Dolutegravir may cause birth defects, European Medicines Agency warns

Women with HIV who might become pregnant advised to avoid dolutegravir unless using effective contraception

Regulatory agencies in the United States and European Union have warned that women with HIV who can become pregnant should not use the integrase inhibitor dolutegravir (Tivicay, also in Triumeq and Juluca) without effective contraception, following a report from Botswana of a higher frequency of birth defects in babies born to mothers who became pregnant while taking dolutegravir.

The Botswana study looked at the incidence of neural tube defects such as spina bifida in infants born to mothers taking antiretroviral drugs at the time they became pregnant. The study looked at babies born to 11,558 mothers taking antiretroviral treatment and found that four of 426 (0.9%) whose mothers became pregnant while taking dolutegravir had a neural tube defect. In comparison, the risk of neural tube defects was 0.1% in women taking other antiretroviral regimens.

The study will continue until February 2019, so more information about the risk will not be available for approximately one year.

In the meantime, regulatory agencies and the World Health Organization have made the following recommendations:

  • The European Medicines Agency says that dolutegravir should not be prescribed to women seeking to become pregnant. If pregnancy is confirmed in the first trimester women should be switched to a suitable alternative regimen if possible.
  • All agencies recommend that women who can become pregnant should use effective contraception when taking dolutegravir.
  • All agencies say that women already taking dolutegravir shouldn’t stop taking the drug without discussing it with their doctor.
  • The US Food and Drug Administration says that alternative regimens should be discussed with women of childbearing age and the World Health Organization says that an efavirenz-based regimen is a safe and effective alternative.
  • The US President’s Emergency Plan for AIDS Relief says that in PEPFAR-supported programmes, all women who wish to become pregnant should use efavirenz-based regimens but dolutegravir should continue to be used as the preferred first-line treatment for all other groups.

The risk of neural tube defects of the kind reported in the Botswana study is highest at the time of conception and in the first trimester of pregnancy. A neural tube defect occurs when the spinal cord, brain, and related structures do not form properly. Spina bifida – a malformed spinal cord – is the most common neural tube defect.

The US Food and Drug Administration notes that no cases of neural tube defects have been reported in the babies of women who started dolutegravir later in pregnancy. (A study presented at the 2017 International AIDS Society conference identified no increase in the risk of adverse birth outcomes in 845 women who started dolutegravir during pregnancy in Botswana.)

As dolutegravir is being made available at low cost in many lower-income countries the President’s Emergency Plan for AIDS Relief has issued guidance for national treatment programmes.


neural tube defect

Abnormalities of the skull or back bone of a developing baby that happen during the first three months of pregnancy and which will affect thebaby from birth. Taking folic acid before becoming pregnant and for the first three months of pregnancy can help to prevent neural tube defects.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

first-line therapy

The regimen used when starting treatment for the first time.

European Medicines Agency (EMA)

Regulatory agency that evaluates medicines for safety and efficacy in Europe, performing a similar role to the Food and Drug Administration (FDA) in the United States. The EMA recommends to the European Commission that a medicine can be marketed in the European Union and European Economic Area.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

“PEPFAR encourages countries to continue with their transition to DTG [dolutegravir] through the implementation of its 2018 Country Operational Plans. DTG offers many benefits, including that it is better tolerated by the patient, leads to improved outcomes such as faster viral suppression.”

The World Health Organization is undertaking a review of its guidance and says that an update will be issued in the coming months. Its statement notes that the risk of neural tube defects is increased by folate deficiency and reiterates its recommendation that all women take a daily folic acid supplement before conception and during pregnancy to help prevent neural tube defects.

Manufacturer ViiV Healthcare says that animal toxicology studies leading to the licensing of dolutegravir showed no evidence of adverse developmental outcomes in rats or rabbits.