Despite the success of combination antiretroviral regimens used during pregnancy in reducing HIV transmission [1–4][1–4][1–4][1–4], concerns remain regarding adverse consequences of in-utero exposure to antiretrovirals [5–7][5–7][5–7]. Numerous manifestations of antiretroviral toxicity have been reported in adults and children with HIV; however, there are fewer reports of toxicities in infants born to mothers with HIV infection and exposed to antiretrovirals through transplacental passage of the drugs . Mitochondrial toxicity is postulated to be one possible mechanism for these events in exposed infants, and can manifest as a variety of clinical and laboratory abnormalities, including hematologic and liver function, myopathy, and central nervous system disorders [8–17][8–17][8–17][8–17][8–17][8–17][8–17][8–17][8–17][8–17]. Drug-specific disorders such as anemia after exposure to maternal zidovudine or combination antiretroviral regimens have also been reported [7,18–20][7,18–20][7,18–20][7,18–20]. Serious adverse effects have been uncommon and may be difficult to distinguish from pregnancy complications such as preeclampsia or prematurity , or other maternal exposures such as illicit drugs, alcohol, tobacco, or HIV infection itself .
Current treatment guidelines for children with in-utero or neonatal antiretroviral exposures recommend that those who develop clinical problems of unknown etiology be evaluated for potential mitochondrial dysfunction, and that follow-up of children with exposure to antiretrovirals continue into adulthood because of concerns of carcinogenicity of nucleoside analogue antiretroviral drugs . Thus, it is important to provide long-term follow-up of children exposed in utero to antiretrovirals to systematically examine a wide spectrum of clinical and laboratory outcomes.
In order to conduct safety monitoring in a rigorous yet cost-effective manner, the Pediatric HIV/AIDS Cohort Study (PHACS) network established the Surveillance Monitoring of ART Toxicities (SMARTT) Study, to identify potential adverse effects of antiretroviral exposures in infants born to HIV-infected women, and to evaluate associations with antiretroviral combinations and specific antiretroviral drugs in order to help inform treatment guidelines for HIV-infected pregnant women [23,24][23,24]. The SMARTT study uses a trigger-based design, which provides efficient use of study and patient resources. This design provides greater precision of estimated adverse event rates by concentrating on those children most likely to have adverse events, as compared with randomly selecting a subgroup of children to study with detailed assessments .
In the SMARTT study, potential adverse effects in multiple domains, such as growth and neurological outcomes, were selected based on literature review and clinical experience. For each domain, trigger thresholds were defined which dictated additional prespecified evaluations. The results of these evaluations were reviewed by a group of clinicians and epidemiologists to determine whether the child met the definition of a “case”, a condition in one or more domains that could result from intrauterine exposure to ART. In this article, we evaluated the association of antiretroviral exposures with overall case status as well as within specific domains which may reflect adverse effects of antiretroviral exposures.
Description of protocol and study population
The PHACS SMARTT study includes two cohorts: the static and dynamic cohorts. Static cohort children and their mothers (or caregivers) were eligible if the youth were age 1 to 12 years at entry and had detailed information on maternal antiretroviral use during pregnancy and infant outcomes from prior prospective studies (PACTG 219C  and the Women and Infants Transmission Study ). The dynamic cohort of HIV-infected women and their infants enrolled between 22 weeks gestation and 1 week after delivery. Both cohorts opened to participating sites in the United States including Puerto Rico in March 2007. The static cohort completed enrollment in 2010 whereas the dynamic cohort continues to enroll. The SMARTT protocol was approved by Human Subject research review boards at each of the participating sites and at the Harvard T. H. Chan School of Public Health. Written informed consent was obtained from the parent or legal guardian at each research site.
At study entry, clinical diagnoses and dates of prenatal antiretroviral use were obtained from medical charts and participant interview. Birth characteristics (gestational age, birth weight, and mode of delivery) were abstracted and maternal HIV disease characteristics were collected both early during pregnancy (earliest available) and prior to delivery, including plasma HIV RNA concentration (viral load), absolute CD4+ lymphocyte (CD4+) cell counts, and CD4%. Trimester-specific information on substance use during pregnancy was obtained by self-reported questionnaire, including alcohol, tobacco, marijuana, opiates, and other substances, as previously described . Caregivers of participating children completed questionnaires on household composition, education and income levels, past history of psychiatric diagnoses or substance use, and other information related to family environment. After enrollment, children and their mothers or caregivers were followed at annual study visits. A complete physical examination was conducted including anthropometric assessments (height, weight, BMI, and skinfold measurements), abstraction of any new diagnoses or illnesses obtained from the medical chart or interview, and collection of limited laboratory measurements including point-of-care capillary blood lactate assessments . Cognitive, hearing, and language assessments were conducted at specified ages.
