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Chou R, Cantor A, Bougatsos C, et al. Screening for HIV in Pregnant Women: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Nov. (Evidence Syntheses, No. 96.)

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Screening for HIV in Pregnant Women: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet].

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Key Question 1. What Are the Benefits of HIV Screening Versus No Screening in Asymptomatic Pregnant Women on Maternal or Child Morbidity, Mortality, or Quality of Life or Rates of Mother-to-Child Transmission?

No randomized trial or observational study compared clinical outcomes (including risk of perinatal transmission) between pregnant women screened and not screened for HIV infection. Given what is established about HIV screening and transmission, a randomized trial would not be considered ethical at this point. Although the number of infants with perinatally acquired HIV transmission has markedly declined in the United States, this is likely due to a combination of increased screening during pregnancy and increased effectiveness and use of interventions to prevent transmission. Some HIV-positive women may also have been identified before pregnancy. We identified no studies estimating the relative impact of these factors on transmission risk.

Key Question 2a. What Is the Yield (Number of New Diagnoses) of Repeat Screening in Asymptomatic Pregnant Women?

No randomized trial or observational study evaluated the yield of repeat prenatal HIV screening compared with one-time screening, or compared the yield of different strategies for repeat screening (e.g., risk-based repeat screening vs. a routine repeat test). Repeat testing of women who screen HIV-negative during early pregnancy could identify those who are infected after initial testing but before delivery. Repeat screening and the optimal timing of repeat testing during pregnancy would depend, in part, on the frequency of new HIV infections. One modeling study discussed in the 2005 USPSTF review1, 2 estimated that repeat testing in the third trimester after a negative test in the first trimester would detect 5.3 new infections per 100,000 average-risk women tested and 192 infections per 100,000 high-risk women tested.38

Key Question 2b. What Are the Adverse Effects (Including False-Positive Results and Anxiety) of Rapid Versus Standard HIV Testing in Asymptomatic Pregnant Women?

Summary

One large (n=7,753), prospective study of women presenting in labor with unknown HIV status (HIV prevalence, 0.7%) found the OraQuick rapid HIV test (OraSure Technologies, Inc., Bethlehem, PA) associated with a positive predictive value of 90 percent and the standard EIA test associated with a positive predictive value of 74 percent when each was compared with Western blot as the reference standard. One other, smaller study (n=910) of pregnant women at any gestational age also found rapid testing associated with a higher positive predictive value compared with standard testing, but only five HIV-positive women were identified. No study compared psychological or other harms associated with rapid versus standard testing or adverse clinical consequences of interventions given as a result of false-positive results.

Evidence

The large (n=7,753), prospective, fair-quality Mother-Infant Rapid Intervention at Delivery (MIRIAD) study provides the strongest evidence on the diagnostic accuracy of the rapid OraQuick test compared with standard EIA HIV testing.28, 39 MIRIAD specifically enrolled women in labor with unknown HIV status (HIV prevalence, 0.7% [52/7,753]) for whom immediate test results were needed to help guide treatment decisions. Initial (2-year) results from MIRIAD28 were included in the prior USPSTF review (Table 1, Appendix B1).39 Final (40-month) results39 found that compared with Western blot as the reference standard, sensitivity was 100 percent for both tests, and specificity was 99.9 and 99.8 percent for rapid and standard testing, respectively. The positive predictive value for the rapid test was higher (90% [52/58]) than for the standard test (74% [52/70]). In clinical practice, a positive standard test result would not be available in time to inform interventions during labor and delivery, and positive standard test results are typically confirmed with Western blot prior to patient notification.

Table 1. Diagnostic Accuracy and Acceptability of Rapid Versus Standard HIV Testing in Pregnant Women.

Table 1

Diagnostic Accuracy and Acceptability of Rapid Versus Standard HIV Testing in Pregnant Women.

