In this study of HIV-1-infected women and their infants in Argentina and Brazil, the overall prevalence of CAs was 6.16/100 LBs. The prevalence of CAs following first trimester exposure to ARVs (6.20/100 LBs) did not appear significantly different from that following second (6.76/100 LBs) or third trimester (4.33/100 LBs) exposure. In addition, the prevalence of CAs did not appear to differ significantly according to ARV class, specific ARVs, and any ARV exposure. Marital status, associated with CAs in univariate analysis, presumably is a proxy for other environmental and/or socioeconomic factors.
The prevalence of CAs within seven days of birth (2.4%) in our study population is similar to that at delivery (2.8%) reported by the Latin American Collaborative Study of Congenital Malformations (ECLAMC)10
, a hospital-based program for the clinical and epidemiological investigation of CAs. ECLAMC reports on CAs among approximately 200,000 births per year, including both major and minor anomalies diagnosed prior to hospital discharge after birth for infants weighing 500 grams or more. Participating countries include Argentina, Brazil, Chile, Ecuador, Peru, and Venezuela.
The overall prevalence of CAs in our study population is within the range reported among the general population in Latin America. Very low rates have been reported in studies utilizing birth certificate data or medical records: 0.4% in Vitoria, Brazil6
, 0.8% in Rio de Janeiro7
, and 1.4% in Pelotas, Brazil8
. In relatively small, retrospective cohort studies of HIV-1-infected women, the observed prevalence of CAs was 2.3% in Buenos Aires, Argentina22
and 2.2% in Rio de Janeiro, Brazil.23
Other studies have reported CA rates ranging from 1.7% in Rio de Janeiro, Brazil9
; 2.2% in Argentina (personal communication, Silvina Ivalo); 4.7% in Brazil24
; and 8.4% in Chile.11
The overall prevalence of CAs in our study population is higher than that reported in other, large studies of HIV-1-infected women and their infants19, 25–27
, and the higher prevalence of CAs observed in our study could be attributed to its prospective design, with follow-up of infants until six months after birth and with reporting of both minor and major anomalies. However, the prevalence of CAs detected within the first seven days of life (2.36/100 LBs) is similar. Most importantly, our results showed no difference in the prevalence of CAs according to trimester of exposure to ARVs, consistent with previous studies of in utero
ARV exposure and infant CAs.
One of the largest sources of data regarding in utero
ARV exposure and CAs is the APR (130 CAs among 4530 LBs, or 2.9 CAs/100 LBs)19
, a voluntary registry, including data from the U.S. and other countries, with prospective assessment of exposure. The great majority of data utilized within the APR are collected at the time of birth or shortly thereafter. However, in some cases data collected through the first 1–6 years after birth are used for categorizing infant CAs. For the overall population exposed to ARVs in this registry, no increase in risk of either CAs overall or specific CAs has been detected to date when compared with observed prevalence for “early diagnoses” in population-based birth defects surveillance systems or with prevalence among those with earliest ARV exposure in the second trimester or third trimester. In analyzing individual drugs with sufficient data to warrant separate analyses, an increased frequency for CAs has been detected for didanosine, but without an increase in the prevalence of a specific anomaly.19
Analyses of data collected within the first 18 months of life for HIV-exposed infants enrolled in the Women and Infants Transmission Study (WITS) (90 CAs among 2527 LBs, or 3.6 CAs/100 LBs) revealed a statistically significant elevated rate of hypospadias after first trimester exposure to zidovudine.25
For the National Study of HIV in Pregnancy and Childhood (NSDHPC) in the United Kingdom and Ireland, most reports of CAs are collected with the first few weeks of life.26
The observed rate of CAs was 232 CAs per 8242 LBs, or 2.8%.26
No increased risk of CAs after in utero
exposure to specific ARVs or different classes of ARVs was observed in this study26
, nor in the European Collaborative Study (55 CAs among 3740 children, or 1.5%).27
HIV-1-infected women may take other potentially teratogenic drugs besides ARVs. Dihydrofolate reductase inhibitors, such as trimethoprim, pyrimethamine, and sulfadiazine, and other folate antagonists, such as carbamazepine, phenytoin, and phenobarbital, may increase the risk of neural tube defects as well as cardiovascular, oral clefts, urinary tract and limb-reduction defects.28–30
A retrospective study concluded that there was no evidence of teratogenicity of ARVs if given alone during the first trimester, but exposure to the combination of ARVs and folate antagonists (n=13) was associated with a significantly higher risk of CA when compared to no exposure (n=198). 31
In the present study, CAs were not associated with exposure to ARVs alone or in combination with folate antagonists. This could be partially explained because 86% of women in the study population were asymptomatic and because of food fortification policies (extra synthetic folic acid in wheat flour) established in several South American countries in recent years.32
Our observed stillbirth rate of 2% is consistent with the rate observed among 859,750 Latin American hospital births from 1982–1986 (2.0%).33
Our 2% stillbirth rate also is consistent with published stillbirth rates among HIV-infected mothers in the US (2%)34
and in Argentina (1.7%).22
This was the first large prospective study in Latin America to address the prevalence of CAs among HIV-1-exposed infants, and to accurately collect data regarding not only in utero exposure to ARVs, but also exposure to folic acid and folate antagonists. However, despite the large sample size, there was limited power to pursue detailed analyses of the prevalence of CAs according to specific ARV exposures, and to analyze specific types of CAs. The results of our analyses do not support changes to current recommendations for the use of ARVs during pregnancy for treatment of HIV-1-infected women and for prevention of mother to child transmission. Continued monitoring of the prevalence of CAs among children of HIV-1-infected women should be pursued.