Human Immunodeficiency Virus in Obstetrics
D. Heather Watts
Table Of Contents
D. Heather Watts, MD
HUMAN IMMUNODEFICIENCY VIRUS TESTING IN PREGNANCY
EFFECT OF PREGNANCY ON MATERNAL HUMAN IMMUNODEFICIENCY VIRUS DISEASE AND THERAPY
MATERNAL HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND PREGNANCY OUTCOME
VERTICAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS
ANTIRETROVIRAL THERAPY FOR REDUCTION OF VERTICAL TRANSMISSION
MODE OF DELIVERY AND VERTICAL TRANSMISSION
OTHER INTERVENTIONS TO REDUCE PERINATAL TRANSMISSION OF HIV
EVALUATION OF THE INFANT BORN TO A HUMAN IMMUNODEFICIENCY VIRUS-INFECTED MOTHER
MANAGEMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN PREGNANCY
Women accounted for 23% of newly diagnosed acquired immune deficiency syndrome (AIDS) cases in the United States in 1999 and represented 32% of newly reported human immunodeficiency virus (HIV) infections.1 Among adolescents with newly diagnosed AIDS in 1999, 58% were female. Worldwide, nearly 36 million women were estimated to be living with HIV infection in 1998, accounting for more than half of the infections worldwide.2 Because 80% of women infected with HIV are in the reproductive age group, coexistent HIV and pregnancy are relatively common.3
The obstetrician has key roles in educating women to prevent acquisition of HIV infection and in providing state-of-the-art care to HIV-infected pregnant women to optimize their health and prevent HIV transmission to the infant. Treatment regimens for HIV and strategies to prevent perinatal transmission have become more complex. The provider caring for an HIV-infected pregnant woman must understand the interactive effects of HIV and pregnancy and be aware of the most current data on interventions for therapy and prevention of transmission. This chapter is designed to assist the practicing obstetrician in caring for HIV-infected pregnant women and includes information for obtaining updated information as current treatment guidelines are revised. Providers are urged to consult these online guidelines for the most current information.
|HUMAN IMMUNODEFICIENCY VIRUS TESTING IN PREGNANCY|
The recommendations for HIV testing in pregnancy have evolved with the epidemic. Initially, HIV infection was believed to be confined to identifiable high-risk groups. As the rate of heterosexual transmission of HIV increased, it became clear that testing pregnant women with self-identified risk factors only detected approximately half of HIV-infected pregnant women.4–6 With the development of interventions including zidovudine to reduce perinatal transmission, the importance of identifying HIV-infected women as early as possible in pregnancy became apparent. The 1995 Public Health Service guidelines recommended counseling all pregnant women about the risk of HIV infection and the benefits of HIV testing and voluntary testing.7 With broader uptake of testing and use of zidovudine for HIV-infected pregnant women, the rate of perinatally acquired AIDS cases dropped by 67% from 1992 to 1997, with a minimal decline in the number of HIV-infected women giving birth in the United States.8 However, although the proportion of HIV-infected women tested during pregnancy has increased, up to 10% of HIV-infected pregnant women did not receive any zidovudine in 1997, suggesting a need for increased detection and treatment.
In an effort to further increase the rate of testing and identification of HIV-infected women and to destigmatize the HIV testing process, in 1999 the Institute of Medicine (IOM) issued a report recommending a shift in testing policy from one of counseling and voluntary testing to universal HIV testing with patient notification as a routine component of prenatal care.9 The key elements of these recommendations are that testing should be universal and routine with notification. Universal means that the test applies to all pregnant women regardless of risk factors and prevalence rates in their area. Routine with notification means that the HIV test is part of the battery of standard prenatal tests and that women are informed that the HIV test is being done and that they may refuse the test. Incorporation of HIV testing into the routine prenatal tests prevents stigmatization based on risk behavior or ethnic group, reduces the cost of testing, and deals with potential geographic shifts in epidemiology. The IOM recommendations have been endorsed by the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP).10 The US Public Health Service (USPHS) is in the process of revising the testing guidelines to be consistent with the IOM recommendations. A new version of the USPHS guidelines is expected in late 2001 and will be available on the Centers for Disease Control and Prevention (CDC) web site at www.cdc.gov/ when finalized. Other recommendations in the IOM report for further reduction in perinatal transmission of HIV include development of comprehensive strategies to ensure access to prenatal care; HIV counseling and testing to prevent infection in women; high-quality, coordinated care to provide interventions to reduce transmission rates; avoidance of breastfeeding by HIV-infected women; and appropriate treatment and services for mothers.
Women who present in labor without prenatal care are at increased risk for HIV seropositivity and should be offered HIV testing. In a recent analysis, 15% of HIV-infected women had no prenatal care and another 20% had fewer than five visits.11 Several studies have found a twofold to fourfold increased risk of HIV seropositivity among women presenting in labor or late pregnancy for care.12–14 Risk factors for late or no prenatal care such as illicit drug use also are risk factors for HIV seropositivity. Because initiation of antiretroviral therapy during labor or for the infant within 24 hours of birth may decrease the risk of infant HIV infection,15,16 testing should be offered as soon as possible after presentation and test results should be available rapidly. Many ethical and logistical issues are involved in offering rapid HIV testing in labor and the immediate postpartum period, and each institution should develop its own policy.17 Combining rapid testing programs for pregnant women and those providing testing of source patients from healthcare worker exposures may increase efficiency.
Testing for women presenting in labor without prior testing can be done by use of a rapid diagnostic test or rapid processing and return of results using standard testing. The standard HIV testing algorithm recommended by the USPHS includes initial screening with a US Food and Drug Administration (FDA)-licensed enzyme immunoassay (EIA) followed by confirmatory testing of specimens repeatedly reactive by EIA using an FDA-licensed supplemental test, usually western blot.18 Although reporting of test results usually takes 1 to 2 weeks, EIA testing can be performed within several hours. Rapid tests for detecting HIV antibodies can be performed in 10 to 30 minutes. Only one rapid test (Single Use Diagnostic System for HIV-1 [SUDS], Abbott Diagnostic, Abbott Park, IL) currently is FDA-licensed and available in the United States, but approval and availability of other rapid tests are expected within the next year. The sensitivity and specificity of the SUDS are similar to those of the EIA tests. Given the relatively low seroprevalence of HIV in most perinatal settings in the United States, the negative predictive value of a single EIA or of the SUDS is high and further testing is not required.18 However, because the positive predictive value of a single rapid test will be low in low-prevalence populations, a reactive rapid test must be confirmed by an additional test. In studies outside of the United States, combinations of two or more different rapid tests have been as reliable as standard EIA/western blot testing.19 Until additional rapid HIV antibody tests are approved for use in the United States and combinations with adequate specificity for use in perinatal settings are determined, rapid testing may be accomplished with a combination of the SUDS test and EIA, or standard testing may be expedited, or providers may choose to individualize counseling and decisions about antiretroviral therapy for women and their neonates with a repeatedly reactive rapid HIV test while awaiting confirmatory testing.
Implementation of universal HIV testing with patient notification does not obviate the need for education of women about the risks and implications of HIV infection and means of protecting themselves. All women's healthcare providers should provide education regarding protection from HIV and other sexually transmitted diseases to their sexually active patients. Before HIV testing, providers should provide verbal or written information on HIV, how it is spread, interventions available to prevent perinatal transmission, and services available for HIV prevention and treatment. Documentation of a woman's consent or refusal of HIV testing in the medical record is recommended. Providers should be aware of regulations in their area that may require more specific counseling and informed consent documentation than those recommended in the IOM report and ACOG/AAP policies. Although women should not be coerced to be tested, women who decline testing during pregnancy should have the reasons for refusal explored and be offered testing again at subsequent visits. Confidentiality of patient information should always be maintained, but providers also must be aware of local requirements for partner notification if women are not able to notify partners.
Although false-positive test results for HIV antibodies do not appear to be increased in pregnancy, the rate of indeterminate western blots may be increased.20 Indeterminate western blot results can be caused by an evolving antibody profile in response to recent HIV infection, loss of antibody in persons with end-stage HIV infection, or nonspecific cross-reacting antibodies not related to HIV. Risk factors for indeterminate results not related to HIV include current or previous pregnancy, autoantibodies such as rheumatoid factor, and recent immunization.20 The rate of seroconversion was low among individuals with indeterminate western blots and was always associated with current high-risk behavior such as unprotected sex with an infected partner or ongoing injection drug use.20,21 If a pregnant woman has a repeatedly reactive EIA and an indeterminate western blot, she should be questioned regarding recent risk behaviors and undergo repeat antibody testing. Nearly all HIV-infected individuals have complete HIV antibody profiles develop within 1 month of exposure. Continued indeterminate results are highly unlikely to be related to HIV infection, especially if the patient's sexual partners are negative and there are no other high-risk behaviors. Although HIV DNA and RNA assays are not approved for diagnostic use, they may sometimes be helpful in distinguishing the reason for indeterminate western blot testing in high-risk individuals.
|EFFECT OF PREGNANCY ON MATERNAL HUMAN IMMUNODEFICIENCY VIRUS DISEASE AND THERAPY|
Pregnancy may have an impact on coexistent maternal medical conditions such as congenital heart disease and autoimmune diseases, but its impact on HIV infection is less clear. The CD4+ lymphocyte count tends to drop in pregnancy in both HIV-infected and uninfected women, while the CD4+ lymphocyte percentage tends to be more stable.22–24 This drop in count could allow enhanced viral replication and disease progression, and antigenic stimulation by fetal tissues during pregnancy could lead to T-cell activation and viral replication. Conversely, the relative immunosuppression of pregnancy could lead to decreased viral replication. Studies on the progression of HIV disease from the United States and Europe do not suggest an increase in disease progression related to pregnancy.22,25–29 Several studies have suggested an increased risk of bacterial pneumonia among HIV-infected women during pregnancy and the postpartum period, perhaps related to respiratory changes in pregnancy.29,30 Studies from developing countries are less clear and suggest a potential effect that could be related to nutritional differences or coexistent infections.26,31,32
As with most serious medical conditions coexisting with pregnancy, the treatment of the HIV-infected mother should be the same as that used if the woman were not pregnant unless clear contraindications to specific therapies exist.33,34 Experience with use of many antiretroviral agents in pregnancy is limited, and long-term follow-up of children exposed to these agents in utero is unavailable. HIV-infected pregnant women should be counseled about the potential benefits of therapy for their own health and reduction of perinatal transmission, about currently available data on risks, and about the lack of long-term information. Preclinical and clinical data pertinent to use in pregnancy for currently approved antiretrovirals are summarized in Table 1.16,33,35–38 The predictive value of in vitro and animal studies for carcinogenicity, mutagenicity, reproductive, and teratogenic effects in humans is unknown. For more detailed information, readers should consult the Safety and Toxicity of Individual Antiretroviral Drugs in Pregnancy hyperlink available in both the “Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents” and “USPHS Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States” available at www.hivatis.org or www.cdc.gov.33,34 This summary is updated as new drugs are approved or new information becomes available. Recommended treatment during pregnancy based on CD4+ cell counts, viral load, and antiretroviral treatment history is discussed in more detail below.
