Reducing Maternal-Infant HIV Transmission

July 2006; updated June 2009

Chapter Contents

Background

Overview of Prevention of Perinatal HIV Transmission

HIV Testing during Pregnancy

HIV Education and Counseling of Pregnant Women

Rapid HIV Testing during Labor

Factors Influencing Perinatal HIV Transmission

Antiretroviral Therapy during Pregnancy

Safety and Toxicity of Antiretroviral Medications during Pregnancy

Adverse Antiretroviral Drug Events during Pregnancy

Patient Education

References

Table 1. Preclinical and Clinical Data Relevant to the Use of Antiretrovirals during Pregnancy

Table 2. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetics, Toxicity Data, and Recommendations

Table 3. Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Perinatal HIV Transmission

Table 4. Clinical Scenarios and Recommendations regarding Mode of Delivery to Reduce Perinatal HIV Transmission

Background

In the absence of antiretroviral (ARV) prophylaxis or other interventions, the rate of mother-to-child transmission (MTCT) of HIV in the United States ranges from 16% to 25%. Certain interventions, notably antiretroviral therapy (ART), are highly effective in reducing the risk of perinatal transmission of HIV. ART and may reduce the transmission rate to as low as 1.5% in selected groups. Pregnant women with HIV infection who wish to carry their pregnancies to term should be educated about the risks of perinatal HIV transmission and offered appropriate medical management and ARV medications to maintain or improve their own health and to reduce the risk of HIV transmission to their infants.

This chapter describes strategies to reduce the risk of MTCT of HIV and presents information on HIV testing during pregnancy. It is not intended to be a comprehensive discussion of these topics, and all HIV-infected pregnant women should be treated by an HIV-experienced obstetrician and an HIV specialist. For centers that do not have HIV specialists available, experts at the National Perinatal HIV Consultation and Referral Service Perinatal Hotline (888-448-8765) are available for consultation. For more information on caring for pregnant women, see chapter Care of HIV-Infected Pregnant Women .

Overview of Prevention of Perinatal HIV Transmission

In 1994, an interim analysis of the Pediatric AIDS Clinical Trial Group study 076 (PACTG 076) found that ARV treatment during pregnancy could significantly reduce the risk of HIV transmission to the infant. Pregnant women in the intervention group took zidovudine (ZDV) orally during the last weeks of pregnancy, received it intravenously during labor and delivery, and gave it to their newborns for 6 weeks. Only 7.6% of those infants were infected with HIV, compared with 22.6% of infants whose mothers in the control group did not receive ZDV. ART for pregnant women with HIV infection rapidly became the standard of care in the United States and other high-income countries. A task force of the U.S. Public Health Service (USPHS) issued recommendations in August 1994 for the use of ZDV for the reduction of perinatal transmission. Those recommendations were expanded to include guidelines for the medical management of pregnant women with HIV infection, including ARV treatment during pregnancy, as well as recommendations regarding other interventions that can further decrease transmission risk, such as cesarean section delivery. The USPHS task force now meets regularly to review and update these guidelines as new research is published and new ARV drugs are approved. These guidelines, the Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States , are available online and in print (see " References " below).

Studies subsequent to PACTG 076 in resource-limited countries as well as resource-abundant areas found that other ARV regimens also reduced the risk of HIV transmission from mother to infant. The Petra study, a placebo-controlled trial in a breast-feeding population in Uganda, South Africa, and Tanzania, found a transmission rate of 9% among women who received oral ZDV plus lamivudine (3TC) intrapartum and for 1 week postpartum and whose infants also received 1 week of ZDV/3TC, compared with a rate of 15% in the placebo group. The HIV NET 012 trial in a breast-feeding population in Uganda compared the efficacy of a single dose of nevirapine (NVP) given to the mother at the onset of labor plus a single dose given to the newborn 48 hours postpartum with oral ZDV given to the mother during labor and to the newborn. The transmission rate was 9% in the NVP arm compared with 21% in the ZDV arm. The results of this study and the low cost of NVP led a number of resource-limited countries to institute NVP prophylaxis as the standard of care for preventing MTCT of HIV. Numerous other trials have demonstrated the efficacy of various ARV strategies, combining different ARVs with different treatment durations, and given to mothers, newborns, or both, in both breast-feeding and non-breast-feeding populations. Some trials have suggested that even late ARV interventions may decrease the infant's risk of HIV infection. A retrospective study of subjects in New York found that the rate of perinatal HIV transmission was 9.3-10% if ZDV was given to both the mothers intrapartum and their newborns or only to the newborn, compared with 26.6% if no ARV medication was given. This study supports the importance of offering ARV interventions to pregnant women with HIV infection whenever they are identified.

In the United States, the PACTG 076 regimen remains the standard of care for preventing perinatal HIV transmission, and usually is incorporated into combination ARV therapy for pregnant women. For international settings, other guidelines have been developed by global agencies such as the World Health Organization (see " References " below) and by individual governments.

Unless otherwise referenced, the information in this chapter is based on the most recent USPHS perinatal guidelines available at the time this chapter was published. Readers should consult the AIDSInfo Web site ( http://aidsinfo.nih.gov ) for the most current recommendations.

