Evaluation of Neural Tube Defects (NTDs) After Exposure to Raltegravir During Pregnancy

Hala Shamsuddin, MD; Casey L. Raudenbush, MSN; Brittany L. Sciba, BSN; Yun-Ping Zhou, MD, PhD; T. Christopher Mast, PhD; Wayne L. Greaves, MD; George J. Hanna, MD; Ronald Leong, MD; Walter Straus, MD


J Acquir Immune Defic Syndr. 2019;81(3):247-250. 

In This Article

Abstract and Introduction


Objective: To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy.

Methods: Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts.

Results: A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate.

Conclusions: Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.


Current HIV-treatment guidelines recommend that all women living with HIV receive antiretroviral therapy.[1–3] For those diagnosed during pregnancy, HIV treatment should be initiated as early in pregnancy as possible, both to improve well-being and survival of mothers and infants and to prevent vertical transmission, regardless of maternal plasma viral load or CD4+ T-cell count.[1–4] In 2007, raltegravir was the first integrase inhibitor approved by the US Food and Drug Administration in combination with other antiretroviral agents for the treatment of adults living with HIV-1. Available data have not identified a potential birth defect signal among infants of women treated with raltegravir 400 mg twice daily during pregnancy.[5]

Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord that occur when the neural tube fails to close. Embryonic neural tube development occurs during the first 28 days after conception.[6] Although the prevalence of NTDs worldwide is highly variable, they rank among the most common categories of birth defects.[7,8] The causes of NTDs are not known, but genetic and environmental factors have been implicated, with up to 70% of the variance in prevalence attributed to genetic factors.[9] Risk factors for NTDs include exposure to certain medications in pregnancy, obesity, poorly controlled diabetes, and folate deficiency.[9]

Raltegravir and dolutegravir are both in the integrase strand transfer inhibitor class of antiretroviral drugs. In a recent birth outcome surveillance study in Botswana to evaluate the prevalence of NTDs associated with exposure to antiretroviral drugs from the time of conception, NTDs were identified in 4 infants born to 426 women who had been receiving a dolutegravir-based regimen at conception (0.94%, 95% confidence interval: 0.37 to 2.4) and in early pregnancy.[10] In comparison, NTDs were identified in 14 infants born to 11,300 women who had been receiving non-dolutegravir–based regimens at conception (0.12%, 95% confidence interval: 0.07 to 0.21) and in no infants born to 2812 women who started a dolutegravir-based regimen later in pregnancy. To determine whether the observed NTDs associated with dolutegravir exposure at conception represent an integrase inhibitor class effect, we performed a review of the available data to assess whether NTDs have been observed among infants whose mothers received raltegravir during pregnancy.