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NEW ORLEANS -- Children exposed to HIV in utero, but who remained uninfected, appeared to be predisposed to obesity and reactive airway disease later in life, a registry study found.

These exposed individuals were significantly more likely to develop obesity in adolescence and young adulthood compared to a group of age- and sex-matched controls (42% vs 25%, respectively), as well as reactive airway disease (40% vs 24%), Lindsay Fourman, MD, of Massachusetts General Hospital in Boston, reported here.

"While we know averting perinatal HIV infection has clear public health benefits, we don't know if there are any long-term consequences to HIV in utero exposure even in the absence of infection, and that's what we were seeking to look at in this study," Fourman said during her presentation at ENDO 2019, The Endocrine Society meeting. "To us, this really indicates there is a strong biological link between in utero HIV exposure and the long-term metabolic health of offspring."

The severity of maternal HIV infection seemed to impact the association too, as children born to women with third trimester CD4 counts <250 cells/mL were at increased risk for higher body mass index (BMI) in later life compared with those of mothers with less severe HIV in the third trimester (odds ratio 8.2, 95% CI 1.5-54.9, P=0.006), she explained.

This link persisted after adjusting for maternal factors like age, BMI, antiretroviral therapy use, HIV duration, and household income (P<0.05).

"We found this to be really remarkable because these two parameters, the CD4 count and BMI in adolescence, are something reflected over 12 years apart in time," Fourman said. "The fact they're so strongly correlated was really striking."

Fourman's group used the Partners Healthcare Research registry to collect data from 50 HIV-exposed but uninfected adolescents ages 13 and older and 48 of their mothers, and 141 unexposed individuals and 71 of their mothers. The group of exposed adolescents and controls were similar in terms of age (median 18 vs 19, respectively), male sex (54% vs 55%), and race (26% white, 40% black, and ~30% Hispanic).

Mothers with HIV were also similar to their respective control group in terms of age at delivery (30 vs 27, respectively), BMI during pregnancy (26 vs 27 kg/m²), and obesity during pregnancy (25% vs 29%), which is important because this is an additional risk factor for offspring obesity, Fourman noted. Women were HIV-positive a mean 4 years prior to their pregnancy, and 93% of mothers with HIV used antiretroviral therapy during pregnancy.

To Fourman, this indicates the link between in utero HIV exposure and future obesity could be caused by inflammation in utero, as she and her team did not find a correlation between individual classes of antiretroviral therapy and obesity. It could also be a result of lifestyle factors, she said.

"There could be something post-birth in the environment that's different growing up in a house with a mother with HIV," Fourman told 番茄社区app, adding that certain questions could only be elucidated in a prospective study, as maternal factors such as stress were unavailable in the registry.

Suman Srinivasa, MD, also of Massachusetts General Hospital, told 番茄社区app that the possibility that antiretroviral therapies could be behind this association could not be ruled out, as certain classes of these medications are known to have toxic effects on adipogenesis, adipocyte differentiation, and mitochondrial dysfunction, which have been linked to weight gain and secondary metabolic complications among HIV-exposed individuals.

"We just don't fully understand how the maternal environment may affect the children of these mothers and whether contemporary antiretrovirals have less metabolic effects," said Srinivasa, who was not involved in the research.

"We know that well-treated individuals with HIV with good immunological control still have evidence of chronic inflammation, which could contribute to secondary metabolic complications," she added. "So rather than [antiretroviral] exposure itself, the association could be related to a pro-inflammatory milieu in the maternal uterine environment."

Fourman emphasized the importance of screening adolescents exposed to HIV in utero, even if they were not infected. Currently, these children are screened for the first 2 years of life to monitor for the development of HIV, but they are not flagged as high risk for other medical conditions beyond that, she said.

As this population, which now accounts for 18 million people worldwide, continues to grow and age, understanding the mechanisms behind these findings will become increasingly important in developing interventions for pregnant women with HIV, Fourman said.

"This study adds to growing evidence that the intra-utero environment is an important but underappreciated determinant of metabolic health," she said. "This population might yield insights to other groups exposed to abnormal intrauterine environments such as individuals born to mothers with obesity or gestational diabetes."

Fourman said limitations of the findings include that data were retrospectively drawn from medical records. Additionally, individuals in the study all reside in the U.S. and have access to standard medical care, so the results were not generalizable to other populations.

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