Preterm delivery and small-for-gestation outcomes in HIV-infected pregnant women on antiretroviral therapy in rural South Africa: Results from a cohort study, 2010-2015

Objectives
Increasingly more women conceive on antiretroviral therapy (ART) with non-nucleoside reverse transcriptase-based regimens. This study assessed the effect of preconception tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)/emtricitabine (FTC)-efavirenz (EFV) and post-conception TDF-(3TC/FTC)-EFV (versus other regimens) on preterm delivery (PTD) and small-for-gestational age (SGA) births.
Methods
We analysed data of 2549 HIV-infected women attending antenatal clinics in KwaZulu-Natal from 2010 through 2015 in this retrospective cohort study. Preconception, TDF-(3TC/FTC)-EFV was compared to nevirapine (NVP)-based regimens and other 3-drug EFV-based regimens. Post-conception, TDF-(3TC/FTC)-EFV was compared to NVP-based ART and zidovudine (ZDV) prophylaxis. Outcomes included PTD <37 weeks and SGA births. Generalized linear mixed effects were used to fit logistic regression models to account for repeat pregnancies.
Results
Among 2549 singleton live births, 10.4% (n = 264) were PTD and 10.4% (n = 265) SGA. PTD declined from 16.3% in 2010 to 9.3% in 2015 and SGA remained stable from 9.9% in 2010 to 10% in 2015.
Preconception NVP-based regimens [adjusted odds ratio (aOR) 0.66; 95% CI 0.27–1.63] and other 3-drug EFV-based regimens (aOR 0.72; 95% CI 0.24–2.12) were not associated with PTD versus TDF-(3TC/FTC)-EFV. NVP-based (aOR 0.75; 95% CI 0.40–1.42) and other 3-drug EFV-based regimens (aOR 1.55; 95% CI 0.76–3.16) were not associated with SGA births versus TDF-(3TC/FTC)-EFV.
Post-conception NVP-based ART (1.77; 95% CI 0.89–3.51) and ZDV (1.03; 95% CI 0.68–1.58) were not associated with PTD versus TDF-(3TC/FTC)-EFV. NVP-based ART (1.55; 95% CI 0.66–3.61) and ZDV (0.89; 95% CI 0.53–1.47) were not associated with SGA versus TDF-(3TC/FTC)-EFV.
Conclusions
Preconception TDF-(3TC/FTC)-EFV and post-conception TDF-(3TC/FTC)-EFV were not associated with PTD or SGA, compared with other regimens. Increasing ART use merits further study of the optimum ART regimen for safe birth outcomes.

## 研究目标
当前越来越多女性在接受非核苷类反转录酶抑制剂方案的抗反转录病毒治疗（antiretroviral therapy, ART）期间受孕。本研究旨在评估孕前应用替诺福韦酯富马酸替诺福韦二吡呋酯（tenofovir disoproxil fumarate, TDF）-拉米夫定（lamivudine, 3TC）/恩曲他滨（emtricitabine, FTC）-依非韦伦（efavirenz, EFV）方案，以及孕期应用TDF-(3TC/FTC)-EFV方案（相较于其他ART方案）对早产（preterm delivery, PTD）及小于胎龄儿（small-for-gestational age, SGA）分娩结局的影响。

## 研究方法
本回顾性队列研究纳入2010年至2015年在南非夸祖鲁-纳塔尔省产前门诊就诊的2549名HIV感染女性的数据进行分析。孕前暴露组方面，将TDF-(3TC/FTC)-EFV方案分别与奈韦拉平（nevirapine, NVP）为基础的ART方案及其他三药依非韦伦方案进行对比；孕期暴露组方面，将TDF-(3TC/FTC)-EFV方案与NVP基ART方案及齐多夫定（zidovudine, ZDV）预防方案进行对比。本研究的主要结局为妊娠<37周的早产（PTD）及小于胎龄儿（SGA）分娩。考虑到重复妊娠的混杂影响，本研究采用广义线性混合效应模型拟合Logistic回归模型进行统计分析。

## 研究结果
本研究共纳入2549例单胎活产儿，其中早产（PTD）发生率为10.4%（n=264），小于胎龄儿（SGA）分娩发生率为10.4%（n=265）。2010年至2015年，早产发生率从16.3%下降至9.3%，而小于胎龄儿分娩发生率则维持稳定，从2010年的9.9%小幅波动至2015年的10.0%。

孕前暴露亚组分析显示，相较于TDF-(3TC/FTC)-EFV方案，奈韦拉平为基础的ART方案[校正比值比（adjusted odds ratio, aOR）=0.66，95%置信区间（CI）：0.27~1.63]及其他三药依非韦伦方案（aOR=0.72，95%CI：0.24~2.12）均与早产发生率无显著关联；同时，奈韦拉平为基础的ART方案（aOR=0.75，95%CI：0.40~1.42）及其他三药依非韦伦方案（aOR=1.55，95%CI：0.76~3.16）也均与小于胎龄儿分娩无显著关联。

孕期暴露亚组分析显示，相较于TDF-(3TC/FTC)-EFV方案，奈韦拉平为基础的ART方案（aOR=1.77，95%CI：0.89~3.51）及齐多夫定预防方案（aOR=1.03，95%CI：0.68~1.58）均与早产发生率无显著关联；而奈韦拉平为基础的ART方案（aOR=1.55，95%CI：0.66~3.61）及齐多夫定预防方案（aOR=0.89，95%CI：0.53~1.47）同样与小于胎龄儿分娩无显著关联。

## 研究结论
相较于其他抗反转录病毒治疗方案，孕前及孕期应用TDF-(3TC/FTC)-EFV方案均与早产及小于胎龄儿分娩无显著关联。随着抗反转录病毒治疗应用人群的不断扩大，亟需开展进一步研究以明确可保障良好妊娠分娩结局的最优ART方案。