US investigators have identified a possible association between the use of antiretroviral therapy during pregnancy and an increased risk of having a baby with a cleft lip or palate. The study, published in the January edition of Cleft Palate-Craniofacial Journal, found preliminary evidence seven anti-HIV drugs may increase the risk of this birth abnormality.
However, the investigators emphasise that their their findings are far from definitive. “Our report, although the first to report this signal, is merely a starting point; further investigations on these drugs’ side effects are required to follow.”
Appropriate use of antiretroviral therapy during pregnancy can reduce the risk of mother-to-child transmission of HIV to below 1%.
However, it is important to understand the possible risks associated with the use of anti-HIV drugs during pregnancy. The protocols of clinical trials routinely exclude pregnant and nursing mothers. Therefore, investigators scrutinised the Food and Drug Administation’s (FDA’s) Adverse Events Reporting System (AERS) to see if therapy with antiretrovirals during pregnancy increased the risk of cleft lip or palate.
Data from April 2004 to October 2009 were examined by the researchers. They calculated crude reporting odds ratios (ROR) to detect potential associations between specific antiretroviral drugs and the birth abnormality.
“Readers should be cognizant of the fact that the RORs calculated in this study should not be interpreted as definitive measure of the associations’ strength without further validation in well-controlled and prospective or retrospective epidemiological studies,” write the authors.
A total of 26 cases of cleft lip or palate that were possibly associated with the use of HIV therapy during pregnancy were identified.
Six of these cases involved exposure to efavirenz (Sustiva, also in the combination pill Atripla), which had a ROR of 196.01 (95% CI, 85.89-447.32). In addition, five cases were reported in the context of 3TC (Epivir) therapy (ROR = 60.23; 95% CI, 24.53-147.89); three after nevirapine (Viramune) treatment (ROR = 27.59; 95% CI, 8.75-86.99); five following the use of lopinavir/ritonavir (Kaletra) during pregnancy (ROR = 26.47; 95% CI, 10.78-64.67); and three cases of the defect were reported after maternal use of Combivir (3TC/AZT), providing a ROR of 24.94 (95% CI, 7.91-78.62).
Elevated RORs were also apparent for Trizivir (3TC/abacavir/AZT) and nelfinavir (Viracept).
“Our report is the first to detect a possible association between cleft lip and palate development and…antiretroviral drugs,” write the investigators.
However, they do not view their results as definitive and point to studies “of antiretroviral use during pregnancy that fail to show a statistical association with cleft lip and palate.”
The authors also note that the abnormality is believed to have a number of risk factors, including both genetic and environmental causes. “Our analyses report crude RORs and do not control for important confounders such as personal characteristics, diet, genetics, and so forth.”
They therefore conclude, “further studies should be performed to assess the relative safety of these drugs and the specific conditions or potential synergies that might lead to the development of cleft lip and palate."
Cartsos VM et al. Antiretroviral prophylaxis and the risk of cleft lip and palate; preliminary signal detection in the Food and Drug Administration’s Adverse Events Reporting System Database. Cleft Palate-Craniofacial Journal, 49: 118-21, 2012.