The study team defined multiple domains reflecting potential adverse effects of antiretroviral exposure during pregnancy based on expert input and existing literature. These included low growth, neurology, neurodevelopment, language, hearing, metabolic, basic hematology and chemistry studies (including liver and renal function tests), and blood lactate. For each domain, a study “trigger” was established using a noninvasive or inexpensive laboratory or clinical evaluation. For example, a metabolic trigger was defined as a BMI exceeding the age- and sex-specific 95th percentile for children aged 2 years or older. The criteria for triggers are provided in Table 1. As described previously , trigger thresholds were chosen to achieve high sensitivity at the expense of lower specificity for identifying potential adverse events, because as a safety study it was desirable to capture all children who might have adverse events related to antiretroviral exposures.
Children who met the study trigger for a particular domain had additional prespecified assessments, such as laboratory testing and evaluation by an appropriate specialist (Table 1). The results of the triggered evaluations were reviewed by the SMARTT Review Panel, a group of clinical and epidemiological experts, using predefined “case” definitions for adverse events in each of the target domains. Following these strict criteria, the Panel determined whether each study participant who met a trigger also met the corresponding case definition for adverse events, while blinded to the specific antiretroviral regimens mothers used during pregnancy. For example, children meeting the metabolic trigger were defined as metabolic “cases” if they had abnormal lipid levels or insulin resistance on further testing. For some domains, a small percentage of participants met a trigger but did not have the follow-up assessments needed to determine case status; these children were not considered evaluable for case determination.
The primary exposure of interest was in-utero antiretroviral exposure. Children were classified according to exposure to antiretroviral drug classes, to combination antiretroviral regimens including HAART (defined as ≥3 drugs from ≥2 classes), and to specific antiretroviral agents. The reference group consisted of children unexposed to the specific antiretroviral drug class or drug being considered. As the critical windows of exposure during pregnancy for most domains are unknown, we also evaluated antiretroviral exposures by trimester of first exposure.
We identified potential confounders based on past literature and descriptive statistics from our cohort, using directed acyclic graphs (see Supplemental Figure 1, http://links.lww.com/QAD/A803) [28–30][28–30][28–30]. We considered the following maternal covariates to be potential confounders: age and race, prepregnancy BMI, chronic health conditions such as pregestational diabetes, HIV viral load and CD4+ cell counts early in pregnancy, and first trimester substance use (including alcohol, tobacco, and illicit drugs ). In addition, socioeconomic measures were evaluated including household income and caregiver education levels. We descriptively summarized pregnancy outcome [low birth weight (LBW, <2500 g), preterm birth (<37 weeks gestation) and mode of birth (vaginal or cesarean delivery)] by case status, but our primary analyses excluded these characteristics and also maternal health measures later in pregnancy, as they may be on the causal pathway given prior evidence of their association with maternal antiretrovirals [21,23,26][21,23,26][21,23,26].
Rates of adverse events and exact 95% confidence intervals (CIs) were estimated overall and by domain. Unadjusted and adjusted log-binomial regression models were used to obtain relative risks (RR) for associations between antiretroviral exposures and case status. Separate analyses were also conducted within the following domains: neurologic, neurodevelopmental, a combined neurologic/neurodevelopmental domain (case in either the neurologic or neurodevelopmental domain), metabolic, growth, and language. Other domains (laboratory, hearing, and blood lactate) had too few cases and were not considered separately. Covariates identified a priori as potential confounders and with P < 0.20 in unadjusted models for case status were included in initial multivariable models, and those with P < 0.10 and/or which changed antiretroviral exposure estimates by more than 10% were retained in final adjusted models.
Sensitivity analyses were conducted further adjusting for LBW to evaluate the impact on findings, and restricting to those who were exposed to HAART during pregnancy to limit potential selection bias. In addition, sensitivity analyses were conducted to account for children with the same mother/caregiver and clustering at the same clinical research site. Analyses were also conducted restricted to the dynamic cohort, which includes only those mother/infant pairs followed prospectively since birth. Last of all, although time-to-event models were not appropriate for evaluating overall case status due to differential timing of age-specific tests (in neurodevelopment, language, and hearing domains) relative to age at entry, incidence rate analyses were conducted using Poisson regression models for domains evaluated at every study visit (metabolic from age 2 years, neurologic, and growth).
