Importance: Prenatal screening for HIV can inform use of interventions to reduce the risk of mother-to-child transmission. The US Preventive Services Task Force (USPSTF) previously found strong evidence that prenatal HIV screening reduced risk of mother-to-child transmission. The previous evidence review was conducted in 2012.

Objective: To update the 2012 review on prenatal HIV screening to inform the USPSTF.

Data Sources: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from 2012 to June 2018, with surveillance through January 2019.

Study Selection: Pregnant persons 13 years and older; randomized clinical trials and cohort studies of screening vs no screening; risk of mother-to-child transmission or maternal or infant harms associated with antiretroviral therapy (ART) during pregnancy; screening yield at different intervals or in different risk groups.

Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality.

Main Outcomes and Measures: Mother-to-child transmission; harms of screening and treatment; screening yield.

Results: Sixty-two studies were included in this review, including 29 new studies. There remains no direct evidence on effects of prenatal screening vs no screening on risk of mother-to-child HIV transmission, maternal or infant clinical outcomes, or the yield of repeat or alternative screening strategies. New evidence confirms that combination ART is highly effective at reducing the risk of mother-to-child transmission, with some new cohort studies reporting rates of mother-to-child transmission less than 1% when combination ART was started early in pregnancy (when begun in first trimester, 0%-0.4%; when begun after first trimester, or at any time if timing of ART initiation not reported, 0.4%-2.8%). New evidence on harms of ART was also largely consistent with the previous review. Evidence from primarily observational studies found prenatal combination ART with a boosted protease inhibitor associated with increased risk of preterm delivery (range, 14.4%-26.1%). For other birth outcomes (low birth weight, small for gestational age, stillbirth, birth defects, neonatal death), results were mixed and depended on the specific antiretroviral drug or drug regimen given and timing of prenatal therapy.

Conclusions and Relevance: Combination ART was highly effective at reducing risk of mother-to-child HIV transmission. Use of certain ART regimens during pregnancy was associated with increased risk of harms that may be mitigated by selection of ART regimen. The 2012 review found that avoidance of breastfeeding and cesarean delivery in women with viremia also reduced risk of transmission and that prenatal screening accurately diagnosed HIV infection.

Human immunodeficiency virus can be transmitted from mother to child during pregnancy and the postpartum period. Based on a 2006 estimate, approximately 8500 HIV-positive persons give birth each year in the United States,¹ and in 2014 an estimated 12% of HIV-infected women were unaware of their status.² From 1985 to 2001, the number of cases of perinatal HIV infections in the United States declined after the widespread adoption of routine prenatal screening, coupled with the use of effective therapies for preventing mother-to- child transmission.³ In 2016, there were 99 cases of perinatal HIV infections.⁴

In 2013, the US Preventive Services Task Force (USPSTF) reaffirmed its prior recommendation to screen all pregnant persons for HIV infection (A recommendation), based on evidence that screening accurately detects HIV infection during pregnancy, and that interventions—in particular antiretroviral therapy (ART)—are associated with marked reduction in risk of mother-to-child transmission. The purpose of this evidence report was to update the 2012 USPSTF review^5,6 on the benefits and harms of prenatal screening for HIV infection, focusing on previously identified research gaps: direct evidence on benefits and harms of screening vs no screening, optimal frequency of screening, and benefits and long-term harms of currently recommended ART regimens.⁷

Scope of Review

Detailed methods and additional study details and results on congenital abnormalities are available in the full evidence report at https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/human-immunodeficiency-virus-hivinfection-screening1. Key studies are highlighted in this manuscript. Figure 1 shows the analytic framework and key questions (KQs) that guided the review.

Data Sources and Searches

The Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and Ovid MEDLINE were searched from 2012 through June 2018. Since June 2018, we continued to conduct ongoing surveillance through article alerts and targeted searches of high-impact journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and therefore the related USPSTF recommendation. The last surveillance was conducted on January 25, 2019, and identified no relevant new studies. Searches were supplemented with expert suggestions and by reviewing reference lists from relevant systematic reviews and prior USPSTF reports.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using predefined eligibility criteria. Randomized clinical trials (RCTs), cohort studies, and case-control studies of pregnant adolescents (13 to <18 years) and adults were eligible for all KQs. Studies that directly evaluated the associations of prenatal HIV screening vs no screening in asymptomatic persons with clinical outcomes (mortality, AIDS and opportunistic infections, quality of life, function, HIV transmission, and harms [maternal or infant]) were eligible for KQ1 and KQ3. Studies that evaluated the yield (number of new diagnoses per tests performed) of screening for HIV infection at different intervals or in different risk groups were eligible for KQ2. Studies that compared associations with currently recommended⁷ full-course (initiated in first or early second trimester) combination ART vs no ART, abbreviated courses of ART, or 1- or 2-drug therapy were eligible for KQ4 and KQ5. Studies could be conducted in any geographic setting, including low- or middle-income countries. For KQ5, cohort studies had to adjust for potential confounders.

