Pregnancy outcomes with efavirenz
Polly Clayden, HIV i-Base
The low quality of evidence regarding the safety of efavirenz in pregnancy (associated with a potential increase in risk of central nervous system defects from preclinical studies), has led to much uncertainty when making recommendations. This is particularly problematic for guidance in resource-limited settings with fewer antiretroviral options and a public health approach.
Nathan Ford from M裥cins Sans Fronti籥s and colleagues conducted a systematic review of databases (to 2 February 2010) in order to identify observational cohorts reporting birth outcomes among infants exposed to maternal efavirenz during the first trimester of pregnancy. The findings from this analysis were published in AIDS ahead of print, May 24, 2010.
The primary endpoint of this study was birth defects of any kind. Secondary outcomes were spontaneous abortions, termination of pregnancy, stillbirths, and preterm delivery.
The investigators found 16 studies that met their inclusion criteria. These included 11 prospective and five retrospective cohorts.
Nine studies were conducted in resource-limited settings: South Africa, Botswana, Ivory Coast, Brazil and one multinational, MTCT-Plus. Six were European and one primarily in the US. Eight were reported in journal articles, six conference abstracts, one (MTCT-Plus) was an unpublished cohort and one the Antiretroviral Pregnancy Registry (APR) report.
Nine prospective studies reported rates for infants exposed to maternal efavirenz (35 defects out of 1132 live births) and non-efavirenz (289 defects out of 7163 live births) containing regimens during the first trimester. This gave a pooled non-significant relative risk of 0.87 (95% CI 0.61-1.24%, p= 0.45).
The investigators found low heterogeneity between studies (I2 = 0, 95% CI 0-56.3%, p= 0.85). There were no significant differences between studies conducted in industrialised counties compared with those in resource-limited settings, p=0.46.
There was an overall incidence of birth defects of 2.9% (95% CI 2.1-4.0%), range 0%-22.6% (95% CI 9.6-41%). Among all cohorts with birth defect data (1256 women with live births) they observed one infant with a neural tube defect (myelomeningocele), giving an incidence proportion of 0.08% (95% CI 0.002-0.44%).
Four prospective studies reported data for both first trimester (31 defects out of 920 live births) and second/third trimester exposure (19 defects out of 695 live births); the pooled relative risk between those groups did not differ (RR=0.91, 95% CI=0.46-1.79%, p=0.79).
Secondary outcomes were not reported consistently across studies. Seven studies reported spontaneous abortions in women with first trimester efavirenz exposure (39 abortuses out of 628 pregnancies); prevalence rates ranged from 2.6% (95% CI 0.1-13.5%) to 16.7% (95%CI 2.1-48.4%). Six studies and MTCT-Plus reported rates of stillbirths (24 out of 715 pregnancies); rates ranged from 0 (95% CI 0-9.3%) to 13% (95% CI 1.7-40.4%). Five studies reported preterm deliveries (55 out of 399 live births); rates ranged from 9.1%(95% CI 1.1-29.1%) to 18.2% (95% CI 7.0-35.5%).
Termination of pregnancy was reported by five prospective studies, three retrospective reviews and MTCT-Plus (81 out of 688 pregnancies); rates ranged from 2.5% (95% CI 0.8-5.7%) to 33.7% (95% CI 23.7-44.9%). The investigators noted that one study found a relative risk of termination 5.73 times higher (95%CI 1.45-22.75%, p=0.0017) among women receiving efavirenz compared to other antiretroviral drugs, indicating a need for careful counseling.
Overall the investigators found no increase in the incidence of birth defects among infants born to women receiving efavirenz in the first trimester. They note several limitations to the evidence base, including few studies reporting risk of bias or attempting to control for potential confounders, and most importantly the limited sample size.
They suggest that although these data should provide reassurance to providers, the low incidence of neural tube defects in the general population means a larger sample size is still needed to rule out the increased risk of this specific defect. They add that given an underlying incidence of neural tube defects in the general population of 0.1-0.4, even a five-fold increase would give an overall incidence of less than 1%.
They write: The balance of risks and benefits of efavirenz in pregnancy merits some recalibration, particularly in resource-limited settings where drug formularies are limited, women of child bearing age represent the majority of those infected with HIV, coinfection with tuberculosis is frequent, and the risk of mortality for those who are eligible for ART is high.
They suggest that better collection of birth outcome data should be performed in resource-limited settings where data are not always routinely captured. It is critical that as efavirenz use increases among women in these countries that support is given to establish adequate pharmacovigilance systems to better define the risk.
This useful analysis is reassuring for providers. As the authors emphasise, evidence with regards to the safety of efavirenz in pregnancy is weak. This uncertainty has led to conflicting recommendations. WHO have taken the view that the benefits outweigh the risks beyond the first trimester; national guidance in Zambia has done the same. In the new South African guidelines, the drug is contraindicated throughout pregnancy, which will make the scale up of treatment a bit more complicated.
It is worth noting that UKCHIC data, the first report in this issue of HTB, shows that even in a well resourced setting with access to alternative antiretrovirals and awareness of the contraindication among providers, almost a fifth of women conceiving HAART were receiving efavirenz (and of these only about half switched).
Given that, whatever is recommended, it is inevitable that efavirenz use in pregnancy will increase with greater access to antiretrovirals, the authors correctly stress the need for pregnancy registries, particularly in African countries to capture these data in order to provide better guidance in the future.
Ref: Ford N et al. Safety of efavirenz in first trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS 2010, Published ahead of print May 24, 2010.