A, Adequate and well-controlled studies of pregnant women fail to show a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during the later trimesters); B, Animal reproduction studies fail to show a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted; C, Safety in human pregnancy has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus; D, Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; X, Studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit; Pk, pharmacokinetic; VSD, ventricular septal defect.
(Centers for Disease Control and Prevention: USPHS task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. Morb Mort Wkly Rep 47 [RR-2]:1---30, 1998. Updated February 2000. Available at www.atis.org.)
Providers treating pregnant women with antiretroviral agents are urged to report their cases to the Antiretroviral Pregnancy Registry as early in the patient pregnancy as possible. The registry collects observational data on antiretroviral exposure during pregnancy to assess the potential for teratogenicity of the drugs and is a collaborative project of pharmaceutical manufacturers and an advisory committee. Prospectively reported cases (identified before the outcome of pregnancy is known) are used for the calculation of rates of defects, while retrospectively reported cases are used only for detecting any specific pattern of defects because of the potential for reporting bias. Patient identifiers are not included in reports to the registry, and registry staff contact the reporting provider to obtain birth outcomes. Reports on findings to date are issued every 6 months. To report cases and obtain the most recent report, contact the Antiretroviral Pregnancy Registry, 1410 Commonwealth Drive, Wilmington, NC 28403, telephone 1–800-258–4263, fax 1–800-800–1052.
Recently, two other concerns regarding potential long-term effects of antiretroviral therapy during pregnancy on the infant and child have been raised: the potential for transplacental carcinogenicity and mitochondrial toxicity. Nonmetastisizing vaginal tumors have been seen in adult rodents treated with continuous, high-dose zidovudine, likely related to reflux of urine with high concentrations of unmetabolized zidovudine onto the vaginal mucosa in rodents.39 No increase in tumors in other organs has been seen in adult rodents, and since humans excrete only metabolized zidovudine in the urine, this effect is not expected in humans. Because of the frequent use of zidovudine in HIV-infected pregnant women, studies of transplacental carcinogenesis have been done for zidovudine but not for any of the other antiretroviral agents. Two studies were done in mice with differing results.40,41 In one study using 25 and 50 times the human dosage in the third trimester of pregnancy, the offspring in the highest dosage group showed a significant increase in the rate of tumors of the lung, liver, and reproductive organs compared with that of untreated control subjects.40 Incorporation of zidovudine into the DNA of tissues of newborn mice was detected, but the incorporation did not correlate with the development of tumors. In the second study, dosages of zidovudine were approximately three times the human dosage, and some of the offspring also were treated. No increase in tumors was observed in the offspring, except for the expected rate of vaginal tumor development in animals who continued to receive zidovudine.41 The animal data were reviewed by an expert panel convened by the National Institutes of Health, and the panel recommended that the benefits of zidovudine in reducing perinatal transmission of HIV outweigh the theoretical risks of transplacental carcinogenesis but that infants exposed to zidovudine in utero should have long-term follow-up to detect any potential adverse effects.42 In 727 children exposed to zidovudine in utero with more than 1100 person-years of follow-up, no tumors have been observed but continued follow-up is indicated.43
Nucleoside analogue drugs such as zidovudine may induce mitochondrial dysfunction by binding to mitochondrial gamma DNA polymerase and interfering with mitochondrial replication.44 The relative potency for inhibition of mitochondrial gamma DNA polymerase in vitro is zalcitabine (highest), didanosine, stavudine, lamivudine, zidovudine, and abacavir (lowest).45 Toxicity such as myopathy related to mitochondrial dysfunction has been reported among HIV-infected persons treated with nucleoside agents, but it generally has been reversible when the drugs are stopped. A French group raised concerns of possible persistent mitochondrial dysfunction among infants with in utero and neonatal nucleoside exposure to either zidovudine or zidovudine/lamivudine when it reported eight cases of HIV-uninfected infants with symptoms possibly related to mitochondrial dysfunction.46 Two infants had progressive neurologic symptoms develop and subsequently died several months after short courses of in utero and neonatal zidovudine/lamivudine for prevention of HIV transmission. Three other infants with mild to moderate symptoms and three with asymptomatic laboratory abnormalities were identified. All abnormalities developed several months after the end of the exposure to nucleoside agents. Mitochondrial abnormalities were not proved as the cause of the symptoms or laboratory abnormalities, and association between the findings and in utero or neonatal exposure to antiretroviral agents has not been established. To evaluate potential nucleoside toxicity, a collaborative effort between several large cohorts in the United States identified and reviewed 353 deaths in more than 20,000 children born to HIV-infected women. No deaths similar to those reported in France were identified, although only 6% of the children had been exposed to the combination of zidovudine/lamivudine.47 Evaluation of living children in these cohorts for potential evidence of mitochondrial dysfunction is ongoing. No differences in growth, immunologic parameters, or cognitive development were observed between children exposed to zidovudine or placebo in Pediatric AIDS Clinical Trials Group (PACTG) 076 and followed up to 5.6 years.48 No deaths or tumors occurred during follow-up. Neurologic adverse events have been reviewed among 1798 children enrolled to the PETRA trial that compared zidovudine/lamivudine to placebo for the prevention of HIV transmission. No increased risk of neurologic events was seen among children exposed to zidovudine/lamivudine compared with that of placebo regardless of intensity of treatment.49 The potential for in utero and neonatal exposure to nucleosides to cause mitochondrial dysfunction later remains unproved. If the association exists, the development of severe or fatal disease appears to be extremely rare and must be compared with the clear benefit of zidovudine in reducing transmission of an ultimately fatal infection.50 These concerns underscore the need for long-term follow-up of antiretroviral-exposed children.
When treating HIV-infected pregnant women with antiretroviral agents or drugs active against opportunistic infections, the physiologic changes of pregnancy must be considered.51 The 45% increase in plasma volume coupled with only a 20% to 30% increase in erythrocyte mass leads to dilutional anemia, which may be exacerbated by drugs that cause bone marrow suppression such as zidovudine. Cardiac output and glomerular filtration rate increase by 30% to 50%, potentially causing increased excretion and decreased levels of drugs with primarily renal clearance. Increased tidal volume and pulmonary blood flow may lead to increased absorption of aerosolized medications such as pentamidine. Changes in metabolic enzyme pathways in the liver may occur as well. Placental transfer of drugs and metabolism by the fetus also may affect maternal drug levels. Ideally, specific pharmacokinetic studies of new antiretroviral agents in pregnancy will be done, but if these data are not available to guide dosing, clinicians must consider the metabolism of the drug and potential impact of pregnancy and monitor efficacy of the chosen regimen by assessing the effect on plasma HIV RNA levels.
|MATERNAL HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND PREGNANCY OUTCOME|
In assessing the impact of maternal HIV infection on pregnancy and infant outcome, it is important to consider other risk factors for adverse pregnancy outcome, such as smoking and illicit drug use, which may be increased among HIV-infected women. As listed in Table 2,30,52–77 studies in the United States and Europe, reported primarily before the routine use of antiretroviral therapy in pregnancy, have not shown increases in adverse pregnancy outcomes in HIV-infected women compared with those of uninfected women. Of note, the outcomes among both groups in these studies tend to have increased proportions of women with low birthweight and preterm birth compared with those of the general population, most likely related to maternal drug use, lack of prenatal care, and other risk behaviors.78 In contrast, the majority of studies from developing countries have shown an increase in low birthweight and preterm birth among HIV-infected women compared with those of uninfected women. In addition, when it has been examined, outcomes appear to be worse for women with symptomatic compared with those of asymptomatic HIV infection. These differential outcomes among women in developing countries may be related to nutritional differences, coinfections such as malaria and syphilis, or other factors.
*p < .05 comparing outcomes in HIV-infected to HIV-uninfected women; *p < .05 comparing women with AIDS to women with HIV infection but not AIDS, BW, birthweight; GA, gestational age; UK, United Kingdom; NYC, New York City; NA, not available; LBW, low birthweight; diff., difference; sx, symptoms.
Studies evaluating the effect of infant HIV infection on birthweight and gestational age, comparing infants exposed but HIV uninfected and those infected, have had variable results. The majority have not shown a clear impact of infant HIV infection on birthweight and gestational age at delivery,58,68,71,79–81 most likely because of the high proportion of infections that occur very late in pregnancy or during labor, delivery, or breastfeeding. Studies reporting a lower birthweight or gestational age among HIV-infected infants compared with that of exposed but uninfected infants had high rates of preterm birth in the cohorts, suggesting that the increased risk of transmission related to prematurity may have contributed to the finding.75,82,83
Studies evaluating risk factors for adverse pregnancy outcome among HIV-infected women have found them to be primarily the same risk factors seen in HIV-uninfected women with a variable contribution of HIV infection. Using low birthweight as the outcome, the most consistent contributors in studies in the United States and Europe have been injection drug use during pregnancy,54,79,80 smoking,54 history of adverse outcome,84,85 bleeding during pregnancy,84 lack of prenatal care,78 CD4 percentage below 14,84 pre-eclampsia,85 and entry HIV culture titer but not viral load, CD4+ lymphocyte count, or delivery culture.85 Risk factors for preterm birth noted in the United States and European studies included current injection drug use,79 prior preterm birth,84,85 multiple gestation,85 bleeding during pregnancy,84 alcohol use,85 pre-eclampsia,85 CD4 percentage below 14,84 and lack of zidovudine use.86 In Africa, risk factors for low birthweight included malaria parasitemia,75,76 trichomoniasis,76 HIV infection,67,76 and maternal weight.77
The impact of antiretroviral therapy on pregnancy outcome is unclear. The drugs could exert a deleterious effect on fetal growth; conversely, the suppression of high levels of HIV replication and immune reconstitution could be beneficial for fetal growth. As noted above, several studies in untreated women have suggested a negative effect of HIV infection or low CD4+ lymphocyte counts on pregnancy outcome and zidovudine appeared to decrease the rate of prematurity in one analysis.84–86 The impact of combination therapy on pregnancy outcome also is unclear. One small retrospective study reported pregnancy outcome among 37 HIV-infected women, 21 of whom received dual nucleoside reverse transcriptase inhibitor therapy and 16 of whom received dual nucleosides plus one or two protease inhibitors.87 A possible association of combination therapy with preterm birth was suggested because 10 (33%) of 30 babies were born prematurely. The preterm birth rate was similar between women receiving nucleoside only compared with that of nucleoside plus protease inhibitor therapy. Other covariates such as maternal disease stage and drug abuse were not evaluated, and a comparison group on no therapy or zidovudine only was not included. A meta-analysis of multiple United States cohort studies and applicable clinical trials is underway to evaluate rates of adverse pregnancy outcome by maternal antiretroviral therapy and other risk factors. Preliminary analyses do not indicate an increased risk of preterm delivery among women receiving combination antiretroviral therapy with or without protease inhibitors compared with those receiving single agent or no therapy.88 The benefits of combination therapy for maternal health and potential reduction of perinatal transmission are great, and given current data, women should continue combination regimens if indicated with careful monitoring for potential pregnancy complications.
|VERTICAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS|
Transmission of HIV from mother to child accounts for more than 90% of pediatric AIDS cases reported in the United States.1 Early in the epidemic before the availability of serologic testing, vertical transmission rates of more than 50% were reported in the United States and Europe. These rates were spuriously high as infected women were identified because of symptomatic disease or previous birth of an infected child and many infected women were not identified. Before the widespread use of antiretroviral therapy in pregnancy, vertical transmission rates of 15% to 33% were reported in the United States and Europe,8,55,80–83,89–93 and rates of 20% to 48% were reported in developing countries.61,64–68,70,94,95 Higher rates of transmission in developing countries are thought to be related to breastfeeding transmission; higher rates of cofactors such as sexually transmitted diseases, chorioamnionitis, and malaria; nutritional deficiencies; viral differences; and differential classification of infants who die before determination of infection status. More recently, vertical transmission rates in the United States and Europe of 3% to 6% with maternal zidovudine therapy15,96–101 and 2% or less with maternal zidovudine therapy and scheduled cesarean delivery or combination antiretroviral therapy with undetectable maternal viral load have been reported.102–106 Optimal treatment of pregnant women to prevent perinatal transmission is discussed below. Although great progress has been made in reducing the rate of vertical transmission of HIV in developing countries, much remains to be done to translate research findings into interventions in developing countries to reduce rates there. In addition, greater efforts must be undertaken throughout the world to prevent infections in women, the ultimate method to prevent perinatal transmission.
Vertical transmission of HIV may occur during the antepartum, intrapartum, or postpartum period. Although it is difficult to differentiate antepartum from intrapartum transmission, data suggestive of antepartum, or in utero, transmission include detection of HIV in fetal tissues from abortuses as early as 8 weeks’ gestation,107–109 isolation of HIV from amniotic fluid,110,111 identification of HIV in placentas from infants born to HIV-infected women,112–114 and the ability to infect trophoblast in vitro.115,116 Fetal cells including thymic cells and cord blood macrophages are highly susceptible to HIV infection in vitro.117,118 A previously suggested “AIDS embryopathy” with a constellation of physical findings thought to be related to early in utero HIV transmission119 has subsequently been discounted as related to maternal drug use or racial variation.120, 121 Based on the rate of detection of virus by culture or antigen or nucleic acid detection at birth compared to later,122–130 the early onset of symptoms related to HIV in a subset of perinatally infected infants,131,132 and patterns of immunoglobulin A response,133,134 it appears that 20% to 60% of perinatal transmission not related to breastfeeding occurs in utero, with the remaining 40% to 80% occurring in late pregnancy or during labor and delivery. Evidence of intrapartum transmission includes the virologic, clinical, and immunologic data discussed above; the frequent detection of HIV in blood and cervicovaginal secretions of infected women that is reduced by antiretroviral therapies shown to reduce transmission135–137; significantly higher infection rates among first-born compared with secondborn twins138; the association of higher transmission rates with increasing duration of membrane rupture90,139,140; and reduced transmission among women delivered by cesarean before labor and membrane rupture.103,104 Thus, although transmission may occur early in pregnancy, most appears to occur near delivery, and interventions directed at late pregnancy and delivery and the neonate would be expected to impact transmission significantly.
Transmission of HIV during the postpartum period through breastfeeding, and rarely through household contacts, has been documented.68,141–144 Two cases of household transmission from infected children to caregivers have been documented, but otherwise household transmission appears to be rare.144 HIV has been detected in both the cell-free and cell-associated fractions of breast milk.145 The risk of transmission during breastfeeding appears to be higher with primary maternal infection during breastfeeding such as with postpartum blood transfusion when maternal viremia is at high levels before an immune response.142 A meta-analysis showed the average rate of transmission with breastfeeding during primary infection to be 29%, with ranges from 16% to 42%.141 The rate of transmission through breastfeeding with established infection is harder to determine because of difficulty differentiating intrapartum and postpartum infections but ranges from 9% to 32% with a median around 14%.141,143 HIV is detected more frequently from colostrum and breast milk in the first 7 days after delivery compared to mature milk, suggesting that transmission rates may be higher early in breastfeeding.145 Epidemiologic data also suggest higher transmission rates earlier compared to later in breastfeeding.146,147 Other factors that increase the risk of transmission during breastfeeding include low CD4+ lymphocyte count in the mother, vitamin A deficiency, and mastitis.148,149 Two studies have found higher transmission rates in infants receiving both breast milk and other liquids compared to those receiving only breast milk.150,151 Mixed feeding, especially if contamination occurs, could produce inflammation in the gastrointestinal tract, which facilitates HIV entry. In a randomized trial of breastfeeding versus formula feeding by cup in Nairobi, Kenya, the HIV infection rates at 24 months of age were reduced from 37% in the breastfeeding group to 21% in the formula feeding group, despite only 70% compliance with not breastfeeding among the women assigned to formula feeding.152 The mortality rate in the children through 2 years of age was high in both groups, 24% in the breast-feeding and 20% in the formula feeding arms, despite a requirement for access to running water and restriction of enrollment to certain districts within the city and free provision of formula, suggesting concerns regarding applicability to large areas of the developing world.
Maternal and obstetric factors consistently associated with an increased risk of transmission when evaluated before widespread use of antiretroviral therapy in pregnancy included advanced maternal disease as defined by clinical AIDS, maternal p24 antigenemia, low CD4+ lymphocyte count/percent or high plasma viral load,54,55,61,64,65,70,80,82,91–94 longer duration of membrane rupture during labor,90,139,140 placental inflammation,61,65,70,83,94,153,154 and concomitant sexually transmitted diseases.64,76,83,94 Factors associated with increased risk of transmission in some but not all studies when evaluated include preterm birth,70,91,155,156 illicit drug use,81,83,139,157,158 maternal vitamin A deficiency,159–161 female gender of the infant,94 and mode of delivery.83,89,91,162–166 The impact of cesarean delivery was difficult to evaluate in early studies because of lack of differentiation of cesarean deliveries done before labor and membrane rupture compared with those done after labor or rupture, variations in management of labor such as use of scalp electrodes and operative vaginal delivery, and lack of differentiation of antepartum compared to intrapartum transmission.
Data from both untreated and treated cohorts of HIV-infected pregnant women have shown an association between increased maternal viral load and an increased risk of vertical transmission, although this association is attenuated among treated women (Table 3).92,96,153,156,158,167–175 Treatment lowers transmission even among women with plasma HIV RNA below 1000 copies/mL before treatment. Although transmission rates are very low among women with HIV RNA levels below 1000 copies/mL, there is no threshold below which transmission can be certain not to occur.
HIV, human immunodeficiency virus; LOD, lower limit of detection; ARV, antiretroviral; Rx, therapy; RTPCR, reverse transcription polymerase chain reaction; NASBA, nucleic acid sequence---based amplification; ZDV, zidovudine
Although high plasma HIV load has been associated consistently with transmission in untreated and treated women, results of studies of other virologic, immunologic, and genetic factors and transmission have been more variable. Some studies have suggested an association between syncytium-inducing or nonsyncytium-inducing strains and transmission, whereas others have not.176–182 Transmission of syncytium-inducing strains does appear to correlate with more rapid disease progression in infants.181,183 Similarly, results regarding whether monocytotropic or lymphocytotropic strains are more likely to be transmitted have been conflicting.177,180,182,184 Thus far, specific viral clade has not been shown to correlate with risk of transmission.185 A small study has suggested that women with increased diversity of viral quasispecies in the genital tract may be more likely to transmit HIV to their infants.186 Results also have been quite variable when evaluating the role of maternal antibodies, including antibody titers and affinity to anti-gp120 and other envelope proteins, or autologous neutralizing antibody titers in preventing vertical transmission, frustrating efforts for development of vaccines for prevention of vertical transmission.176,177,181,184,187–192 Cytotoxic T lymphocyte response to specific HIV epitopes may offer some protection from transmission.193,194 More recently, several investigators have evaluated the potential for a mutation in the CCR5 coreceptor used by HIV to enter cells to protect from perinatal transmission. Most studies were consistent in finding that heterozygosity for the Δ32 mutation did not protect against vertical transmission of HIV but was associated with delayed disease progression among infected children.195,196 A recent study suggests that the CCR2–641 allele may be protective both against vertical transmission and disease progression, but confirmation is required.197
|ANTIRETROVIRAL THERAPY FOR REDUCTION OF VERTICAL TRANSMISSION|
The most striking impact on vertical transmission of HIV was the demonstration in 1994 of the reduction of transmission from antepartum, intrapartum, and neonatal therapy with zidovudine in the PACTG 076 trial.198 Several subsequent observational studies confirmed the benefit of zidovudine in reduction of transmission and actually reported rates of transmission in treated cohorts of 3% to 6%.15,97–101,158,199,200 Recently, several studies of shorter courses of zidovudine or nevirapine have shown benefit in reducing perinatal transmission, even among breastfeeding populations (Table 4).16,175,201–205 Based on the results of these studies, it appears that adding 1 week or less of postpartum maternal or infant therapy to short-course antepartum and intrapartum zidovudine therapy did not further reduce transmission.175,203,205 Intrapartum therapy only, even with zidovudine/3TC, was not better than placebo, whereas intrapartum/postpartum zidovudine/3TC was better than similar zidovudine alone and similar to the two-dose nevirapine regimen. A pharmacokinetic substudy of the Thailand short-course zidovudine trial showed that oral zidovudine was well-tolerated during labor and 83% of the cord blood specimens had drug levels above 0.5 μmol/L, the minimum concentration thought to be active against HIV in vitro.206 Short-course antepartum/intrapartum zidovudine regimens seem to have similar efficacy to the intrapartum/postpartum zidovudine/3TC regimen but are cheaper and do not have the potential added toxicity of combination regimens if therapy can be begun by 36 weeks of gestation. The nevirapine regimen is the simplest, least expensive, and offers the advantage of both maternal and infant doses being administered in the hospital under direct observation. Development of resistance with even single-dose nevirapine has been reported,207 although the duration of persistence and the clinical significance of this finding are unclear. Whether adding the HIVNET 012 nevirapine regimen to zidovudine or combination antiretroviral therapy during pregnancy impacts transmission is under study in the ongoing PACTG 316 trial. Pending the results of that trial, the two-dose nevirapine regimen could be considered for HIV-infected women presenting in labor without any antiretroviral therapy but is not routinely recommended for women with a good response to therapy during pregnancy. The observation that short courses of therapy during pregnancy or postpartum can lead to sustained reductions in transmission, even up to 15 months in breastfeeding populations, is encouraging. Trials of continued maternal or infant antiretroviral therapy during breastfeeding to attempt to reduce transmission further are ongoing.
