An unusual case of hyperlactataemia in a neonate

Introduction

There is growing concern about short- and long-term effects of perinatal exposure to nucleoside reverse-transcriptase inhibitors (NRTIs) in infants who are not HIV infected.^1,2 Mitochondrial gene expression is decreased in antiretroviral (ARV)-exposed infants. These differences persist after the NRTI intake is discontinued, suggesting that changes in mitochondrial proliferation and expression take place during and after ARV exposure. Blood lactate (LA) levels are used as a screening tool for mitochondrial dysfunction. Our case report describes a neonate with symptomatic lactic acidosis in whom all secondary causes were ruled out. It was ascribed to transplacental exposure to NRTI.

Case report

We report a-34-week, 890 g, small-for-gestational age (SGA) male neonate born to second gravida HIV-positive mother by C-section. She was on an ARV regimen since 28 weeks of gestation, consisting of stavudine (30 mg twice/day), lamivudine (150 mg twice/day) and nevirapine as combination tablets. Her CD4 count prior to delivery was 481 cells/mm³ on ARVs. The baby was presented to the neonatal intensive care unit at birth.

On admission, his heart rate was 170/min, respiratory rate 74/min, temperature of 36.6℃ and blood pressure of 64/31 mmHg. His peripheral pulses were well palpable and capillary refill time was 2 s. He had minimal chest retractions and SpO₂ was 93% on room air. His systemic examination was unremarkable.

The haematological parameters showed hemoglobin of 15.4 g%, total leucocyte count 15,400/mm³ and platelet count of 2.46 × 10⁵/mm³. The qualitative C-reactive protein was negative and micro erythrocyte sedimentation rate (ESR) showed 6 mm fall. The peripheral smear did not reveal increased immature to total neutrophil ratio. An arterial blood gas revealed pH of 7.23 (7.35–7.45), pCO₂ of 26 mmHg (35–45 mmHg), LA of 11.3  mmol/l (<1.5 mmol/l) and bicarbonate of 22.7 mmol/l (22–24 mmol/l). His chest radiograph and electrocardiogram were normal. An echocardiography did not reveal any structural anomaly. The alanine aminotransferase was 34 U/l (24–48 U/l), aspartate transaminase was 29 U/l (20–40 U/l) and alkaline phosphatase was 434 IU/l (250–450 U/l). His renal function tests on day 3 and day 10 of life were normal.

The tandem mass spectrometry (TMS) and Urinary Gas chromatography mass spectrometry (GCMS) were reported normal. His pyruvate levels were normal. However, LA to pyruvate ratio was significantly elevated. Subsequently, the arterial LA declined on day 16 to 8.4 mmol/l. The trends in decline of LA levels with corresponding improvement in pH are shown in Figure 1. The DNA-PCR for HIV done at four weeks was negative. The maternal LA level was 1.8 mmol/l (<1.5 mmol/l). OPEN IN VIEWER

The baby was started on oral nevirapine prophylaxis and continued till six weeks of age. At the time of discharge, the baby was thriving with LA levels of 5.9 mmol/l. Subsequent follow-up until five months of corrected gestational age still revealed raised LA of 4.1 mmol/l (<1.5 mmol/l). He has early developmental delay in the form of not attaining complete head control. However, his vision and hearing are normal, as evaluated by relevant tests. Early developmental stimulation therapy has been instituted.

Discussion

There are myriad of causes for lactic acidosis in neonates. These include severe organ dysfunction leading to decreased tissue perfusion as seen in perinatal asphyxia, congenital heart disease (duct dependent lesions), sepsis and intractable seizures. It also includes primary lactic acidosis (mitochondrial disorders) and secondary lactic acidosis (fatty acid oxidation disorders, organic acidosis, urea cycle defects, hepatic and renal failure). NRTI-induced lactic acidosis and hyperlactataemia is a well-known entity in the adult population. However, there is paucity of data on the effect of transplacental transmission of NRTIs to the uninfected neonate.

Our neonate had increased arterial blood LA compared to pyruvate suggesting a shift in equilibrium towards formation of LA. There was no evidence of sepsis, shock, renal or liver failure. Inborn errors of metabolism were ruled out with relevant tests. The background of exposure to ARVs through trans-placental transmission was the only likely cause of hyperlactataemia. Subsequent gradual decline in blood LA levels suggests regeneration of mitochondrial DNA, subsequent to cessation of exposure to NRTI.

The morbidity that ARVs may cause in fetal and early life of HIV-uninfected children is still unclear, and thorough research of this condition is warranted. NRTIs are included in most ARV regimens. These drugs inhibit DNA polymerase gamma (γ), an essential protein for mitochondrial DNA replication in human cells.^3–5 Mitochondria are basic for the generation of adenosine triphosphate through oxidative phosphorylation. As a result an altered oxidoreduction status occurs, shifting the pyruvate/LA equilibrium in the direction of LA. Another study found no association between the use of ARV agents and the development of hyperlactataemia or neurological disorders in HIV-exposed children during their first year of life. ⁶ Peripheral blood mononuclear cells mtDNA levels were lower at birth in infants born to HIV-infected women. ⁷

The identification of children who are affected by NRTI-induced mitochondrial toxicity has become a great challenge for paediatricians. Moreover, the potential for long-term adverse effects on developing organism, especially high-energy-requirement tissues (nervous system) is known. Reports concerning NRTI toxicity in children who are exposed perinatally to ARVs are severe neurologic damage consistent with mitochondrial dysfunction.^8,9 In a study, almost half of HIV-uninfected neonates developed benign and self-limited elevated LA. A significant proportion of neonates with hyperlactataemia had adverse neurologic outcomes. ¹⁰ Another recent study states that ARV use during pregnancy has resulted in a dramatic decrease in mother-to-child transmission of HIV, and the risk of elevated LA in children is low. However, with use of new ARVs regimens, continued monitoring for infant toxicities is essential. ¹¹ A recently published study concludes the safety of perinatal ARV use but also warrants for monitoring of adverse neurodevelopmental outcomes in older children. ¹² Global adverse perinatal outcome, preterm births and SGA neonates were significantly increased in HIV pregnancies. The newborn mtDNA levels, maternal and fetal mitochondrial protein synthesis and maternal glycerol-3-phosphate + complex III function was significantly reduced in HIV-infected women–infant pairs compared to uninfected pairs. ¹³ However, HIV encephalopathy in children with perinatally acquired HIV is also associated with severe morbidity evidenced by frequent hospitalizations, severe immunodeficiency and short survival. ¹⁴ Hence, benefits of Prevention of Maternal to Child Transmission (PMTCT) programmes outweigh the risks associated with their use. However, continued monitoring of antiretroviral therapy (ART)-exposed children should be routine.

Neonates born to HIV-positive mothers who have tachypnoea and were exposed perinatally to NRTIs should be actively screened for arterial LA. Lactic acidosis as an independent (asymptomatic or symptomatic) risk factor is also detrimental for immediate and long-term neurological outcome. This case report raises awareness about this entity which is under reported, especially in developing countries, where the burden of HIV is huge.

Author contributions

All the authors were involved in the management of the patient. Nilay Nirupam reviewed the literature and drafted the manuscript. Ajay Kumar, Sushma Nangia and Arvind Saili critically reviewed the manuscript. All authors approved the final version of the manuscript.