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Original Investigation |

Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed Uninfected Infants FREE

Paige L. Williams, PhD1,2; Marilyn J. Crain, MD3; Cenk Yildirim, MS1; Rohan Hazra, MD4; Russell B. Van Dyke, MD5; Kenneth Rich, MD6; Jennifer S. Read, MD7; Emma Stuard, MD8; Mobeen Rathore, MD9; Hermann A. Mendez, MD10; D. Heather Watts, MD11 ; for the Pediatric HIV/AIDS Cohort Study
[+] Author Affiliations
1Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
2Departments of Biostatistics and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
3Departments of Pediatrics and Microbiology, University of Alabama at Birmingham
4Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
5Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana
6Department of Pediatrics, University of Illinois at Chicago
7Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
8Department of Pediatric Infectious Disease, Bronx-Lebanon Hospital, Bronx, New York
9University of Florida Center for HIV/AIDS Research, Education and Service, Jacksonville
10State University of New York Downstate Medical Center, Brooklyn
11Office of the US Global AIDS Coordinator, US Department of State, Washington, DC
JAMA Pediatr. 2015;169(1):48-55. doi:10.1001/jamapediatrics.2014.1889.
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Published online

Importance  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.

Design, Setting, and Participants  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.

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

Main Outcomes and Measures  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 and Relevance  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.

The use of combination antiretroviral (ARV) regimens for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and for treatment of HIV-infected pregnant women has contributed to a substantial reduction in HIV-infected infants.1 However, the safety of in utero exposure to such combination ARV regimens remains a concern, particularly as newer agents are approved and an increasing percentage of women enter pregnancy already receiving ARV therapy.2

Most prior studies examining the risk of congenital anomalies (CAs) according to in utero ARV exposure have been reassuring, but some evidence has suggested an increased risk of CAs overall or for certain CAs with specific ARVs.313 In the international Antiretroviral Pregnancy Registry, the estimated prevalence of CAs was 2.9% among more than 6900 children with first-trimester ARV exposures, similar to the rate among children exposed in later trimesters.5 The Women and Infants Transmission Study6 found no increase in the overall rate of defects (3.56 per 100 live births) compared with the general population estimate of 2.76 from the Metropolitan Atlanta Congenital Defects Program (MACDP) but reported an increased risk of hypospadias after exposure to zidovudine (zidovudine or azidothymidine) during the first trimester. Two studies12,13 from US-based cohorts have shown an increased overall risk of CAs among infants with first-trimester efavirenz exposure. A single animal study and case reports have also reported CAs associated with efavirenz exposure,14,15 leading to recommendations against its use in pregnancy, although specific risks have not been confirmed.2

Previous studies predominantly included children born before 2007, preventing evaluation of newer ARVs and combinations with increasing use. In the United States, prenatal use of tenofovir disoproxil fumarate, emtricitabine, and lopinavir has increased dramatically since approval in 2000 to 2003 to 40% to 50% use by 2010, while nelfinavir mesylate use has declined substantially following safety warnings.16,17 Atazanavir use increased by 2010 to approximately 20%.16,17 Through 2011, an Italian cohort showed similar trends.18 In addition to changes in specific ARVs, most infants in previously studied cohorts were not exposed to ARVs in the first trimester, a critical window for teratogenicity. We used an ongoing US-based pregnancy cohort, the Surveillance Monitoring of ART Toxicities (SMARTT) Study of the Pediatric HIV/AIDS Cohort Study network, to examine the association of in utero ARV exposures and infant CAs during the past 15 years. Our objectives were (1) to evaluate changes in the rate of CAs over time as new ARVs and regimens were used and (2) to evaluate the association of in utero ARV exposure with CAs.

The protocol was approved by appropriate institutional review boards, with written informed consent by mothers or guardians for study participation for themselves and their children. We analyzed data from HIV-infected pregnant women and their children enrolled in the SMARTT Study.19 This study includes 2 cohorts, static and dynamic. Between 2007 and 2009, the static cohort enrolled mothers or caregivers and their children younger than 12 years who had detailed information on ARV use during pregnancy and pregnancy outcomes. In 2007, the dynamic cohort began enrolling pregnant women and their infants between 22 weeks of gestation and 1 week after delivery into prospective surveillance.

Information on ARV use during pregnancy and medical conditions, including pregnancy outcomes, was collected by medical record abstraction. Congenital anomalies were identified at study-specified newborn and 1-year-old physical examinations for those in the dynamic cohort and from physical examinations performed in prior studies for those in the static cohort. Participants were considered evaluable for this analysis if they were enrolled and had a study visit by July 1, 2012.