HIV Testing during Pregnancy

The success of interventions to reduce the risk of perinatal HIV transmission has underscored the importance of HIV testing and counseling of all pregnant women. Interventions to prevent transmission can be effective only if women know their HIV status and have access to treatment. The USPHS first recommended universal HIV counseling and testing for pregnant women in 1995. Many nationwide professional and governmental organizations, including the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the U.S. Preventive Services Task Force, have endorsed those recommendations. Current recommendations from the U.S. Centers for Disease Control and Prevention (CDC) urge 3 approaches to HIV testing during pregnancy:

• An "opt-out" approach to HIV testing during pregnancy, whereby a pregnant woman is tested unless she specifically declines testing
• Routine testing with a rapid HIV test for women with unknown or undocumented HIV status who present in labor, in order to offer ARV prophylaxis during labor for those who test positive for HIV
• Rapid HIV testing for newborns of mothers of unknown HIV status so that they can receive postexposure ARV prophylaxis, if indicated

State laws regarding HIV testing during pregnancy vary widely, and many are under review. Clinicians should be familiar with relevant state laws regarding HIV testing during pregnancy, opt-out or consent provisions, and regulations about rapid HIV testing during the intrapartum or newborn period.

HIV Education and Counseling of Pregnant Women

Educating pregnant women about the importance of HIV testing is a critical element in preventing perinatal HIV transmission. However, extensive pretest counseling is not essential. A woman must be told that HIV testing is a standard part of prenatal care, that the clinician recommends the tests, and that all pregnant women should be tested for HIV because knowing about HIV infection is important for their health and the health of their babies. Research has shown that a provider's strong endorsement of HIV testing is a major predictor of whether a woman receives an HIV test. Testing should be voluntary and free of coercion, and a woman should know that she can decline testing without the risk of being denied care. A woman's age, cultural background, educational level, and primary language may influence her knowledge about HIV transmission and her willingness to be tested; the clinician should consider these factors carefully when providing education and information.

The following minimum information should be provided through an educational session with a health care provider or through written or electronic media (eg, brochures, videos):

• HIV is the virus that causes AIDS. Approximately 25% of women with HIV who are not treated can transmit the virus to their babies through pregnancy, during labor and delivery, or by breast-feeding.
• A woman could be at risk of HIV infection and not know it.
• Highly effective treatment can protect the infant from being infected with HIV and can improve the mother's health.
• HIV testing is recommended for all pregnant women.
• Women who decline testing will not be denied care.

Women should also be told that test results are confidential to the extent allowed by law and that medical and other services are available for women with HIV infection. Reporting requirements for the specific state should be explained.

Some states require written informed consent before an HIV test is done. Others require patient education and a chart note from the providers. More recently, states are moving to the opt-out approach, whereby a woman is informed that an HIV test will be done unless she declines. Whatever the consent process, a woman should know that an HIV test is being done and should receive at least the information outlined above.

HIV testing should be performed as early in pregnancy as possible to allow for interventions to prevent transmission and for effective management of a woman's HIV infection, if the woman is found to be HIV seropositive. Repeat HIV testing is recommended in the third trimester for women at high risk of acquiring HIV (eg, a history of injection drug use, exchange of sex for money or drugs, multiple sex partners, a partner known to be HIV infected). Any pregnant woman with signs or symptoms of seroconversion should be evaluated for acute HIV infection (see chapter Primary HIV Infection ). Some states, such as Florida, now mandate a third-trimester HIV test for all pregnant women. If a client declines testing, the clinician should inquire about her reasons and follow up at subsequent visits. If a provider is persistent, the woman may choose to have an HIV test at a later visit.

In the United States, the vast majority of pregnant women who are tested for HIV will be HIV seronegative. When giving test results to an HIV-negative woman, the clinician should take the opportunity to discuss risk-reduction strategies to help ensure that a woman remains uninfected by HIV. Women at high risk of HIV infection should be referred for more extensive counseling because recent research indicates that pregnancy may place them at greater risk of acquiring HIV infection.

Counseling a pregnant woman with a positive HIV test result requires knowledge and sensitivity. The clinician should explain that, even though the woman may feel well, she is infected with the virus. The woman should be told about the importance of medical management of HIV for her own health and for the prevention of perinatal transmission, and she should be guided to the medical and social services available in her local community. She also should be referred to an HIV obstetric specialist who can work closely with her primary obstetric and HIV providers to manage her care during the pregnancy. The patient may be surprised or shocked at the HIV diagnosis, or she may have known her status but been reluctant to disclose it. The clinician should emphasize the importance of emotional and social support, assess the patient's social support resources, and offer her referrals as needed.

Rapid HIV Testing during Labor

As discussed earlier, beginning ART during pregnancy offers the greatest chance for preventing MTCT of HIV, but interventions during the intrapartum and neonatal periods also offer opportunities to decrease the risk of HIV transmission. Rapid HIV testing for women who present in labor with unknown or undocumented HIV status can identify HIV-infected women so that interventions can be offered. Newer rapid HIV antibody tests, which are both sensitive and specific, provide results in less than 1 hour. Women who should receive HIV testing during labor include those who have had little or no prenatal care, those who were not offered testing earlier in pregnancy, those who declined previously, and those whose HIV test results are not available at the time of labor. Education and counseling for the woman in labor who needs an HIV test should incorporate the information for prenatal education discussed earlier, and give consideration to the special circumstances of labor. Special educational formats such as flip charts have been developed to help with patient education. Confidentiality should be assured for the information and consent process and for treatment. If an opt-out approach is used in the labor setting, a woman of unknown serostatus should be told that no HIV test is found on her chart, that HIV testing is part of routine care, and that she can decline if she wishes, but that experts recommend HIV testing because available interventions can decrease her baby's risk of becoming infected with HIV if she is found to be positive.

