Abstract
Background: Perinatal HIV transmission has substantially decreased with combination antiretroviral regimens, but complications in children who are HIV-exposed but uninfected, such as microcephaly, warrant ongoing surveillance. We aimed to evaluate whether individual in utero antiretroviral exposures were associated with increased risk of microcephaly based on long-term follow-up of infants and children who are HIV-exposed but uninfected. Methods: We evaluated children aged younger than 18 years who were HIV-exposed but uninfected with at least one head circumference measurement while enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the USA, including Puerto Rico. This prospective cohort study was done by the Pediatric HIV/AIDS Cohort Study network. Microcephaly was defined as having a head circumference Z score <–2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6–36 months old and according to Nellhaus standards (head circumference <2nd percentile) after 36 months (SMARTT criteria); an alternate definition for microcephaly was based on applying Nellhaus standards across all ages (Nellhaus criteria). Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero antiretroviral exposure and microcephaly status, adjusted for potential confounders. Neurodevelopmental functioning was compared in children who are HIV-exposed but uninfected with or without microcephaly. Findings: Between March 21, 2007, and Aug 1, 2017, 3055 participants enrolled in SMARTT had at least one head circumference measurement. The cumulative incidence of microcephaly over a median of 5·1 years of follow-up (IQR 3·0–7·2) was 159 (5·2%, 95% CI 4·4–6·1) by Nellhaus criteria and 70 (2·3%, 1·8–2·9) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4·7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (adjusted RR 2·02, 95% CI 1·16–3·51) and SMARTT criteria (2·56, 1·22–5·37). These associations were more pronounced in children exposed to combination regimens of efavirenz that included zidovudine plus lamivudine than those including tenofovir plus emtricitabine. Protective associations were observed for darunavir exposure (adjusted RR 0·50, 95% CI 0·24–1·00). Children who are HIV-exposed but uninfected with microcephaly had lower mean scores on neurodevelopmental assessments at age 1 and 5 years and a higher prevalence of neurodevelopmental impairment than those without microcephaly. Interpretation: These findings support consideration of alternatives to efavirenz as part of first-line antiretroviral therapy for pregnant women. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
| Original language | English (US) |
|---|---|
| Pages (from-to) | e49-e58 |
| Journal | The Lancet HIV |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2020 |
ASJC Scopus subject areas
- Infectious Diseases
- Epidemiology
- Virology
- Immunology
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Association of maternal antiretroviral use with microcephaly in children who are HIV-exposed but uninfected (SMARTT): a prospective cohort study'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: The Lancet HIV, Vol. 7, No. 1, 01.2020, p. e49-e58.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Association of maternal antiretroviral use with microcephaly in children who are HIV-exposed but uninfected (SMARTT)
T2 - a prospective cohort study
AU - Williams, Paige L.
AU - Yildirim, Cenk
AU - Chadwick, Ellen G.
AU - Van Dyke, Russell B.
AU - Smith, Renee
AU - Correia, Katharine F.
AU - DiPerna, Alexandria
AU - Seage, George R.
AU - Hazra, Rohan
AU - Crowell, Claudia S.
N1 - Funding Information: We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. 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 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; programme director Julie Alperen) and the Tulane University School of Medicine (HD052104; principal investigator Russell Van Dyke; co-principal investigator Ellen Chadwick; 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 (principal investigator Julie Davidson). Funding Information: We did not identify an increased risk of microcephaly for most individual antiretrovirals or drug classes. The key exception to these overall findings was the robust association of in utero efavirenz exposure with a two to three times higher risk of microcephaly. The magnitude of this effect was similar to that for factors reflecting low socioeconomic status, and slightly stronger than that for fetal alcohol exposure. We also noted a protective effect of darunavir and increased risk with fosamprenavir for microcephaly based on Nellhaus criteria, but these associations were less robust. Although microcephaly defined by CDC or WHO criteria was less common, the association with efavirenz seemed stronger (adjusted RRs 2·4–3·7) than when using Nellhaus thresholds (1·8–2·1). These associations persisted across a broad range of sensitivity analyses done to evaluate the potential for bias; stratified analyses by birth characteristics and other maternal risk factors suggested that associations were not primarily attributable to susceptible subgroups of the population. Although the estimated RR for first trimester