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Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 158-161

Severe metabolic disturbance in an human immunodeficiency virus-exposed newborn: Possible effect of In utero antiretroviral exposure

1 Department of Pediatrics, Division of Pediatric Endocrinology, New York University School of Medicine, New York, NY, USA
2 Department of Pediatrics, Division of Pediatric Infectious Disease, New York University School of Medicine, New York, NY, USA

Date of Web Publication2-Aug-2018

Correspondence Address:
Dr. Bina Shah
Department of Pediatrics, Divisions of Pediatric Endocrinology, New York University School of Medicine, 550 First Avenue, New York, NY 10016
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_118_17

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The use of antiretroviral (ARV) medications has successfully reduced maternal transmission of human immunodeficiency virus (HIV)-1 to newborns, but metabolic and mitochondrial toxicities in newborns continue to be a concern. We report the case of a 10-day-old full-term female infant born to an HIV-positive mother presenting with lethargy and respiratory distress. Maternal ARV medications included nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase strand transcriptase inhibitors (INSTIs). Infant ARV prophylaxis included two NRTIs and a nonnucleoside reverse transcriptase inhibitor. At presentation, laboratory tests were significant for hyponatremia, hyperkalemia, severe metabolic acidosis, and acute kidney injury. She was resuscitated with fluids and a stress dose of hydrocortisone (HC), which resulted in improvement of her condition within 48 h. Adrenal profile on the day of admission revealed elevated levels of 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, aldosterone, and elevated plasma renin activity. HC was tapered and the patient was discharged on the day of life (DOL) 26. Adrenocorticotropic hormone (ACTH) stimulation test off HC for one night that was performed on DOL31 showed a normal cortisol response of 35.8 mcg/dL at 60 min. HC was later discontinued. A repeat ACTH stimulation test off HC for 7 days that was performed on DOL59 yielded a normal cortisol response of 27.6 mcg/dL at 60 min. This report reveals severe metabolic disturbances suggestive of adrenal insufficiency (AI) in a neonate exposed to a combination of ARV medications in utero and postnatally with improvement of symptoms after glucocorticoid treatment. The AI was transient in nature, which resolved after cessation of ARV therapy.

Keywords: Antiretroviral exposure to human immunodeficiency virus-exposed neonate, metabolic disturbance, transient adrenal insufficiency

How to cite this article:
Eng L, Raisingani M, Kaul A, Mehta S, Prasad K, David R, Shah B. Severe metabolic disturbance in an human immunodeficiency virus-exposed newborn: Possible effect of In utero antiretroviral exposure. J Clin Neonatol 2018;7:158-61

How to cite this URL:
Eng L, Raisingani M, Kaul A, Mehta S, Prasad K, David R, Shah B. Severe metabolic disturbance in an human immunodeficiency virus-exposed newborn: Possible effect of In utero antiretroviral exposure. J Clin Neonatol [serial online] 2018 [cited 2020 Jul 10];7:158-61. Available from: http://www.jcnonweb.com/text.asp?2018/7/3/158/238391


Prevention of maternal transmission of human immunodeficiency virus-1 (HIV-1) to newborns with antiretroviral (ARV) medications has been enormously successful and safe.[1] There are currently four classes of ARV medications which are recommended in the United States for use during pregnancy: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transcriptase inhibitors (INSTIs). While ARV medications are successful in preventing mother-to-child transmission, metabolic and mitochondrial toxicities in neonates remain a concern.[2] Perinatal ARV exposure may affect the pregnancy with an increased risk of preterm birth.[2] Postnatally, neonates may experience acute, mostly transient, effects of metabolic or mitochondrial dysfunction such as transaminitis, anemia, lactic acidosis, and, more rarely, electrolyte and adrenal disturbances. These adverse effects typically resolve months after discontinuation of the ARV medication, although abnormalities may persist up to 1 year of life.[2] Long-term sequelae including neurological deficits, though rare, have been reported in the literature.[3]

Electrolyte disturbances due to adrenal insufficiency (AI) in association with ARV use have rarely been reported in both the adult and pediatric populations.[1],[4],[5] The PIs are the only class of ARV medications known to be associated with electrolyte disturbances in neonates. Asymptomatic elevation of 17-hydroxyprogesterone (17-OHP) has been seen in neonates with in utero PI exposure.[1] Symptomatic AI has recently been reported in preterm newborns exposed prenatally and postnatally to PIs with a resolution of symptoms after completion of PI treatment.[1] There have been no reports of symptomatic AI in term infants exposed to any other classes of ARV medications including NRTIs and INSTI.

This case report describes an HIV-negative term infant who presented with severe metabolic acidosis with hyponatremia and hyperkalemia, likely due to in utero and/or postnatal ARV exposure, that resolved with fluid resuscitation and glucocorticoid treatment.