One other study (n=910) of pregnant, predominantly Hispanic (about 90%) women at any gestational age (HIV prevalence, 0.5%) found the OraQuick test associated with a positive predictive value of 100 percent (5/5) and EIA associated with a positive predictive value of 36 percent (5/14).40

No study compared psychological or other harms associated with rapid versus standard tests or adverse clinical consequences of interventions given as a result of initial false-positive rapid test results.

Key Question 3a. What Is the Effectiveness of Newer Antiretroviral Regimens for Reducing Mother-to-Child Transmission?

Summary

Consistent with the prior USPSTF review, three new U.S. and European cohort studies published since 2005 found perinatal full-course triple antiretroviral therapy associated with a risk of mother-to-child transmission that ranged from <1 to 2.4 percent compared with 9 to 22 percent with no antiretroviral therapy. Two randomized trials of breastfeeding women in Africa found triple antiretroviral therapy started at 26 to 28 weeks associated with mother-to-child transmission rates of 1 to 5 percent. Other African trials found shorter courses of perinatal antiretroviral therapy and regimens using fewer than three drugs associated with a lower risk of mother-to-child transmission of HIV infection compared with the expected transmission rate without therapy, but were generally associated with higher transmission rates than full-course, three-drug regimens.

Evidence

The landmark Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 study found that a three-phase maternal and infant zidovudine regimen starting at 14 to 34 weeks’ gestation through 6 weeks postpartum decreased the risk of mother-to-child transmission from about 25 percent with placebo to 8 percent in nonbreastfeeding women.41 The 2005 USPSTF review1, 2 identified no completed trials of full-course combination antiretroviral therapy during pregnancy. It included four large U.S. or European cohort studies that all found full-course antiretroviral regimens with more drugs superior to regimens with fewer antiretroviral drugs for preventing mother-to-child transmission.4245 The only study that specifically evaluated the effectiveness of three-or-more-drug regimens compared with no antiretrovirals reported an odds ratio (OR) of 0.13 (95% confidence interval [CI], 0.06 to 0.27) for prevention of mother-to-child transmission.44 Another study reported an adjusted OR of 0.07 (95% CI, 0.02 to 0.23) for two-or-more-drug regimens compared with no antiretrovirals.43 In all of the studies, transmission rates were 1 to 2 percent with combination regimens.4245 The 2005 USPSTF review also included several randomized trials that found that shorter courses of antiretroviral prophylaxis were effective at reducing risk of mother-to-child transmission of HIV infection, though they were not as effective as full-course regimens.4655

We identified no new randomized trials on full-course combination antiretroviral therapy during pregnancy in nonresource poor, nonbreastfeeding settings. Four fair-quality U.S. or European cohort studies published since the 2005 USPSTF review evaluated the effectiveness of combination antiretroviral regimens during pregnancy (Table 2, Appendix B2).5658 Sample sizes ranged from 489 to 7,344. Methodological shortcomings in the studies included inadequate reporting of baseline characteristics5658 or failure to report adjusted risk estimates58 (Appendix B3). The proportion of women who had a Cesarean delivery in these cohorts ranged from 51 to 78 percent.

Table 2. Cohort Studies of Mother-to-Child HIV Transmission While Using Antiretroviral Therapy.

Table 2

Cohort Studies of Mother-to-Child HIV Transmission While Using Antiretroviral Therapy.

One large (n=7,344) cohort study was based on U.S. surveillance data from 1999 to 2001.57 It found full-course single- or multi-drug antiretroviral therapy associated with lower risk of mother-to-child transmission compared with no antiretroviral therapy (2.4% vs. 22%; adjusted OR, 0.09 [95% CI, 0.06 to 0.12]). In women who received antiretroviral therapy, combination regimens with zidovudine plus other drugs were about twice as effective as zidovudine monotherapy for reducing risk of mother-to-child transmission (adjusted OR range, 0.4 to 0.5). Two smaller European cohort studies also reported lower mother-to-child transmission rates with combination antiretroviral therapy (0.6% and 1.0%) compared with no therapy (9% and 18%).56, 58 A fourth study, which analyzed European surveillance data (n=7,573) over a 9-year period and included one of these cohorts,56 found transmission rates of <1 percent with either zidovudine-sparing or zidovudine-containing three-or-more-drug regimens.59

