Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants.
OBJECTIVE
Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents.


OBJECTIVE
To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children.


METHODS
Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012.


METHODS
First-trimester exposure to any ARV and to specific ARV medications.


METHODS
The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics.


RESULTS
Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs.


CONCLUSIONS
Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.
Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts2Departments of Biostatistics and Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Paige L
PL
Williams
Departments of Pediatrics and Microbiology, University of Alabama at Birmingham.
Marilyn J
MJ
Crain
Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts.
Cenk
C
Yildirim
Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
Rohan
R
Hazra
Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana.
Russell B
RB
Van Dyke
Department of Pediatrics, University of Illinois at Chicago.
Kenneth
K
Rich
Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Jennifer S
JS
Read
Department of Pediatric Infectious Disease, Bronx-Lebanon Hospital, Bronx, New York.
Emma
E
Stuard
University of Florida Center for HIV/AIDS Research, Education and Service, Jacksonville.
Mobeen
M
Rathore
State University of New York Downstate Medical Center, Brooklyn.
Hermann A
HA
Mendez
Office of the US Global AIDS Coordinator, US Department of State, Washington, DC.
D Heather
DH
Watts
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000209:etiology*; D044966:Anti-Retroviral Agents / Q000009:adverse effects*; D005260:Female; D005845:Georgia / Q000453:epidemiology; D015658:HIV Infections / Q000188:drug therapy* / Q000635:transmission; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy*; D011261:Pregnancy Trimester, First; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000453:epidemiology; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
D044966:Anti-Retroviral Agents