Data Abstraction and Quality Rating

For each study, one investigator abstracted information on populations, interventions or screening instruments, comparators, outcomes, study designs, and settings. A second investigator reviewed abstractions for accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor using predefined criteria developed by the USPSTF.⁸ 

Data Synthesis

Results were summarized qualitatively. Meta-analysis was not performed because of clinical and methodological heterogeneity among studies. For all KQs, the overall strength of the body of evidence was assessed as high, moderate, low, or insufficient using methods developed by the USPSTF, based on quality of studies, consistency of results between studies, precision of estimates, study limitations, and risk of reporting bias. The applicability of the findings to US primary care populations and settings was also assessed.

Two reviewers independently assessed 1232 unique citations and 162 full-text articles for inclusion (Figure 2). Twenty-nine new studies in 36 articles were included (2 trials in 2 articles^9,10 and 27 cohort studies in 34 articles^11-44), and 33 studies in 35 articles (7 trials in 9 articles,^45-53 25 cohort studies in 25 articles,^54-78 and 1 systematic review⁷⁹) were carried forward from the prior USPSTF report.^5,6

Screening for HIV infection

Key Question 1. What are the benefits of screening for HIV infection in pregnant women on risk of mother-to-child transmission of HIV infection?

No studies met inclusion criteria for KQ1.

Key Question 2. What is the yield (number of new diagnoses per number of tests performed) of repeat HIV screening at different intervals in pregnant women, and how does the yield of screening vary in different risk groups?

No studies met inclusion criteria for KQ2.

Key Question 3. What are the harms of screening for HIV infection in pregnant women?

No studies met inclusion criteria for KQ3.

Effectiveness of Treatment

Key Question 4. What is the effectiveness of currently recommended ART regimens for reducing mother-to-child transmission of HIV infection?

The 2012 USPSTF review included 8 US or European cohort studies^70-73,75-78 (N = 27,776) that found full-course combination ART associated with rates of mother-to-child transmission that ranged from less than 1% to 2.4%, compared with 9% to 22% without ART. The prior USPSTF review included 2 RCTs of breastfeeding women in Africa that found 3-drug ART started at 26 to 28 weeks’ gestation associated with mother-to-child transmission rates of 1% to 5%^51,52 and also included 4 trials that found ART with fewer drugs or more abbreviated courses of therapy also effective (n = 3534).^45-47,53 Five new fair-quality cohort studies^{16,25,26,28,39} conducted in high-income settings (Table 1) (n = 16,381) and 1 new RCT⁹ (n = 3202) conducted in low-income settings (Table 2) evaluated associations with combination ART during pregnancy on rates of mother-to-child transmission. Results were consistent with the findings from the prior review, with mother-to-child transmission rates as low as less than 1% with full-course combination ART.

New evidence found that 1 cohort study evaluated infants (n = 4459) born between 1996 and 2010 in 7 European cohorts who were at high risk of acquiring HIV infection (mother with viral load >50 copies/mL in the last 8 weeks of pregnancy, only received intrapartum ART, or received no antenatal or intrapartum ART).¹⁶ Use of 3 or more antiretroviral drugs was associated with decreased risk of mother-to-child transmission compared with no ART (2.8% vs 14.3%; adjusted odds ratio [OR], 0.36 [95% CI, 0.23-0.57]). Results were similar for treating with 1 or 2 antiretroviral drugs (adjusted ORs, 0.33 [95% CI, 0.19-0.55] and 0.12 [95% CI, 0.04-0.40], respectively). The association of the timing of initiation of ART during pregnancy with mother-to-child transmission was not assessed.

A French cohort study evaluated 4583 women who received combination ART during pregnancy between 2000 and 2011.²⁶ Most regimens were protease inhibitor–based triple therapy (82.5%). The rate of mother-to-child HIV transmission was highest in women who initiated ART during the third trimester and in whom viral loads nearest delivery were detectable (4.4% [95% CI, 2.1%-7.9%]). There were no instances of HIV transmission among 2651 women who started ART before pregnancy, continued ART throughout pregnancy, and had a viral load less than 50 copies/mL at the time of delivery.

