In this prospective study of outcomes in HIV-pregnant women and their infants, eighty congenital anomalies were identified in 61 of 1112 infants, yielding a congenital anomaly rate of 5.49/100 live births. First trimester efavirenz exposure was associated with a significantly increased risk of congenital anomalies (6 of 47, 12.8%).
Our findings support previous reports associating efavirenz exposure during the first trimester with congenital anomalies. (26
) Since efavirenz was first approved by the Food and Drug Administration in 1998, the package labeling has carried a warning about use in pregnancy, based upon animal data indicating an increased risk of developmental anomalies. (26
) Three of 20 infant cynomolgus monkeys exposed to efavirenz throughout gestation at levels equivalent to those seen in humans had congenital anomalies (anencephaly and unilateral anopthalmia, microophthalmia, and cleft palate), compared with none of 20 monkeys in the control group. In 2005, Bristol-Myers Squibb changed the pregnancy category of efavirenz from Category C (Risk of Fetal Harm Cannot Be Ruled Out) to Category D (Positive Evidence of Fetal Risk), based upon four retrospective reports of neural tube defects (three cases of meningomyelocele and one case of Dandy Walker Syndrome) in infants exposed to efavirenz during the first trimester. (27
) In a review of data from Pediatric AIDS Clinical Trials Group (PACTG) protocols 219 and 219C, investigators identified congenital anomalies in five of 32 infants (15.6%) exposed to efavirenz during the first trimester (adjusted OR 4.31, 95% CI: 1.56, 11.86), only one of which was a neural tube defect. (28
) In the 219/219C study there was a congenital anomaly rate of 5.3/100 live births, very similar to the rate observed in our study. The data from 219/219C provide the first evidence of an association of efavirenz with congenital anomalies in a population-based study, although the number of infants with first trimester efavirenz exposure was small. It should be noted that some participants in PACTG 219C were also enrolled in P1025. However, only 15 cases overall were common to both studies, including two children exposed to efavirenz (a case of talipes equinovarus and a neural tube anomaly that had been previously reported). (15
The prevalence of congenital anomalies in the P1025 study population (5.49/100 live births) is higher than that reported for the general population of the United States (approximately 3/100 live births). (29
) Some studies of congenital anomalies among HIV-exposed infants with intrauterine exposure to ARVs have shown prevalences more similar to that of the general population. (). For example, the prevalence of congenital anomalies among infants with in utero
exposure to ARVs was 2.9% for the Antiretroviral Pregnancy Registry, (30
) 2.8–3.1.% for the National Study of HIV in Pregnancy and Childhood in the United Kingdom and Ireland, (31
) and 3.56% for the Women and Infants Transmission Study. (32
) Even lower prevalence of congenital anomalies has been reported from the European Collaborative Study (1.6%). (33
) However, other studies of HIV-infected women and their infants have documented higher rates of congenital anomalies. (28
) Our observed prevalence is similar to the more recent reports from the 219/219C study (28
) and from the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI) analysis of congenital anomalies among HIV-infected women in Argentina and Brazil. (34
) In the NISDI cohort, the overall rate of congenital anomalies for infants born to HIV-infected women was 6.16/100 live births [95% confidence interval 4.6 to 7.7]. As in the current study, approximately 4% of the women in the NISDI cohort had first trimester exposure to efavirenz. In contrast to the P1025 and 219/219C data, there was no evidence of an association of efavirenz with congenital anomalies in the NISDI cohort. (34
Comparison of Studies Evaluating ARV Exposure and Congenital Anomalies
There are differences among the various studies of congenital anomalies in children exposed to antiretrovirals in utero
that may account for the varying prevalence rates reported. Of the studies mentioned, ours demonstrated the highest percentage of infants (46.5%) with earliest in utero
exposure to any ARV during the first trimester. Congenital anomalies may be under-reported in some of the studies. Differential ascertainment across the studies may explain differences in prevalence. In the 219/219C study, for which the cardiovascular system was the most common site for congenital anomalies, 29% of all infants had echocardiograms, most of which were required for clinical research. (28
) Non-ARV drug exposure could account for differences in prevalence: for example, folate antagonist use was evaluated in the 219/219C study, (28
) the NISDI study, (34
) and in the current study, but was not specifically addressed in the other studies. The studies also differ in the number of infants evaluated.
As with the data from 219/219C, (28
) the most common anomalies in our study were cardiovascular, followed by musculoskeletal. In 219/219C, first trimester exposure to zidovudine was associated with a higher risk of cardiovascular anomalies and a lower risk of musculoskeletal anomalies. Due to limited power, we were not able to assess for such associations in this review.
To address possible confounding factors, multivariate models were adjusted for year of birth, maternal age, gestational age at birth, birth weight, and infant HIV infection status. Maternal substance use (alcohol, tobacco, marijuana, cocaine, heroin and methadone) and in utero exposure to folate antagonists and selective serotonin-reuptake inhibitor (SSRI) antidepressants did not enter the multivariate models and were not significantly associated with presence of congenital anomalies in univariate analyses. Combination ARV regimens, whether for treatment or for pMTCT, are recommended during pregnancy. It is not possible to adjust for all other ARV agents when assessing the association of a given ARV with infant congenital anomalies.
The results of this study are consistent with the results of other recent cohort studies suggesting higher prevalences of congenital anomalies among infants born to HIV-infected women than have been reported for the general population. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero
exposure to ARVs and congenital anomalies were identified. Our inability to identify other significant associations in this analysis may be due to lack of power; the limits of the 95% confidence intervals for the adjusted odds ratios indicate the magnitude of associations that are unlikely based on our results (i.e., those associations lying outside the confidence interval). Further research is indicated to evaluate for possible confounding factors. Information available from voluntary retrospective reporting of anomalies is limited by selection bias, in that adverse outcomes may be over-reported. The Antiretroviral Pregnancy Registry collects both prospective and retrospective data, and analyzes them separately. Clinicians caring for HIV-infected pregnant women are encouraged to report prospectively all women receiving ARVs during pregnancy to the Antiretroviral Pregnancy Registry (www.APRegistry.com
), whether or not anomalies are identified.