Abstract
OBJECTIVE:
To characterize associations of exposure to newer antiretroviral medications in the first trimester with congenital anomalies among infants born to persons with HIV in the United States.
DESIGN:
Longitudinal cohort of infants born 2012–2022 to pregnant persons with HIV enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study.
METHODS:
First-trimester exposures to newer ARVs were abstracted from maternal medical records. Trained site staff conducted physical exams and abstracted congenital anomalies from infant medical records. Investigators classified anomalies using the Metropolitan Atlanta Congenital Defects Program classification system. The prevalence of major congenital anomalies identified by age one year was estimated for infants exposed and unexposed to each ARV. Generalized estimating equation models were used to estimate the odds ratio (OR) of major congenital anomalies for each ARV exposure, adjusting for potential confounders.
RESULTS:
Of 2034 infants, major congenital anomalies were identified in 135 (6.6%; 95% CI: 5.6%−7.8%). Cardiovascular (n=43) and musculoskeletal (n=37) anomalies were the most common. Adjusted ORs (95% CI) of congenital anomalies were 1.03 (0.62–1.72) for darunavir, 0.91 (0.46–1.81) for raltegravir, 1.04 (0.58–1.85) for rilpivirine, 1.31 (0.71–2.41) for elvitegravir, 0.76 (0.37–1.57) for dolutegravir, and 0.34 (0.05–2.51) for bictegravir, compared to those unexposed to each specific ARV. Findings were similar after adjustment for nucleoside/nucleotide backbones.
CONCLUSIONS:
The odds of congenital anomalies among infants with first-trimester exposure to newer ARVs did not differ substantially from those unexposed to these specific ARVs, which is reassuring. Continued evaluation of these ARVs with larger studies will be needed to confirm these findings.
Keywords: HIV, pregnancy, antiretroviral agents, congenital anomalies, teratogenicity
INTRODUCTION
International and United States (US) guidelines for pregnant persons with HIV recommend antiretroviral therapy (ART) to achieve and maintain virologic suppression, prevent perinatal transmission of HIV, and improve maternal health.[1,2] Globally in 2021, approximately 80% of pregnant persons with HIV received ART during pregnancy.[3] Coupled with screening for HIV during pregnancy and infant antiretroviral (ARV) prophylaxis, ART use during pregnancy has significantly reduced perinatal HIV transmission, with most high and middle-income countries experiencing rates less than 1%.[4] Given its widespread utilization, the safety of ART use during pregnancy warrants attention, particularly for potential teratogenicity.
Previous studies conducted with large surveillance data and claims databases have not shown significant differences in the risk of congenital anomalies for those exposed to ARV medications during pregnancy compared to those unexposed.[4–6] The Antiretroviral Pregnancy Registry (APR), a global prospective registry of persons with HIV treated with ARVs during pregnancy, has reported a similar prevalence of birth defects compared to that of the general US population (~3%), and has not identified an elevated risk of congenital anomalies for 22 ARVs, which broadly aligns with findings of other observational studies. [7–16] Although extensive research on pregnancy outcomes has been conducted on antenatal exposure to ARV agents, data on the association between first-trimester exposure to ARVs and congenital anomalies are still largely limited to older agents.[16–19] Rapid development and roll-out of newer ARVs make it critical to assess the safety of first-trimester exposure, the key period of fetal organogenesis, to newer ARVs among pregnant individuals living with HIV.
Previously, we characterized the associations of first-trimester exposures to ARV drug classes and to specific agents with congenital anomalies in the prospective Surveillance Monitoring for ART Toxicities (SMARTT) study conducted within the Pediatrics HIV/AIDS Cohort Study (PHACS) network.[11] In a prior analysis of this cohort (enrolled between 2007–2012), individual ARVs were not associated with elevated adjusted odds of congenital anomalies with the exception of atazanavir, for which higher odds of overall anomalies were observed with fetal exposure versus non-exposure (adjusted odds ratio:1.93, 95% confidence interval:1.23–3.03), particularly for skin and musculoskeletal anomalies.[11] Since 2015, numerous novel ARV medications and new fixed-dose combinations have been approved by the Federal Drug Administration (FDA) for use in the US.[20] In the present study, we aimed to evaluate the associations between exposure to newer ARVs in the first trimester and congenital anomalies. We utilized data from pregnant persons with HIV and their infants enrolled in the SMARTT cohort to characterize the associations between first-trimester exposure to ARVs and congenital anomalies.
METHODS
Study Population
We utilized data of pregnant persons with HIV and their liveborn infants in the SMARTT cohort, which began enrollment in 2007 at 22 study sites throughout the US including Puerto Rico.[13]. Enrollment in SMARTT of pregnant persons with HIV occurred between 13 weeks of gestation and 1 week after delivery. In our current analysis, we included infants born between January 1, 2012 and December 31, 2022 to pregnant persons with HIV enrolled in SMARTT. Multiple births (siblings or multifetal gestation) to the same participant were accounted for in the statistical analysis (see below). The study protocol was approved by the Institutional Review Boards at participating sites and at the Harvard T.H. Chan School of Public Health. Pregnant participants provided written consent for their enrollment in the research study and that of their infants.
