Greater weight gain in pregnancy reduces the risk of adverse outcomes for women with HIV

Women with HIV who gained weight during pregnancy after starting dolutegravir-based treatment were less likely to experience birth outcomes such as premature birth, stillbirth or an infant that was small for gestational age, analysis of a large clinical trial has shown.

Weight gained during pregnancy was more likely to be maintained in the year after giving birth by women taking dolutegravir than those taking efavirenz, especially if dolutegravir was taken with tenofovir alafenamide (TAF).

The findings, published in the journal Clinical Infectious Diseases, come from the IMPAACT 2010 / VESTED study, which showed that women who started dolutegravir-based treatment during the second trimester of pregnancy were more likely to have a suppressed viral load at the time of delivery than women randomised to receive efavirenz. A suppressed viral load at the time of delivery greatly reduces the risk of vertical HIV transmission.

The study also found that women who received dolutegravir-based treatment were less likely to experience the most common adverse birth outcomes – stillbirth, premature birth or giving birth to a baby that is small for the stage of pregnancy reached at the time of delivery (gestational age).

The World Health Organization recommends dolutegravir for first-line treatment in all adults, including during pregnancy. An observational study of pregnant women with HIV in Botswana found a slightly increased risk of neural tube defects in infants exposed to dolutegravir during gestation in 2018, but longer-term follow-up, as well as studies in Brazil and the United States, have shown that dolutegravir use during pregnancy does not raise the risk of neural tube defects.

Adverse birth outcomes have multiple causes, including lack of weight gain during pregnancy. But very substantial weight gain during pregnancy can also lead to complications. In view of the greater tendency to gain weight when starting treatment with dolutegravir compared to efavirenz, the IMPAACT 2010 / VESTED trial investigators looked at the relationship between changes in weight during pregnancy and the main adverse birth outcomes.

Participants were randomised to receive either:

• Dolutegravir (DTG), tenofovir alafenamide (TAF) and emtricitabine (FTC)
• Doltutegravir, tenofovir disoproxil fumarate (TDF) and emtricitabine
• Efavirenz, tenofovir disoproxil fumarate and emtricitabine (fixed-dose combination).

Women were eligible to join the study between 14 and 28 weeks of pregnancy if they were previously untreated or had received less than 14 days of antiretroviral treatment in their current pregnancy. The study recruited 643 women in Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, United States and Zimbabwe.

The study participants had a median age of 26 years and 91% were Black or African American. The mean baseline CD4 count was 491 and 30% had a CD4 count below 350 when starting treatment. Eight percent were underweight at study entry (body mass index < 18.5), 53% were in the normal weight range, 23% in the overweight range and 16% in the obese range.

Study participants gained a below-average amount of weight during pregnancy and in the year following delivery. Between starting treatment and giving birth, women assigned to the TAF-containing study arm gained 0.378 kg a week, compared with 0.31 kg in the TDF-containing study arm and 0.291 kg a week in the efavirenz arm. The difference between the TAF arm and both the TDF and the efavirenz arm was statistically significant (p=0.01 and p<0.001 respectively).

Women in the TAF arm were also less likely to experience below-average weight gain (<0.19kg a week) (15%, compared to 23% in the TDF arm and 30% in the efavirenz arm). They were more likely to experience high weight gain (>0.59kg a week) (12%, vs 9% in the TDF arm and 5% in the efavirenz arm).

"Low weight gain before giving birth was associated with a 44% higher risk of adverse birth outcomes."

Women taking dolutegravir maintained a higher weight in the 50 weeks after giving birth, especially those taking TAF, compared with those taking efavirenz. Women taking TAF were 46% more likely than women taking efavirenz to be in the overweight or obese body mass categories 50 weeks after giving birth. Maintaining a higher weight a year after giving birth was also associated with Hispanic/Latina ethnicity, and less strongly, with Asian race compared to Black or African American race or participating in the trial at a site in Asia.

In the study population as a whole, low weight gain before giving birth was associated with a 44% higher risk of adverse birth outcomes. When analysed by treatment assignment, low weight gain in the TAF arm was associated with a 2.7 times higher risk of adverse birth outcomes compared to normal weight gain. The difference in risk between low and normal weight gain was not significant for the other drug combinations used in this study.

Eighteen percent of pregnancies resulted in an adverse birth outcome (premature birth between 32 and 27 weeks of pregnancy or small for gestational age) and 12% resulted in a severe birth outcome (stillbirth, miscarriage, neonatal death, very premature birth before 32 weeks of pregnancy or very small for gestational age). Severe outcomes occurred more often in pregnancies that were accompanied by low weight gain (17%, vs 11% of pregnancies with normal weight gain).

High weight gain did not increase the risk of adverse birth outcomes compared to normal weight gain in the study population as a whole or for any drug combination.

“Our data counter the dogma that INSTI-associated weight gain has only negative effects,” the study investigators say.

However, a causal mediation analysis which tests the contribution of direct and indirect effects to an outcome calculated that less than a third of the difference in adverse pregnancy outcomes was attributable to weight gain prior to giving birth. Other factors accounted for the remainder of the effect, leading the authors to conclude, “there remain significant gaps in our understanding of the mechanisms by which different ART regimens influence pregnancy outcomes.”

The study investigators also note that although their analysis found that greater weight gain during pregnancy was associated with a lower risk of adverse outcomes, they also found that baseline weight was associated with an increased risk, so that every kilogramme of weight at baseline was associated with a 4% higher risk of an adverse birth outcome.

Maintaining a higher weight after giving birth could have implications for future pregnancies.

“This pattern may ultimately be associated with adverse outcomes over time,” the investigators conclude. “A focus on healthy body weight, particularly before conception, may help optimize outcome over recurrent pregnancies as well as health over a woman’s life span.”