[TAG:2]Case Report[/TAG:2]

We report a term female infant born to an HIV-1 positive mother who presented on the day of life (DOL) 10 to an outside emergency room (ER) with a 2-day history of excessive crying and noisy breathing.

Maternal history revealed that she was HIV-1 positive on ARV medications, consisting of Truvada® (combination of emtricitabine/tenofovir-NRTIs) and Isentress® (raltegravir-INSTI). She was nonadherent to taking ARV medications prior to and during the first trimester of pregnancy. However, she reported to be mostly compliant in second and third trimesters. Her viral load was 6010 copies/mL 2 days prior to delivery (acceptable level on treatment is <1000 copies/mL). The prenatal course was otherwise uneventful.

The patient was born via an uncomplicated cesarean section at another hospital. The HIV polymerase chain reaction on DOL1 was reportedly negative on the infant. Postnatally, she was started on triple therapy with zidovudine (AZT-NRTI), lamivudine (3TC-NRTI), and nevirapine (NVP-NNRTI). After discharge on DOL3, the patient was feeding formula well and gaining weight until she developed symptoms on DOL8, for which she presented to the ER.

In the ER, she was afebrile and had tachycardia to 170 beats/min and hypotension with blood pressure of 81/28 mmHg (normal range: 80—95/50—65 mmHg). She was found to be in respiratory distress with cyanosis. Her extremities were cool to touch, but capillary refill was brisk. She was placed on nasal cannula, but was quickly escalated to biphasic positive airway pressure support. A capillary blood gas revealed pH 6.8, pCO2 17 mmHg, undetectable bicarbonate, and base deficit 28 mmol/L. The initial basic metabolic profile showed hyponatremia (serum sodium 129 mmol/L), hyperkalemia (serum potassium >10 mmol/L), severely low bicarbonate (2 mmol/L), and prerenal azotemia (blood urea nitrogen 69 mg/dL and creatinine 2.7 mg/dL) with normal glucose level of 108 mg/dL. Chest X-ray, electrocardiogram, and echocardiogram were all normal. Both blood and surface cultures were negative. She received four boluses of 20 mL/kg normal saline and was started on intravenous fluids at 1.5 times' maintenance. As her clinical condition and metabolic abnormalities resembled a potential adrenal insufficient state, she was given a 2 mg/kg dose of hydrocortisone (HC). Due to the patient's critical condition, a serum cortisol level was not obtained prior to HC administration. The patient was transferred to our institution's Pediatric Intensive Care Unit (PICU) for further management.

After arrival to the PICU, the patient was weaned off respiratory support and her electrolytes normalized within 24 h of receiving the stress dose of HC and fluid resuscitation. ARV medications were discontinued due to concerns of renal toxicity. Her clinical condition gradually improved and stabilized over the next 3 days. The serum adrenal biochemical profile obtained on the day of admission after the stress dose of steroids revealed an elevated 17-OHP (617 ng/dl), dehydroepiandrosterone sulfate (DHEA-S) (1427 ug/dl), androstenedione (3.6 ng/ml), and aldosterone (706 ng/dl) [Table 1]. An ultrasound of the adrenal glands was normal. HC was started at 222 mg/m>2/day and tapered to 14 mg/m>2/day on DOL20. AZT was restarted on DOL12 but switched to 3TC on DOL21 when she developed anemia. She was discharged home on DOL27 on HC. She completed 3TC on DOL42.
Table 1: Laboratory data and treatment

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A 125-ug ACTH stimulation test performed on DOL31 on 3TC and off HC demonstrated adequate adrenal response with 0- and 60-min cortisol levels of 2.8 and 35.8 mcg/dL, respectively. A repeat ACTH stimulation test on DOL 59 off HC again demonstrated adequate adrenal response with 0- and 60-min cortisol levels of 1.2 and 27.6 mcg/dL, respectively. Similarly, ACTH stimulation test at 10 months of age showed normal adrenal function with 0- and 60-min cortisol levels of 14.5 and 34.2 mcg/dL, respectively. The patient is growing and developing well and continues to have normal adrenal function.