Outcome Measure

The outcome of interest was the presence of a CA, defined as an abnormality in the structure of a body part that was documented within the first year of life. Congenital anomalies were recorded on study-specific anomaly and diagnosis forms. All study authors (blinded to ARV exposures) reviewed the reported CAs and classified them according to the Antiretroviral Pregnancy Registry modification of the MACDP classification scheme,5 a well-documented system for categorizing CAs. According to this system, an infant with at least 1 major anomaly or at least 2 conditional anomalies in the absence of a major anomaly is considered a CA case. Additional information was requested from sites if needed to classify potential anomalies. Each CA was reviewed by at least 2 physicians (M.J.C., R.H., R.B.V.D., K.R., J.S.R., M.R., H.A.M., and D.H.W.), and discrepancies were discussed to obtain consensus.

Prenatal ARV Exposures

The primary exposure of interest was reported maternal use of ARVs during the first trimester (<14 weeks of gestation). Highly active ARV therapy (HAART) regimens were defined as those containing 3 or more ARVs from 2 or more drug classes (nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors [PIs], and integrase inhibitors). Children were classified according to first-trimester exposure to any ARV, to individual ARVs, to ARV drug classes, and to HAART.16 We also evaluated these exposures at any time during pregnancy and by timing of the first ARV exposure.

Potential Confounders

Confounding was evaluated using prior knowledge (based on biological mechanisms and previous literature) and descriptive statistics from our cohort through the use of directed acyclic graphs.20,21 Potential confounders evaluated included self-reported race/ethnicity, prepregnancy body mass index, advanced maternal age at delivery (>35 years), health conditions such as pregestational diabetes mellitus, maternal sexually transmitted infections during pregnancy, self-reported substance use (tobacco and alcohol or other drug use), plasma HIV RNA concentration (viral load) and CD4 counts (earliest available measures in pregnancy), and first-trimester use of other medications previously reported to be associated with CA risk (eg, folate antagonists and antidepressants, including selective serotonin reuptake inhibitors).2226 Socioeconomic status also was considered, as reflected by annual household income and caregiver education levels. Low birth weight (<2500 g), preterm birth (<37 weeks of gestation), and delivery by cesarean section were described but not included as potential confounders because these measures could be on the causal pathway between ARV exposure and CA status20,21 and cesarean section might be preferentially performed when a CA was suspected.

Statistical Analysis

Rates of CAs (95% CIs) were estimated overall and by calendar year and compared descriptively with the MACDP rates for the US population. The characteristics of children with and without CAs were compared using χ2 test, Fisher exact test, and Wilcoxon rank sum tests as appropriate. Logistic regression analysis was used to evaluate the association between the in utero ARV exposures described above and confirmed CAs. Adjusted models included birth cohort and other noted confounders with P < .10 in multivariable models. Separate analyses were conducted for certain CA categories (eg, cardiovascular, musculoskeletal, skin, and male genital), although these had limited power.

To confirm the robustness of results, several sensitivity analyses were conducted. Analyses were repeated with restriction to cases having at least 1 major CA (eg, excluding children with only conditional CAs) and exclusion of those with a chromosomal anomaly. We repeated all analyses with restriction to the dynamic cohort because its prospective follow-up from birth reduces the risk of recall bias and misclassification and this restriction eliminates overlap with previous cohorts (Women and Infants Transmission Study,6 Pediatric AIDS Clinical Trials P219C protocol,12 and International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 protocol13). Last, sensitivity analyses that included random effects were conducted to control for multiple children born to the same mother and to adjust for the clustering of children within research sites. Because of observed time trends, analyses were repeated with stratification by, rather than adjustment for, birth cohort but yielded similar results and are not presented. Analyses were conducted using statistical software (SAS, version 9.2; SAS Institute), and 2-sided P ≤ .05 was considered statistically significant. Because the SMARTT Study is a safety investigation, no correction for multiple comparisons was used to minimize the probability of not detecting true associations (type II error); however, the large number of tests increases the risk of spurious associations, and findings warrant confirmation in future studies.

