HIV-positive women starting antiretrovirals before conception have increased risk of having an infant that is small for gestational age

HIV-positive women who take combination antiretroviral therapy (cART) before conception have an increased risk of having a small for gestational age (SGA) baby, according to Dutch research published in PLOS One. Overall, HIV therapy before conception increased the risk of having an SGA infant by approximately a third. But the risk was only significant if the pre-conception regimen was based on a protease inhibitor (PI).

“Our data showed that initiation of cART prior to conception is associated with an increased risk of SGA while cART initiated post-conception is not,” observe the authors. “This risk was clearly seen among women receiving PI-based regimens prior to conception who constituted the largest group. cART initiated prior to conception also revealed a trend towards significance in the increased risk of PTD [pre-term delivery].”

The investigators call for more research, especially into the mechanisms whereby specific antiretroviral drug classes affect foetal growth.

“As most of the current HIV guidelines advise initiating antiretroviral therapy at any CD4 count, the number of pregnant cART users, who began their regimen prior to conception will increase,” comment the investigators. “Studies performed in this new population will help see if pre-conception cART and which regimen is the crucial factor in adverse pregnancy outcomes.”

An infant is classified as small for gestational age if at least 90% of infants born after the same duration of pregnancy weigh more than her (below the tenth percentile for gestational age). Infants that are SGA may have decreased oxygen levels, low blood sugar and a failure to thrive, and will need extra care during the early months of life. The vast majority of SGA infants catch up with other infants in growth by the age of 2 but may need extra feeding.

Mothers are more likely to give birth to infants that are SGA if they have high blood pressure, or diabetes, or chronic kidney disease, or malnutrition, if they smoke or use drugs or alcohol, or if they have an infection. A related condition, intrauterine growth restriction, is the result of restricted blood and oxygen flow to the placenta, or other problems in the placenta that nourishes the growing foetus.

The benefits of cART for HIV-positive pregnant women are well described and include maternal health and a very low risk of mother-to-child HIV transmission. These benefits are considered to far outweigh any possible risks to the infant due to exposure to cART.

However, there are still uncertainties about the timing of cART (started before or after conception) and the type of HIV treatment on the risk of adverse birth outcomes, especially the risk of having an SGA infant.

To clarify these important questions, investigators from the Netherlands designed a retrospective study involving 1022 HIV-positive mothers who gave birth between 1997 and 2015. The primary outcome was the proportion of infants who were SGA. Secondary outcomes were median birth weight (and gestational age in weeks at birth).

The main variables were the initiation of cART and its type (PI or non-nucleoside reserve transcriptase inhibitor – NNRTI – based) before or after conception. Data were also gathered on other factors associated with adverse birth outcomes, such as smoking and drug and alcohol use.

Rates of adverse birth outcomes were also compared to those observed among HIV-negative sub-Saharan African women in Rotterdam.

A total of 1392 singleton births were included in the analysis. cART was used prior to conception by 550 women.

The HIV-positive women who started cART prior to conception were older (33 vs 28 years), more likely to be on a NNRTI-based regimen (48 vs 21%) and to have had a CD4 cell count below 200 cells/mm³ (57 vs 22%), compared to women who started cART during pregnancy.

Approximately a quarter (24%) of infants of HIV-positive mothers were SGA. The corresponding rate in the HIV-negative comparator group was just 1.4%.

The SGA rates for the infants of women who started cART before and after conception were 27% and 22%, respectively, a significant difference (p = 0.01).

In initial analysis, pre-conception use of cART increased the risk of having an SGA infant by approximately 40% (OR = 1.40; 95% CI, 1.11-1.80, p = 0.005). After controlling for potential confounders, pre-conception use of cART continued to be associated with a significantly increased risk of SGA (OR = 1.35; 95% CI, 1.03-1.77, p = 0.028).

Stratifying by type of cART showed that mothers who used a PI-containing regimen before conception had a significantly increased risk of having an SGA baby compared to women who started PI-containing cART after conception (OR = 1.49; 95% CI, 1.08-2.10, p = 0.016). There were no corresponding findings for NNRTI-based cART.

Median birth weight was 0.33kg lower for the infants of the HIV-positive mothers compared to the infants of the HIV-negative mothers.

The lowest median birth weight was observed in the babies of mothers who started cART before conception, especially if this treatment contained a protease inhibitor. Overall, low birth weight was found in 14% of infants whose mothers used cART pre-conception compared to 11% of infants whose mothers started cART after conception. Univariate analysis showed that pre-conception cART increased the risk of low birth weight (OR = 1.35; 95% CI, 1.01-1.80, p = 0.05). However, this association was no longer significant in the analysis that took into account factors such as smoking and gestational age (OR = 1.34; 95% CI, 0.94-1.92, p = 0.11).

Pre-term delivery occurred in 15% of HIV-exposed infants compared to 5% of the infants of HIV-negative mothers. The rate of pre-term delivery was higher among women who started cART before conception compared to those who started treatment after conception (18 vs 13%). cART before conception significantly increased the risk of pre-term delivery in the authors’ first analysis (OR = 1.38; 95% CI, 1.02-1.85, p = 0.04) but fell just short of significance in an analysis that took into account factors such as maternal age, CD4 cell count and smoking (OR = 1.39; 95% CI, 0.99-1.94, p = 0.06).

“Fetal growth restriction, resulting in SGA, is a serious condition with increased morbidity and mortality, including neuro-development delay, as well as hypertension, obesity and diabetes mellitus in adulthood,” conclude the authors. “More information about the mechanisms underlying fetal growth restrictions in HIV-infected pregnant women using cART is needed. Only when the potential impact of cART is fully understood can we determine the optimal individualised regimens for HIV-infected women of childbearing age.”