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Blunted fetal growth by tenofovir in late pregnancy

Kinai, Eia; Hosokawa, Shinichib; Gomibuchi, Hidetoc; Gatanaga, Hiroyukia; Kikuchi, Yoshimia; Oka, Shinichia

doi: 10.1097/QAD.0b013e328358ccaa

aAIDS Clinical Center

bDepartment of Pediatrics

cDepartment of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.

Correspondence to Ei Kinai, MD, AIDS Clinical Center, National Center for Global Health and Medicine, Toyama 1-21-1, Shinjuku-ku, Tokyo, Japan. Tel: +81 3 3202 7181; fax: +81 3 3202 7198; e-mail:

Received 30 July, 2012

Accepted 1 August, 2012

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 [1]. 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.

Fig. 1

Fig. 1

The present case raises two concerns with regard to the safety of TDF in pregnancy. TDF can reduce bone mineral density [2]. Van Rompay et al. [3] 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 [4], 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 [5], 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.

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Conflicts of interest

There are no conflicts of interest.

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