Risk of central nervous system birth defects associated with ART exposure during pregnancy

The Antiretroviral Pregnancy Registry (APR) critically reviews all birth defects associated with antiretroviral use in pregnancy, including central nervous system defects. Registration by clinicians is voluntary and birth defect prevalence is compared to CDCs population-based surveillance system.

In addition to analysis of prospective data, APR complements its analyses by comprehensive review of other data sources including clinical trials, epidemiological studies, and retrospective data.

A poster authored by Karen Beckerman and coworkers presented findings from an APR analysis of central nervous system birth defects.

Over the period 1989 through July 2005, APR has monitored 5169 live births exposed to ART. Of 1980 first trimester exposures, there were 59 birth defects (3.0%, 95% CI 2.3 to 3.8). This overall rate is not significantly different from CDCs rate of 3.1 per 100 live births (95% CI 3.1 to 3.2).

Of first trimester exposures, four cases of central nervous system defects were detected among 1980 live births (0.20 of 100 live births, 95% CI 0.004 to 0.40). Among those with later exposure, 5 had central nervous system defects among 3189 live births (0.16 of 100 live births, 95%CI 0.02 to 0.29). According to national data, about 1 in 235 live births have central nervous system or eye defects.

The central nervous system defects after first trimester exposure included holoprosencephaly, brain growth retardation, and two with hydrocephalus; and, among later exposures, Dandy Walker, lipomeningocele, caudal thalamic notch cyst, and two with hydrocephalus. The authors noted that none of these cases were exposed to efavirenz.

Among retrospective cases, there were four myelomeningocele (neural tube) defects, three with efavirenz exposure, and a Dandy Walker defect with efavirenz exposure as reported in the product label (Sustiva, BMS, 8 of 2004). There were no central nervous system defects in other supplemental studies reviewed.

The authors wrote: Within the detection power of the sample to date, APR data demonstrate no teratogenicity overall. There does not appear to be an increased risk of central nervous system defects in the prospective analysis. In the supplemental data, there do not appear to be any patterns other than the already identified efavirenz signal. Prospective reports of ART exposures are critically important to determine teratogenic potential and may avoid reporting bias inherent in other forms of data collection.

Comment

According to the Spina Bifida Asssociation, spina bifida occurs in 7/10,000 live births in the USA. Thus far, 1980 first trimester exposures to any single or combination of antiretroviral therapy have been prospectively reported to the Antiretroviral Pregnancy Register, mostly from the USA. Therefore, 1 – 2 cases of spina bifida (spina bifida occulta, meningocele & myelomeningocele) might have been expected in this population. Only 228 first trimester exposures to efavirenz have been reported prospectively, with no cases of spina bifida, and therefore there are insufficient numbers to comment on the relative risk of efavirenz and spina bifida.

Amongst retrospectively reported cases there have been 4 cases of spina bifida (myelomeningocele) of which 3 cases are reported in association with efavirenz exposure. Given the well-documented and publicised association or efavirenz exposure with congenital malformations of the CNS in cymologus macaques some reporting bias might be anticipated. The number of babies exposed to efavirenz in the first trimester is not known, but an estimate of such numbers would be useful. Until more robust data are available women of child-bearing potential should be informed of the reported association between efavirenz and myelomeningocele prior to starting therapy and informed of their therapeutic options.

Beckerman K, Watts H, Covington D et al. Assessing the risk of central nervous system birth defects associated with ART exposure during pregnancy. 13th CROI, Denver. Abstract 713.