One good-quality60 and five fair-quality6165 randomized trials published since the 2005 USPSTF review evaluated shorter-course prenatal antiretroviral regimens in primarily breastfeeding African women (Table 3, Appendixes B4 and B5).6065 Sample sizes ranged from 355 to 805 infants. The studies are most applicable in the United States to HIV-infected women identified later in pregnancy, who cannot receive full-course regimens. In general, these studies reported lower transmission rates with antiretroviral therapy than expected without treatment. Studies that evaluated longer courses of treatment and regimens that included at least three drugs reported the lowest transmission rates. One trial of breastfeeding women (n=709) found various three-drug antiretroviral regimens started at 18 to 34 weeks’ gestation (median, 26 to 27 weeks) associated with an overall infant HIV infection rate of 1.1 percent at 6 months.63 Another trial of breastfeeding women (n=805) found zidovudine, lamivudine, and ritonavir-boosted-lopinavir started at 28 weeks’ gestation and continued through weaning from breastfeeding associated with lower risk of infant HIV infection at 12 months compared with zidovudine plus single-dose nevirapine (5.4% vs. 9.5%; p=0.03).60 Three trials, including one of nonbreastfeeding women,62 found shorter-course (starting at 32 to 34 weeks’ gestation) perinatal antiretroviral therapy with one or two drugs (with or without the addition of a single maternal dose of an antiretroviral during labor) associated with mother-to-child transmission rates that ranged from 4 to 12 percent.61, 62, 64 One other trial (n=609) found high rates of mother-to-child transmission with ultra-short-course zidovudine (during labor and given to the infant for 72 hours after birth) plus single-dose maternal and infant nevirapine versus single-dose nevirapine alone (14% vs. 17%), as well as a high rate of infant mortality (7% at 6 weeks).65

Table 3. African-Based Trials of Mother-to-Child HIV Transmission While Using Antiretroviral Therapy.

Table 3

African-Based Trials of Mother-to-Child HIV Transmission While Using Antiretroviral Therapy.

Key Question 3b. What Are the Effects of Antiretroviral Regimens in Pregnant, HIV-Positive Women on Long-Term Maternal Morbidity, Mortality, or Quality of Life?

Summary

No study published since the prior USPSTF review evaluated effects of prenatal antiretroviral therapy on long-term maternal clinical outcomes. The prior USPSTF review included one study (n=226) of U.S. women that found no difference in risk of AIDS-defining events or death after a mean of 4.1 years between women randomized to zidovudine during pregnancy versus placebo in risk of AIDS or death, death alone, or AIDS-defining CDC clinical category C events after a mean of 4.1 years.

Evidence

No study published since the prior USPSTF review evaluated effects of prenatal antiretroviral therapy on long-term maternal clinical outcomes. One good-quality study included in the prior USPSTF review of U.S. women (n=226) originally enrolled in a randomized trial of zidovudine monotherapy for reducing mother-to-child transmission (PACTG 076) found no difference between women randomized to zidovudine versus placebo in risk of AIDS or death (19% vs. 25%; relative risk [RR], 0.73 [90% CI, 0.46 to 1.2]), death alone (3% vs. 2%; RR, 1.5 [90% CI, 0.34 to 6.7]), or AIDS-defining CDC clinical category C events (7% vs. 10%; RR, 0.70 [90% CI, 0.34 to 1.4]) after a mean of 4.1 years.68 At the time of enrollment, women were not receiving or eligible (based on criteria at the time) for antiretroviral therapy, and zidovudine was discontinued after delivery. Although only about 50 percent of eligible women enrolled in the randomized trial participated in this study, there were few differences in demographic and clinical characteristics between participants and nonparticipants, and baseline characteristic similarity between the zidovudine and placebo groups was preserved during the study. The prior USPSTF review also included a study that found women still benefit from antiretroviral therapy after receiving antiretroviral treatment during pregnancy.69

Key Question 3c. What Are the Harms (Including Longer-Term Harms) to the Mother or Child Associated With Antiretroviral Therapy During Pregnancy?