efavirenz was elevated, consistent with other estimated RRs for preconception and postconception efavirenz exposure, it was not significant because of the relatively infrequent first trimester use. In addition, we did not find that preconception initiation of efavirenz exposure had more pronounced effects on microcephaly than postconception initiation. We observed a more pronounced association of efavirenz with microcephaly when used in combination with zidovudine plus lamivudine than with tenofovir disoproxil fumarate plus emtricitabine, although these findings were based on a small number of cases and warrant confirmation. We used novel approaches to account for other antiretroviral drugs in the same regimen, and obtained consistent findings of elevated risk for efavirenz. Efavirenz passes through the placenta, and animal studies have shown reduced bodyweight and changes in the motor cortex of the brain in offspring after perinatal efavirenz exposure; these changes have been attributed to the targeted effects of efavirenz and its metabolites on the CNS, particularly the serotoninergic system. 25 Preliminary findings from our SMARTT study also suggest increased risk of neurological conditions in general with efavirenz exposure. 26 We observed a low rate of 2·3% with microcephaly (by SMARTT criteria) in our population of HIV-exposed uninfected children born to mothers with HIV infection, consistent with CDC standards for American children. We used CDC standards for head circumference to define microcephaly as our study was done solely within the USA, but WHO standards yielded similar overall rates and findings of elevated risk for children exposed to efavirenz. We also considered the criteria for microcephaly proposed by Nellhaus, 18 often used in clinical practice as CDC growth standards are not available for children older than 3 years. Using the Nellhaus criteria, we observed a slightly higher proportion of microcephaly of 5·2%, but still lower than the 7·5% proportion reported for infants who are HIV-exposed but uninfected followed up to 6 months of age in Latin America. 12 Differences in these estimates could be related to the background population; for example, substance use is less common in women enrolled in SMARTT than reported in the Latin American cohort. The higher rate observed in the study of Spaulding and colleagues 12 might also be a result of their two evaluations in the first 6 months of life, when microcephaly is most often identified. Other surveillance programmes have reported much lower proportions for microcephaly, of 4–15 cases per 10 000 births, but have typically focused on microcephaly in the context of birth defects surveillance and used more extreme criteria. 27,28 Identifying a background prevalence of microcephaly in children who are HIV-exposed but uninfected might be important in recognising potential increases with co-infection by Zika virus, cytomegalovirus, or other congenital infections. 28 The implications of microcephaly on longer-term outcomes have been evaluated in the general population but have been understudied in children who are HIV-exposed but uninfected. We showed substantial neurodevelopmental deficits at 1 year old and 5 years old in children with microcephaly. Mean differences in Bayley-III and WPPSI-III outcomes were of clinical significance, translating to a three to five times higher proportion of children with neurodevelopmental impairment in those with than without microcephaly. Our study has limitations inherent with those of an observational cohort study; although we attempted to control for confounding by indication in our analyses, residual confounding might remain. This confounding is particularly important for a drug such as efavirenz, which was subject to intensive scrutiny as a potential teratogen in the late 1990s and early 2000s and might have preferentially been avoided by some clinicians for mothers with shared risk factors for microcephaly in their infants. 29 Recent studies and systematic reviews have not identified increased risk of adverse birth outcomes for women receiving efavirenz during pregnancy, and these studies have considered populations in which a higher percentage of women received efavirenz as a first-line treatment. 29–32 Another limitation of our analysis is that we were unable to account for other important congenital infections, such as cytomegalovirus. The annual visits in our study design meant that early postnatal measurements of head circumference were not collected, which prevented distinction of congenital from acquired microcephaly. However, our analysis had several key strengths, including its well characterised cohort with collection of many potential confounding factors, and the long-term follow-up of children who are HIV-exposed but uninfected. These factors are a recognised advantage of the SMARTT study but might be challenging in low-resource settings. The median follow-up of more than 5 years from birth in this study allowed the identification of microcephaly cases that might not have been captured in infancy, and others have noted that head circumference is a strong predictor of brain volume even for children up to 6 years old and an adequate predictor in children older than 6 years. 