Factors Influencing Perinatal HIV Transmission

As stated earlier, the rate of MTCT in the United States ranges from 16% to 25% in the absence of ART or other interventions. Perinatal transmission is most likely to occur in the intrapartum period. Several factors influence the risk of transmission from mother to infant. The most influential factor seems to be the mother's HIV RNA level (viral load). Clinical trials and observational studies have shown a strong positive correlation between maternal HIV viral load during pregnancy or at delivery and the risk of perinatal HIV transmission, even among women treated with ARVs. Even for women with viral loads <1,000 copies/mL, for whom the risk of MTCT is lower than it is for women with higher viral loads, ARV prophylaxis is a critical factor in reducing HIV transmission. One metaanalysis found that women with HIV RNA <1,000 copies/mL who were receiving ART had a transmission rate of only 1%, compared with a 9.8% transmission rate among women taking no ARVs. For that reason, ARV prophylaxis with full suppression of HIV RNA is recommended for all pregnant women with HIV infection. Other factors associated with increased risk of perinatal transmission include chorioamnionitis, low CD4 cell count, sexually transmitted infections, illicit drug use, cigarette smoking, and unprotected sex with multiple partners.

Obstetric factors also affect the risk of HIV transmission. The risk of HIV infection increases linearly with the increased duration of ruptured membranes, although the effect of ruptured membranes in women with low viral loads is not known. Invasive procedures performed at any time during pregnancy, such as amniocentesis or placement of scalp electrodes, increase the risk by exposing the fetus to maternal blood; these procedures should be avoided. In addition, the mode of delivery, whether vaginal or cesarean section, influences the risk of HIV transmission. Cesarean section decreases the rate of perinatal infection, at least in the absence of other interventions (including ART); see " Mode of Delivery and Intrapartum Management " below for further information.

Breast-feeding increases the risk of HIV transmission by 5-20%. In the United States, where replacement foods and clean water routinely are available, women with HIV should not breast-feed. However, some women with HIV will be under tremendous cultural and family pressure to breast-feed and will need the clinician's ongoing support to use substitute formula.

Because many factors that affect the risk of perinatal HIV transmission may be modified, clinicians should educate pregnant women carefully about the importance of ARV prophylaxis and other strategies to reduce the risk of maternal-fetal transmission of HIV.

Antiretroviral Therapy during Pregnancy

The goals of ART for the pregnant woman are the same as those for any person living with HIV:

• To suppress the level of HIV to as low as possible for as long as possible
• To preserve and restore immune function
• To prolong life and improve quality of life

An additional, and crucial, goal in caring for pregnant women is to reduce the risk of perinatal HIV transmission through maximal HIV suppression. The USPHS recommendations discuss in detail the multiple issues that must be considered when balancing the woman's need for therapy for her own health and for decreasing the risk of transmission to the infant. ART is recommended for all HIV-infected pregnant women, but decisions about ART are complex and should be made by the woman and her health care provider after discussing the risks and benefits. Clinicians are urged to consult an HIV specialist as well as the most current USPHS recommendations when making therapeutic decisions. The following discussion addresses some of the issues in determining ARV treatment and is taken from the current USPHS Perinatal ARV Guidelines .

A fundamental principle of the guidelines is that therapies of known benefit should not be withheld during pregnancy unless they may cause adverse effects to the woman, fetus, or infant and these adverse effects outweigh the potential benefit to the woman. The woman's clinical, virologic, and immunologic status should be the most important factor in guiding treatment decisions. Combination therapy with 3 ARVs, including agents from at least 2 ARV classes, is the standard therapy for adults and it should be recommended to the pregnant woman. Special considerations in choosing drug regimens during pregnancy include changes in dosing requirements because of physiologic changes, the potential effects of ARVs on the woman, and the known and unknown potential effects of ARVs on the fetus or infant.

Safety and Toxicity of Antiretroviral Medications during Pregnancy

Only limited data are available on the safety of ARV drugs in pregnancy, particularly when ARVs are used in combination. The existing safety and toxicity information is derived from animal data, clinical trials, registry data, and anecdotal experience. A few drugs are of special concern when used during pregnancy (Tables 1-2). Efavirenz (Sustiva) is classified by the U.S. Food and Drug Administration (FDA) as a Pregnancy Class D drug because malformations have occurred in monkeys receiving efavirenz during the first trimester. Several cases of neural tube defects have been reported in humans after first-trimester exposure to efavirenz. Efavirenz should be avoided during the first trimester, and women taking efavirenz should be counseled about the risks and the importance of avoiding pregnancy. Use of efavirenz can be considered after the second trimester if no alternative is available. Amprenavir (Agenerase) oral solution is contraindicated during pregnancy because the high levels of propylene glycol it contains may not be metabolized well during pregnancy. The combination of didanosine (ddI) and stavudine (d4T) should be avoided unless no alternative is available. Hydroxyurea, a drug previously thought to boost the response to ARVs, is a potent teratogen in various animal species and should not be used in the first trimester. Information on ARV toxicity during pregnancy should be consulted carefully before treatment choices are made.

The USPHS Perinatal ARV Guidelines include information on each ARV drug, including preclinical and clinical data, pharmacokinetic and toxicity data, and recommendations regarding use during pregnancy. These guidelines are updated routinely as information is received (Tables 1-2). Of course, numerous other medications are contraindicated during pregnancy, and potential toxicity should be considered carefully before any medication is given to a pregnant woman.

Adverse Antiretroviral Drug Events during Pregnancy

Concerns have been raised about complications and toxicities related to ART during pregnancy. For example, a European study found an approximately 2-fold increase in risk of preterm birth among mothers who took combination therapy during pregnancy (whether started before or during pregnancy). A metaanalysis of 7 U.S. clinical trials, however, found that ARV use was not associated with preterm labor, low birth-weight, low Apgar scores, or stillbirth. Until more is known, pregnant women who are taking combination regimens should be monitored closely for complications and toxicities and should be educated about the signs of premature labor.