Study Population and CA Status by Demographic and Maternal Characteristics

The demographic and maternal characteristics of 2580 participants at 22 US medical centers (1380 in the dynamic cohort born between April 2, 2007, and June 29, 2012, and 1200 in the static cohort born between March 27, 1995, and December 27, 2008) enrolled by July 1, 2012, are summarized in Table 1. After team review, 175 infants met the modified MACDP criteria for a confirmed CA case, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%). One hundred sixty-two unique children had at least 1 major CA (prevalence, 6.27%; 95% CI, 5.37%-7.29%), and 13 children had 2 or more conditional CAs but no major anomalies. These 162 children had a total of 242 confirmed major CAs; musculoskeletal (n = 72) and cardiovascular (n = 55) anomalies were most common (eTable 1 in the Supplement). The prevalences of CAs were 3.8%, 5.2%, 8.0%, 8.3%, and 5.7% for children born before 2002, 2002 to 2004, 2005 to 2007, 2008 to 2010, and after 2010, respectively, with a significantly increasing trend (P = .03) in successive years. However, no significant overall difference was observed in prevalences between the static cohort vs the dynamic cohort (6.4% vs 7.1%, P = .53).

Table Graphic Jump LocationTable 1.  Demographic and Maternal Characteristics of 2580 SMARTT Study Infants Overall and by Congenital Anomaly Case Statusa

No significant difference was found in the distribution of CA cases by demographic or socioeconomic characteristics other than birth cohort (Table 1). Cases were more often delivered by cesarean section and more often preterm births than noncases, but no association was observed with higher maternal viral load (HIV RNA concentration >1000 copies/mL) or with tobacco and alcohol or other drug use. The use of selective serotonin reuptake inhibitors was rare during the first trimester, occurring in 30 of 2580 (1.2%), and only one of these infants had a CA. The use of folate antagonists (cotrimoxazole or pyrimethamine) was reported by 107 mothers, 6 (5.6%) of whom had CAs.

Multivariable logistic models for CA case status adjusted for low maternal CD4 count (<250 cells/mm3) early in pregnancy and birth cohort. For musculoskeletal anomalies, adjusted models also included maternal alcohol consumption during the first trimester (adjusted odds ratio [aOR], 2.09; 95% CI, 0.92-4.72). Of 2580 children, 63 (6 cases and 57 noncases) lacked detailed information regarding maternal ARV use needed to identify trimesters of exposure, yielding 2517 children for evaluation of ARV exposures.

Association of In Utero ARV Exposures With CAs

A significantly higher prevalence of CAs was observed for children exposed to HAART (8.1% for exposed vs 5.8% for unexposed) or to PIs (8.5% for exposed vs 5.8% for unexposed) in the first trimester, but these associations did not persist in adjusted models (Table 2). No individual nucleoside reverse transcriptase inhibitors were associated with an increased risk of CAs, but the combination of didanosine plus stavudine, while rare (<1% exposed), was associated with an 8-fold higher odds of CAs. For nonnucleoside reverse transcriptase inhibitors, neither efavirenz nor nevirapine was associated with CAs.

Table Graphic Jump LocationTable 2.  Association of First-Trimester Antiretroviral Exposure With Congenital Anomaliesa

For PIs, a significantly higher prevalence of cases was observed among children exposed to atazanavir (11.7% vs 6.2%), lopinavir (9.4% vs 6.3%), and ritonavir when used as a booster (>99% of use) (9.3% vs 5.8%). Associations persisted in adjusted models for atazanavir and ritonavir (Table 2). Atazanavir was usually used in combination with ritonavir (88.5%) and often with certain nucleoside reverse transcriptase inhibitors. The combinations of atazanavir with ritonavir, tenofovir, or emtricitabine were each associated with an increased risk of CAs, with similar aORs (2.01, 2.00, and 1.85, respectively), while combinations of atazanavir with zidovudine (aOR, 0.89) or lamivudine (aOR, 1.48) showed no significant association. Of the 2 primary regimens that included ritonavir with another PI, atazanavir with ritonavir showed increased odds, while ritonavir-boosted lopinavir did not. Specific anomalies for children exposed to first-trimester atazanavir are listed in eTable 2 in the Supplement.

Associations for ARV exposures at any time during pregnancy indicated a significantly higher risk of CAs for those exposed to the combinations of didanosine plus stavudine or to zidovudine plus lamivudine. When the rate of CAs by timing of the first exposure was examined (eTable 3 in the Supplement), the results were generally consistent with the comparisons of first-trimester exposure. However, for some ARVs the highest prevalence of CAs occurred with the first exposure during the second or third trimester (10.6% for abacavir and 17.1% for stavudine).

Separate analyses conducted by type of anomaly indicated that first-trimester atazanavir exposure was significantly associated with musculoskeletal and skin anomalies (Table 3). Significantly higher odds of musculoskeletal anomalies were observed among infants exposed to didanosine plus stavudine in the first trimester. Ritonavir as a booster was associated with an increased risk of musculoskeletal CAs. We observed a significantly higher odds of male genital anomalies (eg, hypospadias and cryptorchidism) with first-trimester zidovudine exposure and lamivudine exposure.