4 Other strengths of our study included an approach that tailored the examination of each individual antiretroviral drug to the time period appropriate for that medication, given its approval date and use in our cohort. Finally, although many safety studies have examined antiretroviral drugs individually, we accounted for other antiretroviral medications taken concurrently in the same regimen, and also used a comparative safety approach to examine RRs when efavirenz was used with specific nucleoside reverse transcriptase inhibitor backbones. In conclusion, our findings are generally reassuring in supporting the use of combination ART in pregnant women for their own health and to reduce risk of perinatal HIV transmission. However, the increased risk of microcephaly observed with efavirenz use during pregnancy warrants closer examination in other settings. Until recently, efavirenz-based ART was recommended by WHO as the preferred first-line regimen for adults and adolescents, 3,32 and still remains the recommended alternative first-line regimen. Recent reports of potential adverse birth outcomes (neural tube defects) with use of dolutegravir might result in increased use of efavirenz. 32 The implications of our findings thus have broad global implications in low-resource settings in which efavirenz is used more widely, and emphasise the need for continued monitoring of long-term outcomes of new and existing antiretrovirals. Contributors PLW, CSC, RBVD, RH, EGC, and GRS conceived the study design. PLW did statistical analyses and took the lead role in drafting the paper. CY, RS, and ADP prepared data for the statistical analyses. All authors reviewed the manuscript and provided critical scientific revisions, and approved the final version of the manuscript. 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 US Department of Health and Human Services. Study investigators The following institutions, clinical site investigators, and staff participated in PHACS SMARTT in 2017: Ellen Chadwick, Margaret Ann Sanders, Kathleen Malee, Scott Hunter (Ann & Robert H Lurie, Children's Hospital of Chicago, Chicago, Il, USA); William Shearer, Mary Paul, Norma Cooper, Lynnette Harris (Baylor College of Medicine, Houston, TX, USA); Murli Purswani, Emma Stuard, Mahboobullah Mirza Baig, Alma Villegas (Bronx Lebanon Hospital Center, The Bronx, NY, USA); Ana Puga, Dia Cooley, Patricia A Garvie, James Blood (Children's Diagnostic & Treatment Center, Fort Lauderdale, FL, USA); William Borkowsky, Sandra Deygoo, Marsha Vasserman (New York University School of Medicine, New York, NY, USA); Arry Dieudonne, Linda Bettica, Juliette Johnson (Rutgers–New Jersey Medical School, Newark, NJ, USA); Katherine Knapp, Kim Allison, Megan Wilkins, Jamie Russell-Bell (St Jude Children's Research Hospital, Memphis, TN, USA); Nicolas Rosario, Lourdes Angeli-Nieves, Vivian Olivera (San Juan Hospital/Department of Pediatrics, San Juan, Puerto Rico); Stephan Kohlhoff, Ava Dennie, Ady Ben-Israel, Jean Kaye (SUNY Downstate Medical Center, Brooklyn, NY, USA); Russell Van Dyke, Karen Craig, Patricia Sirois (Tulane University School of Medicine, New Orleans, LA, USA); Marilyn Crain, Paige Hickman, Dan Marullo (University of Alabama, Birmingham, AL, USA); Stephen A Spector, Kim Norris, Sharon Nichols (University of California, San Diego, CA, USA); Elizabeth McFarland, Emily Barr, Christine Kwon, Carrie Chambers (University of Colorado, Denver, CO, USA); Mobeen Rathore, Kristi Stowers, Saniyyah Mahmoudi, Nizar Maraqa, Laurie Kirkland (University of Florida, Center for HIV/AIDS Research, Education and Service, Gainesville, FL, USA); Karen Hayani, Lourdes Richardson, Renee Smith, Alina Miller (University of Illinois, Chicago, IL, USA); Gwendolyn Scott, Sady Dominguez, Jenniffer Jimenez, Anai Cuadra (University of Miami, Miami, FL, USA); Toni Frederick, Mariam Davtyan, Guadalupe Morales-Avendano, Janielle Jackson-Alvarez (Keck Medicine of the University of Southern California, Los Angeles, CA, USA); Zoe M Rodriguez, Ibet Heyer, Nydia Scalley Trifilio (University of Puerto Rico School of Medicine, Medical Science Campus, San Juan, Puerto Rico). Declaration of interests We declare no competing interests. Acknowledgments We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. 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 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; programme director Julie Alperen) and the Tulane University School of Medicine (HD052104; principal investigator Russell Van Dyke; co-principal investigator Ellen Chadwick; 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 (principal investigator Julie Davidson). Publisher Copyright: © 2020 Elsevier Ltd
PY - 2020/1
Y1 - 2020/1