HIV, human immunodeficiency virus; ZDV, zidovudine; IV, intravenous; QID, four times/day; BID, twice daily.
In addition to the randomized trials of short-course therapy in developing countries, two observation studies in the United States have suggested benefit from zidovudine initiated in the intrapartum or the newborn period. A study of more than 900 infants in New York state observed transmission rates of 6.1% when zidovudine was begun during pregnancy before labor, 10.0% when begun during labor and given to the neonate, 9.3% when neonatal therapy was begun within 48 hours of birth, 18.4% when begun after 48 hours after birth, and 26.6% if no zidovudine was given.15 Similarly, a study from North Carolina showed a transmission rate of 3.1% with the full PACTG 076 zidovudine regimen, 10.7% with intrapartum and neonatal zidovudine, 26.7% with neonatal therapy only (timing not specified), and 30.9% with no antiretroviral therapy in pregnancy.99 These data suggest some efficacy for zidovudine, especially if begun in the intrapartum period, and show lower transmission rates than the zidovudine arm in the HIVNET 012 study. This difference could be related to breastfeeding in the Ugandan study, 6 weeks of infant therapy in the United States compared to 1 week in the HIVNET trial, or to other factors. These studies underscore the need for HIV testing early in pregnancy; the possible benefits of rapid HIV testing in labor for untested women; and the need to offer therapy with zidovudine, nevirapine, or the untested combination for HIV-infected women presenting in labor or detected after delivery with no therapy during pregnancy.
Combination antiretroviral therapy has become the standard of care for nonpregnant adults with indications for treatment of their HIV infection because of better viral suppression and decreased chance for development of resistant virus. Combination therapy also is being used more frequently for pregnant women as women receiving multiple agents conceive or women choose combination therapy for their own health. Given the strong association of HIV levels and transmission and the greater reduction of viral load with combination compared to monotherapy, combination therapy during pregnancy may reduce the rate of perinatal transmission further. A few small published studies have shown transmission among one (6.7%) of 15, none of 30, and none of 24 women receiving two or more antiretroviral drugs in combination during pregnancy,87,105,106 and several abstracts have been presented with no transmissions among 43, 63, 47, and 34 women, whereas one report found a transmission rate of three (5.8%) of 52 women receiving triple therapy, including a protease inhibitor.208–212 Thus, although the benefits of combination therapy for women who require therapy for their own health are clear, the impact on perinatal transmission is suggested but unproved. Pregnant women should be apprised of the potential benefits of combination antiretroviral therapy for their health, the theoretical impact on perinatal transmission, as well as the potential risks of the therapy, including the side effects of the drugs and unknown short- and long-term effects on the infant.
Although the effect of zidovudine therapy on transmission has been shown in both randomized and observational studies, concerns about the impact of viral resistance on the efficacy of antiretrovirals in pregnancy remain. In the PACTG 076 study, high-level zidovudine resistance was not detected among 96 women who received zidovudine.213 Low-level zidovudine resistance (K70R mutation) developed in one (2.6%) of the 39 women with paired isolates from enrollment and delivery. Zidovudine resistance was not associated with an increased risk of vertical transmission of HIV. Women enrolled to PACTG 076 were required to have CD4+ lymphocyte counts above 200 cells/μL and had relatively low viral loads, thus limiting the chance of development of resistant virus. Among a cohort of women receiving zidovudine for their own health during pregnancy before release of the PACTG 076 results, genotypic resistance to zidovudine was detected more often.214 At least one resistance mutation was observed in 34 (25%) of 142 isolates and either the codon 215 mutation or more than one mutation (potentially high-level resistance) was observed in 14 of these. Perinatal transmission occurred among eight (24%) of 34 with any resistance mutation and 18 (19%) of 96 without any resistance mutation (p = .7). On multivariate analysis after adjusting for duration of ruptured membranes and total lymphocyte count, resistance mutations were associated with an increased risk of transmission, although this finding may be related to the increased risk of resistance mutations among women with high viral loads. The Swiss HIV in Pregnancy Study reported codon 215Y/F zidovudine resistance among six (9.6%) of 62 consecutive women, four of these at initial sampling in pregnancy (three of these with prior zidovudine) and two developing during pregnancy.215 None of the women with this high-level zidovudine resistance transmitted virus to their infants despite the majority receiving the PACTG 076 zidovudine regimen. Perinatal transmission of drug-resistant virus has been reported, but it is not clear whether the presence of viral resistance mutations increases the risk of transmission.216,217 Rapid development of lamivudine resistance has been reported among pregnant women receiving dual-nucleoside therapy, including lamivudine, suggesting that if combination therapy is chosen during pregnancy, triple combinations including a protease inhibitor or nonnucleoside reverse transcriptase inhibitor as recommended for nonpregnant adults should be used to maximize suppression and minimize resistance.218
Despite relatively limited data on the utility of resistance testing for nonpregnant HIV-infected persons and no data on its use in pregnancy, a recent advisory panel has recommended that resistance testing be performed on all pregnant women with detectable virus to aid in choice of therapy.219 Although resistance testing may become the standard of care in the future, it currently is costly and difficult to interpret and data to support its routine use are lacking. Resistance testing may be useful for pregnant women who do not respond to initial highly active therapy, who have persistently detectable virus and a history of multiple therapeutic regimens, or where the prevalence of resistant virus in the community is high.
Despite concerns regarding potential long-term effects of antiretroviral exposure during pregnancy and the neonatal period on growth and development, the benefits of antiretroviral therapy both to maternal health and reduction of perinatal transmission appear to outweigh the as-yet unproven risks. Current guidelines should be consulted to ensure the most up-to-date information as new drugs are approved and new data become available.33
|MODE OF DELIVERY AND VERTICAL TRANSMISSION|
As discussed above, at least half of the incidents of vertical transmission of HIV appear to occur during the intrapartum period. Early studies of the role of cesarean delivery on the rate of transmission were inconclusive because of the combining of cesarean deliveries done before and after labor and membrane rupture.91,162–164 However, several studies have now shown the benefit of scheduled cesarean delivery in reducing vertical transmission of HIV among women receiving no antiretroviral therapy or zidovudine monotherapy. Two prospective cohort studies showed rates of transmission below 2% among women who received zidovudine and underwent cesarean delivery before labor and membrane rupture (scheduled cesarean delivery).102,166 Subsequently, an individual patient data meta-analysis pooling data from 15 North American and European cohorts showed a significantly lower transmission rate among infants delivered by scheduled cesarean delivery compared to urgent cesarean or vaginal delivery, with an unadjusted odds ratio (OR) of 0.45 (95% confidence interval [CI], 0.35 to 0.58) and an OR of 0.43 (0.33 to 0.56) adjusted for zidovudine use, advanced maternal disease, and birthweight.103 The rate of transmission among women not receiving antiretrovirals was 10% when delivered by scheduled cesarean delivery and 19% for other modes of delivery; among women receiving zidovudine (predominantly the PACTG 076 schedule), the rate was 2% with scheduled cesarean and 7% with other modes of delivery. Finally, results from an international randomized trial confirmed a reduction in rate of transmission with scheduled cesarean delivery. In an analysis of the assigned mode of delivery, transmission was 1.8% among those assigned to scheduled cesarean delivery and 10.5% in those assigned to deliver vaginally (OR, 0.2; 95% CI, 0.1 to 0.6).104 Results were similar in the actual mode-of-delivery analysis with women undergoing emergent cesarean delivery having a rate of transmission of 8.8%, similar to those delivering vaginally. In an analysis including zidovudine use, the transmission rate was 4% with scheduled cesarean and 20% for vaginal delivery without zidovudine use (adjusted OR, 0.2; 95% CI, 0 to 0.8), and 1% with scheduled cesarean and 4% with vaginal delivery with zidovudine use (adjusted OR, 0.2; 95% CI, 0 to 1.7). Because of the small number of transmissions (six total) in the group receiving zidovudine, the difference in transmission rates by mode of delivery was not significant, although the magnitude of reduction was similar. Taken together with the meta-analysis and observation data, the difference suggests that scheduled cesarean deliveries may offer added protection from transmission among women not receiving antiretroviral therapy or receiving only zidovudine monotherapy. The studies discussed above were done before the routine use of viral load testing and the widespread implementation of combination therapy in pregnancy. Given the low level of transmission among treated women with viral loads below 1000 copies/mL (see Table 3), it is unclear whether scheduled cesarean delivery offers any benefit to the infant in this situation. The use of cesarean delivery in the treatment of HIV-infected pregnant women is discussed further below.
|OTHER INTERVENTIONS TO REDUCE PERINATAL TRANSMISSION OF HIV|
Given the high seroprevalence of HIV among pregnant women in developing countries and the lack of resources to provide routine prenatal care, HIV testing, and antiretroviral therapy, interventions that are easy to implement, inexpensive, and applicable to all pregnant women regardless of HIV status have been sought. Interventions that have been tested thus far and not found to impact significantly on perinatal transmission of HIV include chlorhexidine vaginal washing,220 multivitamin supplementation,221 and vitamin A supplementation.222 A subset analysis of the chlorhexidine study did show a reduction in transmission in the chlorhexidine group among the women with ruptured membranes for more than 4 hours before delivery and also showed reductions in maternal and infant sepsis and hospital admissions, and infant mortality from sepsis.223 Similarly, the multivitamin supplementation trial showed significantly lower rates of fetal death and stillbirth, low birthweight, and preterm delivery despite no reduction in HIV transmission.221 The vitamin A trial did not show a difference in fetal or infant mortality but did show a reduction in preterm birth, and among the preterm infants, a reduction in HIV transmission with vitamin A supplementation.222 Trials currently underway or anticipated for reduction of perinatal transmission of HIV in developing countries include a phase I study of the safety of vaginal washings with higher concentrations of chlorhexidine in Soweto, vaginal disinfection with benzalkonium chloride suppositories in west Africa, and a phase III trial of short-course antibiotics at 20 to 24 weeks of gestation and during labor to reduce chorioamnionitis and perinatal transmission.224,225
|EVALUATION OF THE INFANT BORN TO A HUMAN IMMUNODEFICIENCY VIRUS-INFECTED MOTHER|
Infants born to HIV-infected women should receive the 6-week zidovudine regimen (2 mg/kg orally every 6 hours) as outlined in PACTG 076.198 Anemia is the most frequent toxicity of the 6-week zidovudine regimen, although suppression of other bone marrow elements also is possible. A complete blood count and differential should be done on the neonate as a baseline and repeat hemoglobin should be done at 6 and 12 weeks of age.33 Potential toxicities of combination therapy in the mother have not been evaluated in detail in the neonate, so more intensive hematologic and chemistry monitoring in the newborn period should be considered for infants born to women receiving combination therapy.
