1-3 mL (currently not available in the US for clinical medical use)
• Note: DO NOT USE Indocyanine Green, Phenazopyridine Hydrochloride, Evans Blue, or Methylene Blue

Early Term PROM

• Leakage reported at 37w0d – 38w6d
  • Perform thorough PROM evaluation leakage
  • Avoid unnecessary early term deliveries

The Wrap Up

• Important clues in this patient’s history include
  • Gush of fluid: Suggests true PROM, but not enough to make the diagnosis
• Physical exam is key
  • Sterile speculum with direct visualization
  • If fluid leaking through cervix or pooling of amniotic fluid in the posterior vaginal vault – PROM diagnosis
• If the above diagnostic requirements are not met
  • Consider biochemical protein marker testing of vaginal fluid to guide further management
  • ACOG does include pH and ferning, but they are associated with significant false positive and false negative rates, depending on the clinical scenario
  • Ultrasound may be of help in determining the correct diagnosis but must, like biochemical testing, be placed in clinical context

Learn More – Primary Sources

ACOG Practice Bulletin No. 217: Prelabor Rupture of Membranes

Nice Guideline (25): Preterm labour and birth

Acid-base determinations in human amniotic fluid throughout pregnancy

Detection of premature rupture of the membranes

AmniSure placental alpha microglobulin-1 rapid immunoassay versus standard diagnostic methods for detection of rupture of membranes

Measurement of placental alpha-microglobulin-1 in cervicovaginal discharge to diagnose rupture of membranes

Ramsauer et al (2013)  The diagnosis of rupture of fetal membranes (ROM): a meta-analysis

Liang et al (2014) Comparative study of placental α-microglobulin-1, insulin-like growth factor binding protein-1 and nitrazine test to diagnose premature rupture of membranes: a randomized controlled trial

Comparison of rapid immunoassays for rupture of fetal membranes

Thomasino et al (2013) Diagnosing rupture of membranes using combination monoclonal/polyclonal immunologic protein detection

FIGO: Good clinical practice advice – Prediction of preterm labor and preterm premature rupture of membranes

RCOG: Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation (Green-top Guideline No. 73)

de Hann et al (1994) Value of the fern test to confirm or reject the diagnosis of ruptured membranes is modest in nonlaboring women presenting with nonspecific vaginal fluid loss

Gorodeski et al (1982) Reevaluation of the pH, ferning and nile blue sulphate staining methods in pregnant women with premature rupture of the fetal membranes

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The views stated within are those of OBGConnect and not those of QIAGEN.