Naphthalene poisoning due to exposure to mothballs is a common cause of toxicity in children worldwide. Naphthalene toxicity is known to cause hemolytic anemia, methemoglobinemia, and hepatic and renal injury. Neonates are more susceptible to the effects of oxidative stress from naphthalene because of their low glutathione stores and immaturity of hepatic enzymes. However, there are no reported cases of chronic fetal exposure to naphthalene during pregnancy. We report a novel case of chronic fetal exposure to naphthalene-containing mothballs that occurred from the second trimester through the third trimester of pregnancy. Our patient presented with hyperbilirubinemia, requiring exchange transfusion, severe hemolytic anemia, pulmonary hypertension, respiratory failure, and renal failure and progressed to develop “bronze baby” syndrome. Pregnant mothers should be diligently screened for such exposures and if found should receive psychiatric evaluation and counseling to prevent such devastating effects in neonates.

The use of mothballs is on the decline in the Unites States, but accidental toxicity, and to a lesser extent intentional exposure, persists. There were 1265 cases of naphthalene exposure noted on the annual report from the National Poison Data System (NPDS),1 and exposure has been persistent over the past few years (1256 and 1273 cases in 2012 and 2013, respectively).2,3 Mothballs are composed of naphthalene, paradichlorobenzene, or camphor.4 Toxicity from naphthalene is the most dangerous and is known to present with hemolytic anemia, methemoglobinemia, and hepatic and renal injury. Case reports and in vitro studies support that naphthalene maybe transmitted via the placenta.5,6 However, there are no documented effects of chronic fetal exposure to naphthalene secondary to maternal ingestion of mothballs.

We report a novel case of chronic fetal exposure to naphthalene-containing mothballs that occurred from the second trimester through the third trimester of pregnancy. Soon after delivery, the infant presented with hyperbilirubinemia, requiring an exchange transfusion, severe hemolytic anemia, pulmonary hypertension, respiratory failure, and renal failure and progressed to develop the “bronze baby” syndrome. The Institutional Review Board at Drexel University College of Medicine approved this case report (institutional review board identification: 1808006513). Written consent to use patient’s medical information was obtained from the patient’s family.

We present the case of a late preterm male infant, born at 34 + 2/7 weeks’ gestational age to a 38-year-old G7P3125 Hispanic woman with adequate prenatal care at an urban medical care facility. The mother provided a past history of deliberate mothball sniffing in previous pregnancies with relapse in the early second trimester of this pregnancy. This quickly escalated to licking the mothballs and eventually frank ingestion of 1 mothball every day. A sample of the mothballs that the mother used is illustrated in Fig 1. The mother underwent a cesarean delivery for nonreassuring fetal heart rate, and the infant required positive-pressure ventilation in the delivery room. Apgar scores were 6 at 1 minute and 8 at 5 minutes of life. The infant was transferred to the delivery hospital NICU for hypoxic respiratory failure and treated with intubation, administration of surfactant, mechanical ventilation, and finally a high-frequency oscillator with inhaled nitric oxide (NO) therapy because of severe pulmonary hypertension. Laboratory work and echocardiography revealed mixed acidosis, hyperbilirubinemia of 14.9 mg/dL at 12 hours of life, and pulmonary hypertension, necessitating a transfer to our level IV NICU equipped with the means for extracorporeal membrane oxygenation.

FIGURE 1

A sample of mothballs ingested by the mother during pregnancy.

FIGURE 1

A sample of mothballs ingested by the mother during pregnancy.

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On admission, the infant required escalation of respiratory support, inotrope therapy, and volume resuscitation with crystalloid and colloid. Repeat echocardiogram revealed suprasystemic right ventricular pressures with right-to-left shunting across the patent ductus arteriosus and bidirectional shunting across the patent foramen ovale. The infant initially required a maximum dosing of dopamine and dobutamine, and, eventually, vasopressin was added. After the introduction of vasopressin, dobutamine was slowly weaned off and dopamine transitioned to epinephrine therapy. All inotropes were slowly weaned off over the next 10 days. Milrinone was introduced for pulmonary hypertension and transitioned to sildenafil by day of life (DOL) 13.

