A rare case of methemoglobinemia in a preterm newborn with unclear etiology

1 Introduction

Methemoglobinemia is a rare blood disorder that leads to functional anemia, tissue hypoxia and cyanosis [1]. It can be congenital or acquired with different genetic mutations and drugs identified as possible causes. After ruling out respiratory, cardiac, noxious, and infectious causes, congenital methemoglobinemia should be investigated in the differential diagnosis of all babies with central cyanosis [2].

2 Case report

A preterm female neonate with a gestational age of 31 weeks and 1 day was admitted to the Neonatal Intensive Care Unit (NICU) with very low birth weight (1.45 kg) and respiratory distress. The infant was delivered via emergency cesarean section due to severe preeclampsia. The mother had a positive COVID-19 test using nasopharyngeal swap and PCR-based assays two weeks prior to delivery, and there was a prenatal diagnosis of oligohydramnios and fetal cardiomegaly with suspicion of heart failure, for which the mother was started on digoxin for three weeks.

At birth, physical examination was normal except for tachypnea, and no dysmorphic features were appreciated. The baby was started on bubble CPAP initially and was weaned off to room air within 24 hours. CXR findings were consistent with transient tachypnea of the newborn (TTN) diagnosis and cardiac echo did not show any structural or functional heart abnormality. COVID-19 PCR test was done for the baby at 24 and 48 hours of age and both tests were negative.

On day ten of life, the baby developed desaturation down to 80% with no other signs of respiratory distress. This was managed using nasal cannula and gradually increasing the flow to keep saturation above 94%, a flow of 2 LPM was needed. However, over the next two days, she had progressive hypoxemia and cyanosis requiring upgrading support to CPAP with an increasing oxygen requirement, then due to persistent desaturation, she was intubated and started on mechanical ventilation. CXRs showed clear lungs and capillary blood gas result was: PH 7.34, PaCO2 26, HCO3 17, BE –5. The baby continued to require a higher oxygen percentage while intubated and even with 100% FiO₂, her saturation remained between 84–89%. She had elevated C- reactive protein (CRP) level of 47 mg/L, cultures were taken, and Vancomycin and Meropenem were started to treat possible late onset neonatal sepsis.

The newborn’s skin was bluish-gray, and her blood was dark brown (chocolate-like), which raised the suspicion of methemoglobinemia as a possible cause of her illness. Venous blood gas analysis was done which showed a Met-Hb percentage of 29.6%. One dose of 1 mg/kg methylene blue was given intravenously over 30 minutes, which resulted in significant improvement of saturation within one hour, and the baby was extubated to 5 LPM High flow nasal cannula with 21% FiO2. Subsequent measurement of Met-Hb percentage in venous blood gas was 2.5%. Blood and urine cultures showed no growth and CRP became negative (0.2 mg/L). Hence, antibiotics were discontinued after 5 days.

After a week the neonate started to have desaturation again, Met-Hb level was measured in venous blood gas and was 23%, a second dose of methylene blue was administered intravenously, then she was started on daily methylene blue 1.5 mg/kg and ascorbic acid 5 mg/kg via orogastric tube. Her condition improved, she was weaned to room air and Met-Hb level remained below 3% for three weeks, after which methylene blue dose was gradually decreased to be stopped completely on day 41 of life. The symptoms did not return, Met-Hb was stable at a percentage of 1.6%, and the baby was discharged home on ascorbic acid.

There was no family history of methemoglobinemia or bluish discoloration of lips or fingernails. Glucose-6-phophate dehydrogenase level was normal in newborn screen. First thyroid function test was done at the age of 6 days, TSH was elevated; 19.9 mU/L (1.2–13.1) and T4 was normal; 19.1 mcg/dL (8–21.8). Decision was not to start levothyroxine immediately, monitor symptoms, and to repeat test every 5–7 days given that T4 is normal and the baby is premature. Nevertheless, TSH level kept rising and reached 42.9 mU/L on day 22 of life, a diagnosis of congenital hypothyroidism was established and the baby was started on levothyroxine 15 mcg once daily.

Hb electrophoresis didn’t show evidence of hemoglobin M disease (Hb A 97.3%, A₂ 2.7%, F < 0.5%). Whole Exome Sequencing (WES) revealed a heterozygous missense variant in the exon 14 of the SPTB gene (SPTB;c.2519 G> A(p.Arg840His)), a variant of uncertain significance that was observed in cases of spherocytosis type 2, but no mutations related to methemoglobinemia were identified.

