Other predictors of growth outcomes in the adjusted models
Increased odds of LBW was observed for female infants [aOR = 1.29, 95% confidence interval (CI) 0.98, 1.70, P = 0.07], those whose mothers had viral load more than 1000 copies/ml prior to delivery (aOR = 1.57, 95% CI 1.11, 2.21, P = 0.01) or used tobacco during pregnancy (aOR = 1.43, 95% CI 1.02, 2.01, P = 0.04), and children from families with annual household income less than $20 000 (aOR = 1.31, 95% CI 0.96, 1.79, P = 0.09). Odds of LBW were lower for infants born before 2002 vs. those born 2008–2010 (aOR = 0.54, 95% CI 0.33, 0.89, P = 0.06). Higher odds of SGA was associated with low income (aOR = 1.95, 95% CI 1.17, 3.25, P = 0.01) and with maternal gonorrhea (aOR = 2.78, P = 0.02) or tobacco use (aOR = 1.55, P = 0.08) during pregnancy. Nonwhite infants had a marginally decreased odds of SGA (aOR = 0.68, 95% CI 0.44, 1.04, P = 0.08).
Several socioeconomic and maternal health measures also showed significant associations with z-scores at birth and age 1 year: female infants had significantly lower newborn visit WAZ and LAZ, lower caregiver education was associated with significantly lower newborn visit WAZ and HCAZ at age 1 year, and low household income was associated with significantly lower z-scores for WAZ and HCAZ at newborn visit and HCAZ at age 1 year. Maternal gonorrhea infection was associated with lower z-scores for all newborn visit measures (WAZ, LAZ, and HCAZ), whereas high maternal viral load prior to delivery was paradoxically associated with significantly higher WAZ and LAZ at age 1 year. Although illicit drug use was relatively uncommon in our cohort (approximately 8%), its use was associated with significantly lower HCAZ at age 1 year, and maternal tobacco use was associated with significantly lower LAZ at age 1 year.
The increasing use of TDF by HIV-infected pregnant women warrants careful evaluation of the safety of this agent. Over 40% of pregnant mothers in our study used TDF during pregnancy in 2010, more than doubling TDF use in the last 5 years. TDF exposure was associated with significantly lower mean LAZ and lower HCAZ at age 1 year but not at birth, an unexpected finding of uncertain significance. The magnitudes of these differences were quite small – corresponding to an average difference of less than 0.5 cm for mean length and mean head circumference – and the biologic mechanisms underlying a delayed effect on infant growth outcomes after in utero TDF exposure are not readily explained. Later growth differences, especially for length in which mean z-scores were less than 0 in the TDF group, should be evaluated in other cohorts. The overall findings of this extensive analysis, however, are highly reassuring. The proportion of children at age one year with low LAZ and low HCAZ (z<−1.5 and z<−1.88) did not differ by TDF exposure. Furthermore, there was no association of TDF exposure with lower weight, shorter length, or smaller head circumference in the newborn period, whether these outcomes were defined based on mean z-scores or on z-scores below thresholds of −1.5 and −1.88. Analyses of longer-term growth and neurodevelopmental outcomes are underway in the SMARTT protocol.
The association of maternal TDF use with lower length and head circumference at 1 year but not in the newborn period was not predicted by animal studies. This observation suggests that maternal TDF use does not affect fetal growth but could lead to a delayed effect on infant growth in the first year, after ongoing exposure to maternal TDF has ceased. Adjustment for maternal HIV disease, demographic factors, and substance use suggests that the impaired infant growth is not related to confounding of maternal TDF use by these well known influences on infant outcomes. In addition, more than 99% of all infants received zidovudine prophylaxis, of whom 10% were given additional antiretroviral drugs for prophylaxis (data not shown), making it unlikely that infant growth differences were related to different neonatal antiretroviral drug exposures. Although newborn length and gestational age at birth are important and often interrelated predictors of length at 1 year, the association of maternal TDF with lower infant length at 1 year persisted despite adjusting for these factors. Women in this US-based study would have been counseled to not breastfeed their infants, eliminating the potential for ongoing infant TDF exposure through breast milk or nutritional differences due to feeding type (breastfeeding vs. formula feeding) in first year of life. Thus, the association of maternal TDF use and lower mean infant length at 1 year does not appear attributable to these cofactors.
Several studies of antiretroviral-exposed infants born to HIV-infected mothers demonstrate the potential for late adverse effects that may be attributable to perinatal antiretroviral exposure. In the Women and Infants Transmission Study (WITS), the significant difference in CD8+ cell counts by antiretroviral exposure status did not appear until 6–24 months of age, even after adjustment for potential confounders . In a cohort of children with apparent mitochondrial dysfunction after perinatal exposure to zidovudine with or without lamivudine, neurologic and developmental problems did not develop until age 4–14 months . Similarly, febrile seizures were significantly more common in antiretroviral-exposed infants than HIV-exposed, antiretroviral-unexposed infants; however, this difference did not appear until age 6–12 months of age . Among antiretroviral-exposed French infants, the overall rate of cancer in long-term follow-up was no different from population-based rates, but there was a higher risk of central nervous system cancer at 1–8 years of age . These examples emphasize the importance of evaluating outcomes both at birth and at later time points when assessing the safety of in utero exposure to antiretroviral drugs.