ARV medications have profoundly decreased mother-to-child transmission of HIV-1 to <1% when adequately treated.[1] Several factors play a role in determining the optimal therapy during pregnancy, but mothers are typically placed on a regimen that includes two NRTIs and one of the following: PIs, non-NNRTIs, or INSTIs. Postnatally, neonates are routinely started on monotherapy with zidovudine NRTI for 4 weeks. For neonates at a higher risk for HIV acquisition, including those with inadequate maternal viral suppression antenatally, combination infant prophylaxis is recommended.[6]

Adverse effects of different classes of ARV medications on neonates are well known, but AI has rarely been reported [Table 2].[7] We report a neonate exposed to in utero and postnatal ARV medications presenting with clinical and biochemical features compatible with transient but potentially life-threatening AI. In general, when AI is suspected on the basis of clinical presentation and proven with electrolyte abnormalities, serum levels of cortisol, 17-OHP, DHEA-S, androstenedione, and aldosterone should be obtained prior to administration of steroids. In our patient, given her critical condition, stabilization and emergent treatment with steroids took precedence over evaluation for the etiology of symptoms. Serum cortisol and confirmatory testing for AI was thus not obtained. Her rapid recovery following the stress dose of corticosteroid supports the presumptive clinical diagnosis of AI. Adrenal profile obtained 2 h after administration of HC showed elevated 17-OHP, DHEA-S, androstenedione, and aldosterone levels. Paradoxical elevation of aldosterone, not consistent with AI, could be explained by physiologic partial aldosterone resistance seen in newborns.[7] Further, repeat aldosterone levels were normal. Subsequent normalization of 17-OHP, DHEA-S, androstenedione, and resolution of AI symptomatology suggests that this was a transient phenomenon.
Table 2: Pre- and post-natal antiretroviral therapy options and adverse effects

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Simon et al. and Kariyawasam et al. noted similar elevations in 17-OHP and DHEA-S in neonates exposed to the PI class of ARV medications.[1],[4] They hypothesized that these elevations were likely due to the interaction of PIs with cytochromes and proposed that the resulting AI could be the result of either inhibition of cortisol synthesis, particularly CYP21, or enhancement of cortisol metabolism and clearance initiated by the enzymes CYP2B1, CYP2B2, and CYP3A4.[1],[4]

Although speculative in our patient, the most likely reason for transient AI was potentially the effect of combination of factors such as exposure to in utero and/or postnatal ARV exposure. In addition, our patient was not exposed to any PIs, suggesting that other ARV medications or a combination of ARV medications may similarly disrupt the cytochrome P450 pathway, thereby leading to the adrenal profile abnormalities. The ARV medications NRTIs do not undergo metabolism through CYP450 enzymes,[8] so it is unlikely to be the cause for AI in our patient. The NNRTI Nevirapine, on the other hand, is known to be an inducer of CYP450 isoenzymes, such as CYP3A4,[9] and could have, by acting alone or in conjunction with NRTIs, enhanced cortisol metabolism and caused AI in our patient. The rapid recovery of the patient suggests that enhanced cortisol clearance might have been the primary cause of her clinical presentation.

With an otherwise unremarkable history except for ARV exposure, and from what is already known about the impact of ARV exposure in neonates, we postulate that our patient's metabolic derangements may be a transient adverse effect of one or a combination of ARV medications. Serum collection for studies of adrenal hormones in HIV-negative ARV-exposed infants would be ideal to determine metabolic abnormalities that might arise in neonates exposed to ARVs in utero or postnatally. The presentation and outcome of this patient emphasize the importance of recognizing metabolic disturbances and considering possible AI in ARV-exposed term infants, which if not treated can be life-threatening.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Simon A, Warszawski J, Kariyawasam D, Le Chenadec J, Benhammou V, Czernichow P, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA 2011;306:70-8.  Back to cited text no. 1
Kirmse B, Baumgart S, Rakhmanina N. Metabolic and mitochondrial effects of antiretroviral drug exposure in pregnancy and postpartum: Implications for fetal and future health. Semin Fetal Neonatal Med 2013;18:48-55.  Back to cited text no. 2
Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354:1084-9.  Back to cited text no. 3
Kariyawasam D, Simon A, Laborde K, Parat S, Souchon PF, Frange P, et al. Adrenal enzyme impairment in neonates and adolescents treated with ritonavir and protease inhibitors for HIV exposure or infection. Horm Res Paediatr 2014;81:226-31.  Back to cited text no. 4
Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: A review of the literature. HIV Med 2008;9:389-96.  Back to cited text no. 5
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available from: https://www.aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf. [Last updated on 2018 Mar 21].  Back to cited text no. 6
Martinerie L, Pussard E, Foix-L'Hélias L, Petit F, Cosson C, Boileau P, et al. Physiological partial aldosterone resistance in human newborns. Pediatr Res 2009;66:323-8.  Back to cited text no. 7
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Drug Interactions Between NRTIs and Other Drugs 2015 Apr 8. Department of Health and Human Services. Available from: http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/286/nrti-drug-interactions. [Last updated on 2017 Oct 17].  Back to cited text no. 8
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Drug Interactions Between NNRTIs and Other Drugs. Department of Health and Human Services 2015 Apr 8. Department of Health and Human Services. Available from: http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/285/nnrti-drug-interactions. [Last updated on 2017 Oct 17].  Back to cited text no. 9


  [Table 1], [Table 2]


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