Birth Defects among Children Born to Human Immunodeficiency Virus-infected Women: Pediatric AIDS Clinical Trials Protocols 219 and 219C

Susan B. Brogly, PhD; Mark J. Abzug, MD; D. Heather Watts, MD; Coleen K. Cunningham, MD; Paige L. Williams, PhD; James Oleske, MD; Daniel Conway, MD; Rhoda S. Sperling, MD; Hans Spiegel, MD; Russell B. Van Dyke, MD

Disclosures

Pediatr Infect Dis J. 2010;28(8):721-727. 

In This Article

Discussion

In HIV-uninfected and HIV-infected children enrolled in protocols 219 and 219C by 1 year of age, we documented a birth defect prevalence of 5.3% including all 117 cases, and 4.7% including 103 major cases only. No differences were found according to infant HIV infection status. While we did not detect an association between overall in utero ARV exposure and defects, associations with particular ARV drugs were identified.

Our study is the first to provide evidence of an association between efavirenz and birth defects in a population-based investigation, although the small number of infants with first trimester efavirenz exposure must be considered. Of the 5 children in our study with birth defects and first trimester efavirenz exposure, only 1 had a neural tube defect and has previously been described[5] and retrospectively reported to the APR. In prospectively reported APR cases, defects were detected in 13 (3.2%) of 407 live births with first trimester efavirenz exposure, which was similar to the overall APR rate; no specific pattern of defects was observed (1 case of meningomyelocele and 1 case of facial cleft with anophthalmia).[13] However, 3 (15%) of 20 infant cynomolgus monkeys with first trimester efavirenz exposure at levels similar to human exposure had defects (anencephaly and unilateral anophthalmia, micro-ophthalmia, and cleft palate).[6] We also detected associations between first trimester lopinavir/ritonavir exposure and defects, but this did not remain significant after adjustment for other covariates, perhaps because of low power. Animal studies have not demonstrated teratogenic effects, but have shown delayed skeletal ossification and skeletal variation at maternally toxic doses.[1]

The rate of birth defects in our cohort was higher than the 2.9% prevalence reported by the APR.[13] Other US[12] and European[8] studies of children born to HIV-infected women have not reported an elevated defect prevalence of birth defects, excluding the PACTG 076 randomized trial in which a rate of major defects of 8% was detected, and all ARV exposure occurred after the first trimester.[17] It is possible that differential ascertainment across studies could account for the differences. A total of 636 children in our study population had echocardiograms, most per study protocol, and more children with (41%) than without defects (28%) had echocardiograms. Early screening echocardiography can detect important subclinical malformations and produce rates of cardiac defects of 5% to 10% higher than expected.[18,19] Additionally, children whose mother had participated in a perinatal protocol were more likely to have a birth defect, possibly suggesting differential ascertainment.

To investigate potential selection bias, we examined enrollment into 219 and 219C among children who had participated in perinatal protocols PACTG 076, 316 and IMPAACT P1025. Despite the higher enrollment of children with defects into our cohort, it was nondifferential with respect to most in utero ARV exposures, and importantly, those with which we detected notable associations. Selection bias of our estimated associations between defects and ARV exposure is not of major concern. It should also be noted that IMPAACT P1025 is a cohort study and no ARV was given as part of the protocol;[20] likewise, in PACTG 316, all women were on clinically indicated ARV and the only randomized component was single-dose nevirapine at labor and delivery.[21]

To control for possible confounding, models were adjusted for perinatal protocol participation, exposure to folate antagonists, and year of birth. We examined other potential confounders of the association between in utero ARV exposure and birth defects, including maternal drug use, but had incomplete information. Some residual confounding may persist. Finally, because of the large number of ARVs available for use during pregnancy, it is impossible to adjust for all other ARVs when estimating effects of a particular ARV, and this should be considered in weighing the evidence from our study as well as other studies.

It is possible that some associations might have been attenuated if particular defects result from exposure to a particular ARV. We attempted to look at more refined categories of birth defects where power was sufficient. A lower risk of musculoskeletal defects and a higher risk of heart defects were found with first trimester zidovudine exposure. These findings were based on a small number of cases and require confirmation in other studies. An association between first trimester zidovudine exposure and septal heart defects was noted in PACTG protocol 185 and in a German study, although selection bias could not be ruled out.[13]

A potential limitation of our study is that children, not pregnant women, enrolled in protocols 219 and 219C. Therefore, birth defects resulting in fetal loss were not included. Birth defects in stillbirths occurring after 20 weeks gestation were included in the Women and Infants Transmission Study[12] and the APR.[13] If defects caused by a specific exposure resulted in an increase in stillbirths then our estimates would likely be attenuated.

In this US cohort of children born to HIV-infected women, we identified a higher prevalence of birth defects than other studies. Overall, first trimester in utero ARV exposure was not associated with an increased risk of defects. However, some associations with first trimester in utero exposure to particular ARVs were identified. Further study is needed to rule out possible confounding, and to examine associations between ARV exposure and specific birth defects. Practitioners are urged to report all pregnant women receiving ARV during pregnancy to the APR (http://www.APRegistry.com) as early as possible and preferably before the pregnancy outcome is known.

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