Abstract
Importance
Most studies examining the association of prenatal antiretroviral exposures with congenital anomalies (CAs) in children born to HIV-infected women have been reassuring, but some suggest increased risk with specific antiretrovirals.
Objectives
To evaluate associations of in utero antiretroviral exposures with CAs in HIV-exposed uninfected children.
Design
prospective cohort study, the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study.
Setting
22 US medical centers
Participants
2580 HIV-exposed, uninfected children enrolled in SMARTT between 2007–2012.
Exposures
First trimester exposure to any antiretroviral and to specific antiretroviral medications.
Main Outcome
The primary endpoint was a CA, based on clinician 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 associations of CAs with first trimester antiretroviral exposures, adjusting for demographic and maternal characteristics.
Results
CAs occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI: 5.85–7.82%); there were 242 confirmed major CAs (72 musculoskeletal, 55 cardiovascular). The prevalence of CAs increased significantly in successive birth cohorts (3.8% for children born <2002 up to 8.3% for 2008–2010). In adjusted models, there was no association of first trimester exposures to any antiretroviral, to combination antiretroviral regimens, or to any drug class with CAs. No individual antiretroviral in the reverse transcriptase inhibitor drug classes was associated with increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir (adjusted odds ratio (aOR)=1.93, 95% confidence interval (CI):1.23,3.03) and for ritonavir used as a booster (aOR=1.52, 95%CI: 1.08,2.14). With first trimester atazanavir, risks were highest for skin and musculoskeletal CAs (aORs=5.24 and 2.55, respectively).
Conclusions and Relevance
Few individual antiretrovirals and no drug classes were associated with increased risk of CAs after adjustment for calendar year and maternal characteristics. While the overall risk remained low, there was a relative increase in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV use during pregnancy still outweigh such risks, although further studies are warranted.
Introduction
The use of combination antiretroviral (ARV) regimens for prevention of mother-to-child transmission of 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 on ARV therapy.2
Most prior studies examining the risk of congenital anomalies (CAs) according to in utero ARV exposure have been reassuring, but a few have suggested increased risk of CAs overall, or for certain CAs with specific ARVs.3–13 In the international Antiretroviral Pregnancy Registry (APR), the estimated prevalence of CAs was 2.9% among over 6,900 children with first trimester ARV exposures, similar to the rate among children exposed in later trimesters.5 The Women and Infants Transmission Study (WITS) found no increase in the overall rate of defects (3.56 per 100 live births) as compared to 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 (ZDV, or AZT) during the first trimester.6 Two recent evaluations from US-based cohorts have shown an increased overall risk of CAs among infants with first trimester efavirenz exposure.12,13 A single animal study and case reports have also reported CAs associated with efavirenz exposure,14,15 leading to recommendations against 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 US, prenatal use of tenofovir, emtricitabine, and lopinavir has increased dramatically since approval in 2000–2003 to 40–50% use by 2010, while nelfinavir use has declined substantially following safety warnings.16–17 Atazanavir use has increased to ~20% by 2010. An Italian cohort showed similar trends through 2011.18 In addition to changes in specific ARVs, the majority of 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 for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, to examine the association of in utero ARV exposures and infant CAs over the last 15 years. Our objectives were (1) to evaluate changes in the rate of CAs over time as new ARVs and regimens were utilized; and (2) to evaluate the association of in utero ARV exposure with CAs.
Methods
We analyzed data from HIV-infected pregnant women and their children enrolled in the SMARTT study.19 This study includes two cohorts: Static and Dynamic. Between 2007 and 2009, the Static Cohort enrolled mothers/caregivers and their children under 12 years of age who had detailed information on ARV use during pregnancy and pregnancy outcomes. The Dynamic Cohort began enrolling pregnant women and their infants between 22 weeks of gestation and one week after delivery into prospective surveillance in 2007. The protocol was approved by appropriate Institutional Review Boards, with written informed consent by mothers/guardians for study participation for themselves and their children.
