Perinatal/Neonatal Case Presentation Perinatal Toxicity of Domestic Naphthalene Exposure

Eleanor J. Molloy, MB, PhD together with cyanosis, prompted transfer of the infant to the Benedict A. Doctor, MD intensive care nursery. Michael D. Reed, PharmD He was symmetrical for gestational age with normal vital signs. Michele C. Walsh, MD The infant was alert with no respiratory distress, a normal chest X- ray and arterial blood gas. However, his appearance was pale and cyanotic with a pulse-oximetry reading of 84% saturation, despite supplemental blow-by 100% oxygen. His hematocrit was 30% and Naphthalene-containing mothballs can cause methemoglobinemia on reticulocyte count 7.9%. There were 136 nucleated red blood cells inhalation. We describe a mother with hemolytic anemia and (RBCs) per 100 white blood cells and the blood smear showed methemoglobinemia associated with elevated levels of naphthalene evidence of acute hemolysis but no Heinz bodies. The baby’s blood following exposure to mothballs. Her newborn infant had identical type was group O, Rh-positive with negative antibody screen and a symptoms requiring mechanical ventilation and an exchange transfusion total bilirubin of 6 mg/dl (102 mmol/l) at birth. Urinalysis revealed for resolution. moderate blood/hemoglobin, proteinuria, with rare RBCs, and no Journal of Perinatology (2004) 24, 792–793. doi:10.1038/sj.jp.7211195 myoglobin. Methemoglobin levels were 11.3 (normal <1%) and 1.3% in the neonatal and maternal samples, respectively. At 7 hours of age, increasing tachypnea and oxygen requirement necessitated intubation and mechanical ventilation with 100% oxygen. He was extubated to room air at 40 hours of age INTRODUCTION by which time his methemoglobin level had decreased to 4.8%. Most neonates admitted to the intensive care unit with cyanosis However, his total bilirubin continued to rise, despite the initiation unresponsive to supplemental oxygen have either cardiovascular or of double phototherapy with super-blue light bulbs (General parenchymal lung disease. A minority will have Electric; F20 T12/BB) at birth. It reached 20 mg/dl (342 mmol/l) methemoglobinemia, readily detectable by the persistent chocolate- with an end-tidal carbon monoxide (ETCOc, Natus Inc.; 9,10) brown appearance of the blood when exposed to air. We present an measured 8.8 ppm (normal <2 ppm) at 50 hours of age, infant born with methemoglobinemia due to antepartum maternal indicating brisk hemolysis. A double-volume exchange transfusion naphthalene inhalation from mothballs. was performed, which lowered his bilirubin to 10 mg/dl (171 mmol/l) although there was a subsequent rebound after exchange to a maximum level of 14 mg/dl (239 mmol/l). He was discharged home in healthy condition at 16 days of age. CASE REPORT We suspected a transplacentally acquired toxin because both the A 15-year-old primigravid African-American woman, blood group mother and the infant had a new onset hemolytic anemia. O, Rh-positive with negative antibody screen, presented with Following persistent questioning of the family, it transpired that an preterm labor at 36 weeks gestation. On admission, she was entire box of moth ﬂakes (100% reﬁned naphthalene) had spilt diagnosed with a hemolytic anemia of unknown etiology and had into a heating vent approximately 1 week prior to delivery. The an unremarkable past medical history. Following oxytocin resultant fumes had necessitated the windows remaining open augmentation for fetal distress she vaginally delivered a hypotonic, despite subzero external environmental temperatures. Naphthalene cyanotic and apneic male infant. He received bag-mask ventilation was not detected in the infant’s blood after exchange transfusion, with spontaneous breathing but persistent cyanosis giving Apgars of and no urine samples were available prior to this procedure. 2 at 1 minute and 6 at 5 minutes. The passage of dark urine, However, a urinary metabolite of naphthalene was found to be present in the mother’s urine sample from admission. Both mother and infant were well 1 year later.

Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. DISCUSSION Address correspondence and reprint requests to Eleanor Molloy, MB, PhD, Division of Neonatology, Rainbow Babies and Children’s Hospital, 11100 Euclid Ave., Cleveland, OH 44106, Methemoglobinemia (methemoglobin concentration >1%) is an 1 USA. important differential diagnosis in all cyanotic patients. (Table 1)

temporal linkage and not proven by assay. Although the parent Table 1 Causes of Methemoglobinemia compound is devoid of hemolytic properties, its oxidative Congenital metabolite, alpha-naphthol, possesses potent hemolytic activity Homozygous deficiency of cytochrome b5 reductase resulting in hemoglobinuria and methemoglobinemia. A single Hemoglobin M previous report of suspected transplacental naphthalene poisoning Acquired exists in the literature5 and a case series of 21 newborns was also Drug exposures described who developed severe hemolysis after inhalation exposure Oral or intravenous nitroglycerin to naphthalene-containing mothballs.6 Naphthalene levels were Topical benzocaine (teething gel, topical ointments, hemorrhoidal cream) Topical or injected local anesthetics not available in this era. Following these reports, most Overdose of phenazopyridine manufacturers have substituted the chemical, Overdose of dapsone paradichlorobenzene, which is less toxic, for naphthalene as the Naphthalene inhalation active compound in most mothball and diaper pail deodorizer Toxic exposures products. Nitrates in well water The treatment of methemoglobin due to a toxic exposure is Recreational inhalation of nitrites (amylnitrite) generally supportive by correcting anemia, exchange transfusion in Aniline dyes (print marks on diapers, leather dyes in new shoes) cases of severe poisoning and removal of the toxin.1 The use of Adapted from: Curry SC, Carlton MW. Hematologic consequences of poisoning. methylene blue, a soluble guanylate cyclase inhibitor, should be In: LM Haddad, MW Shannon, JF Winchester, editors. ‘‘Clinical Management of avoided in infants, as it can cause methemoglobinemia and Poisoning and Drug Overdose’’. 3rd Ed, Philadelphia, PA: WB Saunders; 1998. hemolytic anemia.1 This case is the first documenting exposure by drug assay rather Methemoglobin is formed by the oxidation of ferrous (Fe2 þ ) than history alone. We speculate that the enormous surface area of hemoglobin to ferric (Fe3 þ ) hemoglobin and cannot bind oxygen. the moth flakes combined with heat, led to a massive inhalation It produces marked cyanosis even at concentrations that are not exposure of naphthalene, as evident by ongoing hemolysis and life threatening. Additionally, due to the spectrophotometric presence of the metabolite in the infant’s mother 1 week after the absorbance properties of methemoglobin, readings on pulse- initial exposure. Methemoglobinemia causing cyanosis and 2 oximetry trend toward 85%. However, measurement of PO2 is not respiratory failure is unusual in the perinatal period and maternal affected by the presence of methemoglobin. Therefore, a pulse- poisoning should be considered. oximeter reading that is inconsistent with oxygen saturation calculated using the PO2 measurement is suggestive of methemoglobinemia. This infant’s ventilation was managed using References trends in both PO2 and pulse oximetry while recognizing the 1. Curry S. Methemoglobinemia. Ann Emerg Med 1982;11:214–21. disparity between them. A major potential cause of 2. Delwood L, O’Flaherty D, Pregean EJ, Giesecke AH. Methemoglobinemia and methemoglobinemia among neonates is nitric oxide its effect on pulse oximetry. Crit Care Med 1991;19:988. administration for treatment of hypoxic respiratory failure.3 Infants 3. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full- are more sensitive than adults to methemoglobin-producing agents term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997;336:597–604. due to lower levels of NADH-dependent methemoglobin reductase 4 4. Kravitz W, Elegant LD, Kaiser E, Kagan BM. Methemoglobin values in activity, which may be more pronounced in preterm infants. premature and mature infants and children. Am J Dis Child 1956;91:1. Naphthalene is absorbed following oral, dermal, and inhalation 5. Anziulewicz JA, Dick HJ, Chiarulli EE. Transplacental naphthalene poisoning. exposure and its association with hemolytic anemia is well Am J Obstet Gynecol 1959;78:519–21. described in most textbooks. However, the association of 6. Valaes T, Psyros AD, Phaedron F. Acute hemolysis due to naphthalene methemoglobinemia with naphthalene exposure is based on inhalation. J Pediatr 1963;63:904–15.

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