Nucleoside reverse transcriptase inhibitors can cause mitochondrial dysfunction with long-term use. Clinical disorders linked to mitochondrial dysfunction include symptomatic lactic acidosis and hepatic steatosis, which are seen more commonly in women than in men. Three maternal deaths were reported in the United States in women taking ARV regimens that included ddI and d4T in combination with other ARVs. Patients with lactic acidosis with hepatic steatosis often present with 1-6 weeks of symptoms including nausea, vomiting, abdominal pain, dyspnea, and weakness. Because some of the symptoms of lactic acidosis/hepatic steatosis syndrome can mimic those of pregnancy, clinicians must be alert for early signs and symptoms of lactic acidosis and evaluate them promptly. The combination of ddI and d4T should be avoided during pregnancy, and used only when other effective options are not available ( Table 2 ).

Women, including pregnant women, who begin nevirapine therapy when their CD4 count is >250 cells/µL have a 9.8 times higher incidence of hepatotoxicity than women initiated on nevirapine at lower CD4 counts. Symptoms of hepatotoxicity include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and hepatomegaly. Nevirapine should be initiated as part of an ARV regimen in pregnant women with CD4 cell counts >250 cells/µL only if the benefits clearly outweigh the risks ( Table 2 ).

Hyperglycemia, new-onset diabetes, worsening diabetes, and diabetic ketoacidosis have been reported in patients taking protease inhibitors. In addition, pregnancy itself is a risk factor for hyperglycemia. Clinicians should monitor closely the glucose level of pregnant women taking PIs and should educate them about the symptoms of hyperglycemia. (See chapter Care of HIV-Infected Pregnant Women .)

Recommendations for Antiretroviral Chemoprophylaxis to Reduce Perinatal HIV Transmission

The Perinatal HIV Working Group has offered recommendations on ARV prophylaxis to reduce perinatal HIV transmission based on 7 clinical scenarios:

• HIV-infected women of childbearing potential who are not pregnant and who have indications for initiating antiretroviral therapy
• HIV-infected women who are receiving ART and become pregnant
• HIV-infected pregnant women who have not received previous ARV therapy and have indications for ART
• HIV-infected pregnant women who have not received previous ARV therapy and do not require ARV therapy for their own health
• HIV-infected pregnant women who are ARV-experienced but not currently receiving ARV therapy during the current pregnancy
• HIV-infected women in labor who have had no previous ARV therapy
• Infants born to HIV-infected women who received no ARV therapy during pregnancy or intrapartum prior to or during labor

Recommendations for ART in these 7 clinical scenarios are listed in Table 3.

Table 3. Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Perinatal HIV Transmission

SCENARIO 1: HIV-infected woman of childbearing potential but not pregnant and who has indications for initiating ART SCENARIO 2: HIV-infected woman who is receiving ART and becomes pregnant Initiate combination ART as per adult treatment guidelines. Avoid drugs with teratogenic potential (eg, EFV) in women of childbearing age unless adequate contraception ensured. Exclude pregnancy before starting treatment with EFV. Woman: Continue current ART regimen if successfully suppressing viremia, but avoid use of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (combination d4T/ddI). HIV antiretroviral drug resistance testing is recommended if the woman has detectable viremia on therapy. In general, if woman requires treatment, ARV drugs should not be stopped during the first trimester. Continue ART regimen during intrapartum period (ZDV given as continuous infusion during labor while other ARV agents are continued orally) and postpartum. Scheduled cesarean delivery at 38 weeks gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infant: ZDV for 6 weeks started within 6 to 12 hours after birth. SCENARIO 3: HIV-infected pregnant woman who is ARV naive and has indications for antiretroviral therapy SCENARIO 4: HIV-infected pregnant woman who is ARV naive and does not require ARV treatment for her own health Woman: HIV antiretroviral drug resistance testing is recommended prior to the initiation of therapy and in the event of suboptimal viral suppression after initiation of ART. Initiate ART regimen. Avoid use of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (combination d4T/ddI). Use of ZDV as a component of the antiretroviral regimen is recommended when feasible. NVP can be used as a component of ART for women with CD4 count ≤250 cells/µL, but should be used only as a component of therapy in women with CD4 counts >250 cells/µL if the benefit clearly outweighs the risk owing to an increased risk of severe hepatic toxicity. For women who require immediate initiation of therapy for their own health, treatment should be initiated as soon as possible, including in the first trimester. Continue ART regimen during intrapartum period (ZDV given as continuous infusion during labor while other antiretroviral agents are continued orally) and postpartum. Scheduled cesarean delivery at 38 weeks gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infant: ZDV for 6 weeks started within 6 to 12 hours after birth. Woman: HIV antiretroviral drug resistance testing is recommended prior to the initiation of therapy and in the event of suboptimal viral suppression after initiation of ART. ART is recommended for prophylaxis of perinatal transmission in women who do not require treatment for their own health. Consider delaying ART initiation until after first trimester is completed. Avoid use of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (combination d4T/ddI). Use of ZDV as a component of the antiretroviral regimen is recommended when feasible. NVP should be used only as a component of therapy in women with CD4 counts >250 cells/µL if the benefit clearly outweighs the risk owing to an increased risk of severe hepatic toxicity. Use of ZDV prophylaxis alone is controversial but may be considered for those women with plasma HIV RNA levels <1,000 copies/mL on no therapy. Continue ART regimen during intrapartum period (ZDV given as continuous infusion during labor while other antiretroviral agents are continued orally). Evaluate need for continued therapy postpartum; discontinue ART unless has indications for continued therapy. If regimen includes drug with long half-life like NNRTI, consider stopping NRTIs 7 days after stopping NNRTI. (Data on this are limited.) Scheduled cesarean delivery at 38 weeks gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infant: ZDV for 6 weeks started within 6 to 12 hours after birth. SCENARIO 5: HIV-infected pregnant woman who is ARV experienced but not currently receiving ARV drugs SCENARIO 6: HIV-infected woman who has received no ARV therapy before labor Woman: Obtain full antiretroviral treatment history and evaluate need for antiretroviral treatment for own health. Perform HIV antiretroviral drug resistance testing prior to initiating repeat antiretroviral prophylaxis or therapy and in the event of suboptimal viral suppression after initiation of ART. Initiate ART, with regimen chosen based on resistance testing and prior therapy history. Avoid use of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (combination d4T/ddI). Use of ZDV as a component of the ARV regimen is recommended when feasible. NVP should be used only as a component of therapy in women with CD4 counts >250 cells/µL if the benefit clearly outweighs the risk owing to an increased risk of severe hepatic toxicity. Continue ART regimen during intrapartum period (ZDV given as continuous infusion during labor while other antiretroviral agents are continued orally). Evaluate need for continued therapy postpartum; discontinue ART unless has indications for continued therapy. If regimen includes drug with a long half-life like NNRTI, consider stopping NRTIs 7 days after stopping NNRTI. (Data on this are limited.) Scheduled cesarean delivery at 38 weeks' gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery. Infant: ZDV for 6 weeks started within 6 to 12 hours after birth. ZDV: Woman: ZDV given as continuous infusion during labor. Infant: ZDV for 6 weeks started within 6 to 12 hours after birth. OR Combination ZDV + Single-Dose NVP: Woman: ZDV given as continuous infusion during labor, plus single-dose NVP at onset of labor. Consideration should be given to adding 3TC during labor and maternal ZDV/3TC for 7 days postpartum, which may reduce development of NVP resistance. Infant: Single-dose NVP plus ZDV for 6 weeks. OR Woman: ZDV given as continuous infusion during labor. Infant: Some clinicians may choose to use ZDV in combination with additional drugs in the infant, but appropriate dosing for neonates is incompletely defined and the additional efficacy of this approach in reducing transmission is not known. Consultation with a pediatric HIV specialist is recommended. Evaluate need for initiation of maternal therapy postpartum. SCENARIO 7: Infant born to HIV-infected mother who has received no ARV therapy prior to or during labor ZDV given for 6 weeks to the infant, started as soon as possible after birth. OR Some clinicians may choose to use ZDV in combination with additional drugs, but appropriate dosing for neonates is incompletely defined and the additional efficacy of this approach in reducing transmission is not known. Consultation with a pediatric HIV specialist is recommended.