Information on ARV use during pregnancy and medical conditions, including pregnancy outcomes, was collected by medical chart abstraction. CAs 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. CAs were recorded on study-specific anomaly and diagnosis forms. Study authors blinded to ARV exposures reviewed the reported CAs and classified them according to the Antiretroviral Pregnancy Registry modification of the MACDP classification scheme5, a well-documented system for categorizing CAs. According to this system, an infant with at least one major anomaly, or at least two 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 two team members, and discrepancies were discussed to obtain consensus.
Prenatal Antiretroviral (ARV) Exposures
The primary exposure of interest was reported maternal use of ARVs during the first trimester (<14 weeks gestation). Highly active antiretroviral therapy (HAART) regimens were defined as those containing three or more ARVs from two or more drug classes (nucleoside reverse transcriptase inhibitors, NRTIs; non-nucleoside reverse transcriptase inhibitors, NNRTIs; 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 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, advanced maternal age at delivery (>35 years), pre-pregnancy body mass index (BMI), health conditions such as pre- gestational diabetes, maternal sexually transmitted infections (STIs, see Table 1) during pregnancy, plasma HIV RNA concentration (viral load) and CD4 counts (earliest available measures in pregnancy), self-reported substance use (alcohol, tobacco, and drug use), and first trimester use of other medications previously reported to be associated with CA risk [e.g., folate antagonists and antidepressants including selective serotonin reuptake inhibitors (SSRIs)].22–26 Socioeconomic status also was considered, as reflected by household income and caregiver education levels. Low birth weight (<2500grams), preterm birth (<37 weeks gestation), and delivery by Cesarean section were described but not included as potential confounders since these measures could be on the causal pathway between ARV exposure and CA status,20–21 and the latter procedure might be preferentially performed when a CA was suspected.
Table 1.
Demographic and Maternal Characteristics of 2580 SMARTT Infants Overall and by Congenital Anomaly Status
| Characteristic | Total (N=2580) | Congenital Anomaly Status
|
P-Value | |
|---|---|---|---|---|
| Not a case (N=2405) | Case (N=175) | |||
| Cohort | ||||
| Dynamic | 1,380 (53%) | 1,282 (53%) | 98 (56%) | 0.53 |
| Static | 1,200 (47%) | 1,123 (47%) | 77 (44%) | |
| Birth Cohort | ||||
| < 2002 | 391 (15%) | 376 (16%) | 15 (9%) | 0.018 |
| 2002–2004 | 343 (13%) | 325 (14%) | 18 (10%) | |
| 2005–2007 | 525 (20%) | 483 (20%) | 42 (24%) | |
| 2008–2010 | 940 (36%) | 862 (36%) | 78 (45%) | |
| 2011–2012 | 381 (15%) | 359 (15%) | 22 (13%) | |
| Female sex | 1,254 (49%) | 1,177 (49%) | 77 (44%) | 0.21 |
| Race | ||||
| White | 701 (27%) | 651 (27%) | 50 (29%) | 0.87 |
| Black/African American | 1,703 (66%) | 1,592 (66%) | 111 (63%) | |
| Other | 14 (1%) | 13 (1%) | 1 (1%) | |
| Latino/Hispanic | 845 (33%) | 781 (32%) | 64 (37%) | 0.28 |
| Mother over 35 years old at birth of child | 336 (13%) | 307 (13%) | 29 (17%) | 0.20 |
| Household Income<$20,000 per year | 1,683 (65%) | 1,570 (65%) | 113 (65%) | 0.72 |
| Caregiver not High School Graduate | 894 (35%) | 831 (35%) | 63 (36%) | 0.68 |
| Birth Characteristics | ||||
| Cesarean-section delivery | 1,402 (54%) | 1,293 (54%) | 109 (62%) | 0.026 |
| Low birth weight (<2.5 kg) | 483 (19%) | 440 (18%) | 43 (25%) | 0.045 |
| Preterm birth (Gestational age<37 wks) | 527 (20%) | 477 (20%) | 50 (29%) | 0.008 |
| Pregnancy Complications | ||||
| Toxemia or pre-eclampsia | 145 (6%) | 129 (5%) | 16 (9%) | 0.040 |
| Diabetes – gestational | 116 (4%) | 108 (4%) | 8 (5%) | 0.85 |
| Diabetes – pre-gestational | 51 (2%) | 45 (2%) | 6 (3%) | 0.15 |