Two smaller cohort studies, 1 from Canada²⁵ (n = 645) and 1 from the United Kingdom and Ireland³⁹ (n = 2406) reported rates of mother-to-child HIV transmission with combination ART of 1% and 0.5%, respectively. In the United Kingdom/Ireland study, ritonavir-boosted lopinavir was associated with a higher transmission rate when ART was initiated during the third trimester (1.9%).³⁹ An Israeli cohort study²⁸ (n = 796) found combination ART during pregnancy associated with decreased risk of vertical transmission (adjusted OR, 0.4 [95% CI, 0.1-0.8]); transmission rates were 1.5% with vaginal delivery and 0.6% with cesarean delivery. Results were not stratified by timing of ART administration.

One new, fair-quality RCT, the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial (n = 3490),⁹ was conducted in India and Africa among HIV-infected women (92% breastfeeding) with CD4 cell counts of or greater than 350/mm³ at 14 weeks’ or later gestation (Table 2). The rate of mother-to-child transmission was 1.8% with zidovudine alone, 0.5% with ART with zidovudine, lamivudine, and lopinavir/ritonavir, and 0.6% with ART with tenofovir, emtricitabine, and lopinavir/ritonavir (difference in rate for combined ART regimens vs zidovudine alone, −1.3% [95% CI, −2.1% to −0.4%]).

Harms of Treatment

Key Question 5. What are the harms of currently recommended ART regimens given during pregnancy to the mother and infant?

Birth Outcomes

The 2012 USPSTF review⁵ included 1 RCT⁴⁸ (n = 560) and 3 prospective cohort studies^57,59,64 (n = 10,313) that found maternal exposure to combination ART with a protease inhibitor associated with increased risk of preterm delivery (<37 weeks) compared with nonnucleoside reverse transcriptase inhibitor–based ART (OR, 2.0 [95% CI, 1.3-3.3]),⁴⁸ combination ART without a protease inhibitor (adjusted OR, 1.8 [95% CI, 1.1-3.0]),⁵⁷ dual therapy (adjusted OR, 1.2 [95% CI, 1.0-1.4]),⁶⁴ or monotherapy (adjusted OR, 3.4 [95% CI, 1.1-10])⁵⁹. A fourth cohort study⁶⁵ (n = 4939) found combination therapy associated with increased risk of preterm delivery (adjusted OR, 1.4 [95% CI, 1.1-1.8]) compared with monotherapy or dual therapy, regardless of whether the antiretroviral regimen included a protease inhibitor.

One new open-label RCT conducted in Africa⁹ and 21 new cohort studies (reported in 30 articles)^{11-15,17-24,26,27,29-38,40-44} evaluated the association between maternal exposure to ART and risk of preterm delivery, low birthweight, and other birth outcomes. Sample sizes ranged from 183 to 13,124 (total n = 71,472). Eight studies were conducted in the United States, 7 in Canada or Europe, and the remainder in Africa or Latin America. One cohort study, the Antiretroviral Pregnancy Registry¹² (n = 22,360), is an international (69 countries) voluntary registry; 74% of data currently are from the United States. ART regimens and comparisons varied across studies. Most cohort studies did not include a control group of women who did not receive ART; other methodological limitations were high attrition and unclear blinding of outcome assessors or data analysts.

The fair-quality RCT (PROMISE [n = 3490])⁹ found ART with zidovudine, lamivudine, and lopinavir/ritonavir associated with increased risk of preterm delivery (20.5% vs 13.1%, P < 0.001) and low birth weight (23.3% vs 12.0%, P < 0.001) vs zidovudine monotherapy. PROMISE also found that ART with tenofovir, emtricitabine, and lopinavir/ritonavir was associated with increased risk of low birth weight (16.9% vs 8.9%, P = 0.004) vs zidovudine monotherapy.⁹ Tenofovir-containing ART was associated with increased risk of early infant death vs zidovudine-containing ART (4.4% vs 0.6%, P < 0.001) and increased risk of very preterm (before 34 weeks) delivery (6.0% vs 2.6%, P = 0.04), but there was no significant difference between tenofovir-containing ART vs zidovudine monotherapy in risk of early infant death (4.4% vs 3.2%, P = 0.43) or stillbirth.⁹ Methodological limitations of the trial included open-label design and the addition of a third randomization group (tenofovir-containing ART) during the course of the trial. In addition, there was an unexplained reduction in rate of neonatal death and stillbirth associated with zidovudine-containing ART after the addition of the tenofovir containing ART group. Five cohort studies found no consistent association between any ART or tenofovir-containing ART and risk of stillbirth, with some studies showing decreased risk of stillbirth.^{21,27,30,43,44}

Consistent with the prior USPSTF review, 1 new RCT⁹ and 4 new cohort studies^19,37,40,43 found ART containing a boosted protease inhibitor associated with an increased risk of preterm birth vs treatment without a boosted protease inhibitor (n = 7584). However, 2 new cohort studies (n = 1140) found treatment with a protease inhibitor associated with a decreased risk of preterm delivery¹⁹ or no significant difference in risk¹⁷ when compared with no ART.