Summary

New evidence (27 studies) on infant and maternal harms associated with perinatal exposure to antiretroviral therapy was generally consistent with the evidence included in the 2005 USPSTF review.1, 2 Of one randomized trial and 10 cohort studies reporting on the association between perinatal antiretroviral therapy and risk of preterm delivery or low birth weight, the trial and six cohort studies found perinatal antiretroviral therapy associated with increased risk of preterm delivery, but no clear association with low birth weight. Although studies found an association between exposure to perinatal antiretroviral therapy and increased risk during infancy of laboratory markers of mitochondrial dysfunction, hematological abnormalities, and echocardiographic markers of impaired myocardial growth, the clinical significance of these findings remains unclear. Four studies showed no association between perinatal exposure to antiretroviral drugs and risk of congenital abnormalities, and two studies showed no clear association between perinatal exposure to antiretroviral drugs and infant neurodevelopment. A large cohort study found exposure to antiretroviral drugs during pregnancy associated with increased risk of maternal anemia. No study evaluated long-term maternal harms associated with short-term exposure to antiretroviral therapy during pregnancy, or antiretroviral therapy started during pregnancy and continued after pregnancy.

Evidence

Infant harms

Preterm birth and other birth outcomes. The 2005 USPSTF review1, 2 identified one good-quality U.S. meta-analysis of five prospective cohort studies and one good-quality, large European prospective cohort study that found no association between exposure to combination antiretroviral therapy and low birth weight.70, 71 Evidence regarding the association between combination antiretroviral therapy and increased rates of premature delivery was mixed. The meta-analysis found no increase in risk of premature delivery for infants exposed to combination therapy with (adjusted OR, 1.5 [95% CI, 0.72 to 3.0]) or without a protease inhibitor (OR, 0.95 [95% CI, 0.51 to 1.7]) compared with no treatment,70 but the large, prospective European Collaborative Study reported an increased risk of premature delivery (before 37 weeks’ gestation) associated with combination antiretroviral therapy initiated during pregnancy (RR, 1.9 [95% CI, 1.3 to 2.7]) or prior to pregnancy (RR, 2.0 [95% CI, 1.4 to 3.0]) versus no treatment.71 Use of monotherapy or dual therapy during pregnancy was not associated with increased risk of premature delivery.

One randomized trial72 and 10 cohort studies7382 published since the prior USPSTF review reported risk of prematurity, low birth weight, and other birth outcomes following in utero exposure to antiretroviral therapy (Appendix B6). Sample sizes ranged from 57 to 8,793. Eight studies, including the randomized trial, were rated fair-quality72, 73, 75, 77, 78, 8082 and three were rated poor-quality74, 76, 79 (Appendixes B7 and B8). Methodological shortcomings included differences in baseline characteristics between groups and poor reporting of attrition. Six studies reported risk estimates adjusted for important confounders such as maternal age, CD4 count, and viral load.73, 75, 77, 79, 81, 82