Adapted from: Centers for Disease Control and Prevention. Table 4. Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Perinatal Human Immunodeficiency Virus Type 1 (HIV-1) Transmission. In: Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States . April 29, 2009. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.

The USPHS Perinatal ARV Guidelines emphasize that the PACTG 076 regimen is effective not only for women whose clinical status is similar to that of the participants in the original study, but also for women with advanced HIV disease, low CD4 counts, and previous ZDV therapy.

Because the goals of ART for a pregnant woman are not only to maintain her health, but also to prevent transmission to her infant, the considerations regarding ART differ from those for nonpregnant adults. Because the HIV viral load strongly influences the risk of HIV transmission, a primary goal of therapy should be to suppress the viral load maximally (to undetectable levels, if possible) during pregnancy and throughout delivery; this goal guides treatment decisions. For this reason, ART is recommended for all pregnant women, regardless of their CD4 counts, HIV RNA levels, or clinical status. By contrast, for certain nonpregnant adults, specifically those with CD4 counts >350 cells/µL and without certain clinical conditions, the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents state that decisions about ART initiation should be individualized. For pregnant women, the guidelines recommend that ZDV should be included in the ARV regimen if possible, that the rest of the 3-part ZDV prophylaxis regimen used in PACTG 076 be administered intrapartum and postpartum, ie, intravenous ZDV during labor, and that ZDV be given orally to the newborn for 6 weeks. The specific ART regimen should be selected with a view to the limited information available about the efficacy and potential toxicities of ARV combinations during pregnancy. The USPHS offers recommendations on the use of specific ARV agents during pregnancy ( Table 2 ).

Mode of Delivery and Other Intrapartum Management

All pregnant women with HIV infection should receive the intrapartum and neonatal components of ZDV prophylaxis used in the PACTG 076 protocol, as outlined earlier. ZDV should be given to the woman intravenously during labor in a 1-hour initial loading dose of 2 mg per kilogram body weight followed by a continuous infusion of 1 mg/kg body weight per hour until delivery. The newborn should receive ZDV syrup at a dose of 2 mg/kg body weight per dose every 6 hours beginning 8-12 hours after birth and continuing for the first 6 weeks of life.

Early studies before the availability of viral load testing found that cesarean delivery performed before the onset of labor or rupture of membranes significantly reduced the risk of perinatal transmission. However, now that many HIV-infected pregnant women in the United States and other high-income settings are receiving combination ART, transmission rates of 1.2-1.5%, unadjusted for mode of delivery, have been reported. Because the transmission rate is so low among women taking effective ART, it is difficult to determine whether cesarean section offers any additional benefit. For women with a viral load <1,000 copies/mL, it is unlikely that cesarean section would provide additional benefit.