| Diabetes – either of above | 161 (6%) | 148 (6%) | 13 (7%) | 0.51 |
| Maternal Immunologic and Virologic Status | ||||
| HIV RNA > 1000 copies/mL at delivery | 390 (15%) | 368 (15%) | 22 (13%) | 0.38 |
| Early HIV RNA > 1000 copies/mL | 1,316 (51%) | 1,227 (51%) | 89 (51%) | 1.00 |
| CD4<250 cells/mm3 at delivery | 368 (14%) | 350 (15%) | 18 (10%) | 0.17 |
| Early CD4<250 cells/mm3 | 470 (18%) | 447 (19%) | 23 (13%) | 0.099 |
| Maternal Substance Use During Pregnancy | ||||
| Hard drug use1 | 68 (3%) | 63 (3%) | 5 (3%) | 0.81 |
| Illicit drug use including hard drugs1 | 206 (8%) | 191 (8%) | 15 (9%) | 0.77 |
| Alcohol use | 196 (8%) | 180 (7%) | 16 (9%) | 0.46 |
| Tobacco use | 446 (17%) | 414 (17%) | 32 (18%) | 0.76 |
| Maternal Medication Use During Pregnancy | ||||
| Methadone treatment | 22 (1%) | 22 (1%) | 0 (0%) | 0.40 |
| Pain medication | 99 (4%) | 91 (4%) | 8 (5%) | 0.55 |
| 1st trimester SSRI | 30 (1%) | 29 (1%) | 1 (1%) | 0.72 |
| 1st trimester folate antogonist | 107 (4%) | 101 (4%) | 6 (3%) | 0.84 |
| Maternal Sexually Transmitted Infection (STI) During Pregnancy | ||||
| Gonorrhea | 72 (3%) | 64 (3%) | 8 (5%) | 0.15 |
| Chlamydia | 215 (9%) | 199 (9%) | 16 (10%) | 0.67 |
| Trichomonas | 282 (13%) | 268 (13%) | 14 (9%) | 0.17 |
| Syphilis | 76 (3%) | 72 (3%) | 4 (2%) | 0.82 |
| Any of above STIs | 511 (19%) | 478 (20%) | 33 (19%) | 0.84 |
SSRI selective serotonin reverse inhibitor
Hard drugs include cocaine, heroin, and opium. Illicit drugs include these hard drugs as well as marijuana, ecstasy, methamphetamines, and hallucinogens.
P-value calculated by Chi-Square test for birth cohort, and Fisher’s exact test for all other characteristics. The above characteristics were unavailable for some participants, including race (n=162) ethnicity (n=3), maternal age (n=53), household income (n=185), caregiver education (n=25), delivery mode (n=52), preterm birth (n=45), low birth weight (n=23), diabetes (n=91, maternal VL (n=194), maternal CD4 (n=159), substance use during pregnancy (n=196), and maternal STIs (n=146 gonorrhea, 147 chlamydia, 149 syphilis, 355 trichomonas).
Statistical Methods
Rates of CAs and 95% confidence intervals (CIs) were estimated overall and by calendar year, and compared descriptively to the MACDP rates for the US population. The characteristics of children with and without CAs were compared using Chi-square tests, Fisher’s exact test, and Wilcoxon ranksum tests as appropriate. Logistic regression analysis was used to evaluate associations between in utero ARV exposures described above and confirmed CAs. Adjusted models included birth cohort and other noted confounders with p<0.10 in multivariable models. Separate analyses were conducted for certain CA categories (e.g., cardiovascular, musculoskeletal, skin, male genital), although these had limited power.
To confirm the robustness of results, several sensitivity analyses were conducted. Analyses were repeated restricting to cases with at least one major CA (e.g., excluding children with only conditional CAs) and excluding those with a chromosomal anomaly. We repeated all analyses restricting to the Dynamic Cohort, since its prospective follow-up from birth reduces the risk of recall bias and misclassification, and this restriction eliminates overlap with previous cohorts (P219C, P1025, WITS).7,12,13 Last of all, sensitivity analyses including 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. Due to observed time trends, analyses were repeated stratifying by, rather than adjusting for, birth cohort but yielded similar results and are not presented. Analyses were conducted using SAS Version 9.2 (SAS Institute, Cary, NC) and two-sided p-values ≤0.05 were considered statistically significant. Because SMARTT is a safety study, no correction for multiple comparisons was employed 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 thus findings warrant confirmation in future studies.