Exposure Measures
We evaluated first-trimester exposure to individual newer ARVs, defined as maternal use of a specific ARV any time within the first 14 weeks of gestation, as dated by ultrasound, physical exam, and/or using the last menstrual period (LMP) as the start of pregnancy. The ARVs we considered were those approved since 2011 (rilpivirine (RPV) - 2011, elvitegravir (EVG) - 2012, dolutegravir (DTG) - 2013, and bictegravir (BIC) - 2018) and those not evaluated in our previous study due to limited numbers with exposure (darunavir (DRV) and raltegravir (RAL)). Individuals in an exposed ARV group may have been exposed to other ARV agents during the first trimester or later in pregnancy. The reference group in each ARV analysis was infants never exposed to the specific ARV agent during the first trimester. For sufficient power in the statistical analysis, we restricted adjusted analyses to ARVs with at least 50 first-trimester fetal exposures. Maternal ARV utilization was abstracted from the SMARTT participant’s medical chart by trained study staff and confirmed by maternal interview.
Outcome Measures
The outcome of interest was the presence of a major congenital anomaly reported by SMARTT study staff based on study-specified physical examinations at the infant’s birth and/or at the infant’s 1-year visit, and on information abstracted from infant medical records. Two authors (S.H.D. and P.L.W.), blinded to ARV exposure status, independently reviewed the anomaly descriptions reported by the participating sites, and adjudicated the anomaly to specific groups according to the established Centers for Disease Control and Prevention (CDC) guidelines in the Metropolitan Atlanta Congenital Defects Program (MACDP) classification scheme.[21] A teratologist was consulted for difficult determinations, as details of results from ultrasounds or echocardiography was not always available. Since multiple anomalies can be reported for an individual, any infant with at least one major congenital anomaly according to the MACDP was counted as having the outcome for an ARV of interest to which there was first-trimester fetal exposure.
Covariates
We described maternal and infant characteristics in the cohort, including demographics, health metrics and comorbidities, non-ARV medication use, substance use, and delivery outcomes. Potential confounders, including infant birth year, maternal age at delivery, pregestational body-mass index (BMI) category, pregestational diabetes, and first-trimester alcohol use, were selected a priori based on prior literature and by assessing covariate balance by ARV exposure groups.[22–24]
Statistical Analysis
To ensure complete data on first-trimester ARVs and congenital anomalies, we utilized a complete-case analytic approach for the exposure and outcome. The number and proportion of infants with anomalies were reported for each ARV, compared to those unexposed to that ARV. A missing indicator approach was used for those with no information on pre-pregnancy BMI category (29%), pregestational diabetes (2.7%), and first-trimester alcohol use (3.0%).
To evaluate the association of first-trimester exposure to the ARVs of interest with the occurrence of a major congenital anomaly, generalized estimating equation (GEE) models were used with a logit link to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each ARV. The unique maternal participant identifier was used as the clustering variable in the model to account for potential correlation across births (siblings or multifetal gestation) to the same participant. The adjusted model included the potential confounders. To enhance clinical interpretation, we also fit a GEE linear regression model with an identity link to calculate the estimated risk difference and 95% CI for each ARV exposure, with adjustment for the same covariates noted above.
Sensitivity Analyses
Since ART regimens normally include a backbone of two nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) ARVs, we also conducted a sensitivity analysis additionally adjusting for ever exposure in the first trimester to commonly used NRTI backbones, classified as tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) plus emtricitabine (FTC) (TDF or TAF + FTC), zidovudine (ZDV) plus lamivudine (3TC) (ZDV + 3TC), or other backbones. Given the relatively recent approval and increasing use of TAF and suggestion of elevated prevalence of anomalies (3.87%, 95% CI: 2.80–5.19) reported by the APR for TAF exposure [7], we also analyzed the risk of congenital anomalies after exposure to TAF. Additional sensitivity analyses were conducted excluding infants with chromosomal abnormalities (such as Trisomy 21), and estimating the association between periconceptional exposure (LMP + 14 days) to ARVs of interest and congenital anomalies. All analyses were conducted using SAS Version 9.4 (SAS Institute, Cary, NC).
RESULTS
We identified 2140 infants born between 2012 and 2022 to persons with HIV enrolled in the SMARTT cohort; 106 infants were excluded due to incomplete data on first-trimester exposure to the ARVs of interest and/or missing data on congenital anomalies. The final study population included 2034 infants born to 1670 unique persons with HIV in the SMARTT cohort.
