Tenofovir disoproxil fumarate (TDF) is recommended for pregnant women coinfected with HIV and hepatitis B virus to prevent mother-to-infant transmission of both viruses . However, the safety of TDF in pregnancy is still controversial, especially with regard to its effects on fetal growth and bone mineralization.
Here, we describe a 32-year-old HIV-1-infected Asian pregnant woman, who showed blunted fetal growth during TDF treatment. She had been treated during the first 33 weeks of pregnancy with abacavir, lopinavir/ritonavir and raltegravir based on multiple viral mutations. As plasma concentrations of raltegravir were persistently low, treatment was switched to TDF at 35 weeks of gestation, until delivery at 38 weeks. The fetal growth curves of biparietal diameters and femur length were within the normal ranges before starting TDF; however, the growth of both parameters was significantly blunted after starting TDF (Fig. 1). Furthermore, tubular reabsorption rates for phosphate, urinary β2-microglobulin and alkaline phosphatase were 88%, 2776 μg/L and 435 U/L, respectively, during the TDF-treatment period, compared with 97%, 140 μg/L and 182 U/L, respectively, during the non-TDF-treatment period. Plasma TDF concentration in the mother was 3536 ng/mL at 4 h after dosing and 776 ng/mL in cord blood. The infant was delivered by cesarean section without HIV-1 infection, and weighed 2218 g (−2 SDs for Japanese infants), with a height of 45.0 cm (−1.5 SD), and a head circumference of 29.5 cm (−2 SD). Furthermore, moderate tubular dysfunction was observed at birth (serum calcium: 7.4 mg/dL, serum phosphate: 4.6 mg/dL, alkaline phosphatase: 560 U/L, urine β2-microglobulin: 1780 μg/L), together with a high plasma TDF concentration [102 ng/mL at 24 h after delivery (28 h after mother's dosing)]. Although the body length was persistently short throughout the first 3 months (less than −2 SD), the hand X-ray at 1 and 3 months showed no signs of osteopenia or rickets.
The present case raises two concerns with regard to the safety of TDF in pregnancy. TDF can reduce bone mineral density . Van Rompay et al.  reported that treatment of infant macaque with high-dose TDF caused proximal tubular dysfunction, growth retardation and osteomalacia. Our findings suggest that administration of TDF during pregnancy caused fetal disordered bone growth through modest proximal tubular dysfunction. However, it is not clear whether maternal TDF-associated tubular dysfunction will cause future bone growth retardation in infants. A large cohort study reported that significantly shorter height was observed at age 1 year in TDF-exposed infants , which is generally considered as one of the symptoms of mild rickets. However, in our case, despite the persistently shorter height of the infant (less than −2 SD) throughout the first 3 months of life, hand X-ray at 3 months showed no findings of osteopenia or rickets. Second, plasma TDF concentrations in our case were 10-fold higher than the previously reported values , probably reflecting the mother's small body size (weight: 47 kg), and consequently higher placental transfer of TDF to the fetus. Asian pregnant women, who have smaller body size, may impose a more severe effect on fetal growth retardation than that reported previously. The effect of TDF in pregnancy and its impact on fetal growth needs to be evaluated in more detail.
Conflicts of interest
There are no conflicts of interest.
1. 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. 2011. http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf
2. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone mineral density and fracrtures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS clinical trials group A5224s, a substudy of ACTG A5202
. J Infect Dis
3. Van Rompay KKA, Brignolo LL, Meyer DJ, Jerome C, Tarara R, Spinner A, et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy) propyl] adenine (tenofovir) to newborn and infant rhesus macaques
. Antimicrob Agents Chemother
4. Siberry GK, Williams PL, Mendez H, Seage GR III, Jacobson DL, Hazra R, et al. for the Pediatric HIV/AIDS Cohort Study (PHACS)Safety of tenofovir use during pregnancy; early growth outcomes in HIV-exposed uninfected infants
5. Flynn PA, Mirochnick M, Shapiro DE, Bardequez A, Rodman J, Robbins B, et al. PACTG 394 Study TeamPharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants
. Antimicrob Agents Chemother