Results
Study Population and CA Status by Demographic and Maternal Characteristics
The demographic and maternal characteristics of the 2580 participants (N=1380 Dynamic born 2007–2012, N=1200 Static born 1995–2008) enrolled by July 1, 2012 are shown 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%). There were 162 unique children with at least one major CA (6.27%, 95% CI: 5.37, 7.29) and 13 children with two or more conditional but no major anomalies. These 162 children had a total of 242 confirmed major anomalies; musculoskeletal (N=72) and cardiovascular (N=55) anomalies were most common (eTable1). The prevalence of CAs was 3.8%, 5.2%, 8.0%, 8.3%, and 5.7% for children born <2002, 2002–2004, 2005–2007, 2008–2010, and >2010, with a significantly increasing trend (p=0.033) in successive years. However, there was no significant overall difference in prevalences between the Static and Dynamic Cohorts (6.4% vs 7.1%, p=0.53).
There was no significant difference 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 than non-cases, but there was no association with higher maternal viral load (>1000 copies/mL), or with alcohol, tobacco, or other substance use. Use of SSRIs was rare during the first trimester (n=30, 1.2%), and only one of these infants had a CA. Use of folate antagonists (cotrimoxazole or pyrimethamine) was reported by 107 mothers, six (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 use during the first trimester (aOR=2.09, 95%CI: 0.92,4.72). Of the 2580 children, 63 (6 cases, 57 non-cases) 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
There was a significantly higher prevalence of CAs for children exposed to HAART or to PIs in the first trimester (8.1% vs 5.8%, and 8.5% vs 5.8%, respectively), but these associations did not persist in adjusted models (see Table 2). No individual NRTIs 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 NNRTIs, neither efavirenz nor nevirapine was associated with CAs.
Table 2.
Association of First Trimester Antiretroviral (ARV) Exposures with Congenital Anomalies
| Percent Exposed | Defect Rate | Unadjusted Model | Adjusted Model | ||
|---|---|---|---|---|---|
|
| |||||
| Exposed | Unexposed | OR (95% CI) | OR (95% CI) | ||
| By ARV Drug Class | |||||
| Any ARV | 48.4 | 93/1219 (7.6%) | 76/1298 (5.9%) | 1.33 (0.97, 1.82) | 1.20 (0.87, 1.67) |
| HAART | 40.7 | 83/1025 (8.1%) | 86/1492 (5.8%) | 1.44 (1.05, 1.97) | 1.35 (0.98, 1.87) |
| NNRTIs | 8.5 | 13/214 (6.1%) | 156/2303 (6.8%) | 0.89 (0.50, 1.60) | 0.97 (0.54, 1.74) |
| NRTIs | 48.1 | 92/1211 (7.6%) | 77/1306 (5.9%) | 1.31 (0.96, 1.80) | 1.19 (0.86, 1.65) |
| PIs | 35.2 | 75/887 (8.5%) | 94/1630 (5.8%) | 1.51 (1.10, 2.07) | 1.39 (1.00, 1.92) |
| Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | |||||
| Abacavir (ABC) | 8.8 | 15/222 (6.8%) | 154/2295 (6.7%) | 1.01 (0.58, 1.74) | 0.94 (0.53, 1.65) |
| Didanosine (ddI) | 2.1 | 5/52 (9.6%) | 164/2465 (6.7%) | 1.49 (0.59, 3.80) | 1.51 (0.59, 3.86) |
| Emtricitabine (FTC) | 14.9 | 28/374 (7.5%) | 141/2143 (6.6%) | 1.15 (0.75, 1.75) | 1.14 (0.74, 1.74) |
| Lamivudine (3TC) | 31.7 | 63/797 (7.9%) | 106/1720 (6.2%) | 1.31 (0.95, 1.81) | 1.14 (0.81, 1.60) |
