SUMMARY:

Indigo carmine was the dye of choice to definitively diagnose premature rupture of membranes (PROM) for decades. It was also helpful when performing amniocentesis in multifetal gestation to help distinguish the various sacs.  However, availability has been an issue and in response, Ireland et al. (Obstetrics and Gynecology 2017) have written an expert commentary to review alternatives.  The authors conclude that sodium fluorescein and phenol-sulfonphthalein may be the best options (although the latter is not available currently for medical use in the US).

Sodium Fluorescein

Clinical use possible: Recommendation ‘B’ – based on limited or inconsistent scientific evidence

• Yellow-green fluorescence in alkaline fluids using UV light source
• Alternative dye for cystoscopy
• Dose (amnio instillation)
  • 2-5 mL 10% (200 – 500mg)
  • 1-4 ml 5% (50-200 mg) has been suggested as sufficient
• While there are potential IV side effects such as yellowing of sclera/palms, nausea, emesis and allergic reaction, no adverse events have been reported with amnio instillation
• Original technique describes speculum exam of cervix at 15 and 45 minutes post injection using a long-wave ultraviolet light
  • Yellow-green fluorescent fluid leaking from cervix confirms the diagnosis
  • Fluorescence will rapidly appear in urine and confusion may be resolved with either visualization of cervical leak or tampon

Phenol-sulfonphthalein

Clinical use possible: Recommendation ‘B’ – based on limited or inconsistent scientific evidence

• pH indicator dye, also known as phenol red
• Used for renal blood flow studies
• Dose (amnio instillation)
  • 1 – 3mL
  • Other studies have confirmed ability of this dye to accurately identify PROM
• No side effects reported
• Not currently available in the US for medical use beyond clinical laboratory reagent

Indocyanine Green (emits near-infrared fluorescence when exposed to light)

Clinical use possible but currently experimental: Recommendation ‘C’ – based on consensus or expert opinion

• Used in the study of cardiac and liver function and ophthalmology
• No studies on amnio instillation reported
• Rare anaphylaxis during ophthalmologic studies
• Further studies required

Phenazopyridine Hydrochloride

Clinical use not recommended: Recommendation ‘D’ – recommendation against the service

• Also known as Pyridium
• Oral azo dye, used as a UTI analgesic that stains urine orange/red
• Dose (amnio instillation)
  • 400 mg orally
• Crosses placenta with high false positive rate

Evans Blue

Clinical use not recommended: Recommendation ‘D’ – recommendation against the service

• Azo dye used for plasma volume studies
• Dose (amnio instillation)
  • 5 mL
• Amnio instillation resulted in neonatal staining at delivery, persistence in newborn blood and possible muscular/subcutaneous tissue atrophy

Methylene Blue

Clinical use contraindicated: Recommendation ‘D’ – recommendation against the service

• Cationic thiazine dye resulting in blue color when oxidized
• Indigo carmine became dye of choice due to known neonatal side effects of intra-amniotic methylene blue which include
  • Hemolysis
  • Hyperbilirubinemia
  • Methemoglobinemia
  • Intestinal obstruction (possibly due to fetal methemoglobinemia, hypoxemia and consequent reduced blood flow to intestinal tract)

Learn More – Primary Sources:

Intra-amniotic Dye Alternatives for the Diagnosis of Preterm Prelabor Rupture of Membranes

A technic for the detection of rupture of the membranes. A review and preliminary report (Sodium Fluorescein)

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Maternal Fetal Medicine Specialist Locator-SMFM

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