Because of transfer of maternal immunoglobulin G antibody across the placenta, serologic testing of the infant is not useful for diagnosis of HIV infection in the first several months of life. Standards of care for diagnosis and management of the infant born to an HIV-infected mother should be followed, which currently include testing by DNA polymerase chain reaction by 48 hours of age, at 1 to 2 months, and at 4 to 6 months of age, with an additional test at 2 weeks of age being optimal.226,227 Positive testing at or before 48 hours of age is thought to be indicative of infection in utero, whereas negative testing initially followed by positive testing at or beyond 2 weeks of age is thought to indicate transmission in late pregnancy or intrapartum, assuming no exposure through breastfeeding. Most infants subsequently proved to be infected have a positive DNA polymerase chain reaction test result by 2 weeks of age, so that testing at this point may allow early intensification of antiretroviral therapy rather than continuing zidovudine prophylaxis.227,228 Diagnosis of HIV infection in the infant is not delayed by the PACTG 076 regimen,198,229 but the impact of maternal or neonatal combination antiretroviral therapy on diagnostic testing is unknown. Diagnostic tests should be repeated after completion of infant antiretroviral prophylaxis in the infant with earlier negative testing result. All infants born to HIV-infected women should start receiving prophylaxis against Pneumocystis carinii pneumonia at 6 weeks of age after completion of zidovudine prophylaxis, and prophylaxis should be continued until infant HIV infection has been definitively ruled out with testing at 4 to 6 months of age or indefinitely in the infected infant, depending on response to antiretroviral therapy.230 Infants with proven HIV infection should be treated by infectious disease specialists with experience in treating pediatric HIV infection according to current recommendations.227
|MANAGEMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN PREGNANCY|
Women entering pregnancy with a history of HIV infection or with a positive antibody test result for the first time during pregnancy should have their status confirmed by repeat antibody testing. Evaluation of the HIV-infected pregnant woman is summarized in Table 5. Included in the history should be documentation of previous and current antiretroviral drug therapy and whether previous children have been assessed for possible HIV infection. Immunization history should be assessed including hepatitis B and pneumococcal vaccine status. Pregnant women without evidence of immunity to hepatitis B should be offered vaccination, and HIV-infected women who have not received pneumococcal vaccine within the past 5 years should be offered this vaccine. Influenza vaccine should be offered to all pregnant women who are in the second or third trimester during peak influenza season.231 Because of the transient increase in plasma HIV levels, which can be seen after immunization and the theoretical concern that this increase may amplify the risk of perinatal transmission, pregnant women should receive adequate antiretroviral therapy before immunizations.231 Cervical cytology and, if indicated, Neisseria gonorrhoeae and Chlamydia trachomatis testing should be collected with the pelvic examination. Routine screening and treatment of bacterial vaginosis in HIV-infected pregnant women should be considered as bacterial vaginosis appears to be more frequent in HIV-infected women, and it increases the potential for postoperative infections.232–235 Baseline neurologic function and funduscopic examination should be documented. Although not routinely recommended for HIVuninfected pregnant women, antibody status to Toxoplasma gondii, cytomegalovirus (CMV), and herpes simplex virus should be documented in the HIV-infected woman if not done previously to assess maternal risk of symptomatic infection and potential fetal risk. In rare instances, transmission of T. gondii or CMV from an HIV-infected mother with previously documented antibody to the specific pathogen has been documented in women with severe immunosuppression.236,237 This transmission should be avoided by earlier initiation and optimization of maternal antiretroviral therapy. HIV-infected women are at increased risk for genital herpes seropositivity and potentially reactivation.238 Tuberculin testing should be done if not done within the past year.
History including symptoms suggestive of seroconversion illness or exposures
to HIV, hospitalizations, immunizations, previous liveborn children
who may need testing for HIV
Complete blood count, including differential and platelet count
HIV, human immunodeficiency virus.
Once the CD4+ lymphocyte count and viral load results are available, women can be counseled regarding antiretroviral therapy for maternal health and prevention of transmission. Women who are following a stable antiretroviral regimen with suppression to undetectable viral levels at the time of pregnancy diagnosis should continue this regimen unless drugs with specific concerns for teratogenicity such as efavirenz or hydroxyurea are included. If women are initiating antiretroviral therapy during pregnancy, they may choose to wait until after the first trimester to minimize risk during organogenesis. This decision depends on maternal disease stage as measured by viral load and CD4+ lymphocyte count and patient preference. Women with a CD4+ lymphocyte count below 500 cells/mL or women with a plasma HIV RNA level above 10,000 copies/mL by bDNA or 20,000 copies/mL by reverse transcriptase polymerase chain reaction should be encouraged to begin combination therapy as outlined for nonpregnant individuals to maximize their health and reduce the risk of perinatal transmission.34 Unless contraindicated because of previous toxicity or known viral resistance, zidovudine should be included in the regimen. If stavudine is included in a combination regimen during pregnancy, then zidovudine should be avoided because of the possible antagonism. Oral stavudine should be discontinued during labor and intravenous zidovudine given if not contraindicated. For women with CD4+ lymphocyte counts above 500/mL and plasma HIV RNA below 10,000 copies/mL, combination therapy should be discussed and provided if the pregnant woman chooses. Use of combination therapy to suppress the viral load below 1000 copies/mL, and ideally to undetectable levels, may further reduce the risk of perinatal transmission and obviate the need for cesarean delivery to reduce intrapartum transmission. The indications for and patient preferences for continuing combination therapy can then be reassessed after delivery in this group. If patients in this category decline combination therapy, then zidovudine monotherapy should be offered. Time-limited use of zidovudine alone for prophylaxis of transmission is controversial, but no increase in progression was seen in the short term239 or up to 4 years after delivery among women receiving zidovudine compared to placebo during pregnancy.240 Development of viral resistance was unusual among the women enrolled to PACTG 076 who all had CD4+ lymphocyte counts above 200 cells/mL at enrollment.213 For women with higher viral loads and lower CD4+ cell counts, combination therapy should be encouraged to minimize development of resistance, maternal disease progression, and perinatal transmission. Response to therapy should be monitored with repeat viral load testing 4 weeks after beginning or changing therapy. Once viral load has been suppressed to undetectable levels, levels can be monitored every 3 months. Current guidelines should be followed for changing therapy if poor response or rebound occurs.34 Women should be monitored on a regular basis for toxicity as indicated for specific drugs. A baseline sonogram should be done at 18 to 20 weeks of gestation to verify dating and rule out major anomalies. Follow-up scans in the third trimester should be considered to monitor fetal growth among women receiving antiretroviral therapy.
Adherence to the multidrug antiretroviral regimens currently in use may be more difficult in pregnancy, especially in the first trimester and the early postpartum period. If nausea and vomiting lead to the need for temporary discontinuation of medications, all antiretrovirals should be discontinued and reinstituted simultaneously to minimize the chance for development of resistance. To maximize adherence, time should be spent educating the patient regarding the goals of therapy and consequences of good compared with poor adherence.34 The treatment plan should be negotiated with the woman, not dictated. The regimen should be as simple as possible and chosen to minimize potential adverse effects. Written information regarding timing and requirements of the regimen (e.g., taking with food or on an empty stomach) should be provided. The woman's concerns regarding potential fetal effects should be addressed before starting therapy. Family, friends, and others such as case managers should be recruited if possible to help with implementation of the regimen. Indications for and patient's ability to comply with therapy should be reassessed after delivery since the loss of reduction of perinatal transmission as an impetus and the demands of newborn care may make adherence more difficult. Discontinuation of therapy for a period rather than continuation with poor adherence may decrease the chance for development of resistance and loss of agents for future therapy.
In general, prophylaxis for opportunistic infections in pregnancy should be used as it would be in nonpregnant women.241 Ideally, antiretroviral therapy would be initiated early enough to maintain the CD4+ cell count at levels above which prophylaxis is not indicated, but the same CD4+ lymphocyte counts or percents should be used as indications for therapy in the pregnant woman. Primary prophylaxis for P. carinii pneumonia should be offered to women with CD4+ lymphocyte counts below 200 cells/mL, to women with unexplained fever for 2 weeks or more, or to women with a history of oropharyngeal candidiasis. Secondary prophylaxis should be offered for all women with previous P. carinii pneumonia. Trimethoprim-sulfamethoxazole, one double-strength tablet daily, is first choice for prophylaxis in pregnancy. Alternatives include aerosolized pentamidine, 300 mg monthly via Respirgard II nebulizer, or oral dapsone 100 mg daily. Prophylaxis for Mycobacterium avium complex should be offered for CD4+ lymphocyte counts less than 50 cells/mL. Azithromycin, 1200 mg once weekly, is the first choice for therapy during pregnancy. Trimethoprim-sulfamethoxazole also provides prophylaxis against toxoplasmic encephalitis in women who are seropositive for antibodies to T. gondii. Because toxoplasmic encephalitis rarely is encountered in pregnancy, other primary prophylactic regimens, including pyrimethamine, are best avoided until after delivery. For women with previous toxoplasmic encephalitis, an appropriate prophylaxis regimen should be offered throughout pregnancy. Women with a positive tuberculin skin test without prior treatment or contact with active tuberculosis with no evidence of active disease themselves may receive isoniazid or rifampin prophylaxis during pregnancy. For women with no evidence of active tuberculosis but exposure to multidrug-resistant tuberculosis, prophylactic therapy may best be deferred until after delivery. For treatment of active tuberculosis during pregnancy, especially for multidrug-resistant tuberculosis, the regimen should be developed in consultation with obstetric and infectious disease specialists. Primary prophylaxis for other conditions including mucosal candidiasis and other fungal infections is best avoided during pregnancy. Treatment of invasive fungal disease should be provided as it would be for a nonpregnant individual. Similarly, prophylaxis for CMV disease is not recommended during pregnancy because of the potential toxicity of the drugs and limited experience with their use in pregnancy. However, for women with life-threatening or sight-threatening CMV infections during pregnancy, treatment should be provided in consultation with obstetric and infectious disease specialists.