Despite intensive phototherapy, total bilirubin levels increased within 6 hours of admission to 19.9 mg/dL at 18 hours of life with a reticulocyte count of 13.6%, indicating significant hemolysis. He received a double-volume exchange transfusion soon after, followed by intravenous immunoglobulin infusion twice over the next 24 hours. His absolute reticulocyte count remained elevated to a maximum of 15.2% by DOL 6, followed by a progressive decline over the next 10 days. On manual differential, the infant demonstrated nucleated red blood cells (RBCs) as high as 388 cells per mm3, which resolved over the first 7 DOLs (Fig 2). Our patient also had thrombocytopenia (23 000 on DOL 1), which progressively improved to >100 000 after the first week of life. Elevated transaminases (aspartate aminotransferase 450 U/L and alanine aminotransferase 62 U/L) as well as direct hyperbilirubinemia of 2.81 mg/dL were also noted on admission. The infant subsequently developed bronze baby syndrome with elevated direct bilirubin (peak 10.88 mg/dL), indirect bilirubin (peak 22.74 ng/dL), and hepatocellular injury (Fig 3). Elaborate workup failed to identify a blood group incompatibility or obvious etiology for severe hemolysis. The hemolysis and liver injury were attributed to chronic exposure to naphthalene. The poison control center was called for guidance, and the toxicology department was consulted. The recommended treatment of naphthalene toxicity was a double-volume exchange transfusion, which the infant had already undergone. On their recommendation, we also obtained levels of naphthalene and its metabolites; however, the results were negative, which was expected because the infant had already undergone an exchange transfusion. The full sepsis workup result was negative; however, the infant was treated for 10 days with broad-spectrum antibiotics for presumed sepsis. Liver ultrasound, renal ultrasound, renal function tests, and urinalysis were within the normal limits for his gestation. Surprisingly, our patient did not have evidence of methemoglobinemia, which has also been reported in the setting of subacute naphthalene exposure for a week.5 An eye examination was also obtained and did not reveal any cataracts or retinal hemorrhages. Oxygen support was weaned slowly, and the infant was eventually in room air by DOL 30. Brain MRI done at 6 weeks of life revealed a normal noncontrast study of the brain. He required surgery for a gastrostomy tube placement because of feeding difficulties. The infant slowly recovered during his prolonged NICU stay and was discharged from the hospital at 2.5 months of age. On follow-up, the patient is now 8 months old, tolerating oral feeds with normal growth, and gaining developmental milestones while on supportive therapies.

FIGURE 2

The trend of total bilirubin, direct bilirubin, nucleated RBC, and reticulocytes over the first 8 days. IVIg, intravenous immunoglobulin.

FIGURE 2

The trend of total bilirubin, direct bilirubin, nucleated RBC, and reticulocytes over the first 8 days. IVIg, intravenous immunoglobulin.

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FIGURE 3

Bronze baby syndrome due to severe direct hyperbilirubinemia after intensive phototherapy.

FIGURE 3

Bronze baby syndrome due to severe direct hyperbilirubinemia after intensive phototherapy.

Close modal

Commercially available mothballs can contain naphthalene, paradichlorobenzene, or camphor as their active ingredient. In the United States, paradichlorobenzene has largely replaced both camphor and naphthalene because of its decreased toxicity.7 Naphthalene mothballs can contain up to 99.9% of naphthalene and are available worldwide for use as an insect repellent. In 2016, the National Poison Data System reported 1260 cases of exposure to naphthalene-containing mothballs. Almost 65% of cases were noted in children <5 years of age, 19% required treatment in a health care facility, and 3 of the patients had a major adverse medical outcome. Only 2.9% of these reported cases were intentional abuse.1 Numerous case reports and case reviews have been published describing serious morbidity and mortality resulting from accidental and intentional ingestion of mothballs.8,10 However, there is no documented description of the effects of chronic maternal naphthalene ingestion during pregnancy on the fetus. In a case series from 1951, 21 cases of naphthalene exposure during the perinatal period were described. These infants presented with anemia, hyperbilirubinemia, and reticulocytosis, with 12 of the 21 infants requiring exchange transfusion.6 In a more recent case report, authors described accidental inhalational exposure to naphthalene 1 week before delivery in a 15-year-old pregnant woman with resultant methemoglobinemia and hemolysis in the mother and child. The infant presented with fetal distress and cyanosis, requiring an exchange transfusion for treatment.5 