Characteristics of study population
A total of 2680 SMARTT participants (1198 from the static cohort and 1482 from the dynamic cohort) were enrolled and had trigger data submitted as of 31 December 2012 and were thus considered evaluable (see Table 2). After a median follow of 2.4 years (range 0.1–5.7 years), almost half (47.8%) met a trigger in at least one domain and 25% met the criteria for a case in at least one domain. Overall, 48% of the participants were female, 66% Black, and 33% Hispanic. As reported previously, there is a high rate of prematurity (21%) and LBW (19%) in this population . Tobacco and alcohol use during pregnancy were relatively common (19 and 8%, respectively), although hard drug use (cocaine, heroin, or opium) was relatively rare (3%).
There was a significant difference in case status by birth cohort and race, with a higher percentage of cases born in earlier years and among white and Hispanic participants. There were also differences in prevalence of cases by other socio-demographic factors (caregiver marital status and education), but not by maternal HIV status (CD4+ or viral load) or substance use. The most commonly met triggers were metabolic (28.8%) and reduced growth (18.5%), and the least common were laboratory triggers (Table 1). Cases were most often met in the language (13.2%) and metabolic (11.4%) domains. Overall, 52% of those meeting a trigger and evaluated for case status met the case definition, ranging from 9 to 99% for different domains (Table 1).
Association of demographic and maternal characteristics with case occurrence
A summary of covariates included in adjusted models for overall case status and for each separate domain is provided in Supplemental Table 1, http://links.lww.com/QAD/A802. The final model for overall case status included protective effects of black race or Puerto Rican origin and later birth cohort (2010 or later vs. <2010) and increased risk of case status for those with low caregiver education and maternal tobacco use in the first trimester. LBW was associated with 42% increased risk of case status (95% CI: 22%, 65%) and was included in sensitivity analyses. For models fit within specific domains, first trimester tobacco was associated with higher risk of neurologic, neurologic/neurodevelopmental, and growth cases, low caregiver education was associated with case status in the neurologic/neurodevelopmental and language domains, and pregestational diabetes was associated with case status in the neurologic, neurologic/neurodevelopmental, and metabolic domains.
Association of in-utero antiretroviral exposures with case occurrence
The unadjusted and adjusted associations of in-utero antiretroviral exposures with overall case status are summarized in Table 3 and Fig. 1 for exposures at any time during pregnancy. In unadjusted models, exposure to a HAART regimen and to specific antiretrovirals including emtricitabine, tenofovir, raltegravir, atazanavir, darunavir, and ritonavir (as a booster) were each associated with protective effects on risk of case status, whereas exposures to zidovudine and nelfinavir were associated with significantly higher risks. However, after adjustment, there was no association of any antiretroviral regimen, drug class, or individual antiretroviral drug with overall case status, and adjusted RRs were very close to 1 (Fig. 1). Findings were similar when evaluated by trimester of the first antiretroviral exposure. HAART and exposure to the same individual antiretrovirals in the first trimester were associated with lower risk of case status in unadjusted models, but not after adjusting for birth cohort and other factors (Supplemental Table 2, http://links.lww.com/QAD/A802). Zidovudine (either first or second/third trimester vs. unexposed) and first trimester exposure to either nelfinavir or stavudine were associated with increased risk in unadjusted models (RRs of 1.31 to 1.47), but not after adjustment. Although rarely used, first exposure to fosamprenavir later in pregnancy (second or third trimester, 1.2% exposed) was associated with increased risk of overall case status [adjusted RR (aRR)=1.73, 95% CI: 1.23, 2.43].
Association of in-utero antiretroviral exposures with case occurrence in specific domains
Across individual domains, few significant associations of any drug class or individual antiretroviral with increased risk of case status were observed in adjusted models (Table 4). However, zidovudine exposure was associated with increased risk of metabolic case in both unadjusted and adjusted models. The combination of didanosine plus stavudine, although now rarely used (<1% exposed), was associated with a 12-fold higher risk of a neurodevelopmental case, and almost five-fold higher risk of language case. First trimester stavudine exposure was also associated with a two-fold increased risk of a language case, with similar (though nonsignificant) RR for overall stavudine exposure. When the combined outcome of either neurologic or neurodevelopmental case status was evaluated, there was an increased risk with didanosine exposure (aRR = 2.16, 95% CI: 1.14, 4.10) for first trimester exposure; aRR = 1.75, 95% CI: 0.99, 3.08 for overall exposure), and similar magnitude associations within both individual domains. However, for other antiretroviral drugs, associations were occasionally in opposite directions for these two domains; for example, nonnucleoside reverse transcriptase inhibitors (NNRTIs) were associated with marginally increased risk for neurologic case but decreased risk for neurodevelopmental impairment.