Mode of delivery should be determined by the woman in concert with her provider, taking into account current therapy, most recent plasma HIV RNA results, and other obstetric concerns. For women who choose not to take antiretroviral therapy or who choose zidovudine monotherapy, scheduled cesarean delivery appears to offer benefit in reducing intrapartum transmission of HIV. For women who maintain plasma HIV RNA levels above 1000 copies/mL despite antiretroviral therapy, planned cesarean delivery also may reduce the risk of transmission. Rates of transmission are low for women receiving zidovudine or other therapies with HIV RNA levels below 1000 copies/mL, and it is unclear whether cesarean delivery in this situation reduces transmission further. This information should be explained to the woman, and her decision regarding mode of delivery should be respected as cesarean delivery clearly involves increased risks to the mother.
In HIV-uninfected women, cesarean delivery is associated with an increase in morbidity and mortality compared with that of vaginal delivery.242 Some of these complications are related to the indications for cesarean delivery, but much of the morbidity is related to peripartum infections. Women who undergo scheduled cesarean delivery may have a lower risk of infectious complications than those who undergo cesarean deliveries performed after labor or rupture of membranes, but HIV may confer an increased risk. Current studies evaluating the risk of complications by mode of delivery among HIV-infected women suggest a similar increase in magnitude of complications related to cesarean delivery as that seen in HIV-uninfected women. In the European randomized trial discussed above, postpartum fever occurred in two (1.1%) of 183 women delivering vaginally and in 15 (6.7%) of 225 women delivering by cesarean delivery (p = .002).104 Severe anemia occurred in two women after vaginal delivery and four women after cesarean delivery (p = .70). In an analysis of peripartum complications according to mode of delivery among the 497 women enrolled to PACTG 185, endometritis, wound infection, and pneumonia were increased among women delivered by scheduled or urgent cesarean delivery compared with vaginal delivery, but blood transfusion, urinary tract infection, or other complications were not increased.243 Complication rates were within the range reported previously among similar HIV-uninfected women, and among this cohort of women, all enrolling with a CD4+ lymphocyte count less than 500 cells/μL, complications were not related to CD4+ cell count or viral load. A similar analysis among 1186 women enrolled to the Women and Infants Transmission Study showed a significantly increased rate of postpartum fever without infection but not hemorrhage or severe anemia, endometritis, or urinary tract infection among women undergoing elective cesarean delivery compared with spontaneous vaginal delivery.244 In this analysis, increased rates of morbidity were seen with CD4+ lymphocyte percentage below 29%, and decreased rates were seen in women who used combination antiretroviral therapy. In both of these studies, cesarean delivery without labor and ruptured membranes was done for other obstetric indications such as previous cesarean delivery and not for prevention of HIV transmission, potentially resulting in higher complication rates.
In contrast to the cohort studies, three retrospective studies and one prospective case-control study have suggested an increased risk of perioperative complications among HIV-infected compared with uninfected women delivering by cesarean delivery, often after labor or ruptured membranes.245–248 In the retrospective studies, the use of postpartum antibiotics was significantly more frequent among HIV-infected compared with HIV-uninfected women, although the rate of postpartum endometritis was increased significantly in only one of the three studies. The diagnosis of wound infection was more common among HIV-infected women in two of the three studies, whereas the need for blood transfusion was not increased significantly in any of the three studies. Cases of pneumonia occurred only among HIV-infected women in all of the studies. In all three retrospective studies, complication rates were inversely related to CD4+ lymphocyte count or percentage. In the prospective study, which included 33 HIV-infected women and 168 matched control women, the risk of postpartum fever or blood transfusion was not increased significantly with HIV infection, but postpartum pneumonia was increased significantly. More advanced clinical disease (CDC category B or C) but not CD4+ lymphocyte count was associated with development of any postpartum complication in the prospective evaluation. Thus, HIV-infected women undergoing cesarean delivery should be monitored closely for development of pneumonia or other infectious complications, especially those women with low CD4+ lymphocyte counts.
Women should be counseled about the available data on the potential benefits of cesarean delivery to the infant and the risks to themselves. Antiretroviral therapy should be optimized for both maternal health and reduction of vertical transmission. There does not appear to be any benefit in reduction of transmission if cesarean delivery is done after labor or membrane rupture. If a scheduled cesarean delivery is chosen, this procedure may be scheduled at or after 38 completed weeks of gestation to minimize the chance of labor or rupture occurring before the procedure.249 If cesarean delivery is planned, intravenous zidovudine should be begun at least 3 hours before the procedure. Other antiretroviral medications should be continued orally as practical. The use of prophylactic antibiotics to reduce the risk of endometritis and wound infection should be considered, although the use of antibiotic prophylaxis in this setting has not been studied.
If vaginal delivery is chosen, intravenous zidovudine should be begun at the onset of labor, administering 2 mg/kg over 1 hour followed by a 1 mg/kg infusion until delivery. Other antiretroviral medications except for stavudine should be continued during labor. The membranes should be kept intact as long as possible and use of scalp electrodes, forceps, and vacuum extraction should be avoided if possible. Given the increased risk of genital herpes reactivation among HIV-infected women, a careful examination of the perineum and cervix should be performed to detect genital lesions at the onset of labor.238
To minimize the risk of infant inoculation with HIV, the infant should be washed thoroughly before any injections or invasive tests such as glucose levels are performed. Routine nasal gastric suction should not be performed.
The risk of exposure of an individual healthcare worker to HIV does not appear to be increased at cesarean delivery compared with vaginal delivery, although the number of people involved usually is greater.250 Universal precautions against exposure to blood-borne pathogens should be taken for all deliveries and may be implemented more easily for planned cesarean delivery.251 Potential exposure of healthcare workers should not be a factor in the decision regarding mode of delivery for an HIV-infected woman.
As discussed above, transmission of HIV by breastfeeding has been well-documented. In areas where safe alternatives are available, HIV-infected women should not breastfeed. Routine postpartum care should be provided. HIV-infected women, especially those undergoing cesarean delivery, may be at increased risk for pneumonia and should be evaluated carefully if fever develops. The postpartum period normally is one of emotional lability for many women. HIV-infected women have the added emotional burden of the uncertainty of their infants’ infection status and guilt over possible transmission. In addition, adherence to antiretroviral regimens may be especially difficult with the added demands of newborn care. Thus, adequate physical and psychosocial support for the HIV-infected woman and her newborn must be ensured.
Adequate continued medical follow-up of the woman with assessment of indications for continued antiretroviral therapy and ongoing HIV and gynecologic care must be provided. Infant follow-up for routine pediatric care, assessment of HIV infection status, and long-term toxicity monitoring must be ensured. Contraceptive plans after delivery should be discussed with the woman during pregnancy, and contraception should be provided before hospital discharge. Barrier methods of contraception are recommended to prevent HIV transmission and acquisition of other sexually transmitted diseases. If hormonal contraception is being considered, potential interaction with antiretroviral and opportunistic infection prophylaxis drugs must be assessed.34 Currently licensed nucleoside reverse transcriptase inhibitors do not appear to have significant interactions with hormonal contraceptives, but ritonavir, nelfinavir, and possibly amprenavir decrease ethinyl estradiol levels significantly and may affect contraceptive efficacy of oral contraceptives. Efavirenz and indinavir increase estradiol levels, although the significance of this finding is unclear. No data are available on potential interactions of hormonal contraceptives and saquinavir, nevirapine, or delavirdine. Rifampin and rifabutin lower hormonal levels and decrease contraceptive efficacy of oral contraceptives. Interactions of antiretroviral agents with depot medroxyprogesterone are under study, and no data are available on interactions with Norplant. Although the risk of pelvic infections and excessive bleeding among HIV-infected women using an intrauterine contraceptive device has been theorized to be increased, data have not supported an increased risk.252 Intrauterine devices can be offered to carefully selected HIV-infected women without severe immunocompromise as they are to HIV-uninfected women. Sterilization can be offered as for HIV-uninfected women.
HIV-infected pregnant women will continue to present challenges to the obstetrician/gynecologist. Although primary prevention of HIV infection in women is the ultimate goal, the obstetrician also must be able to offer state-of-the-art care to maximize the health of the mother and her fetus and infant. Providers should use the most current information available to provide the best care possible.
