Adequate levels of folate protect against neural tube defects when taking dolutegravir

Low levels of folate (vitamin B9) increased the risk of neural tube defects in the foetuses of mice fed dolutegravir during pregnancy, underlining the importance of folic acid supplements for women of childbearing age and fortification of food with folic acid, researchers from Baylor College of Medicine in the journal AIDS.

Folate is found in leafy green vegetables, tropical fruits, pulses and whole grains. Folic acid is a more potent formulation of folate that can be taken as a supplement or added to foodstuffs.

"Dolutegravir is known to block the uptake of folic acid, suggesting that this could explains a trend towards a higher rate of neural tube defects."

Folic acid (folate or vitamin B9) reduces the risk of neural tube defects by approximately 80% if taken daily before conception and during pregnancy. It also reduces the risk of developing anaemia during pregnancy. There is mixed evidence about the effectiveness of folic acid in preventing babies from being born with a cleft palate.

In 2018, a prospective observational study in Botswana, Tsepamo, reported a higher frequency of neural tube defects in infants born to mothers with HIV who received dolutegravir around the time of conception when compared to efavirenz. Longer-term follow-up in Botswana found that the difference in risk became non-significant as more births were reported.

Dolutegravir is known to block the uptake of folic acid, suggesting that this effect explains the trend towards a higher rate of neural tube defects in women receiving dolutegravir in Botswana.

Studies in other countries where foodstuffs are fortified with folic acid, notably Brazil and the United States, found no evidence of an increased risk of neural tube defects associated with dolutegravir treatment.

To investigate whether low folate levels do indeed contribute to the development of neural tube defects when dolutegravir is used, researchers at Baylor College of Medicine, Houston, carried out a study in mice. Professor Robert Cabrera and colleagues at Baylor have been investigating the links between folate and dolutegravir-related neural tube defects since 2019.

They compared the effects of dolutegravir exposures during gestation in foetuses obtained from mice that had been fed on either low folate or normal folate diets and then given dolutegravir in drinking water during the first half of pregnancy.

Mice received the low folate (0.3mg/kg) or normal folate (3mg/kg) diet for four weeks. After mating, pregnant mice continued to receive this diet and also received a human equivalent dose of dolutegravir (n=43) or a dose five (n=40) or ten times (n=41) higher than the human therapeutic dose from day 6 until day 12 of pregnancy. A control group (n=45) received the low or normal folate diet only, without dolutegravir. Mice were euthanised at day 18 and the foetuses were examined for neural tube defects.

The study found no effect of dolutegravir on maternal weight gain. The low folate diet did not produce signs of folate deficiency such as megaloblastic anaemia.

The low folate diet was associated with a lower number of live foetuses at higher dolutegravir doses when compared to the low folate control group.

Dolutegravir dose was not associated with any differences in foetal weight, the number of foetuses per pregnant mouse or foetal loss.

Four foetuses in three different litters had neural tube defects. All had been exposed to dolutegravir and all were from mice fed a low-folate diet. The incidence of neural tube defects was estimated at 0.415% per litter compared with a background incidence of 0.1% in the type of laboratory mouse used in this experiment (p=0.0007). There was no significant difference in incidence according to dolutegravir dose.

Cleft palate occurred in three foetuses in the dolutegravir-treated group but not in the control group, at varying doses and in both low-folate and normal-folate groups. The incidence of cleft palate was one in 63 litters compared to one in 300 in this type of laboratory mouse (p=0.0167).

Abnormalities of the ribs were more common in dolutegravir-exposed foetuses regardless of dietary folate level, reflecting a possible effect of dolutegravir on foetal skeletal development.

The study investigators say that their findings support the conclusion that folate-fortified populations are protected from neural tube defects caused by dolutegravir.

Which populations have a greater risk of low folate levels?

As a result of a large clinical trial, which showed the effectiveness of folic acid supplementation in preventing babies from being born with neural tube defects, many countries including the United States introduced a policy of requiring cereal and grain products to be fortified with folic acid. Some other countries, including many in Europe, preferred to opt for voluntary fortification. Instead, they give folic acid supplements to pregnant women and women trying for a baby.

A systematic review of studies looking at folate levels in the general population, not just women of childbearing age, showed a substantial difference in average folate levels between countries with mandatory requirements for folate fortification of foods and countries with either voluntary fortification policies or no policies. Levels were almost twice as high in countries with mandatory fortification compared to voluntary fortification, and three times higher than in countries with no fortification policy.

The review found that mandatory fortification was also associated with a 50% lower prevalence of neural tube defects compared to no policy, whereas a voluntary fortification policy was associated with a 20% lower prevalence.

By 2023, almost all countries in eastern and southern Africa had mandatory fortification policies apart from Namibia, Botswana, eSwatini and Lesotho, although they each import substantial amounts of grain from neighbouring South Africa - where fortification is mandatory. Most countries in west Africa have mandatory fortification policies too.

Zambia has no policy on fortification and nor do most other countries in central Africa.

Fortification is mandatory throughout North and South America. Policies vary in Asia, from voluntary fortification in India and China to mandatory fortification in Indonesia and Vietnam, to no policy in Cambodia and Pakistan.

In 2018, many countries in Africa with high HIV prevalence opted to avoid giving dolutegravir to pregnant women or women of childbearing age until more evidence was available. Subsequent research findings have reassured policymakers that the rate of neural tube defects associated with dolutegravir use is not unusual but further work is needed to make folic acid supplementation standard care for pregnant women with HIV where there is a risk that dietary folate intake is low.