The American College of Obstetricians and Gynecologists recommends consideration of cesarean section at 38 weeks for HIV-infected women with a viral load >1,000 copies/mL at or near the time of delivery. The woman and her health care providers should decide about mode of delivery before the onset of labor, based on her current viral load, her health status, and discussion about other concerns. Pregnant women who have not achieved optimal virologic control, and whose viral load remains >1,000 copies/mL in the weeks before delivery, should be counseled about the risks and benefits of cesarean section. A planned cesarean section should be scheduled for 38 weeks' gestation, because the benefits of cesarean section once the membranes have ruptured are unknown. Intravenous ZDV should be started 3 hours before the scheduled cesarean section. Prophylactic antibiotics are recommended at the time of cesarean section in HIV-infected women, to decrease the risk of maternal infection. The USPHS Perinatal ARV Guidelines outline 4 scenarios in which the clinician must decide whether cesarean section is needed (Table 4). The data on the benefits of cesarean section are complex and must be balanced with the increased risk to the mother after surgery. The clinician may want to consult an obstetric/HIV specialist to discuss specific situations.

Questions remain about the management of labor when a vaginal delivery is planned. Because the duration of ruptured membranes is a risk factor for perinatal transmission, pregnant women with HIV infection should be counseled to go to a hospital for care at the first signs of labor or rupture of membranes. If the membranes rupture spontaneously before labor occurs or early in labor, the clinician should consider interventions to decrease the interval to delivery, such as administration of oxytocin. Procedures that increase the neonate's exposure to maternal blood, such as the use of scalp electrodes or artificial rupture of membranes, should be avoided.

Table 4. Clinical Scenarios and Recommendations regarding Mode of Delivery to Reduce Perinatal HIV Transmission

Mode of Delivery Clinical Scenario Recommendations Scenario A: An HIV-infected woman presenting in late pregnancy (after about 36 weeks' gestation), known to be HIV-infected but not receiving ART, and who has HIV RNA level and lymphocyte subsets pending but unlikely to be available before delivery Therapy options should be discussed in detail (see Table 2 ). The woman should be started on ART. The woman should be counseled that scheduled cesarean section is likely to reduce the risk of transmission to her infant. She should also be informed of the increased risks to her of cesarean section, including increased rates of postoperative infection, anesthesia risks, and other surgical risks. If cesarean section is chosen, the procedure should be scheduled at 38 weeks' gestation, based on the best available clinical information. When scheduled cesarean section is performed, the woman should receive continuous intravenous ZDV infusion beginning 3 hours before surgery and her infant should receive 6 weeks of ZDV therapy after birth. Options for continuing or initiating combination ART after delivery should be discussed with the woman as soon as her viral load and lymphocyte subset results are available. Scenario B: An HIV-infected woman who initiated prenatal care early in the third trimester, is receiving highly active combination ART, and has an initial virologic response, but has HIV RNA levels that remain substantially >1,000 copies/mL at 36 weeks' gestation The current combination ARV regimen should be continued because the HIV RNA level is dropping appropriately. The woman should be counseled that, although she is responding to ART, it is unlikely that her HIV RNA level will fall below 1,000 copies/mL before delivery. Therefore, scheduled cesarean section may provide additional benefit in preventing intrapartum transmission of HIV. She also should be informed of the increased risks to her of cesarean section, including increased rates of postoperative infection, anesthesia risks, and surgical risks. If she chooses scheduled cesarean section, it should be performed at 38 weeks' gestation according to the best available gestational dating parameters, and intravenous ZDV should be begun at least 3 hours before surgery. Other ARV medications should be continued on schedule as much as possible before and after surgery. The infant should receive oral ZDV for 6 weeks after birth. The importance of adhering to therapy after delivery for the woman's own health should be emphasized. Scenario C: An HIV-infected woman taking combination ART with an undetectable HIV RNA level at 36 weeks' gestation The woman should be counseled that her risk of perinatal transmission of HIV with a persistently undetectable HIV RNA level is low, probably 2% or less, even with vaginal delivery. There is no information currently available to evaluate whether performing a scheduled cesarean section will decrease her risk further. Cesarean section increases the risk of complications for the woman as compared with vaginal delivery, and these risks must be balanced against the uncertain benefit of cesarean section in this case. Scenario D: An HIV-infected woman who has opted for scheduled cesarean section but presents in early labor or shortly after rupture of membranes Intravenous ZDV should be started immediately because the woman is in labor or has ruptured membranes. If labor is progressing rapidly, the woman should be allowed to deliver vaginally. If cervical dilatation is minimal and a long period of labor is anticipated, some clinicians may choose to administer the loading dose of intravenous ZDV and proceed with cesarean section to minimize the duration of membrane rupture and avoid vaginal delivery. Others might begin oxytocin augmentation to enhance contractions and potentially expedite delivery. If the woman is allowed to labor, scalp electrodes and other invasive monitoring and operative delivery should be avoided if possible. The infant should be treated with 6 weeks of ZDV therapy after birth.

Adapted from: Centers for Disease Control and Prevention. Table 7. Clinical Scenarios and Recommendations Regarding Mode of Delivery to Reduce Perinatal Human Immunodeficiency Virus Type 1 (HIV-1) Transmission. In: Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States . October 12, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9. Key to abbreviations: ART = antiretroviral therapy; PACTG 076 = Pediatric AIDS Clinical Trial Group study 076; ZDV = zidovudine; ARV = antiretroviral.

