METHYLENE BLUE

Fetal Risk Summary

Methylene blue has been administered orally for its weak urinary germicide properties or injected into the amniotic fluid to diagnose premature rupture of the membranes. For oral dosing, nine exposures in the 1st trimester have been reported (1, p. 299). No congenital abnormalities were observed. For use anytime during pregnancy, 46 exposures were reported (1, pp. 434–35). Based on three malformed infants, a possible association with malformations (type not specified) was found.

Diagnostic intraamniotic injection of methylene blue has resulted in hemolytic anemia, hyperbilirubinemia, and methemoglobinemia in the newborn (2,3,4,5,6,7,8,9,10 and 11). Doses of the dye in most reports ranged from 10 to 70 mg, but in one case, 200 mg was injected into the amniotic cavity (7). Deep blue staining of the newborn may occur after injection of the agent into the amniotic fluid (7,8 and 9,11). One author suggested that smaller doses, such as 1.6 mg, would be adequate to confirm the presence of ruptured membranes without causing hemolysis (2).

In a 1989 report, 1 mL of a 1% solution (10 mg) was used to diagnose suspected membrane rupture in a woman with premature labor at 26 weeks of gestation (12). A 920-g girl was born 18 hours later who was stained a deep blue. The clinical assessment of hypoxia was impaired by the skin color, as was pulse oximetry. A transcutaneous oxygen monitor was eventually used to measure arterial blood gas so that ventilator therapy could be regulated. No evidence of hemolysis was observed. The bluish tinge persisted for more than 2 weeks in spite of frequent baths.

Inadvertent intrauterine injection in the 1st trimester has been reported (13). No adverse effects were reported in the full-term neonate.

Multiple ileal occlusions were found in seven newborns born to mothers with twin pregnancies, at three different medical centers, who had received diagnostic intraamniotic methylene blue into one of the amniotic sacs at 15–17 weeks' gestation (14). The doses in these cases ranged from 10 to 30 mg. Four of the infants required surgery for intestinal obstruction, but no information was given on the other three. The authors speculated that the mechanism of the adverse effect was related either to hemolysis or to acute intestinal hypoxia secondary to methylene blue–induced release of norepinephrine and subsequent vasoconstriction (14).

In an abstract published in 1992, data on jejunal and ileal atresia in twins were reported from Australia (15). Higher risks of atresia were found in twins, compared to singletons, and in twins delivered from older mothers. When undiluted 1% methylene blue was used in one group, one twin in nine of 40 (22.5%) twin pregnancies had atresia, compared to three cases among 53 (5.7%) in those exposed to a 0.25% solution.

A third report of the above complication appeared in 1992 (16). Intraamniotic methylene blue, 10–20 mg, was used in 86 of 89 consecutive twin pregnancies for prenatal diagnosis. No dye was used in three pregnancies for technical reasons. Jejunal atresia occurred in 17 (19%) of the pregnancies; in 15 of the affected cases, it was possible to determine that the affected fetus had been the one exposed to the dye. All of the infants required surgery to relieve the intestinal obstruction. A portion of this report also described 67 newborns who were treated for jejunal atresia, 20 of whom were one of a set of twins (16). Of the 20 newborns from twins, 18 had been exposed to methylene blue during 2nd-trimester amniocentesis. Because the incidence of jejunal atresia was much higher than expected and because the dye appears to cause the defect, the authors of the study (16) and an accompanying commentary (17) recommended avoidance of methylene blue for this purpose. The commentary also alluded to the vasoconstrictor properties of methylene blue as a possible mechanism (17).

A brief 1993 report described the use of methylene blue dye in women with twins who underwent amniocentesis in the Atlanta, Georgia, area between 1977 and 1991 (18). A total of 195 women were included, 4 (2%) of whom were administered methylene blue during the procedure. Of the eight fetuses, one had anencephaly (no association with the dye), but no cases of small intestinal atresia were observed.