| Stavudine (d4T) | 2.7 | 4/68 (5.9%) | 165/2449 (6.7%) | 0.87 (0.31, 2.41) | 1.11 (0.40, 3.12) |
| Tenofovir (TDF) | 17.1 | 32/431 (7.4%) | 137/2086 (6.6%) | 1.14 (0.77, 1.70) | 1.14 (0.76, 1.71) |
| Zidovudine (ZDV) | 28.8 | 57/726 (7.9%) | 112/1791 (6.3%) | 1.28 (0.92, 1.78) | 1.10 (0.78, 1.56) |
| ddI + d4T | 0.3 | 2/7 (28.6%) | 167/2510 (6.7%) | 5.62 (1.08, 29.2) | 8.19 (1.53, 43.4) |
| ZDV + 3TC | 27.2 | 57/684 (8.3%) | 112/1833 (6.1%) | 1.40 (1.00, 1.95) | 1.19 (0.84, 1.69) |
| Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | |||||
| Efavirenz (EFV) | 3.7 | 7/94 (7.4%) | 162/2423 (6.7%) | 1.12 (0.51, 2.47) | 1.13 (0.51, 2.50) |
| Nevirapine (NVP) | 4.6 | 7/115 (6.1%) | 162/2402 (6.7%) | 0.90 (0.41, 1.96) | 1.03 (0.47, 2.26) |
| Protease Inhibitors (PIs) | |||||
| Atazanavir (ATV) | 8.8 | 26/222 (11.7%) | 143/2295 (6.2%) | 2.00 (1.28, 3.11) | 1.95 (1.24, 3.05) |
| Darunavir (DRV) | 2.1 | 1/54 (1.9%) | 168/2463 (6.8%) | 0.26 (0.04, 1.88) | 0.30 (0.04, 2.21) |
| Fosamprenavir (FPV) | 1.7 | 4/42 (9.5%) | 165/2475 (6.7%) | 1.47 (0.52, 4.18) | 1.35 (0.47, 3.86) |
| Lopinavir (LPV/r) | 13.5 | 32/341 (9.4%) | 137/2176 (6.3%) | 1.54 (1.03, 2.31) | 1.37 (0.90, 2.09) |
| Nelfinavir (NFV) | 8.7 | 15/220 (6.8%) | 154/2297 (6.7%) | 1.02 (0.59, 1.76) | 0.91 (0.51, 1.65) |
| Ritonavir (as booster) | 25.2 | 59/635 (9.3%) | 110/1882 (5.8%) | 1.65 (1.19, 2.30) | 1.56 (1.11, 2.20) |
| Saquinavir (SQV) | 1.3 | 2/33 (6.1%) | 167/2484 (6.7%) | 0.90 (0.21, 3.77) | 0.98 (0.23, 4.15) |
OR=odds ratio, CI=confidence interval, HAART=highly active antiretroviral treatment.
Each row reflects a separate logistic regression model, both unadjusted and adjusted for low maternal CD4 count (< 250 cells/mm3) early in pregnancy and birth cohort.
For PIs, there was a significantly higher prevalence of cases 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%). The associations persisted in adjusted models for atazanavir and ritonavir (Table 2). Atazanavir was usually used in combination with ritonavir (92%), and often with certain NRTIs. The combinations of atazanavir with ritonavir, tenofovir, or emtricitabine were each associated with increased risk of CAs, with similar adjusted ORs (2.01, 2.00, and 1.85, respectively), while combinations of atazanavir with either ZDV or lamivudine showed no significant association (aORs=0.89 and 1.48, respectively). Of the two primary regimens including ritonavir with another PI, atazanavir with ritonavir showed increased odds while ritonavir-boosted lopinavir did not (Table 2). Specific anomalies for children exposed to first trimester atazanavir are shown in eTable2
Associations for ARV exposures at any time during pregnancy indicated a significantly higher risk of CAs for those exposed to the combinations of either didanosine plus stavudine or to ZDV plus lamivudine. When the rate of CAs by timing of first exposure was examined (eTable3), the results were generally consistent with the comparisons of first trimester exposure. For some ARVs, however, the highest prevalence of CAs occurred with first exposure during the second or third trimester (abacavir: 10.6%, stavudine: 17.1%).
