Phosphaturia in HIV-Exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy

Abstract

Background: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third-trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. The potential mechanisms underlying this observation are unknown.

Methods: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in the third trimester vs none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4 to 30 days, to compare slopes by TDF exposure.

Results: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 vs -0.08/day (difference -0.50/day [95% CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels were lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] vs 26 [22, 37] ng/mL). No differences were observed for other biomarkers.

Conclusions: Third-trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

Keywords: 25-OH vitamin D; HEU; TDF; in utero exposure; percent tubular reabsorption of phosphate; renal.

Figure 1.

LOESS plots for neonatal renal and bone biomarkers by age at specimen collection (0–30 days since birth) for individual TDF-exposed and TDF-unexposed participants. Clockwise from top left: serum creatinine, serum phosphate, estimated eGFR (estimated glomerular filtration rate), urine NTx/cr (cross-linked N-telopeptide of type 1 collagen normalized for creatinine), serum PTH (parathyroid hormone), serum 25-OH vitamin D, and PTRP (percentage tubular reabsorption of phosphate) from 0–30 days of age. The vertical line divides the participants into the 0–3- and 4- to 30-day age groups. The reference range for serum creatinine in the neonate is 0.3–0.9 mg/dL (first 14 days of life) and 0.1–0.4 mg/dL (15 days to 2 years of age). For serum phosphate the range is 5.6–10.5 mg/dL (first 14 days of life) and 4.8–8.4 mg/dL (15 days to 1 year of age). Normal PTRP is >80% across all ages. With eGFR the reference range (± standard deviation) in the first week of life is 41 ± 15, and between 2 and 8 weeks 66 ± 25 mL/min/m². Reference ranges for 25(OH)D is 30–100 ng/mL (deficiency < 20 ng/mL, insufficiency 20 to <30 ng/mL), and for PTH, 10–65 pg/mL. No normative values for NTX/cr are available for neonates and children. Abbreviations: eGFR, estimated glomerular filtration rate; NTx/cr, urine NTx normalized for urine creatinine; PTH, parathyroid hormone; PTRP, percentage tubular reabsorption of phosphate; TDF, tenofovir disoproxil fumarate.

Figure 2.

Linear regression lines for neonatal renal and bone biomarkers by age at specimen collection (4–30 days since birth) for individual TDF-exposed and TDF-unexposed participants. Clockwise from top left: serum creatinine, serum phosphate, estimated eGFR (estimated glomerular filtration rate), urine NTx/cr (cross-linked N-telopeptide of type 1 collagen normalized for creatinine), serum PTH (parathyroid hormone), serum 25-OH vitamin D, and PTRP (percentage tubular reabsorption of phosphate) from 4–30 days of age. Abbreviations: eGFR, estimated glomerular filtration rate; NTx/cr, urine NTx normalized for urine creatinine; PTH, parathyroid hormone; PTRP, percentage tubular reabsorption of phosphate; TDF, tenofovir disoproxil fumarate.