Postpartum Follow-Up of the Woman with HIV Infection

Women with HIV infection who have delivered recently need access to a comprehensive array of services for themselves and their infants. The clinician should refer the postpartum woman not only to her primary obstetric and HIV providers for family planning and HIV management, but also to a pediatric HIV specialist for care for her infant. She should also be referred as needed for mental health, substance abuse, and social support services. The clinician should be alert for indications of postpartum depression and should offer treatment promptly. Adherence to ARV regimens may be particularly difficult in the immediate postpartum period because of the physical changes postpartum and the demands of a new baby.

Women should be evaluated for their ongoing need for ART postpartum. If ART was given only or primarily to reduce the risk of perinatal transmission, and the woman's CD4 count has always been >350 cells/µL, the woman and her clinician may wish to consider discontinuing therapy after pregnancy, with the option to resume ART when she meets the criteria for treatment. On the other hand, for women with a CD4 nadir <350 cells/µL or a history of symptoms caused by HIV, long-term ART should be recommended.

In discontinuing ART, all drugs should be stopped at once if they have similar half-lives. If an NNRTI is in the regimen, it should be discontinued a short time (eg, 7 days) before the other ARVs, to decrease the risk of developing resistance to the NNRTI.

Follow-Up of the HIV-Exposed Infant

The HIV-exposed infant should be referred to a pediatric HIV specialist for diagnostic testing and monitoring of health status. Newborns should be discharged home with a supply of ZDV oral syrup. The newborn should receive ZDV syrup at a dose of 2 mg/kg body weight per dose every 6 hours beginning 8-12 hours after birth and continuing for 6 weeks.

Traditional HIV antibody testing cannot be used with infants because maternal antibodies may persist for up to 18 months. Diagnosis of HIV infection in infants requires virologic testing with HIV DNA polymerase chain reaction (PCR) or HIV RNA PCR. The DHHS Pediatric ARV Guidelines recommend testing at birth to 14 days, at 1-2 months, and at 3-6 months. HIV DNA PCR is a sensitive test that detects viral DNA in the patient's peripheral monocytes. Although the sensitivity of DNA PCR is <40% if performed <48 hours after birth, by 2-4 weeks of age, the sensitivity is >90%. HIV RNA PCR detects extracellular viral RNA in the plasma and is as sensitive as DNA PCR for early diagnosis in infants. Some clinicians recommend using the HIV RNA assay as a confirmatory test for an infant with a positive DNA PCR result. This approach confirms the diagnosis and can help guide treatment decisions. HIV viral culture is also sensitive, but it is expensive and results may not be available for 2-4 weeks.

HIV can be diagnosed in an infant on the basis of 2 positive virologic tests done on separate blood samples at any time. HIV reasonably can be excluded in an infant with 2 negative virologic tests done at >1 month of age, with 1 being done at >4 months of age. Antibody testing is recommended at age 12-18 months to document seroreversion.

Infants should have a baseline complete blood count and should be monitored for anemia while they are taking ZDV. The DHHS Perinatal ARV Guidelines recommend Pneumocystis jiroveci pneumonia (PCP) prophylaxis for HIV-exposed infants beginning at 6 weeks (when the ZDV is completed) and continuing until age 6 months or until HIV infection can be ruled out.

Parents and family care givers need to be educated that the infant must be monitored closely until an HIV diagnosis is made or is ruled out. They also need to know that the infant's exposure to ARV agents in utero is an important part of the infant's medical history and should be shared with future health care providers. Although no long-term consequences of ARV exposure have been confirmed, the child may be at risk of long-term problems.

Antiretroviral Pregnancy Registry

To improve tracking of pregnancy-related adverse effects and fetal effects, an Antiretroviral Pregnancy Registry has been established as a collaborative project among the pharmaceutical industry, pediatric and obstetric providers, the CDC, and the National Institutes of Health. The registry collects observational data on HIV-infected pregnant women taking ARV medications to determine whether patterns of fetal or neonatal abnormalities occur. Pregnant women taking ARVs can be placed in this confidential follow-up study by calling 800-258-4263, 8:30 am to 5:30 pm eastern time; the fax number is 800-800-1052. Information is confidential and patients' names are not used. Providers are encouraged to add to the available information on fetal risk by using this registry at first contact with a pregnant woman taking ARVs. More information can be obtained at http://www.APRegistry.com .

Patient Education

• The clinician should provide the pregnant woman with the most current information on the risk of mother-to-child HIV transmission and the importance of ARV prophylaxis.
• The clinician and the pregnant woman should have a detailed discussion about whether she needs ART for her health and the ARV regimen that would be most appropriate for her to decrease the risk of perinatal transmission.
• The clinician should review the critical importance of adherence to ARV regimens before prescribing a regimen.
• Once a regimen is begun, the clinician should review possible adverse effects of the drugs and give the woman specific instructions about managing them if they are mild or getting medical advice if they represent a more serious adverse effect, such as ongoing fatigue, persistent nausea and vomiting, or signs of hyperglycemia.
• Early in the third trimester, the clinician and patient should discuss the risks and potential benefits of cesarean section based on her viral load and clinical status.
• Intrapartum management, including intrapartum ZDV, should be discussed with the patient so that she knows that she should tell the delivery team about her HIV status when she presents in labor.
• The signs of early labor should be explained to the pregnant woman and she should know that she should seek care immediately if her membranes rupture or she believes she is in labor.
• The clinician should discuss infant feeding plans with the mother and reinforce that she should not breast-feed. The clinician may need to provide ongoing support for formula feeding.
• The clinician should discuss follow-up plans and make referrals for the pregnant woman and her infant. If at all possible, the woman should meet the pediatric HIV team before delivery or in the postpartum period. The importance of ARV prophylaxis and follow-up for the newborn should be stressed.