Naphthalene is a polycyclic aromatic hydrocarbon, which is metabolized by the liver. It is oxidized to α-naphthol and other metabolites, which induces oxidative stress. This results in oxidation of the iron in the globulin chain, from ferrous to ferric state, leading to the formation of methemoglobin. When oxidized hemoglobin becomes denatured, the heme groups and globin chains dissociate and precipitate in the RBCs, which leads to the formation of Heinz bodies and increased susceptibility of the RBC to hemolysis. Hemolysis leads to hyperbilirubinemia, and reticulocytosis occurs to restore a normal hemoglobin concentration. The high nucleated RBCs seen in our patient also support the presence of hemolytic anemia leading to increased erythropoiesis.11 The resultant anemia takes 3 to 5 days to peak with acute exposure.7 Individuals who have glucose-6-phosphate deficiency do not produce as much nicotinamide adenine dinucleotide phosphate. Such individuals have lower levels of glutathione (a necessary antioxidant), and thus are at higher risk for severe hemolysis and methemoglobinemia after exposure to naphthalene.8 Neonates are also more susceptible to the effects of oxidative stress from naphthalene because they have thinner skin and decreased stores of reduced glutathione.8 Immaturity of hepatic enzymes results in decreased conjugation and excretion of naphthalene metabolites. Although intravascular hemolysis is the most common feature described, naphthalene toxicity can also be associated with anemia, leukocytosis, fever, hemoglobinuria, jaundice, renal insufficiency, and sometimes, disturbances in liver function.12 The infant in our case had severe pulmonary hypertension and hyperbilirubinemia possibly secondary to severe hemolysis and chronic anemia. Of note, his newborn screen result was negative for mutations associated with glucose-6-phosphatase dehydrogenase deficiency. Naphthalene toxicity does not appear to be solely based on the amount of naphthalene exposure; even 1 mothball has been reported to cause toxicity in an infant.7 Surprisingly, the mother in our case did not complain of any symptoms; however, our patient suffered from the effects of toxicity.

There is a vast amount of data in the literature that supports causation of pulmonary hypertension in patients with chronic hemolysis. Breakdown of RBCs also leads to the release of asymmetric dimethylarginine. Asymmetric dimethylarginine inhibits endothelial NO synthase–mediated production of NO from L-arginine.13 Free hemoglobin released from the hemolyzing RBC reacts with NO to form inactive nitrate and methemoglobin, leading to endothelial dysfunction.14 This can further cause vasoconstriction and elevated pulmonary pressures.13 Hemolysis also results in the release of arginase-1, which alters arginine metabolism and decreases the bioavailability of NO.15 These changes lead to pulmonary vascular remodeling and increased pulmonary vascular resistance. In our case, we suspect chronic hemolysis secondary to naphthalene exposure resulted in prolonged refractory pulmonary hypertension.

Over the course of the first week of his life, our patient also developed bronze baby syndrome. Bronze baby syndrome is a rare complication of phototherapy and is only noted in infants with elevated levels of both conjugated and unconjugated bilirubin associated with hepatocellular injury. The exact etiology of bronzing is unknown, but the leading theory is that this occurs because of photodestruction of porphyrins that are released during hemolysis.16 

In our patient, maternal ingestion of naphthalene-containing mothballs during her third month of pregnancy resulted in hemolytic anemia, reticulocytosis, leukocytosis, and indirect hyperbilirubinemia in the infant. He required exchange transfusion for the treatment of hyperbilirubinemia and naphthalene toxicity. He also suffered severe pulmonary hypertension presumed to be secondary to chronic hemolytic anemia. He was successfully treated with several inotropes and eventually discharged on sildenafil. A limitation of our case report is that we did not obtain naphthalene levels before the exchange transfusion. Although having a measurement of the naphthalene levels in our patient would have definitively confirmed the patient’s diagnosis, the circumstantial evidence is extremely strong in favor of the diagnosis.

Small amounts of naphthalene ingested during pregnancy can cause adverse effects on the fetus because naphthalene can cross the placenta. Pregnant mothers with such history should get psychiatric evaluation and counseling to help prevent chronic naphthalene abuse. Even small amounts of naphthalene can cause intravascular hemolysis in neonates, which can lead to severe hyperbilirubinemia as well as liver injury, as evidenced in our case scenario. Naphthalene toxicity in severely ill children should be treated with exchange transfusion in addition to supportive management.

Dr Sahni conceptualized and designed the case report, drafted the initial manuscript, and reviewed and revised the manuscript for important intellectual content; Dr Vibert designed the case report and reviewed and revised the manuscript for important intellectual content; Dr Bhandari analyzed and interpreted the data and reviewed and revised the manuscript for important intellectual content; Dr Menkiti conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

DOL

day of life

NO

nitric oxide

RBC

red blood cell

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.