N2 - Background: Perinatal HIV transmission has substantially decreased with combination antiretroviral regimens, but complications in children who are HIV-exposed but uninfected, such as microcephaly, warrant ongoing surveillance. We aimed to evaluate whether individual in utero antiretroviral exposures were associated with increased risk of microcephaly based on long-term follow-up of infants and children who are HIV-exposed but uninfected. Methods: We evaluated children aged younger than 18 years who were HIV-exposed but uninfected with at least one head circumference measurement while enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the USA, including Puerto Rico. This prospective cohort study was done by the Pediatric HIV/AIDS Cohort Study network. Microcephaly was defined as having a head circumference Z score <–2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6–36 months old and according to Nellhaus standards (head circumference <2nd percentile) after 36 months (SMARTT criteria); an alternate definition for microcephaly was based on applying Nellhaus standards across all ages (Nellhaus criteria). Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero antiretroviral exposure and microcephaly status, adjusted for potential confounders. Neurodevelopmental functioning was compared in children who are HIV-exposed but uninfected with or without microcephaly. Findings: Between March 21, 2007, and Aug 1, 2017, 3055 participants enrolled in SMARTT had at least one head circumference measurement. The cumulative incidence of microcephaly over a median of 5·1 years of follow-up (IQR 3·0–7·2) was 159 (5·2%, 95% CI 4·4–6·1) by Nellhaus criteria and 70 (2·3%, 1·8–2·9) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4·7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (adjusted RR 2·02, 95% CI 1·16–3·51) and SMARTT criteria (2·56, 1·22–5·37). These associations were more pronounced in children exposed to combination regimens of efavirenz that included zidovudine plus lamivudine than those including tenofovir plus emtricitabine. Protective associations were observed for darunavir exposure (adjusted RR 0·50, 95% CI 0·24–1·00). Children who are HIV-exposed but uninfected with microcephaly had lower mean scores on neurodevelopmental assessments at age 1 and 5 years and a higher prevalence of neurodevelopmental impairment than those without microcephaly. Interpretation: These findings support consideration of alternatives to efavirenz as part of first-line antiretroviral therapy for pregnant women. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
AB - Background: Perinatal HIV transmission has substantially decreased with combination antiretroviral regimens, but complications in children who are HIV-exposed but uninfected, such as microcephaly, warrant ongoing surveillance. We aimed to evaluate whether individual in utero antiretroviral exposures were associated with increased risk of microcephaly based on long-term follow-up of infants and children who are HIV-exposed but uninfected. Methods: We evaluated children aged younger than 18 years who were HIV-exposed but uninfected with at least one head circumference measurement while enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the USA, including Puerto Rico. This prospective cohort study was done by the Pediatric HIV/AIDS Cohort Study network. Microcephaly was defined as having a head circumference Z score <–2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6–36 months old and according to Nellhaus standards (head circumference <2nd percentile) after 36 months (SMARTT criteria); an alternate definition for microcephaly was based on applying Nellhaus standards across all ages (Nellhaus criteria). Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero antiretroviral exposure and microcephaly status, adjusted for potential confounders. Neurodevelopmental functioning was compared in children who are HIV-exposed but uninfected with or without microcephaly. Findings: Between March 21, 2007, and Aug 1, 2017, 3055 participants enrolled in SMARTT had at least one head circumference measurement. The cumulative incidence of microcephaly over a median of 5·1 years of follow-up (IQR 3·0–7·2) was 159 (5·2%, 95% CI 4·4–6·1) by Nellhaus criteria and 70 (2·3%, 1·8–2·9) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4·7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (adjusted RR 2·02, 95% CI 1·16–3·51) and SMARTT criteria (2·56, 1·22–5·37). These associations were more pronounced in children exposed to combination regimens of efavirenz that included zidovudine plus lamivudine than those including tenofovir plus emtricitabine. Protective associations were observed for darunavir exposure (adjusted RR 0·50, 95% CI 0·24–1·00). Children who are HIV-exposed but uninfected with microcephaly had lower mean scores on neurodevelopmental assessments at age 1 and 5 years and a higher prevalence of neurodevelopmental impairment than those without microcephaly. Interpretation: These findings support consideration of alternatives to efavirenz as part of first-line antiretroviral therapy for pregnant women. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
UR - http://www.scopus.com/inward/record.url?scp=85077311080&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077311080&partnerID=8YFLogxK
U2 - 10.1016/S2352-3018(19)30340-6
DO - 10.1016/S2352-3018(19)30340-6
M3 - Article
C2 - 31740351
AN - SCOPUS:85077311080
SN - 2352-3018
VL - 7
SP - e49-e58
JO - The Lancet HIV
JF - The Lancet HIV
IS - 1
ER -