Maternal and Infant Characteristics by Outcome Status and ART Exposure in Study Population
The characteristics of the study population are presented in Table 1 stratified by the presence of at least one major congenital anomaly. The distributions of maternal and infant characteristics were generally similar for infants with and without at least one major congenital anomaly. Approximately 25% of pregnant persons were white, and the average age at delivery was 30 years. About two-thirds had an annual household income less than $20,000 at study entry. Maternal use of other medications, such as valproic acid and retinoic acid, was minimal in both groups. Only birth year (grouped as 2012–2015, 2016–2019, 2020–2022) differed substantially between infants with or without congenital anomalies, with a greater proportion of infants with congenital anomalies born in earlier years. Median birth weight and gestational age were similar for infants with and without congenital anomalies. The proportion of infants with periconceptional exposure to any ARVs was also comparable in both groups (54.4% among those with at least one major congenital anomaly, 49.2% among those without).
Table 1:
Maternal and Infant Characteristics of Participants by Occurrence of at Least One Major Congenital Anomaly
| Maternal and Infant Demographics1 | Total (n=2034) |
No Major Congenital Anomaly (n=1899) |
At Least One Major Congenital Anomaly (n=135) |
|---|---|---|---|
| Race | |||
| White | 500 (25%) | 469 (25%) | 31 (23%) |
| Black | 1420 (70%) | 1323 (70%) | 97 (72%) |
| Other | 20 (1%) | 18 (1%) | 2 (1%) |
| Unknown | 94 (5%) | 89 (5%) | 5 (4%) |
| Ethnicity | |||
| Not Hispanic/Latino | 1475 (73%) | 1372 (72%) | 103 (76%) |
| Hispanic or Latino | 556 (27%) | 524 (28%) | 32 (24%) |
| Unknown | 3 (0%) | 3 (0%) | 0 (0%) |
| Age at delivery (years) | |||
| Median (Q1, Q3) | 29.7 (25.5, 34.4) | 29.7 (25.5, 34.4) | 29.4 (25.6, 34.6) |
| Household income for year of birth | |||
| <= $20,000 | 1344 (66%) | 1252 (66%) | 92 (68%) |
| >$20,000 | 504 (25%) | 478 (25%) | 26 (19%) |
| Unknown | 186 (9%) | 169 (9%) | 17 (13%) |
| Pre-pregnancy BMI Category (kg/m2) | |||
| Underweight/Normal (<25) | 468 (23%) | 438 (23%) | 30 (22%) |
| Overweight (25–29.9) | 363 (18%) | 336 (18%) | 27 (20%) |
| Obese (30+) | 604 (30%) | 557 (29%) | 47 (35%) |
| Unknown | 599 (29%) | 568 (30%) | 31 (23%) |
| Pregestational diabetes | 60 (3%) | 55 (3%) | 5 (4%) |
| Earliest CD4 count during pregnancy (cells/uL) | |||
| < 200 | 221 (11%) | 212 (11%) | 9 (7%) |
| 200–500 | 713 (35%) | 666 (35%) | 47 (35%) |
| >500 | 1034 (51%) | 958 (50%) | 76 (56%) |
| Unknown | 65 (3%) | 63 (3%) | 3 (2%) |
| Earliest HIV-RNA level during pregnancy (copies/mL) | |||
| <1,000 | 1272 (63%) | 1187 (63%) | 85 (63%) |
| 1,000–10,000 | 332 (16%) | 309 (16%) | 23 (17%) |
| >10,000 | 392 (19%) | 368 (19%) | 24 (18%) |
| Unknown | 38 (2%) | 35 (2%) | 3 (2%) |
| STIs during pregnancy 2 | 954 (47%) | 888 (47%) | 66 (49%) |
| Medication use in first trimester | |||
| SSRI | 29 (1%) | 25 (1%) | 4 (3%) |
| Folate antagonist3 | 88 (4%) | 80 (4%) | 8 (6%) |
| Retinoic acid | 3 (0%) | 3 (0%) | 0 (0%) |
| Substance use in first trimester | |||
| Alcohol | 154 (8%) | 144 (8%) | 10 (7%) |
| Tobacco | 299 (15%) | 276 (15%) | 23 (17%) |
| Illicit Drugs4 | 31 (2%) | 30 (2%) | 1 (1%) |
| Cannabis | 183 (9%) | 172 (9%) | 11 (8%) |
| Preterm birth (gestational age <37 weeks) | 320 (16%) | 299 (16%) | 21 (16%) |
| Low birth weight (<2500 g) | 327 (16%) | 305 (16%) | 22 (16%) |
| Delivery Mode | |||
| Vaginal | 927 (46%) | 872 (46%) | 55 (41%) |
| Cesarean delivery | 1090 (54%) | 1010 (53%) | 80 (59%) |
| Unknown | 17 (1%) | 17 (1%) | 0 (0%) |
| Infant Birth Cohort (calendar year) | |||
| 2012–2015 | 979 (48%) | 895 (47%) | 84 (62%) |
| 2016–2019 | 808 (40%) | 769 (40%) | 39 (29%) |
| 2020–2022 | 247 (12%) | 235 (12%) | 12 (9%) |
| Infant Sex | |||
| Male | 1062 (52%) | 985 (52%) | 77 (57%) |
| Female | 972 (48%) | 914 (48%) | 58 (43%) |
Distribution of characteristics was calculated among the total study population and is indicated as N and %, except for maternal age. The proportion with missing data is reported as ‘Unknown’ for some characteristics in Table 1, but other variables with missing data include: pregestational diabetes (n=56), STIs during pregnancy (n=34), preterm birth (n=13), and first-trimester exposures to SSRIs (n=1), folate antagonists (n=1), retinoic acid (n=1), alcohol use (n=61), tobacco use (n=69), illicit drug use (n=60), and marijuana use (n=62).
