Treatment Issues: Newsletter of Current Issues in HIV/AIDS - Volume 19, Number 12, December 2005
Polly Clayden, HIV i-Base, London

At the 12th Annual Retrovirus Conference held in Denver earlier this year, a poster authored by Karen Beckerman and coworkers presented findings from an analysis of central nervous system birth defects that found no increase in the rate of birth defects in babies born to mothers taking antiretroviral (ARV) drugs during pregnancy compared to babies from the general population.

The Antiretroviral Pregnancy Registry (APR) critically reviews all reported birth defects associated with ARV use in pregnancy, including central nervous system defects. Registration by clinicians is voluntary and birth defect prevalence is compared to the Center for Disease Control's (CDC) 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.

Over the period 1989 through July 2005, APR has monitored 5,169 live births exposed to ARVs. Of 1,980 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 CDC's rate of 3.1 per 100 live births (95% CI 3.1 to 3.2).

Of first trimester ARV exposures, four cases of central nervous system defects were detected among 1,980 live births (0.20 of 100 live births, 95% CI 0.004 to 0.40). Among those with ARV exposure later during pregnancy, 5 had central nervous system defects among 3,189 live births (0.16 of 100 live births, 95% CI 0.02 to 0.29). According to national data, about 1 in 235 (0.4%) 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 (Sustiva). Use of efavirenz during pregnancy is contraindicated due to serious birth defects seen in the offspring of animals and women treated with efavirenz during pregnancy.

Among retrospective cases, there were four neural tube defects, three with efavirenz exposure, and a Dandy Walker defect with efavirenz exposure, which is 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 (0.07%) live births in the USA. Thus far, 1,980 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, 1­2 cases of spina bifida (spina bifida occulta, meningocele and 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 publicized association or efavirenz exposure with congenital malformations of the CNS in animals (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 spina bifida prior to starting therapy and be informed of their therapeutic options.

Women starting efavirenz therapy should be advised not to rely solely on hormone-based birth control, such as pills, injections, or implants, but to use an additional form of barrier contraception, such as a condom or diaphragm. Women who wish to become pregnant should talk to their doctor about other ARV options. Women who become pregnant while taking efavirenz should talk to their doctor right away.

References
Beckerman K, Watts H, Covington D et al. Assessing the risk of central nervous system birth defects associated with ART exposure during pregnancy. Conf Retroviruses Opportunistic Infect. 2006 Feb 5-8;13th: Abstract No. 713.

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