Table Graphic Jump LocationTable 3.  Analyses Conducted by Type of Anomaly

For some less commonly used ARVs, including raltegravir (1.5% exposed), enfuvirtide (0.3% exposed), maraviroc (0.1% exposed), and etravirine (0.4% exposed), no first-trimester exposures were found. Raltegravir was the only one of these ARVs associated with any CAs, with a rate of 4.2% (3 of 71 exposed at any time during pregnancy) compared with 6.8% for raltegravir unexposed.

Sensitivity Analyses

When restricting cases to children with major anomalies and when excluding 11 children with chromosomal anomalies (eTable 1 in the Supplement), the significant associations with first-trimester atazanavir, ritonavir (as a booster), and the combination of didanosine plus stavudine persisted, with similar estimated effects. Similarly, sensitivity analyses accounting for multiple children per mother and for clustering within research site provided results almost identical to those in Table 2.

In the dynamic cohort, a higher percentage of infants were exposed during the first trimester to HAART (47.2%) and to PIs (41.9%), but none were exposed to didanosine plus stavudine. In adjusted models, no significant associations for first-trimester exposures were observed for the dynamic cohort, and the association for atazanavir was attenuated (aOR, 1.55; 95% CI, 0.91-2.63). However, when ARV exposures at any time during pregnancy were evaluated, significantly higher odds of CAs were observed among infants in the dynamic cohort exposed to lamivudine (aOR, 2.13; 95% CI, 1.26-3.60), zidovudine (aOR, 2.06; 95% CI, 1.23-3.44), zidovudine plus lamivudine (aOR, 2.43; 95% CI, 1.45-4.06), and abacavir (aOR, 1.58; 95% CI, 1.00-2.49). In contrast, a protective association was found with darunavir exposure (aOR, 0.21; 95% CI, 0.05-0.84).

Examination of ARV exposures within the dynamic cohort by trimester of the first exposure indicated that the increased risk for zidovudine, lamivudine, and their combination was observed for both the first and later trimesters compared with those never exposed to these specific ARVs or combinations. The increased risk for abacavir in the dynamic cohort was only observed for those first exposed later in pregnancy compared with abacavir unexposed (aOR, 2.20; 95% CI, 1.31-3.71). For musculoskeletal anomalies, those exposed to first-trimester atazanavir had significantly increased odds of CAs (aOR, 2.49; 95% CI, 1.25-4.95).

We observed an overall prevalence of 6.78 CAs among every 100 live births, which is considerably higher than that in prior studies of HIV-exposed infants in the United States and the United Kingdom, with reported prevalences ranging from 2.8% to 5.5%,47,12,13 and higher than the rate of 3.2% in a recent Italian cohort,10 but it is similar to the 6.2% rate reported by a Latin American study.27 We observed an increasing trend in the rate of CAs from before 2002 through 2010, followed by a slight decline through 2012. The higher rates of CAs may reflect a real increase consistent with temporal trends demonstrated in population studies,28,29 increased ascertainment given the study-required evaluation for anomalies, and longer follow-up than some studies. They may also be partially attributable to the increasing percentage of mothers receiving ARVs early in pregnancy, which was less than 30% in earlier studies4,6,7,12,13 but is approximately 50% of the present cohort.

The association of first-trimester atazanavir exposure with CAs, particularly musculoskeletal and skin anomalies, has not previously been reported to our knowledge and warrants further investigation. The International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 protocol13 also reported higher rates of CAs with first-trimester atazanavir exposure (9.2% vs 5.3% for atazanavir unexposed; aOR, 1.83), although not attaining significance. Most prior studies included births before 2007 and did not reflect the increasing use of this particular ARV up to 20% by 2010 since its 2003 approval.16 Furthermore, exposures to particular ARV combinations may be associated with higher risks. We observed higher odds of CAs for first-trimester atazanavir exposure when combined with ritonavir, tenofovir, or emtricitabine, all with increased use during the past decade,1618 than with older ARVs (zidovudine or lamivudine). In contrast, when ritonavir was used to boost PIs other than atazanavir (primarily lopinavir), it was not associated with higher odds. Finally, while various specific anomalies were reported for atazanavir-exposed children, the increased risk was highest for musculoskeletal and skin anomalies of generally milder severity.