Certain individual antiretrovirals were associated with significant protective effects in adjusted models, particularly for metabolic cases (Table 4). Only 4.7% of participants met case criteria in more than one domain. Although this outcome was hypothesized to be a more specific indicator of an antiretroviral-associated adverse outcome, no antiretroviral drug classes or individual drugs were associated with increased risk of case status in multiple domains. Efavirenz was associated with increased risk of neurologic case, and lopinavir with language impairment, although neither attained statistical significance (Table 4).
Although LBW was strongly associated with case status, further adjustment for LBW in addition to the other covariates yielded results very similar to those in Table 3 (not shown), suggesting that LBW did not play a role as a mediator or confounder. The difference between unadjusted and adjusted RRs was primarily attributable to adjustment for birth cohort.
Analyses restricted to the 2132 HAART-exposed children yielded similar results to those presented in Table 3. The same six antiretroviral drugs showed protective associations in unadjusted but not in adjusted models, and both zidovudine and nelfinavir continued to be associated with increased risk in unadjusted but not in adjusted models. Analyses accounting for clustering of children within the same family or research site also yielded results very similar to those in Table 3, with no associations observed for any antiretroviral drug or drug class with case status. Within the dynamic cohort, there were again no associations between in-utero antiretroviral exposures and case status based in adjusted models controlling for race and birth cohort (Supplemental Table 3, http://links.lww.com/QAD/A802).
For individual domains evaluated at each study visit (growth, neurologic, and metabolic), Poisson regression models for comparison of incidence rates confirmed previous findings based on RRs (which do not account for follow-up time). More specifically, zidovudine exposure was associated with higher incidence of metabolic cases (incidence rate = 6.10 vs. 3.88 cases per 100 person-years for zidovudine-exposed vs. unexposed), which persisted after adjustment [adjusted incidence rate ratio (aIRR) = 1.61, 95% CI: 1.01, 2.58, P = 0.047; see Supplemental Table 4, http://links.lww.com/QAD/A802]. HAART and lopinavir exposure were also confirmed to have protective associations with incidence of metabolic cases. Children exposed to efavirenz had higher incidence of neurologic cases (incidence rate = 4.89 vs. 2.78 cases per 100 person-years), although this difference did not attain statistical significance before or after adjustment (aIRR = 1.77, 95% CI: 0.95, 3.28, P = 0.069).
We developed the SMARTT study as a surveillance system for monitoring potential toxicities related to intrauterine antiretroviral exposures in infants born to mothers with HIV infection. Overall, our findings were very reassuring and suggested no increased risk of adverse event case status for any antiretroviral drug class or individual drug. Not only were no associations detected, but adjusted risk ratios were very close to 1. From a safety perspective, the lack of association is important; given both the size of this study and the relatively high background rate of adverse outcome (25%), there was high power to detect relatively small differences (5–8% increase in case prevalence at 80% power, depending on percentage exposed).
Although no associations with overall case status were observed, some isolated findings for specific outcomes and specific antiretroviral drugs were noted. In particular, didanosine was associated with increased risk of both neurologic and neurodevelopmental cases, whether used early in pregnancy or at any time during pregnancy. In addition, the combination of didanosine plus stavudine, although rarely used (<1%), was associated with greater than a 12-fold increased risk of a neurodevelopmental case, and stavudine was also associated with a higher risk of language impairment. The high potential for mitochondrial toxicity, including lactic acidosis, during pregnancy with didanosine plus stavudine has led to recommendations against use of this combination . Other mechanisms of toxicity, such as epigenetic effects and metabolic toxicities, may also play a role [38–40][38–40][38–40]. Although previous animal studies and case reports have noted potential associations of in-utero efavirenz exposure with neural tube defects or other neurological outcomes [31–33][31–33][31–33], we observed only slightly elevated risk of neurological case (9.8% for EFV-exposed vs. 6.0% for EFV-unexposed) which did not attain statistical significance.
