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

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 th 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.

**背景** 目前，针对HIV阳性孕妇的抗逆转录病毒联合疗法（cART），其获益——改善孕产妇健康、预防母婴传播（pMTCT）——已超过该疗法带来的不良影响。但随着抗逆转录病毒联合疗法种类日益丰富，一个问题随之浮现：何种类型的cART对孕妇及育龄女性最为安全？本研究依托荷兰一项大型HIV队列，探讨了抗逆转录病毒联合疗法的使用时机与不同类别暴露对不良妊娠结局的影响。

**材料与方法** 本研究纳入1997年至2015年间ATHENA队列中登记的单胎HIV暴露婴儿（HEU）。我们采用多因素logistic回归分析，分别针对单胎及多胎妊娠，评估小于胎龄儿（SGA，即出生体重低于同胎龄对应百分位）、低出生体重及早产的预测因素。

**结果** 本研究共纳入1022名母亲所分娩的1392名婴儿。其中331名（23.8%）为SGA患儿。与妊娠启动后开始使用cART的孕妇相比，孕前启动cART的孕妇诞下SGA婴儿的风险显著升高（比值比OR=1.35，95%置信区间CI：1.03~1.77，P=0.03）。相较于妊娠期间启动蛋白酶抑制剂（PI）类cART的孕妇，孕前启动该类方案的孕妇发生SGA的风险最高。单因素分析显示，孕前使用cART与早产存在显著关联；但多因素分析仅观察到无统计学意义的升高趋势（OR=1.39，95%CI：0.94~1.92，P=0.06），对比孕前与妊娠后启动cART的孕妇。在多因素分析中，孕前启动cART的孕妇相较于妊娠后启动者，其低出生体重风险并未显著升高（OR=1.34，95%CI：0.94~1.92，P=0.11）。

**结论** 在本研究纳入的HIV阳性孕妇队列中，孕前使用cART（尤其是蛋白酶抑制剂（PI）类方案）与宫内生长受限所致的小于胎龄儿显著相关。数据显示，相较于妊娠后使用cART，孕前使用该疗法与早产风险仅存在无统计学意义的升高趋势。未来仍需开展更多研究，以阐明使用cART的HIV阳性孕妇在胎儿生长过程中胎盘内发生的分子机制。唯有掌握此类机制，我们才能进一步理解HIV与cART对胎儿的潜在影响，从而为育龄HIV感染女性确定最优的个体化用药方案。