4. Barbacci MB, Dalabetta GA, Repke JT et al: Human immunodeficiency virus infection in women attending an inner-city prenatal clinic: Ineffectiveness of targeted screening. Sex Transm Dis 17: 122– 126, 1990
6. Lindsay MK, Adefris W, Peterson HB et al: Determinants of acceptance of routine voluntary human immunodeficiency virus testing in an inner-city prenatal population. Obstet Gynecol 78: 678– 680, 1989
10. American College of Obstetricians and Gynecologists. American Academy of Pediatrics and American College of Obstetricians and Gynecologists joint statement on human immunodeficiency virus screening. Washington, DC, 1999
11. Centers for Disease Control and Prevention: Success in implementing Public Health Service Guidelines to reduce perinatal transmission of HIV: Louisiana, Michigan, New Jersey, and South Carolina, 1993, 1995, 1996. MMWR Morb Mort Wkly Rep 47:688–691, 1998
13. Donegan SP, Steger KA, Recla L et al: Seroprevalence of human immunodeficiency virus in parturients at Boston City Hospital: Implications for public health and obstetric practice. Am J Obstet Gynecol 167: 622– 629, 1992
15. Wade NA, Birkhead GS, Warren BL et al: Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med 339: 1409– 1414, 1998
16. Guay LA, Musoke P, Fleming T et al: Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354: 795– 802, 1999
21. Celum CL, Coombs RW, Lafferty W et al: Indeterminate human immunodeficiency virus type 1 Western blots: Seroconversion risk, specificity of supplemental tests, and an algorithm for evaluation. J Infect Dis 164: 656– 664, 1991
23. Tuomala RE, Kalish LA, Zorilla C et al: Changes in total, CD4+ , and CD8+ lymphocytes during pregnancy and 1 year postpartum in human immunodeficiency virus-infected women. Obstet Gynecol 89: 967– 974, 1997
24. Miotti PG, Liomba G, Dallabetta GA et al: T lymphocyte subsets during and after pregnancy: Analysis in human immunodeficiency virus type 1-infected and -uninfected Malawian mothers. J Infect Dis 165: 1116– 1119, 1992
25. Alliegro MB, Dorrucci M, Phillips AN et al: Incidence and consequences of pregnancy in women with known duration of HIV infection. Italian Seroconversion Study Group. Arch Intern Med 157: 2585– 2590, 1997
28. Burns DN, Landesman S, Minkoff H et al: The influence of pregnancy on human immunodeficiency virus type 1 infection: Antepartum and postpartum changes in human immunodeficiency virus type 1 viral load. Am J Obstet Gynecol 178: 355– 359, 1998
29. Weisser M, Rudin C, Battegay M et al: Does pregnancy influence the course of HIV infection? Evidence from two large Swiss cohort studies. J Acquir Immune Defic Syndr Hum Retrovirol 15: 404– 410, 1998
33. Centers for Disease Control and Prevention: USPHS task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR Morb Mort Wkly Rep 47 (RR-2):1–30, 1998. Updated February 2000. Available at www.atis.org
34. Centers for Disease Control and Prevention: Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR Morb Mort Wkly Rep 47 (RR-5):1–82, 1998. Updated January, 2000. Available at www.atis.org
35. Wang Y, Livingston E, Patil S et al: Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus-infected pregnant women and their neonates: An AIDS Clinical Trials Group study. J Infect Dis 180: 1536– 1541, 1999
36. Moodley J, Moodley D, Pillay K et al: Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 178: 1327– 1333, 1998
37. Mirochnick M, Fenton T, Gagnier P et al: Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis 178: 368– 374, 1998
39. Ayers KM, Clive D, Tucker WE Jr et al: Nonclinical toxicology studies with zidovudine: Genetic toxicity tests and carcinogenicity bioassays in mice and rates. Fundam Appl Toxicol 32: 148– 158, 1996
40. Olivero OA, Anderson LM, Diwan BA et al: Transplacental effects of 3'-azido-2'3'-dideoxythymidine (AZT): Tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst 89: 1602– 1608, 1997
42. Reggy AA, Rogers MF, Simonds RJ: Using 3'-azido 2'3'-dideoxythymidine (AZT) to prevent perinatal human immunodeficiency virus transmission and risk of transplacental carcinogenesis. J Natl Cancer Inst 89: 1566– 1567, 1997
43. Hanson IC, Antonelli TA, Sperling RS et al: Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol 20: 463– 467, 1999
47. Perinatal Safety Review Working Group: Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: Absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquired Immunodefic Syn 25:261–268, 2000
48. Culnane M, Fowler MG, Lee SS et al: Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. JAMA 281: 151– 157, 1999
49. Lange J, Stellato R, Brinkman K et al: Review of neurological adverse events in relation to mitochondrial dysfunction in the prevention of mother to child transmission of HIV: PETRA study. Second Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants. September 1–6, 1999, Montreal, Canada, abstract 250
55. Mayers MM, Davenny K, Schoenbaum EE et al: A prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history of intravenous drug use or of intravenous drug-using sex partners, in the Bronx, New York City. Pediatrics 88: 1248– 1256, 1991
57. Mauri A, Picciaone E, Deiana P et al: Obstetric and perinatal outcome in human immunodeficiency virus-infected pregnant women with and without opiate addiction. Europ J Obstet Gynecol Reprod Biol 58: 135– 140, 1995
62. Halsey NA, Boulos R, Holt E et al: Transmission of HIV-1 infections from mothers to infants in Haiti. Impact on childhood mortality and malnutrition. The CDC/JHU AIDS Project Team. JAMA 264: 2088– 2092, 1990
64. Lepage P, Dabis F, Hitimana D-G et al: Perinatal transmission of HIV-1: Lack of impact of maternal HIV infection on characteristics of livebirths and on neonatal mortality in Kigali, Rwanda. AIDS 5: 295– 300, 1991
66. Bulterys M, Chao A, Munyemana S et al: Maternal human immunodeficiency virus 1 infection and intrauterine growth: A prospective cohort study in Butare, Rwanda. Pediatr Infect Dis J 13: 94– 100, 1994
71. Taha TET, Dallabetta GA, Canner JK et al: The effect of human immunodeficiency virus infection on birthweight, and infant and child mortality in urban Malawi. Internatl J Epidemiol 24: 1022– 1029, 1995
76. Sutton MY, Sternberg M, Nsuami M et al: Trichomoniasis in pregnant human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women: Prevalence, risk factors, and association with low birth weight. Am J Obstet Gynecol 181: 656– 662, 1999
79. Spinillo A, Iasci A, Del Maso J et al: The effect of fetal infection with human immunodeficiency virus type 1 on birthweight and length of gestation. Europ J Obstet Gynecol Repro Biol 57: 13– 17, 1994
82. Abrams EJ, Matheson PB, Thomas PA et al: Neonatal predictors of infection status and early death among 332 infants at risk of HIV-1 infection monitored prospectively from birth. Pediatrics 96: 451– 458, 1995
84. Stratton P, Tuomala RE, Abboud R et al: Obstetric and newborn outcomes in a cohort of HIV-infected pregnant women: A report of the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 20: 179– 186, 1999
85. Lambert JS, Watts DH, Mofenson L et al: Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. AIDS 14: 1389– 1399, 2000
87. Lorenzi P, Spicher VM, Laubereau B et al: Antiretroviral therapies in pregnancy: Maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 12: F241– 247, 1998
88. Shapiro D, Tuomala R, Samelson R et al: Antepartum antiretroviral therapy and pregnancy outcomes in 462 HIV-infected women in 1998-1999 (PACTG 367). 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000, San Francisco, CA (Abstract 664)
92. Mayaux M-J, Dussaix E, Isopet J et al: Maternal virus load during pregnancy and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohort studies. J Infect Dis 175: 172– 175, 1997
97. Boyer PJ, Dillon M, Navaie M et al: Factors predictive of maternal-fetal transmission of HIV-1. Preliminary analysis of zidovudine given during pregnancy and/or delivery. JAMA 271: 1925– 1930, 1994
98. Frenkel LM, Wagner LE 2nd, Demeter LM et al: Effects of zidovudine use during pregnancy on resistance and vertical transmission of human immunodeficiency virus type 1. Clin Infect Dis 20: 1321– 1326, 1995
99. Fiscus SA, Adimora AA, Schoenbach et al: Trends in human immunodeficiency virus (HIV) counseling, testing, and antiretroviral treatment of HIV-infected women and perinatal transmission in North Carolina. J Infect Dis 180: 99– 105, 1999
101. Mayaux M-J, Teglas JP, Mandelbrot L et al: Acceptability and impact of zidovudine for prevention of mother-to-child human immunodeficiency virus transmission in France. J Pediatr 131: 857– 862, 1997
102. Mandelbrot L, Le Chenadec J, Berrebi A et al: Perinatal HIV-1 transmission: Interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. JAMA 280: 55– 60, 1998
103. The International Perinatal HIV Group: The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1: A meta-analysis of 15 prospective cohort studies. N Engl J Med 340:977–987, 1999
104. The European Mode of Delivery Collaboration: Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: A randomised clinical trial. Lancet 353:1035–1039, 1999
111. Viscarello RR, Cullen MT, DeGennaro NJ et al: Fetal blood sampling in HIV-seropositive pregnancies before elective midtrimester termination of pregnancy. Am J Obstet Gynecol 167: 1075– 1079, 1992
128. Quinn TC, Kline R, Moss MW et al: Acid dissociation of immune complexes improves diagnostic utility of p24 antigen detection in perinatally acquired human immunodeficiency virus infection. J Infect Dis 167: 1193– 1196, 1993
129. McIntosh K, Pitt J, Brambilla D et al: Blood culture in the first 6 months of life for the diagnosis of vertically transmitted human immunodeficiency virus infection. J Infect Dis 170: 996– 1000, 1994
131. Blanche S, Tardieu M, Duliege A-M et al: Longitudinal study of 94 symptomatic infants with perinatally acquired human immunodeficiency virus infection: Evidence for a bimodal expression of clinical and biological symptoms. Am J Dis Child 144: 1210– 1215, 1990
134. Parekh BS, Shaffer N, Coughlin R et al: Human immunodeficiency virus 1-specific IgA capture enzyme immunoassay for early diagnosis of human immunodeficiency virus 1 infection in infants. Pediatr Infect Dis J 12: 908– 913, 1993
137. Chuachoowong R, Shaffer N, Siriwasin W et al: Short-course antenatal zidovudine reduces both cervicovaginal human immunodeficiency virus type 1 RNA levels and risk of perinatal transmission. J Infect Dis 181: 99– 106, 2000
139. Burns DN, Landesman S, Muenz LR et al: Cigarette smoking, premature rupture of membranes and vertical transmission of HIV-1 among women with low CD4+ levels. J Acquir Immune Defic Syndr 7: 718– 726, 1994
142. Palasanthiran P, Ziegler JB, Stewart GJ et al: Breast-feeding during primary maternal human immunodeficiency virus infection and risk of transmission from mother to infant. J Infect Dis 167: 441– 444, 1993
148. Nduati RW, John GD, Richardson BA et al: Human immunodeficiency virus type 1-infected cells in breast milk: Association with immunosuppression and vitamin A deficiency. J Infect Dis 172: 1461– 1468, 1995
149. Semba RD, Kumwenda N, Hoover DR et al: Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 180: 93– 98, 1999