In contrast to some prior studies,12,13 we observed no association of CAs with first-trimester efavirenz exposure. A meta-analysis30 also found no increased risk of overall CAs with efavirenz exposure. We confirmed an increased risk of male genital anomalies with first-trimester zidovudine exposure6,31; this association remained marginally significant in the dynamic cohort and was thus not entirely attributable to overlap with prior studies.

Our study has several strengths, including its large size, the use of the well-validated MACDP classification system, and complete information on maternal health, substance use, and pregnancy complications. We also considered other medications used during pregnancy such as selective serotonin reuptake inhibitors and folate antagonists. However, a limitation of our study is the possibility of selection bias: mothers of static cohort infants with CAs may have been more willing to participate, which could have artificially increased the prevalence of CAs and may have accounted for the higher rate during 2005 to 2010 compared with more recent years. Conversely, allowing enrollment up to 1 week after birth may exclude infants with severe CAs incompatible with life. In addition, the MACDP classification system, while providing specific objective criteria for identifying anomalies, may not allow discrimination by defect severity. Misclassification and lack of specificity of CA outcomes, as well as potential exposure misclassification, could have resulted in attenuation of findings; therefore, we evaluated specific CAs and both individual ARVs and combinations of ARVs in increasing use.

In conclusion, our study was reassuring in confirming the lack of an increased risk of CAs among children exposed to ARVs during the first trimester of pregnancy. We observed a higher prevalence of CAs than has been reported in the general population, but after adjustment for calendar year and maternal characteristics, no relative increase in risk was observed for those exposed vs unexposed to HAART or to PI-based regimens early in pregnancy. However, while the absolute risk of CAs was low, some individual drugs, particularly atazanavir, showed relative increases in the risk of overall CAs and specific anomalies, which warrant further study. As World Health Organization 2013 ARV guidelines are implemented globally, an increasing percentage of women with HIV will be expected to enter pregnancy already receiving ARVs.32 Therefore, risks associated with in utero ARV exposures must be considered to identify optimal regimens based on their safety profiles.

Accepted for Publication: July 31, 2014.

Corresponding Author: Paige L. Williams, PhD, Department of Biostatistics, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115 (paige@sdac.harvard.edu).

Published Online: November 10, 2014. doi:10.1001/jamapediatrics.2014.1889.

Author Contributions: Drs Williams and Watts were the primary authors who conceived and designed the study. Dr Williams had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Williams, Hazra, Van Dyke, Rich, Read, Stuard, Rathore, Mendez, Watts.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Williams.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Williams.

Obtained funding: Van Dyke.

Administrative, technical, or material support: Williams, Yildirim, Van Dyke, Rich, Read, Stuard, Rathore, Mendez, Watts.

Study supervision: Williams, Van Dyke.

Conflict of Interest Disclosures: Tulane University receives financial support from Gilead Sciences for partial support of the Pediatric HIV/AIDS Cohort Study. Dr Van Dyke receives no salary support or other funds from this funding source. No other disclosures were reported.

Funding/Support: The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard School of Public Health (HD052102, 3 U01 HD052102-05S1, and 3 U01 HD052102-06S3) (principal investigator George Seage and project director Julie Alperen) and the Tulane University School of Medicine (HD052104 and 3U01HD052104-06S1) (principal investigator Russell B. Van Dyke, coprincipal investigator Kenneth Rich, and project director Patrick Davis). Data management services were provided by the Frontier Science and Technology Research Foundation, Inc (principal investigator Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (principal investigator Julie Davidson).

Role of the Funder/Sponsor: Under the above cooperative agreements, representatives of the National Institutes of Health were part of the study team; therefore, the sponsor was involved in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, and approval of the manuscript.

Disclaimer: The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or the US Department of State.

Additional Contributions: We thank the children and families for their participation in the Pediatric HIV/AIDS Cohort Study, as well as the individuals and institutions involved in the conduct of the study.