STIs defined as gonorrhea, chlamydia, trichomonas, and syphilis
Folate antagonist defined as methotrexate, lomtrex, trimethoprim, pyrimeth, permetrex, Bactrim, septra
Illicit drugs defined as cocaine, heroin, and opium, ecstasy, methamphetamines, and hallucinogens
Abbreviations: BMI (body-mass index), SSRI (selective serotonin reuptake inhibitor), STI (sexually transmitted infection)
First-Trimester Fetal Exposure to ARVs
We report the maternal and infant characteristics among infants exposed to each ARV of interest in Table 2. The distribution of birth cohorts aligned with the approval year and adoption of the agents (i.e., majority of infants with first-trimester exposure to bictegravir, approved by the FDA in 2018, were born in 2020–2022). Age at delivery, prevalence of alcohol use, and pre-pregnancy BMI distribution for each exposure group were generally comparable to the overall study population.
Table 2:
Maternal and Infant Characteristics of Participants by ARV Exposure in First Trimester
| Maternal and Infant Demographics1 | Total (n=2034) |
RPV-exposed (n=291) |
DRV-exposed (n=268) |
EVG-exposed (n=193) |
DTG-exposed (n=186) |
RAL-exposed (n=152) |
BIC-exposed (n=52) |
|---|---|---|---|---|---|---|---|
| Race | |||||||
| White | 500 (25%) | 93 (32%) | 74 (28%) | 44 (23%) | 46 (25%) | 49 (32%) | 9 (17%) |
| Black | 1420 (70%) | 186 (63%) | 174 (65%) | 142 (74%) | 132 (71%) | 83 (55%) | 41 (79%) |
| Other | 20 (1%) | 1 (0%) | 1 (0%) | 1 (0%) | 0 (0%) | 3 (2%) | 0 (0%) |
| Unknown | 94 (5%) | 11 (4%) | 19 (7%) | 6 (3%) | 8 (4%) | 17 (11%) | 2 (4%) |
| Ethnicity | |||||||
| Not Hispanic/Latino | 1475 (73%) | 195 (67%) | 178 (66%) | 143 (74%) | 136 (73%) | 89 (59%) | 36 (69%) |
| Hispanic or Latino | 556 (27%) | 95 (33%) | 90 (34%) | 50 (26%) | 50 (27%) | 62 (41%) | 16 (31%) |
| Unknown | 3 (0%) | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (0%) | 0 (0%) |
| Age at delivery (years) | |||||||
| Median (Q1, Q3) | 29.7 (25.5, 34.4) | 29.5 (25.8, 34.4) | 29.9 (25.7, 34.8) | 29.8 (26.3, 35.1) | 30.0 (26.2, 33.6) | 31.0 (27.1, 36.6) | 28.5 (25.0, 33.9) |
| Household income for year of birth | |||||||
| <= $20,000 | 1344 (66%) | 197 (68%) | 164 (62%) | 118 (61%) | 111 (60%) | 105 (69%) | 32 (61%) |
| >$20,000 | 504 (25%) | 71 (24%) | 73 (27%) | 59 (31%) | 58 (32%) | 10 (7%) | 12 (23%) |
| Unknown | 186 (9%) | 23 (8%) | 31 (12%) | 16 (8%) | 17 (9%) | 37 (7%) | 8 (15%) |
| Pre-pregnancy BMI Category (kg/m2) | |||||||
| Underweight/Normal | 468 (23%) | 68 (23%) | 75 (28%) | 45 (23%) | 44 (24%) | 36 (24%) | 5 (10%) |
| Overweight | 363 (18%) | 49 (17%) | 43 (16%) | 32 (17%) | 29 (16%) | 30 (20%) | 5 (10%) |
| Obese | 604 (30%) | 95 (33%) | 72 (27%) | 55 (29%) | 62 (33%) | 34 (23%) | 20 (38%) |
| Unknown | 599 (29%) | 79 (27%) | 78 (29%) | 61 (32%) | 51 (27%) | 52 (34%) | 22 (42%) |
| Pregestational diabetes | 60 (3%) | 8 (1%) | 8 (3%) | 11 (6%) | 6 (3%) | 3 (2%) | 2 (4%) |
| Earliest CD4 count during pregnancy (cells/uL) | |||||||
| < 200 | 221 (11%) | 17 (6%) | 37 (14%) | 23 (12%) | 15 (8%) | 28 (18%) | 5 (9%) |