The prior review⁵ found no consistent evidence of an association between maternal exposure to ART and increased risk of other adverse birth outcomes (eg, low birthweight, small for gestational age). New evidence identified for this update also found mixed evidence on these birth outcomes. Four new cohort studies^21,27,31,34 evaluated the association of ART with risk of low birth weight.

Overall Congenital Abnormalities

The 2012 USPSTF review found no association between perinatal exposure to ART and overall congenital abnormalities, based on 3 cohort studies (n = 13,396).^55,56,63 Five new cohort studies (n = 40,436),^{12,18,20,36,41} including the Antiretroviral Pregnancy Registry,¹² evaluated the association between use of combination ART in pregnancy and risk of congenital anomalies. All of the newer cohort studies included patients who received preferred⁷ nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, tenofovir, or emtricitabine) for use in pregnancy. Most antiretroviral agents and classes were not associated with an increased risk of congenital abnormalities, but findings were limited by small numbers of studies, imprecision in estimates, and multiple comparisons.

Cardiovascular Congenital Anomalies

The 2012 USPSTF review included 1 cohort study⁶⁰ (n = 382) that found no significant association between in utero exposure to zidovudine and abnormalities in left ventricular structure or function, although another study⁶¹ found an association between in utero ART and echocardiographic findings with unknown clinical significance in children up to age 2 years.

One subsequent RCT and 2 cohort studies (in 3 publications) also reported mixed results for the association between in utero ART exposure and adverse cardiovascular findings.^23,35,41 AUS cohort study of HIV-uninfected children (n = 2580) found no statistically significant association between in utero exposure to currently recommended ART drugs and increased risk of cardiovascular defects (adjusted OR, 1.83 [95% CI, 0.96-3.49]).⁴¹ Another study (n = 214,240) found no significant association between ART exposure during the first trimester on cardiovascular anomalies compared with no exposure (adjusted OR, 0.75 [95% CI, 0.31-1.85]).¹³

A French cohort study of 12,888 children found first-trimester exposure to zidovudine associated with congenital heart defects compared with no zidovudine exposure (1.5% vs 0.77%; adjusted OR, 2.2 [95% CI, 1.5-3.2]).^35,36 A secondary analysis of 400 HIV-uninfected children exposed to ART in utero²³ found that at a median of 4 years of age, exposure to some antiretroviral medications, especially in the first trimester, was associated with echocardiographic abnormalities without significant cardiovascular compromise (left ventricular stress velocity index z scores in ART exposed vs unexposed children, −0.22 [95% CI, −0.42 to −0.01]; P = 0.04; left ventricular posterior wall thickness z scores in ART exposed vs unexposed children, 0.20 [95% CI, 0.03-0.37]; P = 0.02).

A nested RCT within a cohort study of combination ART (zidovudine, lamivudine, and ritonavir-boosted lopinavir) vs protease inhibitor monotherapy (ritonavir-boosted lopinavir alone) performed echocardiographic assessments at ages 1 month (n = 53) and 1 year (n = 42). There was no significant difference in echocardiographic parameters in boys, but in girls combination therapy was associated with higher left ventricular shortening fraction at 1 month (−3.61 [95% CI, −6.57 to −0.65], P = 0.02).³⁵

Neurodevelopmental Outcomes in Children

The 2012 USPSTF review included 3 cohort studies (n = 4779) that found no significant association between in utero exposure to ART and long-term adverse effects on child growth and development.^54,58,68 Two new publications of a US cohort of HIV exposed, uninfected children found no significant association between in utero ART exposure and lower scores on intelligence tests.^29,42 Exposure to tenofovir was associated with higher scores on the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) test than no exposure to tenofovir (WPPSI-III performance IQ scores, 100.8 vs 96.1; P = 0.03). Another publication from this study found in utero exposure to combination ART associated with less neurodevelopmental impairment vs no exposure (adjusted relative risk, 0.47 [95% CI, 0.27-0.83]).⁴²