Group Information: The following institutions (in alphabetical order), clinical site investigators, and staff participated in conducting the Pediatric HIV/AIDS Cohort Study’s Surveillance Monitoring of ART Toxicities Study in 2012: Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, and Lynette Harris; Bronx-Lebanon Hospital Center: Murli Purswani, Emma Stuard, and Anna Cintron; Children’s Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Doyle Patton, and Deyana Leon; Ann & Robert H. Lurie Children’s Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, and Scott Hunter; New York University School of Medicine: William Borkowsky, Sandra Deygoo, and Helen Rozelman; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Lourdes Angeli-Nieves, and Vivian Olivera; State University of New York Downstate Medical Center: Hermann A. Mendez, Ava Dennie, and Susan Bewley; St Jude Children’s Research Hospital: Katherine Knapp, Kim Allison, and Megan Wilkins; Tulane University Health Sciences Center: Russell B. Van Dyke, Karen Craig, and Patricia Sirois; University of Alabama at Birmingham: Marilyn J. Crain, Newana Beatty, and Dan Marullo; University of California, San Diego: Stephen Spector, Jean Manning, and Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, and Robin McEvoy; University of Florida, Jacksonville: Mobeen Rathore, Kristi Stowers, and Ann Usitalo; University of Illinois at Chicago: Kenneth Rich, Lourdes Richardson, Delmyra Turpin, and Renee Smith; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, and Susan Adubato; University of Miami: Gwendolyn Scott, Claudia Florez, and Elizabeth Willen; University of Puerto Rico Medical Center: Zoe Rodriguez, Ibet Heyer, and Nydia Scalley Trifilio; and University of Southern California: Toinette Frederick, Mariam Davtyan, and Maribel Mejia.

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Brogly  SB, Abzug  MJ, Watts  DH,  et al.  Birth defects among children born to human immunodeficiency virus–infected women: Pediatric AIDS Clinical Trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727.
PubMed   |  Link to Article
Knapp  KM, Brogly  SB, Muenz  DG,  et al.  Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170.
PubMed   |  Link to Article
De Santis  M, Carducci  B, De Santis  L, Cavaliere  AF, Straface  G.  Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med. 2002;162(3):355.
PubMed   |  Link to Article
Saitoh  A, Hull  AD, Franklin  P, Spector  SA.  Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. 2005;25(8):555-556.
PubMed   |  Link to Article
Griner  R, Williams  PL, Read  JS,  et al; Pediatric HIV/AIDS Cohort Study.  In utero and postnatal exposure to antiretrovirals among HIV-exposed but uninfected children in the United States. AIDS Patient Care STDS. 2011;25(7):385-394.
PubMed   |  Link to Article
Phiri  K, Fischer  MA, Mogun  H,  et al.  Trends in antiretroviral drug use during pregnancy among HIV-infected women on Medicaid: 2000-2007. AIDS Patient Care STDS. 2014;28(2):56-65.
PubMed   |  Link to Article
Floridia  M, Ravizza  M, Guaraldi  G, Pinnetti  C, Martinelli  P, Tamburrini  E; Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy.  Use of specific antiretroviral regimens among HIV-infected women in Italy at time of conception: 2001-2011. AIDS Patient Care STDS. 2012;26(8):439-443.
PubMed   |  Link to Article
Williams  PL, Seage  GR  III, Van Dyke  RB,  et al; Pediatric HIV/AIDS Cohort Study.  A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of HIV-infected mothers. Am J Epidemiol. 2012;175(9):950-961.
PubMed   |  Link to Article
Hernán  MA, Hernández-Díaz  S, Werler  MM, Mitchell  AA.  Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol. 2002;155(2):176-184.
PubMed   |  Link to Article
Wilcox  AJ, Weinberg  CR, Basso  O.  On the pitfalls of adjusting for gestational age at birth. Am J Epidemiol. 2011;174(9):1062-1068.
PubMed   |  Link to Article
Louik  C, Lin  AE, Werler  MM, Hernández-Díaz  S, Mitchell  AA.  First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356(26):2675-2683.
PubMed   |  Link to Article
Huybrechts  KF, Palmsten  K, Avorn  J,  et al.  Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-2407.
PubMed   |  Link to Article
de Jonge  L, Zetstra-van der Woude  PA, Bos  HJ, de Jong-van den Berg  LT, Bakker  MK.  Identifying associations between maternal medication use and birth defects using a case-population approach: an exploratory study on signal detection. Drug Saf. 2013;36(11):1069-1078.
PubMed   |  Link to Article
van Gelder  MM, de Jong-van den Berg  LT, Roeleveld  N.  Drugs associated with teratogenic mechanisms. Part II: a literature review of the evidence on human risks. Hum Reprod. 2014;29(1):168-183.
PubMed   |  Link to Article
Tassiopoulos  K, Read  JS, Brogly  S,  et al.  Substance use in HIV-infected women during pregnancy: self-report versus meconium analysis. AIDS Behav. 2010;14(6):1269-1278.
PubMed   |  Link to Article
Joao  EC, Calvet  GA, Krauss  MR,  et al; NISDI Perinatal Study Group.  Maternal antiretroviral use during pregnancy and infant congenital anomalies: the NISDI Perinatal Study. J Acquir Immune Defic Syndr. 2010;53(2):176-185.
PubMed   |  Link to Article
Cambra  K, Ibañez  B, Urzelai  D,  et al.  Trends in the prevalences of congenital anomalies and age at motherhood in a southern European region: a population-based study. BMJ Open. 2014;4(3):e004244. doi:10.1136/bmjopen-2013-004244.
PubMed   |  Link to Article
Richard-Tremblay  AA, Sheehy  O, Bérard  A.  Annual trends in use of periconceptional folic acid and birth prevalence of major congenital malformations. Curr Drug Saf. 2013;8(3):153-161.
PubMed   |  Link to Article
Ford  N, Calmy  A, Mofenson  L.  Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2011;25(18):2301-2304.
PubMed   |  Link to Article
Agopian  AJ, Langlois  PH, Ramakrishnan  A, Canfield  MA.  Epidemiologic features of male genital malformations and subtypes in Texas. Am J Med Genet A. 2014;164A(4):943-949.
PubMed   |  Link to Article
Ishikawa  N, Shimbo  T, Miyano  S,  et al.  Health outcomes and cost impact of the new WHO 2013 guidelines on prevention of mother-to-child transmission of HIV in Zambia. PLoS One. 2014;9(3):e90991. doi:10.1371/journal.pone.0090991.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Demographic and Maternal Characteristics of 2580 SMARTT Study Infants Overall and by Congenital Anomaly Case Statusa
Table Graphic Jump LocationTable 2.  Association of First-Trimester Antiretroviral Exposure With Congenital Anomaliesa
Table Graphic Jump LocationTable 3.  Analyses Conducted by Type of Anomaly

