Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age

Abstract

BackgroundThe benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands.Materials and methodsWe included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery.ResultsA total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03−1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94−1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94−1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception.ConclusionIn our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age.

Placental growth disorders and perinatal adverse outcomes in Brazilian HIV-infected pregnant women

“…Despite the high proportion of SGA born fetuses in this study and the presence of PI categorized ART, there was no statistical difference. These data differ from findings of a study that identified a higher risk for restricted fetal growth in pregnant women using regimens based on PI initiated before gestation [13], and from a study conducted by Van der Merwe et al 2011that showed an association between SGA birthweight and the use of PI regimens [42].…”

“…However, a common difficulty in previous studies is the need to control outcomes not only for comorbidities that affect growth and are prevalent in general gestations and in HIV-infection status (hypertensive disorders, smoking, diabetes, illicit drugs, fetal malformation, congenital syphilis and maternal body mass index (BMI) disorders) but also for the use of highly active antiretroviral therapy (HAART) [9,10]. In the literature related to adverse perinatal outcomes, conflicting data have been presented regarding the occurrence of restricted growth and preterm births in pregnant women infected with HIV under antiretroviral schemes with and without protease inhibitors (PI) before and after conception [10][11][12][13][14]. In this context, and considering the evidence that the postnatal growth of the children of HIV-infected women is often delayed or fails to meet expected values even without the occurrence of vertical transmission (VT) of the virus [15],new studies about fetal and placental growth in HIV-infected pregnant women are justified.…”

Characteristics of HIV-positive pregnant women and HIV- and antiretroviral therapy-exposed fetuses: A case-control study

“…Regarding the SGA rate, HIV infection itself and ART both contributed to a higher SGA rate [11,19]. Among the ART regimens, one mouse-based model revealed that PI will affect the IUFG by decreasing the progesterone level, which leads to fetal growth restriction [14].…”

“…Small-for-gestational age (SGA), preterm birth (PTB), or low birth weight (LBW) in HIV-positive women is widely observed in several cohort studies [7][8][9][10][11][12]. The possible risk factors for SGA include Hepatitis B infection and ART initiation later than 14 weeks gestation.…”

“…Apart from the HIV infection itself [13], ART exposure also poses a risk for SGA in HIV-exposed fetus. Several observational studies reported that ART use, especially protease inhibitors, is related to SGA or intrauterine growth restriction (IUGR) [11,12,14,15].…”