| 200–500 | 713 (35%) | 76 (26%) | 113 (42%) | 63 (33%) | 71 (38%) | 40 (26%) | 14 (27%) |
| >500 | 1034 (51%) | 189 (64%) | 107 (40%) | 100 (52%) | 92 (49%) | 80 (52%) | 31 (60%) |
| Unknown | 65 (3%) | 9 (3%) | 11 (4%) | 7 (11%) | 8 (12%) | 4 (3%) | 2 (4%) |
| Earliest HIV-RNA level during pregnancy (copies/mL) | |||||||
| <1,000 | 1272 (63%) | 237 (81%) | 184 (69%) | 158 (82%) | 130 (70%) | 112 (74%) | 35 (67%) |
| 1,000–10,000 | 332 (16%) | 27 (9%) | 33 (12%) | 14 (7%) | 24 (13%) | 8 (5%) | 7 (14%) |
| >10,000 | 392 (19%) | 25 (9%) | 43 (16%) | 17 (9%) | 28 (15%) | 31 (21%) | 9 (17%) |
| Unknown | 38 (2%) | 2 (0%) | 8 (3%) | 4 (2%) | 4 (2%) | 1 (0%) | 1 (2%) |
| STIs during pregnancy 2 | 954 (47%) | 122 (42%) | 125 (47%) | 89 (46%) | 89 (48%) | 78 (51%) | 30 (58%) |
| Medication use in first trimester | |||||||
| SSRI | 29 (1%) | 4 (1%) | 4 (1%) | 3 (2%) | 3 (2%) | 1 (1%) | 4 (8%) |
| Folate antagonist3 | 88 (4%) | 11 (4%) | 17 (6%) | 8 (4%) | 3 (2%) | 11 (7%) | 0 (0%) |
| Retinoic acid | 3 (0%) | 1 (0%) | 1 (0%) | 1 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
| Substance use in first trimester | |||||||
| Alcohol | 154 (8%) | 14 (5%) | 22 (8%) | 14 (7%) | 15 (8%) | 14 (9%) | 0 (0%) |
| Tobacco | 299 (15%) | 25 (9%) | 40 (15%) | 28 (15%) | 25 (13%) | 13 (9%) | 1 (2%) |
| Illicit Drugs4 | 31 (2%) | 3 (1%) | 3 (1%) | 1 (1%) | 0 (0%) | 2 (1%) | 0 (0%) |
| Cannabis | 183 (9%) | 20 (7%) | 26 (10%) | 14 (7%) | 22 (12%) | 13 (9%) | 5 (10%) |
| Preterm birth (gestational age <37 weeks) | 320 (16%) | 34 (12%) | 54 (20%) | 40 (21%) | 36 (19%) | 26 (17%) | 7 (13%) |
| Low birth weight (<2500 g) | 327 (16%) | 35 (12%) | 48 (18%) | 31 (16%) | 35 (19%) | 21 (14%) | 4 (8%) |
| Delivery Mode | |||||||
| Vaginal | 927 (46%) | 144 (49%) | 129 (48%) | 78 (40%) | 83 (45%) | 57 (38%) | 17 (33%) |
| Cesarean delivery | 1090 (54%) | 147 (51%) | 136 (51%) | 114 (59%) | 100 (54%) | 95 (63%) | 35 (67%) |
| Unknown | 17 (1%) | 0 (0%) | 3 (1%) | 1 (1%) | 3 (2%) | 0 (0%) | 0 (0%) |
| Infant Birth Cohort (calendar year) | |||||||
| 2012–2015 | 979 (48%) | 108 (37%) | 127 (47%) | 36 (19%) | 24 (13%) | 65 (43%) | 0 (0%) |
| 2016–2019 | 808 (40%) | 139 (48%) | 120 (45%) | 121 (63%) | 118 (63%) | 53 (35%) | 11 (21%) |
| 2020–2022 | 247 (12%) | 44 (15%) | 21 (8%) | 36 (19%) | 44 (24%) | 34 (22%) | 41 (79%) |
| Infant Sex | |||||||
| Male | 1062 (52%) | 156 (53%) | 122 (46%) | 98 (51%) | 107 (58%) | 88 (58%) | 25 (48%) |
| Female | 972 (48%) | 135 (46%) | 146 (55%) | 95 (49%) | 79 (43%) | 64 (42%) | 27 (52%) |
Distribution of characteristics was calculated among the total study population and is indicated as N and %, except for maternal age. The proportion with missing data is reported as ‘Unknown’ for some characteristics in Table 1, but other variables with missing data include: pregestational diabetes (n=56), STIs during pregnancy (n=34), preterm birth (n=13), and first-trimester exposures to SSRIs (n=1), folate antagonists (n=1), retinoic acid (n=1), alcohol use (n=61), tobacco use (n=69), illicit drug use (n=60), and cannabis use (n=62).