A 1993 article reviewed the teratogenicity and newborn adverse effects resulting from intraamniotic injection of methylene blue (19). The most frequent adverse effects in newborns were hyperbilirubinemia, hemolytic anemia with or without Heinz body formation, blue staining of the skin, and occasionally methemoglobinemia and fetal death. Respiratory distress was also frequently observed but may have been related to other causes. The structural defects observed were jejunal-ileal atresias, but the mechanism of the bowel injury is unknown. Based on the pharmacologic properties of the dye, the most likely mechanism was thought to be vascular disruption caused by methylene blue–induced arterial constriction. However, methemoglobinemia- and hemolytic anemia–induced hypoxia causing a shunting of blood away from the intestine with resulting ischemia and atresia, or a direct toxic effect from the dye when swallowed with amniotic fluid were other possible mechanisms (19).

In summary, the intraamniotic injection of methylene blue to detect ruptured membranes should be discouraged. If indicated, other dyes, such as indigo carmine or Evans blue appear to be safer alternatives, although both have limited pregnancy data (see Indigo Carmine and Evans Blue) (19).

[*Risk Factor D if injected intraamniotically.]

Breast Feeding Summary

No data are available.

References

1. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
2. Plunkett GD. Neonatal complications. Obstet Gynecol 1973;41:476–7.
3. Cowett RM, Hakanson DO, Kocon RW, Oh W. Untoward neonatal effect of intraamniotic administration of methylene blue. Obstet Gynecol 1976;48:74S–5S.
4. Kirsch IR, Cohen HJ. Heinz body hemolytic anemia from the use of methylene blue in neonates. J Pediatr 1980;96:276–8.
5. Crooks J. Haemolytic jaundice in a neonate after intra-amniotic injection of methylene blue. Arch Dis Child 1982;57:872–3.
6. McEnerney JK. McEnerney LN. Unfavorable neonatal outcome after intraamniotic injection of methylene blue. Obstet Gynecol 1983;61:35S–6S.
7. Serota FT, Bernbaum JC, Schwartz E. The methylene-blue baby. Lancet 1979;2:1142–3.
8. Vincer MJ, Allen AC, Evans JR, Nwaesei C, Stinson DA. Methylene-blue-induced hemolytic anemia in a neonate. Can Med Assoc J 1987;136:503–4.
9. Spahr RC, Salsburey DJ, Krissberg A, Prin W. Intraamniotic injection of methylene blue leading to methemoglobinemia in one of twins. Int J Gynaecol Obstet 1980;17:477–8.
10. Poinsot J, Guillois B, Margis D, Carlhant D, Boog G, Alix D. Neonatal hemolytic anemia after intra-amniotic injection of methylene blue. Arch Fr Pediatr 1988;45:657–60.
11. Fish WH, Chazen EM. Toxic effects of methylene blue on the fetus. Am J Dis Child 1992;146:1412–3.
12. Troche BI. The methylene-blue baby. N Engl J Med 1989;320:1756–7.
13. Katz Z, Lancet M. Inadvertent intrauterine injection of methylene blue in early pregnancy. N Engl J Med 1981;304:1427.
14. Nicolini U, Monni G. Intestinal obstruction in babies exposed in utero to methylene blue. Lancet 1990;336:1258–9.
15. Lancaster PAL, Pedisich EL, Fisher CC, Robertson RD. Intra-amniotic methylene blue and intestinal atresia in twins (abstract). J Perinat Med 1992;20 (Suppl 1):262.
16. Van Der Pol JG, Wolf H, Boer K, Treffers PE, Leschot NJ, Hey HA, Vos A. Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins. Br J Obstet Gynaecol 1992;99:141–3.
17. McFadyen I. The dangers of intra-amniotic methylene blue. Br J Obstet Gynaecol 1992;99:89–90.
18. Cragan JD, Martin ML, Khoury MJ, Fernhoff PM. Dye use during amniocentesis and birth defects. Lancet 1993;341:1352.
19. Cragan JD. Teratogen update: methylene blue. Teratology 1999;60:42–48.