Separate analyses conducted by type of anomaly indicated that first trimester atazanavir exposure was significantly associated with musculoskeletal and skin anomalies (Table 3). There was significantly higher odds of musculoskeletal anomalies among infants exposed to didanosine plus stavudine in the first trimester. Ritonavir as a booster was associated with increased risk of musculoskeletal CAs. We observed a significantly higher odds of male genital anomalies (eg., hypospadias and cryptorchidism) with first trimester ZDV exposure and lamivudine exposure (Table 3).
Table 3.
Associations of First Trimester Exposure to Specific Antiretrovirals with Specific Anomalies
| ARV Exposure/Type of Anomaly | Defect Rate | Unadjusted Models | Adjusted Models* | |
|---|---|---|---|---|
|
|
|
|||
| Exposed | Unexposed | OR (95% CI) | OR (95% CI) | |
| Atazanavir (ATV) | ||||
| Cardiac | 7/222 (3.2%) | 33/2295 (1.4%) | 2.23 (0.98, 5.11) | 2.02 (0.88, 4.64) |
| Musculoskeletal | 11/222 (5.0%) | 46/2295 (2.0%) | 2.55 (1.30, 5.00) | 2.57 (1.30, 5.08) |
| Skin | 3/222 (1.4%) | 6/2296 (0.3%) | 5.23 (1.30, 21.0) | 6.01 (1.43, 25.3) |
| Ritonavir (RTV, as booster) | ||||
| Cardiac | 16/635 (2.5%) | 24/1882 (1.3%) | 2.00 (1.06, 3.79) | 1.83 (0.96, 3.49) |
| Musculoskeletal | 22/635 (3.5%) | 35/1882 (1.9%) | 1.89 (1.10, 3.25) | 1.79 (1.02, 3.14) |
| Lopinavir/RTV (LPV/RTV) | ||||
| Cardiac | 6/341 (1.8%) | 34/2176 (1.6%) | 1.13 (0.47, 2.71) | 0.79 (0.40, 2.34) |
| Musculoskeletal | 11/341 (3.2%) | 46/2176 (2.1%) | 1.54 (0.79, 3.01) | 1.40 (0.70, 2.83) |
| Zidovudine (ZDV) | ||||
| Male Genital | 8/726 (1.1%) | 6/1791 (0.3%) | 3.31 (1.15, 9.59) | 3.18 (1.10, 9.22) |
| Lamivudine (3TC) | ||||
| Male Genital | 8/797 (1.0%) | 6/1720 (0.3%) | 2.90 (1.00, 8.38) | 2.77 (0.96, 8.03) |
| Didanosine and Stavudine (ddI+d4T) | ||||
| Cardiac | 0/7 (0%) | 40/2510 (1.6%) | N/A | N/A |
| Musculoskeletal | 1/7 (14.3%) | 56/2510 (2.2%) | 7.30 (0.86, 61.7) | 8.29 (0.96, 71.8) |
ARV=antiretroviral, OR=odds ratio, CI=confidence interval
Models adjusted for: any anomaly low maternal CD4 count (< 250 cells/mm3) early in pregnancy and birth cohort; cardiac anomaly birth cohort; musculoskeletal anomaly low maternal CD4 count early in pregnancy and first trimester maternal alcohol consumption; skin anomaly low maternal CD4 count early in pregnancy; male genital anomaly maternal age >35 years at delivery.
For some less commonly-used ARVs, including raltegravir (1.5% exposed), enfuvurtide (0.3%), maraviroc (0.1%), and etravirine (0.4%), there were no first trimester exposures. Raltegravir was the only one of these ARVs with any CAs, with a rate of 4.2% (3 of 71 exposed at any time during pregnancy) as compared to 6.8% for raltegravir-unexposed.
Sensitivity Analyses
When restricting cases to children with major anomalies and when excluding 11 children with chromosomal anomalies (eTable1), the significant associations with first trimester atazanavir, ritonavir (as a booster), and the combination of didanosine plus stavudine persisted, with very 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, there was significantly higher odds of CAs among Dynamic infants exposed to lamivudine (aOR=2.13, 95%CI:1.26,3.60), ZDV (aOR=2.06, 95%CI: 1.23,3.44), ZDV plus lamivudine (aOR=2.43, 95%CI:1.45,4.06), and abacavir (aOR=1.58, 95%CI:1.00,2.49). In contrast, there was a protective association with darunavir exposure (aOR=0.21, 95%CI:0.05,0.84).