STIs defined as gonorrhea, chlamydia, trichomonas, and syphilis
Folate antagonist defined as methotrexate, lomtrex, trimethoprim, pyrimeth, permetrex, Bactrim, septra
Illicit drugs defined as cocaine, heroin, opium, ecstasy, methamphetamines, and hallucinogens
Abbreviations: ARV (antiretroviral) , BIC (bictegravir), BMI (body-mass index), DRV (darunavir), DTG (dolutegravir), EVG (elvitegravir), RAL (raltegravir), RPV (rilpivirine), SSRI (selective serotonin reuptake inhibitor), STI (sexually transmitted infection)
Among the ARVs of interest, rilpivirine had the highest number of first-trimester exposures (n=291, 14.3%), followed by darunavir (n=268, 13.2%), elvitegravir (n=193, 9.5%), and dolutegravir (n=186, 9.1%) (Table 3). Darunavir was commonly boosted either by ritonavir or cobicistat, and elvitegravir was often boosted by cobicistat (see Supplementary Table 1 for most common regimens including each ARV of interest). Lower proportions of infants had first-trimester exposure to raltegravir (n=152, 7.5%) and bictegravir (n=52, 2.6%), with ~5% of bictegravir exposures also exposed to rilpivirine or darunavir (Supplementary Table 1). Regarding exposure to NRTI backbones, the proportion exposed to TDF or TAF + FTC among the ARV exposure groups of interest during the first trimester ranged from 48% for dolutegravir to over 95% for rilpivirine, elvitegravir, and bictegravir, while <10% received ZDV+3TC with first-trimester ARVs of interest (data not shown).
Table 3:
Association between First-Trimester ARV Exposure and Occurrence of at Least One Major Congenital Anomaly in SMARTT Study (2012–2022) (N=2034 for all analyses)
| Exposure in First Trimester | # Infants Exposed in First Trimester | Congenital Anomaly Prevalence in Exposed % (95% CI) |
Congenital Anomaly Prevalence in Unexposed % (95% CI) |
Unadjusted Model OR (95% CI) |
Adjusted Model1 OR (95% CI) |
|---|---|---|---|---|---|
| Rilpivirine (RPV)-exposed vs RPV-unexposed | 291 | 19/291 6.5% (4.0%−10.0%) |
116/1743 6.7% (5.5%−8.0%) |
0.97 (0.56, 1.71) |
1.04 (0.59, 1.85) |
| Darunavir (DRV)-exposed vs DRV- unexposed | 268 | 18/268 6.7% (4.0%−10.4%) |
117/1766 6.6% (5.5%−7.9%) |
1.01 (0.61, 1.68) |
1.03 (0.62, 1.72) |
| Elvitegravir (EVG)-exposed vs EVG-unexposed | 193 | 13/193 6.7% (3.6%−11.2%) |
122/1841 6.6% (5.5%−7.8%) |
1.02 (0.57, 1.85) |
1.31 (0.71, 2.41) |
| Dolutegravir (DTG)-exposed vs DTG-unexposed | 186 | 8/186 4.3% (1.9%−8.3%) |
127/1848 6.9% (5.8%−8.1%) |
0.61 (0.30, 1.26) |
0.76 (0.37, 1.57) |
| Raltegravir (RAL)-exposed vs RAL-unexposed | 152 | 9/152 5.9% (2.7%−10.9%) |
126/1882 6.7% (5.6%−7.9%) |
0.88 (0.44, 1.75) |
0.91 (0.46, 1.81) |
| Bictegravir (BIC)-exposed vs BIC-unexposed | 52 | 1/52 1.9% (0.05%−10.3%) |
134/1982 6.8% (5.7%−8.0%) |
0.27 (0.04, 2.01) |
0.34 (0.05, 2.51) |
Adjusted for infant birth year, maternal age at delivery, pre-pregnancy body mass index (BMI) category, pregestational diabetes, and first-trimester alcohol use
Prevalence of congenital anomalies and associations with first-trimester exposure to ARVs
Among the 2034 infants, 135 had at least one major congenital anomaly (6.6%; 95%CI: 5.6%−7.8%) (Table 1). Among these 135 infants, the most common type of anomaly was cardiovascular (n=43, 31.9%), followed by musculoskeletal (n=37, 27.4%) and central nervous system (n=24, 17.8%) (Supplementary Table 2). The prevalence of congenital anomalies among siblings (n=656 infants) was 6.4%, similar to the prevalence in the overall study population, while that among twins (n=92 infants) was 4.3%. The prevalence of congenital anomalies among infants with first-trimester fetal exposure to the ARVs of interest ranged between 1.9% to 6.7% (Table 3), with wide confidence intervals. Prevalence of anomalies by organ system are summarized separately within each ARV exposure group, but not evaluated in statistical models due to small numbers of outcomes (Supplementary Table 3).