References

• American Academy of Pediatrics. Human immunodeficiency virus screening. Joint statement of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists . Pediatrics. 1999 Jul;104(1 Pt 1):128.
• American College of Obstetricians and Gynecologists. Prenatal and perinatal human immunodeficiency virus testing: expanded recommendations . ACOG Committee Opinion No. 304. Washington, DC: The American College of Obstetricians and Gynecologists; 2004. [Registration required.]
• American College of Obstetricians and Gynecologists. Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection . ACOG Committee Opinion No. 234. Washington, DC: The American College of Obstetricians and Gynecologists; 2000. [Registration required.]
• Anderson JE, Koenig LJ, Lampe MA, et al. Achieving universal HIV screening in prenatal care in the United States: provider persistence pays off . AIDS Patient Care STDS. 2005 Apr;19(4):247-52.
• Anderson JR. HIV and Reproduction. In: Anderson JR, ed. A Guide to the Clinical Care of Women with HIV, 2005 Edition . Rockville, MD: Health Services and Resources Administration; 2005. Available online at hab.hrsa.gov/publications/womencare05.
• Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2003. Wilmington, NC: Registry Coordinating Center; 2003. Accessed March 23, 2006.
• Bulterys M, Jamieson D, O'Sullivan MJ, et al. Rapid HIV-1 testing during labor: a multicenter study . JAMA. 2004 Jul 14;292(2):219-23.
• Centers for Disease Control and Prevention. U.S. Public Health Service recommendations for human immunodeficiency virus counseling and voluntary testing for pregnant women . MMWR Recomm Rep. 1995 Jul 7;44(RR-7):1-15.
• Centers for Disease Control and Prevention. Rapid HIV-1 Antibody Testing during Labor and Delivery for Women of Unknown HIV Status: A Practical Guide and Model Protocol . January 30, 2004. Available online at www.cdc.gov/hiv/rapid_testing/rt-labor&delivery.htm.
• Centers for Disease Control and Prevention. Advancing HIV prevention: new strategies for a changing epidemic--United States, 2003 . MMWR. 2003 Apr 18;52(15):329-32. Available online at www.cdc.gov/mmwr/preview/mmwrhtml/mm5215a1.htm.
• Centers for Disease Control and Prevention. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States . April 29, 2009. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.
• Centers for Disease Control and Prevention. Revised recommendations for HIV screening of pregnant women . MMWR Recomm Rep. 2001 Nov 9;50(RR-19):63-85. Available online at www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a2.htm.
• Centers for Disease Control and Prevention. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus . MMWR Recomm Rep. 1994 Aug 5;43(RR-11):1-20.
• Chou R, Smits AK, Huffman LH, et al. Prenatal screening for HIV: A review of the evidence for the U.S. Preventive Services Task Force . Ann Intern Med. 2005 Jul 5;143(1):38-54.
• 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. 1994 Nov 3;331(18):1173-80.
• Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission . J Acquir Immune Defic Syndr. 2002 Apr 15;29(5):484-94.
• European Collaborative Study, Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy . AIDS. 2000 Dec 22;14(18):2913-20.
• Fowler MG, Simonds RJ, Roongpisuthipong A. Update on perinatal HIV transmission . Pediatr Clin North Am. 2000 Feb;47(1):21-38.
• Garcia PM, Kalish LA, Pitt J. et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission . Women and Infants Transmission Study Group. N Engl J Med. 1999 Aug 5;341(6):394-402.
• Gray RH, Li X, Kigozi G, et al. Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study . Lancet. 2005 Oct 1;366(9492):1182-8.
• Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial . Lancet. 1999 Sep 4;354(9181):795-802.
• Institute of Medicine, Committee on Perinatal Transmission of HIV, Commission on Behavioral and Social Sciences and Education, et al. Stoto M, Almario D, McCormick M, eds. Reducing the Odds: Preventing Perinatal Transmission of HIV in the United States. Washington, DC: National Academy Press; 1999.
• International Perinatal HIV Group. Duration of ruptured membranes and vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort studies . AIDS. 2001 Feb 16;15(3):357-68.
• Ioannidis JP, Abrams EJ, Ammann A, et al. (2001). Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml . J Infect Dis. 2001 Feb 15;183(4):539-45.
• Kourtis AP, Bulterys M, Nesheim SR, et al. Understanding the timing of HIV transmission from mother to infant . JAMA. 2001 Feb 14;285(6):709-12.
• Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand . N Engl J Med. 2004 Jul 15;351(3):217-28.
• Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine . Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. 1999 Aug 5;341(6):385-93.
• Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1 . J Infect Dis. 2003 Mar 1;187(5):725-35.
• Paul SM, Burr CK, DiFerdinando GT. Updated recommendations for reducing vertical HIV transmission . N J Med. 2003 Sep;100(9 Suppl):27-31.
• Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. 2002 Apr 6;359(9313):1178-86.
• Royce, RA, Walter EB, Fernandez MI, et al. Barriers to universal prenatal HIV testing in 4 US locations in 1997 . Am J Public Health. 2001 May;91(5):727-33.
• Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group . Lancet. 1999 Mar 6;353(9155):773-80.
• 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. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group . N Engl J Med. 1996 Nov 28;335(22):1621-9.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . November 3, 2008. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7. Accessed June 15, 2009.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection . February 23, 2009. Accessed June 15, 2009.
• 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. 1998 Nov 12;339(20):1409-14.
• World Health Organization. Antiretroviral Drugs and the Prevention of Mother-to-Child Transmission of HIV Infection in Resource-Limited Settings: Recommendations for a Public Health Approach (2005 Revision)--Brief Meeting Report . Geneva: World Health Organization; June 28-29, 2005.