151. Coutsoudis A, Pillay K, Spooner E et al: Influence of infant feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: A prospective cohort study. Lancet 354: 471– 476, 1999
153. Van Dyke RB, Korber BT, Popek E et al: The Ariel Project: A prospective cohort study of maternal-child transmission of human immunodeficiency virus type 1 in the era of maternal antiretroviral therapy. J Infect Dis 179: 319– 328, 1999
159. Semba RD, Miotti PG, Chiphangwi JD et al: Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet 343: 1593– 1597, 1994
160. Burns DN, Fitzgerald G, Semba R et al: Vitamin A deficiency and other nutritional indices during pregnancy in human immunodeficiency virus infection: Prevalence, clinical correlates, and outcome. Women and Infants Transmission Study Group. Clin Infect Dis 29: 328– 334, 1999
164. Kuhn L, Bobat R, Coutsoudis A et al: Cesarean deliveries and maternal-infant HIV transmission: Results from a prospective study in South Africa. J Acquir Immune Defic Syndr Hum Retrovirol 11: 478– 483, 1996
165. Mandelbrot L, Mayaux M-J, Bongain A et al: Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: The French perinatal cohorts. Am J Obstet Gynecol 175: 661– 667, 1996
166. Kind C, Rudin C, Siegrist CA et al: Prevention of vertical transmission: Additive protective effect of elective cesarean section and zidovudine prophylaxis. AIDS 12: 205– 210, 1998
167. Dickover RE, Garratty EM, Herman SA et al: Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission: Effect of maternal zidovudine treatment on viral load. JAMA 275: 599– 605, 1996
168. Sperling RS, Shapiro DE, Coombs RW et al: Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 335: 1621– 1629, 1996
170. Burns DN, Landesman S, Wright DJ et al: Influence of other maternal variables on the relationship between maternal virus load and mother-to-infant transmission of human immunodeficiency virus type 1. J Infect Dis 175: 1206– 1210, 1997
171. Fang G, Burger H, Grimson R et al: Maternal plasma human immunodeficiency virus type 1 RNA level: A determinant and projected threshold for mother-to-child transmission. Proc Natl Acad Sci USA 92: 12100– 12104, 1995
174. Mazza C, Ravaggi A, Rodella A et al: Influence of maternal CD4 levels on the predictive value of virus load over mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). J Med Virol 58: 59– 62, 1999
175. Shaffer N, Chuachoowong R, Mock PA et al: Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomized controlled trial. Lancet 353: 773– 780, 1999
176. Lathey JL, Tsou J, Brinker K et al: Lack of autologous neutralizing antibody to human immunodeficiency virus type 1 (HIV-1) and macrophage tropism are associated with mother-to-infant transmission. J Infect Dis 180: 344– 350, 1999
182. DeRossi A, Ometto L, Masiero S et al: Viral phenotype in mother-to-child HIV-1 transmission and disease progression of vertically acquired HIV-1 infection. Acta Paediatr 421 (Suppl): 22– 28, 1997
183. Pasquier C, Cayrou C, Blancher A et al: Molecular evidence for mother-to-child transmission of multiple variants by analysis of RNA and DNA sequences of human immunodeficiency virus type 1. J Virol 72: 8493– 8501, 1998
184. Devash Y, Calvelli TA, Wood DG et al: Vertical transmission of human immunodeficiency virus is correlated with the absence of high-affinity/avidity maternal antibodies to the gp120 principal neutralizing domain. Proc Natl Acad Sci U S A 87: 3445– 3449, 1990
186. Panther LA, Tucker L, Xu C et al: Genital tract human immunodeficiency virus type 1 (HIV-1) shedding and inflammation and HIV-1 env diversity in perinatal HIV-1 transmission. J Infect Dis 181: 555– 563, 2000
188. Lallemant M, Baillou A, Lallemant-Le Coeur S et al: Maternal antibody response at delivery and perinatal transmission of human immunodeficiency virus type 1 in African women. Lancet 343: 1001– 1005, 1994
191. Khouri YF, McIntosh K, Cavacini L et al: Vertical transmission of HIV-1. Correlation with maternal viral load and plasma levels of CD4 binding site anti-gp120 antibodies. J Clin Invest 95: 732– 737, 1995
192. Robertson CA, Mok JYQ, Froebel KS et al: Maternal antibodies to gp120 V3 sequence do not correlate with protection against vertical transmission of human immunodeficiency virus. J Infect Dis 166: 704– 709, 1992
193. Xia J, Roberts CGP, Nixon DF et al: Longitudinal and cross-sectional analysis of cytotoxic T lymphocyte responses and their relationship to vertical human immunodeficiency virus transmission. J Infect Dis 178: 1317– 1326, 1998
194. Plaeger S, Bermudez S, Mikyas Y et al: Decreased CD8 cell-mediated viral suppression and other immunologic characteristics of women who transmit human immunodeficiency virus to their infants. J Infect Dis 179: 1394– 1399, 1999
198. Connor EM, Sperling RS, Gelber R et al: Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment: Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 331: 1173– 1180, 1994
199. Matheson PB, Abrams EJ, Thomas PA et al: Efficacy of antenatal zidovudine in reducing perinatal transmission of human immunodeficiency virus type 1. J Infect Dis 172: 353– 358, 1995
200. Fiscus SA, Adimora AA, Schoenbach VJ et al: Perinatal HIV infection and the effect of zidovudine therapy in transmission in rural and urban counties. JAMA 275: 1483– 1488, 1996
201. Wiktor SZ, Ekpini E, Karon J et al: Short-course zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote d'Ivoire: A randomised trial. Lancet 353: 781– 785, 1999
202. Dabis F, Msellati P, Meda N et al: 6-month efficacy, tolerance and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and Burkina Faso: A double-blind placebo-controlled multicentre trial. Lancet 353: 786– 792, 1999
204. Saba J, on behalf of the PETRA Trial Study Team: Interim analysis of early efficacy of three short ZDV/3TC combination regimens to prevent mother-to-child transmission of HIV-1: The PETRA Trial. Sixth Conference on Retroviruses and Opportunistic Infection. Chicago, IL, January 31-February 4, 1999 (abstract 57)
205. Lallemant M, Jourdain G, LeCoeurs et al: A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med 343: 982– 991, 2000
207. Jackson JB, Becker-Pergola G, Guay L et al: Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission AIDS 14:111–115, 2000
208. Beckerman KP, Benson M, Dahud S et al: Control of maternal HIV-1 disease during pregnancy. In: Conference supplement of the 12th World AIDS Conference, Geneva, June 28-July 3, 1998 (abstract 12151)
209. The Women and Infants Transmission Study Investigators: Trends in mother-to-infant transmission of HIV in the WITS cohort: Impact of 076 and HAART therapy. Presented at the Second Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants. Montreal, Canada, September 1–6, 1999 (abstract 212)
210. Stek A, Khoury M, Kramer F et al: Maternal and infant outcomes with highly active antiretroviral therapy during pregnancy. In: Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 4, 1999
211. Morris A, Zorrilla C, Vajaranant M et al: A review of protease inhibitor (PI) use in 89 pregnancies. In: Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 4, 1999
212. Helfgott A, Eriksen N, Lewis S et al: Highly active antiretroviral therapy for the prevention of perinatal HIV. Poster presentation at the Society for Maternal Fetal Medicine annual meeting, Miami Beach, Florida, January 2000 (abstract 289)
213. Eastman PS, Shapiro DE, Coombs RW et al: Maternal viral genotypic zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in Pediatric AIDS Clinical Trials Group Protocol 076. J Infect Dis 177: 557– 564, 1998
214. Welles SL, Pitt J, Colgrove R et al: HIV-1 genotypic zidovudine drug resistance and the risk of maternal-infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group. AIDS 14: 263– 271, 2000
217. Johnson VA, Woods C, Hamilton CD et al: Vertical transmission of an HIV-1 variant resistant to multiple reverse transcriptase and protease inhibitors. Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 4, 1999 (abstract 266)
218. Clarke JR, Braganza R, Mirza A et al: Rapid development of genotypic resistance to lamivudine when combined with zidovudine in pregnancy. J Med Virol 59: 364– 368, 1999
219. Hirsch MS, Brun-Vezinet F, D'Aquila RT et al: Antiretroviral drug resistance testing in adult HIV-1 infection: Recommendations of an international AIDS Society-USA panel. JAMA 283: 2417– 2426, 2000
221. Fawzi WW, Msamanga GI, Spiegelman D et al: Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1 infected women in Tanzania. Lancet 351: 1477– 1482, 1998
222. Coutsoudis A, Pillay K, Spooner E et al: Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. AIDS 13: 1517– 1524, 1999
224. Msellati P, Meda N, Leroy V et al: Safety and acceptability of vaginal disinfection with benzalkonium chloride in HIV infected pregnant women in west Africa: ANRS 049b phase II randomised, double blinded placebo controlled trial. Sex Transm Infect 75: 420– 425, 1999
227. Centers for Disease Control and Prevention: Guidelines for the use of antiretroviral agents in pediatric HIV infection. Morb Mort Wkly Rep 47 (RR-4):1–43, 1998. Updated January 2000. Available at www.atis.org
228. Dunn DT, Brandt CD, Krivine A et al: The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contribution of intrauterine and intrapartum transmission. AIDS 9: F7– 11, 1995
229. Kovacs A, Xu J, Rasheed S et al: Comparison of a rapid nonisotopic polymerase chain reaction assay with four commonly used methods for the early diagnosis of human immunodeficiency virus type 1 infection in neonates and children. Pediatr Infect Dis J 14: 948– 954, 1995
230. Centers for Disease Control and Prevention: 1995 revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR Morb Mort Wkly Rep 44:1–11, 1995
236. Scwebke K, Henry K, Balfour HH Jr et al: Congenital cytomegalovirus infection as a result of nonprimary cytomegalovirus disease in a mother with acquired immunodeficiency syndrome. J Pediatr 126: 293– 295, 1995
238. Hitti J, Watts DH, Burchett SK et al: Herpes simplex virus seropositivity and reactivation at delivery among pregnant women infected with human immunodeficiency virus-1. Am J Obstet Gynecol 177: 450– 454, 1997
239. Sperling RS, Shapiro DE, McSherry GD et al: Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 study. AIDS 12: 1805– 1813, 1998
240. Bardeguez A, Mofenson LM, Fowler MG et al: Lack of clinical or immunologic disease progression with transient use of zidovudine (ZDV) to reduce perinatal HIV transmission in PACTG 076. 12th World AIDS Conference, Geneva, Switzerland. June 28-July 3, 1998 (abstract 12233)
241. Centers for Disease Control and Prevention: 1999 USPHS/IDSA guidelines for the prevention of opportunistic infection in persons infected with human immunodeficiency virus: US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). MMWR Morb Mort Wkly Rep 48:1–66, 1999
244. Read J, Kpamegan E, Tuomala R et al: Mode of delivery and postpartum morbidity among HIV-infected women: The Women and Infants Transmission Study (WITS). In: Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 4, 1999 (abstract 683)
251. Centers for Disease Control and Prevention: Update: Universal precautions for prevention of transmission of human immunodeficiency virus, hepatitis B virus, and other bloodborne pathogens in health-care settings. MMWR Morb Mortal Wkly Rep 37:377–388, 1988