The patient continues to be followed in outpatient clinics, ascorbic acid was discontinued at the age of 11 months and she remained well with no recurrence of symptoms or elevation in Met-Hb for one year and further genetic testing was not warranted.

Met-Hb percentage and Hb levels over the course are presented in the table below [Table 1].

Cyanosis is a common finding in newborns with a broad differential diagnosis. Hematologic disorders remain one of the possibilities with methemoglobinemia as one of the rare disorders that has been observed in early life, which can be either congenital or acquired [3–7].

Three genes were identified as causes of hereditary methemoglobinemia with cytochrome b5 reductase deficiency (Cyb5R) being the most common. It is an autosomal recessive disorder and most patients will have a pathogenic variant encoded by cytochrome b5 reductase 3 (Cyb5R3). Cytochrome b5 reductase takes part in many oxidation and reduction reactions, it is involved in the reduction of methemoglobin to hemoglobin by transferring reducing equivalents from NADH to cytochrome b5, and its deficiency would increase methemoglobin level in the blood [8–10].

Less common genetic causes are hemoglobin M disease and cytochrome b5 (electron acceptor) deficiency. Hemoglobin M disease is caused by variants in alpha, beta or gamma globin genes, most common variants result in substitution of tyrosine for histidine in the proximal or distal site in heme pocket, this will form iron-phenolate complex which resists reduction of Fe^3 + [11, 12].

Cytochrome b5 deficiency is extremely rare and may be associated with ambiguous genitalia [13]. However, in our case the patient did not have any abnormal physical examination findings other than cyanosis and her genetic work up did not reveal any of these mutations.

Methemoglobinemia can be acquired as a result of either endogenous or exogenous exposures. Sepsis has been proposed as a possible source of endogenous exposure when Met-Hb is produced due to increased NO generation triggered by proinflammatory cytokines and bacterial lipopolysaccharides [7, 14]. Exogenous substances include poisoning or medications, such as topical anesthetics (Benzocaine, Lidocaine), inhaled NO, antimalarial agents (Chloroquine, Primaquine), Dapsone, and Nitrites, which were reported in cases of methemoglobinemia [15–17]. For this newborn, cultures were negative and definitive diagnosis of sepsis was not made, antibiotics did not seem to alter course of the disease and Met-Hb level continued to be elevated when inflammatory markers were negative. In addition, there was no history of antenatal or postnatal exposure to any of the drugs or toxins known to cause Methemoglobinemia.

Due to the rarity of the disease and the wide differential for cyanosis in neonates, the diagnosis of methemoglobinemia can be missed or delayed. Nevertheless, the finding of a dark chocolate brown colored blood and hypoxemia that does not respond to higher FiO2 should raise the suspicion for the disease. Met-Hb level can be measured by different methods, blood gas analysis is a simple test that can show the percentage, a level of > 3% is considered abnormal [6, 18]. Pulse co-oximetry can also be used, which allows for identification and quantitation of all hemoglobin species, including methemoglobin. It is a widely used method for diagnosis, however, the device was not available in the hospital and not used for this patient [19].

Treatment is usually warranted when levels reach above 30% and for symptomatic patients with levels of 20–30%. Methylene blue 1 mg/kg is given intravenously over 5 to 30 minutes, another dose may be needed if symptoms persist after one hour. G6PD deficiency should be ruled out before initiating therapy with methylene blue due to risk of hemolysis [20–23].

Ascorbic acid can be used as well, especially when methylene blue is not available or contraindicated. Our patient required two doses of intravenous methylene blue 6 days apart, then she was started on daily oral methylene blue 1.5 mg/kg and ascorbic acid 5 mg/kg, a regimen that was tried before on neonates [20–22]. Therapy was then tapered and stopped with no recurrence of symptoms, which supports the unclear and transient nature of her illness.

The neonate was also diagnosed with hypothyroidism, and WES revealed a variant of uncertain significance observed in spherocytosis type 2, a disease she did not have based on her clinical symptoms and hematological workup for the patient and her parents. Cases with these combined findings were not reported in literature before and to our knowledge there is no clear correlation between hypothyroidism or spherocytosis and methemoglobinemia.

4 Conclusion

Methemoglobinemia is a rare cause of cyanosis in newborns. A diagnosis that can be challenging without eliminating the more common entities. Blood gas analysis is a simple reliable test that shows the percentage of Met-Hb, and treatment with methylene blue or ascorbic acid has been used successfully in neonates. Although many causes of congenital or acquired cases have been identified, some cases seem to have unclear etiology and will warrant further research in the future.