Maternal Harms

The 2012 USPSTF review included 3 studies (n = 4117) that found receipt of ART during pregnancy associated with increased risk of gestational diabetes (adjusted OR, 3.5 [95% CI, 1.2-10]) and anemia (adjusted OR, 1.6 [95% CI, 1.1-2.4]), compared with no ART.^62,66,67

In the PROMISE trial (n = 3490; see KQ4 for study details),⁹ antenatal zidovudine-based combination ART was associated with a higher rate of maternal grade 2 or higher adverse events than zidovudine alone (21% vs 17%, P = 0.008). There was no increased risk in all-cause mortality, anemia, or diabetes among ART regimens.⁸⁰ There were few study withdrawals attributable to adverse events.

As in previous USPSTF reviews,^6,81 there remains no direct evidence on effects of prenatal screening vs no screening on risk of mother-to-child HIV transmission or maternal or infant clinical outcomes, or the yield of repeat or alternative screening strategies. Table 3 summarizes the other evidence reviewed in this update.

New evidence^16,25,26,39 confirms findings from the 2012 USPSTF review that combination ART is highly effective at reducing the risk of mother-to-child transmission, with some cohort studies reporting rates of mother-to-child transmission of less than 1% when started early in pregnancy.^26,39 New evidence on harms of ART was also largely consistent with the 2012 USPSTF review. Evidence from primarily observational studies found prenatal combination ART with a boosted protease inhibitor associated with increased risk of preterm delivery.^9,19,37,43 For other birth outcomes (low birth weight, small for gestational age, stillbirth, birth defects, neonatal death), results were mixed and depended on the specific antiretroviral drug or drug regimen given and timing of prenatal therapy. Preferred drug regimens in pregnancy are frequently revised as drugs are developed and safety data become available.

Limitations

This review had several limitations. First, inclusion was restricted to English-language articles, although no non–English language articles that would have met inclusion criteria were identified. Second, meta-analysis was not possible because of differences in study designs, populations, study setting, antiretroviral regimens evaluated, and outcomes. Because pooling was not performed, it was also not possible to formally assess for publication bias with graphical or statistical methods. Third, observational studies, which are more susceptible to bias and confounding than well-conducted RCTs, were included, although inclusion was restricted to observational studies that performed statistical adjustment for potential confounding. Fourth, RCTs of combination ART have only been conducted in Africa, which could reduce their applicability to US practice because of differences in the antiretroviral drugs evaluated, delayed initiation of ART, inclusion of women who breastfeed, and other factors. Fifth, most studies reported results for individual ART agents and classes rather than for ART regimens as a whole, making it difficult to apply findings to currently recommended regimens.

Combination ART was highly effective at reducing risk of mother-to-child HIV transmission. Use of certain ART regimens during pregnancy was associated with increased risk of harms that may be mitigated by selection of ART regimen. The 2012 review found that avoidance of breastfeeding and cesarean delivery in women with viremia also reduced risk of transmission and that prenatal screening accurately diagnosed HIV infection.

Source: This article was first published in the Journal of the American Medical Association on June 11, 2019. (JAMA. doi:10.1001/jama.2019.2593).

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00009-i, Task Order No. 7, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We gratefully acknowledge the AHRQ Medical Officer (Howard Tracer, MD).We also acknowledge past and current USPSTF members who contributed to topic deliberations. The USPSTF members, external peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 2 content experts (Brenna Hughes, MD, Duke University; and Lynne Mofenson, MD, Elizabeth Glaser Pediatric AIDS Foundation) and 4 federal partner reviewers from the National Institute of Child Health and Human Development, President’s Emergency Plan for AIDS Relief, the Centers for Disease Control and Prevention, and the Department of Veterans Affairs. Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. Refer to the USPSTF Procedure Manual for further details.^8
a Include false-positive results; anxiety and effects of labeling; and partner discord, abuse, or violence.
^b Include adverse maternal and infant outcomes associated with use of antiretroviral therapy.

Additional articles are indicated for the included studies where relevant. KQ indicates key question; USPSTF, US Preventive Services Task Force.

Abbreviations: AOR, adjusted odds ratio; ART, antiretroviral therapy; HAART, highly active antiretroviral therapy; NNRTI, nonnucleoside reverse  transcriptase inhibitor; NR, not reported; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
^a All studies were rated fair quality.

Abbreviations: ART, antiretroviral therapy; KQ, key question; NA, not applicable; PI, protease inhibitor; RCT, randomized clinical trial; SMARTT, Surveillance Monitoring for ART Toxicities; USPSTF, US Preventive Services Task Force.