Metabolic cases, reflecting both obesity and either dyslipidemia or insulin resistance, were most consistently associated with individual antiretroviral drugs and regimens. Zidovudine was associated with increased risk of metabolic cases whereas several other NRTIs, protease inhibitors as a class, and individual protease inhibitors showed protective associations. The protective findings for in-utero exposure to protease inhibitors and metabolic outcomes are in contrast to the elevated risk of dyslipidemia observed in HIV-infected children treated with protease inhibitors . Most youth (70%) were exposed to protease inhibitors as part of effective combination therapy, and these protective associations may have been partially attributable to residual confounding as mothers not using protease inhibitors may have differed in ways not accounted for by our covariate adjustment.
One of the most striking findings of our study was the high background rate of adverse events meeting the criteria for “cases” in this population. The most common domains within which cases were observed were metabolic and language, with over 10% of youth affected; the high rates of these conditions may partially reflect other risk factors associated with home environment, socioeconomic status, and nutrition within our cohort, but these rates are likely representative of youth born to HIV-infected mothers in the United States and other high resource settings.
The adverse outcomes of interest in this evaluation did not include pregnancy outcomes such as preterm birth, LBW, and congenital anomalies, which have been addressed in separate reports [21,35,36][21,35,36][21,35,36]. A comprehensive safety assessment must consider a wide range of possible adverse outcomes. However, we evaluated multiple domains of interest which could reflect mitochondrial dysfunction, epigenetic effects, or other mechanisms of toxicity related to intrauterine exposures [38–40][38–40][38–40]. A potential limitation of our trigger-based approach is that it may have missed certain adverse events, and all domains were treated equally which may not reflect the relative clinical significance of toxicities across different domains. In addition, antiretroviral drugs could have opposing effects on different domains, which would tend to obscure associations with overall case status. Further in-depth evaluations of separate domains are still warranted. In addition, older children typically had longer follow-up and thus greater numbers of trigger evaluations; this may have led to increased risk in unadjusted analyses for “older” antiretroviral drugs like zidovudine and nelfinavir. We accounted for this by controlling for birth cohort and conducting time-to-event analyses for domains evaluated at every visit, which yielded consistent findings. Nonetheless, strengths of our study were the systematic evaluation and classification of adverse outcomes blinded to antiretroviral exposure over multiple domains, the large size and long-term follow-up, and the ability to control for many other potential confounders such as maternal health and substance use. As more women with HIV enter pregnancy already on antiretroviral based on current recommendations, there is a critical need to identify optimal regimens for both maternal and child safety in surveillance studies such as SMARTT.
We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. We recognize the contributions of the members of the SMARTT Review Panel: Pim Brouwers, Laurie Butler, Lucy Civitello, Marilyn Crain, Carol Elgie, Angela Ellis, Rohan Hazra, Kenneth Rich, George Seage, George Siberry, Russell Van Dyke, Paige Williams, and Cenk Yildirim.
Author contributions: P.L.W., R.H., R.B.V., K.R., M.J.C., and G.R.S. conceived the study design. P.L.W. conducted statistical analyses and took the lead role in drafting the article. C.Y., A.E., and L.B. prepared data for the statistical analyses. All coauthors reviewed the manuscript and provided critical scientific revisions, and approved the final version of the manuscript.
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 T.H. Chan School of Public Health (HD052102) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). 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: Julie Davidson).
The following institutions, clinical site investigators and staff participated in conducting PHACS SMARTT in 2014, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Patricia Garvie, James Blood; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Helen Rozelman; Rutgers - New Jersey Medical School: Arry Dieudonne, Linda Bettica, Susan Adubato; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera; SUNY Downstate Medical Center: Hermann Mendez, Ava Dennie, Susan Bewley; Tulane University Health Sciences Center: Chi Dola, Robert Maupin, 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, Jenna Wallace, Carrie Chambers, Christine Reed; University of Florida/Jacksonville: Mobeen Rathore, Kristi Stowers, Ann Usitalo; University of Illinois, Chicago: Kenneth Rich, Lourdes Richardson, Renee Smith; University of Miami: Gwendolyn Scott, Claudia Florez, Elizabeth Willen; University of Southern California: Toni Frederick, Mariam Davtyan, Maribel Mejia; University of Puerto Rico Medical Center: Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio.
Funding: The Pediatric HIV/AIDS Cohort Study (PHACS) 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 T.H. Chan School of Public Health (HD052102) and the Tulane University School of Medicine (HD052104).
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 U.S. Department of Health and Human Services.
Conflicts of interest
There are no conflicts of interest.
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