Examination of ARV exposures within the Dynamic Cohort by trimester of first exposure indicated that the increased risk for ZDV, lamivudine, and their combination was observed for both first and later trimesters as compared to 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 as compared to 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).
Discussion
We observed an overall prevalence of 6.78 CAs for every 100 live births, which is considerably higher than many prior studies of HIV-exposed infants in the U.S. and the U.K, with reported prevalences ranging from 2.8% to 5.5%4–7, 12,13 and higher than the rate of 3.2% in a recent Italian cohort,10 but 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 prior to 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 various population studies,28–29 increased ascertainment given the study-required evaluation for anomalies, and longer follow-up than some studies. It may also be partially attributable to the increasing percentage of mothers receiving ARVs early in pregnancy, which was less than 30% in earlier studies,4,6,7,12,13 but is almost 50% of the current cohort.
The association of first trimester atazanavir exposure with CAs, particularly musculoskeletal and skin anomalies, has not previously been reported and warrants further investigation. Of note, the P1025 study 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.13 Most prior studies included births prior to 2007, and thus did not reflect increasing use of this particular ARV since its approval in 2003, up to 20% by 2010.16 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 over the last decade,16–18 than with older ARVs (ZDV 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 a variety of 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 recent meta-analysis also found no increased risk of overall CAs with efavirenz exposure.30 We confirmed an increased risk for male genital anomalies with first trimester ZDV exposure;6,31 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, relatively complete information on maternal health, substance use and pregnancy complications, and use of the well-validated MACDP classification system. We also considered other medications used during pregnancy, such as SSRIs 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 2005–2010 as compared to more recent years. Conversely, allowing enrollment up to one 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. Both misclassification and lack of specificity of CA outcomes as well as potential exposure misclassification could have resulted in attenuation of findings; thus, we evaluated specific CAs and both individual ARVs and combinations of ARVs in increasing use.
In conclusion, our study was reassuring in confirming a lack of increased risk of CAs among children exposed to ARVs during the first trimester of pregnancy. We observed a higher prevalence of CAs than have been reported in the general population, but after adjustment for calendar year and maternal characteristics, there was no relative increase in risk for those exposed versus unexposed to HAART or to PI-based regimens early in pregnancy. However, while the absolute risk of CAs was relatively low, some individual drugs, particularly atazanavir, showed relative increases in 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 on ARVs.32 Thus, risks associated with in utero ARV exposures must be considered in order to identify optimal regimens based on their safety profiles.
Supplementary Material
Acknowledgments
Funding: 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 University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1) (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 (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). Under these 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. 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 U.S. Department of State.
We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. The following institutions, clinical site investigators and staff participated in conducting PHACS SMARTT in 2012, in alphabetical order: Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon; Ann & Robert H. Lurie Children’s Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Helen Rozelman; 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: Russell Van Dyke, 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, Emily Barr, Robin McEvoy; University of Florida/Jacksonville: Mobeen Rathore, Kristi Stowers, Ann Usitalo; University of Illinois, Chicago: Kenneth Rich, Lourdes Richardson, Delmyra Turpin, Renee Smith; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, Susan Adubato; University of Miami: Gwendolyn Scott, Claudia Florez, Elizabeth Willen; University of Southern California: Toinette Frederick, Mariam Davtyan, Maribel Mejia; University of Puerto Rico Medical Center: Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio.
Footnotes
Contributions: PLW and DHW were the primary authors who conceived and designed the study. PLW 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. PLW was responsible for conducting statistical analyses, and led the writing of the manuscript. MC, CY, RH, RBV, KR, JSR, ES, MR, HM, and DHW provided input on the study design, interpretation of analyses, and revisions to manuscript. Tulane University receives financial support from Gilead Sciences for partial support of the PHACS project. Dr Van Dyke receives no salary support or other funds from this funding source. All other authors declare that they have no conflicts of interest related to this manuscript.
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