Suggested mechanisms by which fetal/neonatal antiretroviral exposure could result in persistent or delayed abnormalities have focused on nucleoside reverse transcriptase inhibitor (NRTI) toxicity to nuclear DNA of hematopoietic stem cells and NRTI damage to mitochondrial DNA [17,18]. TDF does not appear to have as much potential to cause mitochondrial dysfunction, as zidovudine and other NRTIs in in-vitro studies [19,20], but adverse effects on host DNA are plausible based on its nucleotide structure and mechanism of action. After oral administration, TDF is converted in the systemic circulation to tenofovir, which crosses the placenta. Tenofovir undergoes phosphorylation intracellularly to its active form, tenofovir diphosphate (TDP), which competitively inhibits HIV reverse transcriptase and causes DNA chain termination. The long intracellular half-life of TDP contributes to convenient dosing of TDF and its potent anti-HIV effect. Circulating tenofovir is renally cleared through glomerular filtration and tubular secretion, but renal elimination in the fetus would be expected to be much slower than in adults. As a result, the fetus may accumulate substantially more intracellular TDP, resulting in high, potentially more toxic levels as well as much longer persistence of intracellular TDP, exerting effects beyond the end of exposure to maternal TDF at birth. If these effects include reduced bone mass accrual, as suggested by some studies of TDF in adults and children [21–24], the end result may be attainment of smaller head circumference and length. However, there is currently no direct evidence from animal or human studies that can confirm the potential for maternal TDF exposure to cause a delayed effect on infant growth.
The strengths of our investigation include large sample size, the prospective data collection of antiretroviral medications during pregnancy within the Dynamic cohort, and the evaluation of growth outcomes at both birth and age 1 year. The size of the study provides 80% power to detect differences in mean z-scores ranging from 0.18 (newborn) to 0.29 (at age 1 year). The study is also well powered to detect increased odds of LBW or SGA, with 80% power to detect ORs of 1.5–1.8. The use of a comparison group exposed to combination regimens without TDF reduces the chance results could be compromised by selection bias and controls for association of maternal combination regimens with LBW observed in some, though not all, studies [25–28].
Like all cohort studies, a limitation of this study is the nonrandom assignment of TDF to women during pregnancy, which may result in unmeasured confounding, despite the adjustment for covariates expected to be important. None of the comparisons presented would be significant if adjusted for the three to four comparisons made per outcome (e.g., LBW, WAZ at birth, WAZ at age 1); however, because this was a safety study with a limited number of comparisons addressing a single antiretroviral drug, our concern for maintaining low type I error rates was balanced with equally high concern for minimizing type II error rates (i.e., minimizing the chance of not detecting true associations with TDF).
On the whole, these data provide reassurance about the lack of major detrimental effects on fetal and infant growth when TDF is used in combination antiretroviral regimens in pregnancy. The unexpected observation of lower mean length and head circumference at 1 year of age warrants further studies monitoring longer term growth outcomes of TDF-exposed infants in SMARTT and other large HIV-exposed, uninfected cohorts.
G.K.S. and P.W. are the primary authors who conceived and designed the study. All authors are directly involved in the design and conduct of the PHACS protocol. P.W. was primarily responsible for conducting analyses of the data. G.K.S. and P.W. led the writing of the manuscript. All authors collectively contributed to interpreting results and drafting and editing of the article.
The authors thank the children and families for their participation in the Pediatric HIV/AIDS Cohort Study (PHACS) protocol ‘Surveillance Monitoring for ART Toxicities’ (SMARTT), and the individuals and institutions involved in the conduct of PHACS SMARTT. Data management services were provided by Frontier Science and Technology Research Foundation (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat Inc. (Principal Investigator: Mercy Swatson).
The following institutions, clinical site investigators, and staff participated in conducting PHACS SMARTT in 2009, in alphabetical order: Baylor College of Medicine: William Shearer, Norma Cooper, Lynette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Doyle Patton; Children's Hospital of Philadelphia: Richard Rutstein, Carol Vincent, Nancy Silverman; Children's Memorial Hospital: Ram Yogev, Kathleen Malee, Scott Hunter, Eric Cagwin; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Helen Rozelman; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Patricia Garvie; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera; SUNY Downstate Medical Center: H.M., Ava Dennie, Susan Bewley; SUNY Stony Brook: Sharon Nachman, Margaret Oliver, Helen Rozelman; Tulane University Health Sciences Center: Russell Van Dyke, Karen Craig, Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Newana Beatty, Dan Marullo; University of California, San Diego: Stephen Spector, Jean Manning, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, Robin McEvoy; University of Florida/Jacksonville: Mobeen Rathore, Kathleen Thoma, Ann Usitalo; University of Illinois, Chicago: K.C.R., Delmyra Turpin, Renee Smith; University of Maryland, Baltimore: Douglas Watson, LaToya Stubbs, Rose Belanger; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, Susan Adubato; University of Miami: Gwendolyn Scott, Erika Lopez, Elizabeth Willen; University of Southern California: Toinette Frederick, Mariam Davtyan, Maribel Mejia; University of Puerto Rico Medical Center: Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio.
The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, National Institute of Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102–04) (Principal Investigator: G.R.S.; Project Director: Julie Alperen) and the Tulane University School of Medicine (U01 HD052104–01) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: K.C.R.; Project Director: Patrick Davis).
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institutes of Health or the Department of Health and Human Services.
These data were presented at the 18th International AIDS Conference; 2010; Vienna, Austria.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
antiretroviral drugs; infant growth; perinatal HIV exposure; pregnancy; tenofovir disoproxil fumarate