The randomized trial (n=530) found protease inhibitor-based antiretroviral therapy associated with greater risk of preterm delivery than nonnucleoside reverse transcriptor-based antiretroviral therapy (OR, 2.0 [95% CI, 1.3 to 3.3]).72 Three prospective cohort studies (n=183 to 8,793) also found maternal exposure to combination antiretroviral therapy with a protease inhibitor associated with increased risk of preterm delivery (<37 weeks) compared with combination antiretroviral therapy without a protease inhibitor (adjusted OR, 1.8 [95% CI, 1.1 to 3.0]),75 dual therapy (adjusted OR, 1.2 [95% CI, 1.0 to 1.4]),81 or monotherapy (adjusted OR, 3.4 [95% CI, 1.1 to 10]),77 after adjustment for potential confounders (Table 4). None found exposure to combination therapy without a protease inhibitor associated with increased risk of preterm delivery. However, a fourth large (n=4,939) cohort study found combination therapy associated with increased risk of preterm delivery (<37 weeks) (adjusted OR, 1.4 [95% CI, 1.1 to 1.8]; p=0.02) and very preterm delivery (<32 weeks) (OR, 2.6 [95% CI, 1.3 to 5.3]; p=0.007) compared with monotherapy or dual therapy, with no difference in risk according to whether the antiretroviral regimen included a protease inhibitor or not.82 Among four studies that did not adjust for confounders, one found an association between prenatal antiretroviral therapy and preterm delivery,80 but three other studies found no clear association.74, 76, 78

Table 4. Preterm Birth Outcomes.

Table 4

Preterm Birth Outcomes.

Seven cohort studies (n=352 to 8,192) published since the 2005 USPSTF review found no clear association between maternal use of antiretroviral therapy and low birth weight or intrauterine growth restriction.7376, 78, 81, 82

Mitochondrial dysfunction. Although molecular evidence of mitochondrial dysfunction has been reported in infants exposed in utero to antiretroviral therapy,83, 84 the clinical significance of such dysfunction remains unclear. The 2005 USPSTF review1, 2 included three prospective cohort studies that found no clear evidence of clinical mitochondrial dysfunction in infants exposed to antiretroviral therapy in utero, despite evidence of high rates of elevated lactic acid levels.71, 85, 86 Population-based studies included in the 2005 USPSTF review reported no deaths due to mitochondrial dysfunction among antiretroviral-exposed, HIV-negative infants.8789

Three studies published since the 2005 USPSTF review evaluated risk of mitochondrial dysfunction based on laboratory findings following in utero exposure to antiretroviral therapy, but none evaluated clinical outcomes associated with findings of mitochondrial dysfunction.9092

Congenital abnormalities. The 2005 USPSTF review1, 2 identified one large, good-quality European prospective cohort study that found no association between exposure to any combination of antiretroviral drugs and risk of congenital anomalies.71

Three fair-quality European cohort studies (n=1,414 to 8,576) published since the 2005 USPSTF review each found no association between perinatal exposure to antiretroviral therapy and congenital abnormalities9395 (Appendixes B6 and B8). Followup ranged from 6 months to 17 years. One large study (n=7,573) of European surveillance data over a 9-year period found no difference in the risk of infant congenital abnormalities with maternal use of zidovudine-sparing versus zidovudine-containing three-or-more-drug regimens.59

Neurodevelopmental outcomes. The 2005 USPSTF review1, 2 included one good-quality prospective cohort study that found no association between in utero and postnatal zidovudine exposure and long-term adverse effects on growth or development in exposed infants through age 4 years.71

We identified two cohort studies published since the 2005 USPSTF review1, 2 that evaluated neurodevelopmental outcomes following in utero and postnatal exposure to antiretroviral therapy96, 97 (Appendixes B6 and B8). Both utilized the Bayley Scales of Infant Development-II, which includes a Mental Development Index (MDI) and Psychomotor Development Index (PDI). One good-quality prospective study (n=63) found no statistically significant difference in MDI scores in antiretroviral-exposed children compared with unexposed control groups at ages 18 to 36 months, after adjustment for maternal substance abuse.96 A second, larger (n=1,840), fair-quality prospective study found slightly higher (better) MDI and PDI scores in antiretroviral-exposed children compared with unexposed children at age 2 years after adjustment for confounders, but the differences were small (<3 points on a 100-point scale) and did not reach statistical significance.97