References

Townsend  CL, Cortina-Borja  M, Peckham  CS, de Ruiter  A, Lyall  H, Tookey  PA.  Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS. 2008;22(8):973-981.
PubMed   |  Link to Article
Watts  DH.  Treating HIV during pregnancy: an update on safety issues. Drug Saf. 2006;29(6):467-490.
PubMed   |  Link to Article
Patel  D, Thorne  C, Fiore  S, Newell  ML; European Collaborative Study.  Does highly active antiretroviral therapy increase the risk of congenital anomalies in HIV-infected women? J Acquir Immune Defic Syndr. 2005;40(1):116-118.
PubMed   |  Link to Article
Townsend  CL, Willey  BA, Cortina-Borja  M, Peckham  CS, Tookey  PA.  Antiretroviral therapy and congenital abnormalities in infants born to HIV-infected women in the UK and Ireland, 1990-2007. AIDS. 2009;23(4):519-524.
PubMed   |  Link to Article
Antiretroviral Pregnancy Registry. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2013. 2013. http://www.apregistry.com/forms/interim_report.pdf. Accessed September 17, 2014.
Watts  DH, Li  D, Handelsman  E,  et al.  Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr. 2007;44(3):299-305.
PubMed   |  Link to Article
Watts  DH, Huang  S, Culnane  M,  et al.  Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication. J Perinat Med. 2011;39(2):163-170.
PubMed   |  Link to Article
Covington  DL, Conner  SD, Doi  PA, Swinson  J, Daniels  EM.  Risk of birth defects associated with nelfinavir exposure during pregnancy. Obstet Gynecol. 2004;103(6):1181-1189.
PubMed   |  Link to Article
Roberts  SS, Martinez  M, Covington  DL, Rode  RA, Pasley  MV, Woodward  WC.  Lopinavir/ritonavir in pregnancy. J Acquir Immune Defic Syndr. 2009;51(4):456-461.
PubMed   |  Link to Article
Floridia  M, Mastroiacovo  P, Tamburrini  E,  et al; Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy.  Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011. BJOG. 2013;120(12):1466-1475.
PubMed
Phiri  K, Hernandez-Diaz  S, Dugan  KB,  et al.  First trimester exposure to antiretroviral therapy and risk of birth defects. Pediatr Infect Dis J. 2014;33(7):741-746.
PubMed   |  Link to Article
Brogly  SB, Abzug  MJ, Watts  DH,  et al.  Birth defects among children born to human immunodeficiency virus–infected women: Pediatric AIDS Clinical Trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727.
PubMed   |  Link to Article
Knapp  KM, Brogly  SB, Muenz  DG,  et al.  Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170.
PubMed   |  Link to Article
De Santis  M, Carducci  B, De Santis  L, Cavaliere  AF, Straface  G.  Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med. 2002;162(3):355.
PubMed   |  Link to Article
Saitoh  A, Hull  AD, Franklin  P, Spector  SA.  Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. 2005;25(8):555-556.
PubMed   |  Link to Article
Griner  R, Williams  PL, Read  JS,  et al; Pediatric HIV/AIDS Cohort Study.  In utero and postnatal exposure to antiretrovirals among HIV-exposed but uninfected children in the United States. AIDS Patient Care STDS. 2011;25(7):385-394.
PubMed   |  Link to Article
Phiri  K, Fischer  MA, Mogun  H,  et al.  Trends in antiretroviral drug use during pregnancy among HIV-infected women on Medicaid: 2000-2007. AIDS Patient Care STDS. 2014;28(2):56-65.
PubMed   |  Link to Article
Floridia  M, Ravizza  M, Guaraldi  G, Pinnetti  C, Martinelli  P, Tamburrini  E; Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy.  Use of specific antiretroviral regimens among HIV-infected women in Italy at time of conception: 2001-2011. AIDS Patient Care STDS. 2012;26(8):439-443.