In unadjusted models for each of the ARV exposures, the odds of major congenital anomalies among infants with first-trimester fetal exposure to the ARV were not meaningfully different from the odds among infants without exposure (Table 3). The results remained consistent after adjusting for confounders. Adjusted ORs (95% CI) of congenital anomalies were 1.03 (0.62–1.72) for darunavir, 0.91 (0.46–1.81) for raltegravir, 1.04 (0.58–1.85) for rilpivirine, 1.31 (0.71–2.41) for elvitegravir, 0.76 (0.37–1.57) for dolutegravir, and 0.34 (0.05–2.51) for bictegravir, compared to those unexposed to each specific ARV (Figure 1). Similarly, in adjusted models, estimated risk differences and their corresponding 95% CIs did not provide any evidence of a substantial increase in risk of defects (Supplementary Table 4).
Figure 1: Adjusted Associations for First-Trimester ARV Exposure and Occurrence of at Least One Major Congenital Anomaly (N=2034).
ORs adjusted for infant birth year, maternal age at delivery, pre-pregnancy body mass index (BMI) category, pregestational diabetes, and first-trimester alcohol use
Abbreviations: ARV (antiretroviral), BIC (bictegravir), DRV (darunavir), DTG (dolutegravir), EVG (elvitegravir), RAL (raltegravir), RPV (rilpivirine)
Sensitivity analyses
When adjusting for NRTI backbone exposure, the ORs for the ARVs of interest were slightly attenuated from the main adjusted estimates but continued to show no association with congenital anomalies (Supplementary Table 5). Among infants exposed to TAF, we did not observe an increased risk of congenital anomalies compared to those unexposed to TAF or to those exposed to TDF (Supplementary Table 6). Results were also similar to those of the main analysis after excluding 10 infants with a chromosomal anomaly (Supplementary Table 7). Among those with complete data on periconceptional and first-trimester ARV exposures (n=2025), 50–75% of those exposed in the first trimester had been exposed at conception. The adjusted ORs for congenital anomalies for those exposed versus not exposed from conception to rilpivirine, elvitegravir, and raltegravir were slightly higher than those shown in Table 3 for first-trimester associations, but results remained consistent with the main analysis (Supplemental Table 8).
DISCUSSION
To understand the safety of newer ARVs used during pregnancy, the present study aimed to characterize the odds of congenital anomalies among infants born to persons with HIV with first-trimester fetal exposure to newer ARVs including elvitegravir, dolutegravir, rilpivirine, and bictegravir; raltegravir and darunavir were also included, as the number of exposed in the previous analysis of the SMARTT cohort was too low to be considered. We utilized a US-based prospective cohort of persons with HIV enrolled during pregnancy with study evaluation for congenital anomalies in their infants. The overall prevalence of anomalies in the study population was 6.6 for every 100 live births born to persons with HIV. In our unadjusted and adjusted models, we did not observe meaningful differences in the odds of congenital anomalies among infants with first-trimester exposure to the ARVs of interest compared to infants without first-trimester exposure to these agents.
Our prevalence of congenital anomalies aligns with the estimate previously reported in the SMARTT cohort between 2007–2012 (n=175 out of 2580 infants; 6.8%, 95% CI: 5.6%−7.8%). The consistent estimates between the present and the prior SMARTT study suggest that the associations of congenital anomalies with ARV exposure have not changed substantially in the cohort over time, even as newer ARV agents have been approved and used during pregnancy. The prevalence in our study is similar to estimates in studies of ARV exposure conducted in Argentina, Brazil, and Spain, collectively reporting a prevalence between 6% to 7% [25,26] but higher than the latest 2.9% prevalence reported by the APR and the 3%−4% observed in other studies in the US and Europe, including reported prevalence in the general population.[5,7,11,27–29] The discrepancy in the estimated prevalence for our cohort and the APR may be attributed to the differences in the methods of outcome ascertainment between the two reports: the APR relies on healthcare providers of individuals participating in the registry to voluntarily report cases of anomalies in the newborn to the registry, which may lead to underreporting, whereas the SMARTT study involves medical record abstraction and structured monitoring of congenital anomalies at two examinations in the infant’s first year of life. Other reasons for differences in the observed prevalence of congenital anomalies compared to the literature may be attributed to differences in follow-up time to diagnosed malformations (SMARTT includes long-term follow-up of infants), awareness of congenital anomalies (SMARTT is conducted at academic research institutions), and the definitions of major anomalies. For instance, we considered anomalies based on MACDP classification, including those that may have an assumed etiology (i.e., chromosomal anomalies) or known genetic component (e.g. polydactyly) [5,9]. When we excluded individuals with chromosomal anomalies (N=10) from the analysis, the prevalence was 6.2% and the associations were essentially unchanged.
