A small number of cases of neural tube defects in babies born to mothers who were taking dolutegravir at the time of conception are prompting expanded study of the use of the drug in pregnant women.
Rebecca Zash, MD
In June 2018, investigators published the results of a large-scale observational study designed to clarify the safety of dolutegravir in HIV-positive women who are pregnant. They used data from 8 government hospitals in Botswana from 2014 through 2016, and compared the outcomes of pregnancies in which the woman was on dolutegravir-based antiretroviral treatment to the outcomes of pregnancies in which the woman was on efavirenz-based therapy.
The results, published in The Lancet Global Health, were encouraging. Of the 1729 pregnant women on dolutegravir, 33.2% had an adverse birth outcome of any kind, and 10.7% had a severe birth outcome. Those rates were in line with the rates among the 4593 pregnant women on efavirenz who gave birth during the study (35.0% and 11.3%, respectively).
“Although further studies are needed to determine the safety of dolutegravir exposure from conception and to confirm its efficacy for the prevention of mother-to-child HIV transmission, these results should pave the way for wider use of dolutegravir in pregnancy throughout the world,” the authors, led by Rebecca Zash, MD, of Beth Israel Deaconess Medical Center, in Boston, concluded.
As those study results were being published, however, the researchers started to note a small but potentially significant problem. The data showed an increase in neural tube defects among infants born to mothers who had been on dolutegravir at the time of conception. An unplanned interim analysis showed that as of May 1, 2018, neural tube defects were noted in 86 (0.1%) of the 88,755 births in the 8 hospitals. However, among the 426 women who had been on dolutegravir at the time of conception, 4 of the infants had neural tube defects (0.94%).
In a letter to the New England Journal of Medicine published late July 2018, Zash and colleagues stated that the new data are a potential early signal of an issue with dolutegravir, but they added that it’s too soon to know the significance of the numbers.
“Our study is ongoing, and more data are needed to confirm or refute this signal, given the small number of events and the small difference in prevalence,” Zash and colleagues wrote.
Indeed, in addition to raising questions about the use of dolutegravir in pregnant women, the new data highlight the difficulty in making prescribing decisions for this population. One complicating factor is that many pregnancies are unplanned, making it difficult for physicians to avoid prescribing drugs that may be best for a non-pregnant woman, but which may cause adverse effects if the woman became pregnant.
Zash noted that none of the 2812 women who initiated dolutegravir therapy after becoming pregnant gave birth to children with neural tube defects.
“That is because neural tube defects form in the first approximately 28 days after conception—so you have to be on the drug during this very early part of pregnancy to be at risk (if the drug causes neural tube defects),” she told MD Magazine®. “[All] women on dolutegravir at conception are at risk; but, basically none of the women who start [dolutegravir] during pregnancy are at risk. (The median time to starting dolutegravir during pregnancy is 17 weeks).”
In an accompanying article in NEJM, Sonja A. Rasmussen, MD, Wanda Barfield, MD, MPH, and Margaret A. Honein, PhD, MPH, noted that years ago, early data suggested efavirenz might cause neural tube defects, prompting regulators in the United States and Europe to discourage its use in the first trimester.
“Subsequent studies have not confirmed this finding, and efavirenz is now considered an alternative to dolutegravir,” Rasmussen and her co-authors noted. “These examples emphasize the importance of a balanced response to preliminary signals.”
Ultimately, the author concluded that prescribing medications to pregnant women is a balancing act, and physicians need to make careful, data-driven decisions. However, they agreed that in this instance, more data is needed, and they cautioned against using the current neural tube defect numbers to justify leaving pregnant women out of such studies.
“[S]hifting the default from exclusion of pregnant women to a careful consideration of benefits and risks can ensure that pregnant women and their fetuses receive the care they need,” they wrote.
Zash said her team’s research in Botswana will continue and expand. They had already re-submitted a grant to continue their research through 2022 at the time they learned about the neural tube defect signal. Since then, they expanded their number of sites from 8 to 14, and plan to add 4 additional sites by next month.
“By doing this we hope to capture as many births as possible from women who had already become pregnant while taking dolutegravir before we told Botswana our findings (mid-May 2018),” she said. “All these additional women should give birth by the end of March 2019, which is when we hope to be able to share our next analysis.”