PubMed   |  Link to Article
Williams  PL, Seage  GR  III, Van Dyke  RB,  et al; Pediatric HIV/AIDS Cohort Study.  A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of HIV-infected mothers. Am J Epidemiol. 2012;175(9):950-961.
PubMed   |  Link to Article
Hernán  MA, Hernández-Díaz  S, Werler  MM, Mitchell  AA.  Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol. 2002;155(2):176-184.
PubMed   |  Link to Article
Wilcox  AJ, Weinberg  CR, Basso  O.  On the pitfalls of adjusting for gestational age at birth. Am J Epidemiol. 2011;174(9):1062-1068.
PubMed   |  Link to Article
Louik  C, Lin  AE, Werler  MM, Hernández-Díaz  S, Mitchell  AA.  First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356(26):2675-2683.
PubMed   |  Link to Article
Huybrechts  KF, Palmsten  K, Avorn  J,  et al.  Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-2407.
PubMed   |  Link to Article
de Jonge  L, Zetstra-van der Woude  PA, Bos  HJ, de Jong-van den Berg  LT, Bakker  MK.  Identifying associations between maternal medication use and birth defects using a case-population approach: an exploratory study on signal detection. Drug Saf. 2013;36(11):1069-1078.
PubMed   |  Link to Article
van Gelder  MM, de Jong-van den Berg  LT, Roeleveld  N.  Drugs associated with teratogenic mechanisms. Part II: a literature review of the evidence on human risks. Hum Reprod. 2014;29(1):168-183.
PubMed   |  Link to Article
Tassiopoulos  K, Read  JS, Brogly  S,  et al.  Substance use in HIV-infected women during pregnancy: self-report versus meconium analysis. AIDS Behav. 2010;14(6):1269-1278.
PubMed   |  Link to Article
Joao  EC, Calvet  GA, Krauss  MR,  et al; NISDI Perinatal Study Group.  Maternal antiretroviral use during pregnancy and infant congenital anomalies: the NISDI Perinatal Study. J Acquir Immune Defic Syndr. 2010;53(2):176-185.
PubMed   |  Link to Article
Cambra  K, Ibañez  B, Urzelai  D,  et al.  Trends in the prevalences of congenital anomalies and age at motherhood in a southern European region: a population-based study. BMJ Open. 2014;4(3):e004244. doi:10.1136/bmjopen-2013-004244.
PubMed   |  Link to Article
Richard-Tremblay  AA, Sheehy  O, Bérard  A.  Annual trends in use of periconceptional folic acid and birth prevalence of major congenital malformations. Curr Drug Saf. 2013;8(3):153-161.
PubMed   |  Link to Article
Ford  N, Calmy  A, Mofenson  L.  Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2011;25(18):2301-2304.
PubMed   |  Link to Article
Agopian  AJ, Langlois  PH, Ramakrishnan  A, Canfield  MA.  Epidemiologic features of male genital malformations and subtypes in Texas. Am J Med Genet A. 2014;164A(4):943-949.
PubMed   |  Link to Article
Ishikawa  N, Shimbo  T, Miyano  S,  et al.  Health outcomes and cost impact of the new WHO 2013 guidelines on prevention of mother-to-child transmission of HIV in Zambia. PLoS One. 2014;9(3):e90991. doi:10.1371/journal.pone.0090991.
PubMed   |  Link to Article

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Multimedia

Supplement.

eTable 1. Frequency of Specific Major Congenital Anomalies Within Anomaly Categories

eTable 2. Anomalies Reported Among Children Exposed to Atazanavir During the First Trimester

eTable 3. Association of Timing of the First ARV Exposure During Pregnancy With Congenital Anomalies by ARV Drug Class and for Specific ARV Drugs

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