Other infant harms. The 2005 USPSTF review1, 2 identified one prospective cohort study that found no association between in utero exposure to zidovudine and acute or chronic abnormalities in left ventricular structure or functioning based on serial echocardiography through ages10 to 14 months.98

One prospective cohort study published since the 2005 USPSTF review found in utero exposure to antiretroviral therapy associated with echocardiographic findings of impaired myocardial growth (decreased left ventricular mass and septal wall thickness) but improved left ventricular contractility compared with no exposure through age 2 years, though the clinical significance of these findings was not evaluated99 (Appendixes B6 and B8). There were no differences between exposed and unexposed infants in these echocardiographic parameters through ages 2 to 5 years. Three observational studies each found in utero exposure to antiretroviral drugs associated with increased risk of neutropenia or anemia through age 24 months100102 (Appendixes B6 and B8). Average difference in neutrophil count for exposed versus unexposed children ranged from about 0.150 to 0.550 × 109 cells/L.100, 102 No study evaluated the association between lower neutrophil counts following in utero exposure to antiretroviral drugs and adverse clinical outcomes. One study found no difference in incidence of cancer in uninfected infants exposed to perinatal antiretroviral therapy at 5.4 years (10/9,127 children [0.1%]) compared with the general population, though among exposed infants the combination of didanosine and lamivudine was associated with higher risk compared with zidovudine monotherapy (hazard ratio [HR], 14 [95% CI, 2.5 to 74])103 (Appendixes B6 and B8).

Maternal harms

Receipt of antiretroviral therapy during pregnancy is associated with the nonobstetric adverse events typically associated with the specific drugs and regimens, but these often resolve after stopping the offending drug or drug combination, and effective alternatives are usually available.24 Regularly updated guidelines summarizing adverse events associated with specific antiretroviral drugs, classes, and combinations are available, and specific antiretroviral combinations associated with serious complications are not recommended.24

The 2005 USPSTF review1, 2 included one good-quality meta-analysis that found no association between perinatal zidovudine monotherapy and maternal death or long-term harms.104 A large observational study found gestational diabetes mellitus the only complication associated with antiretroviral therapy, and was most likely with combination therapy that included a protease inhibitor initiated early in the pregnancy.105 The 2005 USPSTF review also included one clinical trial that was discontinued early due to a high rate (29%) of treatment-limiting hepatic or cutaneous toxicity with continuous use of nevirapine with zidovudine during pregnancy, including one death and one case of Stevens-Johnson syndrome.106 These events occurred most frequently in women with CD4 counts >0.250 × 109 cells/L. However, three randomized trials found no difference between a single maternal intrapartum dose of nevirapine with or without antiretroviral therapy and no nevirapine in risk of liver function test abnormalities or hepatitis.51, 53, 107

We identified one large (n=2,543), fair-quality U.S. cohort study published since the 2005 USPSTF review that found antiretroviral use associated with increased risk of maternal anemia compared with nonuse (adjusted OR, 1.6 [95% CI, 1.1 to 2.4])108 (Appendixes B6 and B8). It also found late use of antiretroviral therapy (started between 25 and 32 weeks’ gestation) associated with increased risk of gestational diabetes compared with nonuse (adjusted OR, 3.5 [95% CI, 1.2 to 10]), but causality was unclear since screening for gestational diabetes is typically performed at 24 to 28 weeks’ gestation and women may have been diagnosed prior to initiation of antiretroviral therapy. Another, smaller (n=167) fair-quality cohort study found exposure to combination therapy associated with a trend toward increased risk of gestational diabetes compared with exposure to monotherapy with zidovudine or no antiretroviral therapy, but the difference was not statistically significant (12% vs. 0%; unadjusted RR, 0.11 [95% CI, 0.01 to 1.7])109 (Appendixes B6 and B8).

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