As for the teratogenicity of the ARVs of interest, our study provides additional evidence on the safety of using these ARVs during pregnancy. A prior study in France identified a potential signal for higher prevalence of congenital anomalies among infants exposed to raltegravir at conception compared to those exposed to darunavir (6.4% vs. 2.3%, p=0.08).[30] Our study did not identify elevated odds of congenital anomalies among infants with exposure to raltegravir in the first trimester or at conception compared to those unexposed. The discrepancy may be attributed to different referent groups, but larger studies with similar designs are needed to provide clarity on the discrepant findings in the literature. We also did not observe an increased risk for congenital anomalies among infants with TAF exposure, unlike the potential signal that the APR reported on first-trimester exposure to TAF.[7] We will continue to evaluate the risk of anomalies associated with TAF exposure in future studies. In addition, to our knowledge, this is the first report that has characterized the association between first-trimester bictegravir exposure and congenital anomalies among infants born to persons with HIV. The study contributes to the understanding of bictegravir safety, for which there are limited data on teratogenicity or toxicity during pregnancy.[7] Lastly, our study did not have enough events to identify the relative odds of neural tube defects with dolutegravir exposure. However, updated reports from the Botswana-based Tsepamo study and other cohorts have overturned concern about an association between fetal exposure to dolutegravir and neural tube defects.[6,14,31,32] Similarly, we did not find elevated odds of overall major congenital anomalies comparing those exposed vs. unexposed to dolutegravir.
The strengths of our study include its prospective design, careful evaluation of all infants for the presence of congenital anomalies, and a large study population to identify congenital anomalies. The SMARTT cohort includes extensive information on maternal and infant characteristics that was used for confounder adjustment in our statistical models. Given the presence of study sites throughout the US, the findings of this study are generalizable to pregnant persons with HIV in the US. However, there are several limitations to our study. For exposure definitions, we utilized a binary classification for exposure to each ARV, which does not fully represent treatment regimens. The rationale is that major teratogens would be apparent across combinations. In addition, the smaller number of participants on specific ARV combinations makes comparison of treatment regimens more challenging. We controlled for residual confounding from exposure to common NRTI backbones in a sensitivity analysis, and the adjusted associations were similar to that of the primary analysis. Our reported associations were imprecise, so modest effects are still possible, and more data are needed to ascertain the associations of congenital anomalies with these ARVs. Although there were at least 50 infants exposed to each ARV of interest, signal detection of small effects on congenital anomalies overall or large effects on rare anomalies requires larger numbers of exposed in the first trimester. Statistical power to study congenital anomalies remains a challenge for prospective pregnancy cohorts given the limited number exposed to specific ARVs during pregnancy and low prevalence of the outcomes. However, enrollment of larger sample sizes will involve greater costs, time, and logistical challenges. In addition, although the MACDP classification system was used to identify the presence of congenital anomalies, there may be outcome misclassification on the anomaly, which may have attenuated the associations. Finally, it is important to note that these data are from a cohort restricted to live births and may be prone to selection bias by the exclusion of pregnancy termination, spontaneous abortion, or fetal demise, which may be more likely to have congenital anomalies. However, we expect non-differential selection between the exposed and unexposed in the live birth cohort.
The present study adds to the current knowledge of the safety of ARVs. Future studies should consider adjustment for exposure to all concurrent ARV exposures, such as by using hierarchical models to estimate individual and class effects on the outcome of congenital anomalies.[33] Furthermore, with larger numbers, we could compare the risks of congenital anomalies among specific ART regimens, rather than individual agents, to better characterize the risks of treatment during pregnancy. Since pregnant persons with HIV are treated with multiple agents, research focused on the safety of ART regimens will inform guidelines and help clinicians identify appropriate treatments for pregnant persons with HIV. Animal models and pharmacokinetic studies will also contribute to inform the potential teratogenicity of newer ARVs while exposed pregnancies in prospective cohorts accrue over time.[34] The results of this study support the findings of other studies on the use of ARVs in pregnancy, as newer ARVs do not appear to increase the risk of congenital anomalies and certainly optimize maternal health while preventing perinatal transmission.
Supplementary Material
Acknowledgements:
We thank the participants and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. The Pediatric HIV/AIDS Cohort Study (PHACS) network was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Office of The Director, National Institutes of Health (OD), National Institute of Dental & Craniofacial Research (NIDCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the National Heart, Lung, and Blood Institute (NHLBI) through grants to the Harvard T.H. Chan School of Public Health (P01HD103133, Principal Investigators: Ellen Chadwick, Sonia Hernandez-Diaz, Jennifer Jao, Paige Williams; Program Director: Liz Salomon and HD052102: Principal Investigator: George R Seage III; Program Director: Liz Salomon) and with 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 (Data Management Center Director: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (Project Director: Tracy Wolbach).
Conflicts of Interest:
SHD reports a grant to her institution from Takeda for unrelated topics and consultation for Moderna, UCB, and J&J for unrelated topics. The other authors do not have conflicts of interest to declare.
Footnotes
Note: 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.
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