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2002 Selected Articles

Contemporary Management of Human Immunodeficiency Virus Infection During Pregnancy

Washington Clark Hill, MD; Michael K. Lindsay, MD, MPH

The dramatic reduction in the rate of perinatal human immunodeficiency virus (HIV) transmission in the United States between 1984 and 1997 represents a major public health success (Figure 1). This success is attributable to three major factors: widespread antepartum HIV counseling and testing, advances in the understanding of the timing and mechanism of perinatal transmission, and broader use of antepartum, intrapartum, and postpartum antiretroviral therapy.

FIGURE 1. Perinatally Acquired AIDS Cases,* 1984 through March 1997, United States

*Source: Update: Perinatally Acquired HIV/AIDS—United States, 1997. MMWR 1997 Nov 21;46:1088.

ANTEPARTUM TESTING AND COUNSELING

In 1995, the United States Public Health Service (USPHS) issued seven key recommendations encouraging clinicians to offer voluntary HIV counseling and testing to all pregnant women.¹ These recommendations were issued because of the encouraging results of Pediatric AIDS (Acquired Immunodeficiency Virus) Clinical Trial Group, protocol 076 (ACTG 076). This protocol evaluated the safety and efficacy of zidovudine (ZDV, AZT, Retrovir) versus placebo in HIV-infected parturients who received less than 6 months of prior antiretroviral therapy and had CD4+ cell counts greater than 200/mm.² Infected women were randomized to receive either placebo or 500 mg/d of ZDV during pregnancy, intravenous (IV) ZDV during labor, and administration of ZDV syrup to the neonate for the first 6 weeks of life. The risk of perinatal transmission was significantly lower in the treatment group than in the placebo group (8.3% versus 25.5%). Administration of the ZDV regimen resulted in a 66% reduction in the risk of perinatal transmission.²

Although routine voluntary HIV antibody counseling and testing is a sound public health strategy, it has not been successful in identifying all HIV-infected parturients. There are two major obstacles to the identification of all HIV-infected parturients. First, all pregnant women do not voluntarily consent to HIV antibody testing. Data from the Centers for Disease Control and Prevention (CDC) gathered in the 14-state Pregnancy Risk Assessment Monitoring System survey revealed that 70% of pregnant women recalled discussing HIV testing with their health care provider during prenatal care, and at least 50% reported being tested during the antepartum or intrapartum period. Test acceptance was higher in public health care settings, in patients covered by Medicaid, in blacks, and in women with low educational attainment.³

Second, women who receive no prenatal care are at high risk of being HIV-infected. Studies have shown that the HIV seroprevalence among this group is 2-fold to 3-fold higher than in women who receive prenatal care.⁴ These women place their infants at high risk of acquiring HIV infection perinatally because they receive either abbreviated courses of antiretroviral drugs or no therapy at all. In some urban medical centers, unregistered women may represent up to 20% of all women delivering. In 1998, the Institute Of Medicine (IOM) was charged with devising a prenatal testing strategy that would further decrease the rate of perinatal HIV infection in the United States by identifying and treating more HIV-infected pregnant women. After careful deliberation, the IOM endorsed a proposal calling for universal HIV testing with patient notification as a routine component of prenatal care. The proposal called for the integration of the HIV antibody test into the standard prenatal laboratory battery, eg, blood type determination, syphilis serology, hepatitis B serology. All pregnant women would be informed that HIV antibody testing would be conducted, and would have a right to refuse testing. Testing would be universal, and not based on maternal risk factors or HIV prevalence.⁵

The USPHS will soon issue updated guidelines on HIV counseling and testing in pregnancy. The major impetus for producing new guidelines is the concern by some clinicians that the current guidelines, which call for pretest counseling and written informed consent, are burdensome and serve as a disincentive to prenatal antibody testing and identification of all HIV-infected women.

TIMING AND MECHANISM OF PERINATAL TRANSMISSION

Evidence from epidemiologic studies suggests that HIV infection can be transmitted from mother to infant during the antepartum, intrapartum, and postpartum period. The majority (70% to 80%) of perinatal transmission occurs during the intrapartum period. The strongest predictor of perinatal transmission is the maternal viral load. To date, no viral load below which mother-to-child transmission does not occur has been identified. However, HIV-infected women receiving antiretroviral therapy with viral loads of less than 1,000 copies/mL appear to be at low risk of transmission. The most likely mechanism of perinatal transmission is ascending infection from the vagina through the cervix to the fetus during labor in a setting of ruptured membranes.⁶ Advances in the understanding of the timing and mechanism of perinatal transmission have been instrumental in helping to formulate current clinical management strategies. These strategies include the use of antiretroviral agents to maximally suppress viral load, modification of obstetric practices, and use of rapid HIV testing to screen women presenting for labor and delivery who received little or no prenatal care.

ANTIRETROVIRAL THERAPY

The dramatic reduction in perinatal transmission following the introduction of the ACTG 076 protocol is the basis for the current recommendation that HIV-infected women receive antiretroviral drugs in the antepartum and intrapartum period, and that therapy be provided for the newborn. Abbreviated regimens of ZDV have been shown to decrease perinatal HIV transmission, but not to the same degree as the full regimen. Data from observational studies in both the United States and the developing world have revealed that shorter drug regimens than the three-part ACTG 076 protocol are effective in reducing the risk of perinatal HIV transmission.^7-9

A retrospective cohort study from the New York State Pediatric HIV PCR Testing Service showed that the rate of perinatal HIV transmission among 939 HIV-exposed infants varied depending on the timing of ZDV administration.⁷ The study covered a 2-year period from 1995 to 1997. The authors found that when treatment was begun in the antepartum period, the transmission rate was 6.1%, compared with 10% when it was initiated during the intrapartum period, 9.3% when started neonatally within the first 48 hours of life, and 18.4% when implemented 3 days after delivery or later. In the absence of treatment, the transmission rate was 26.6%. The authors concluded that an abbreviated regimen administered up to 48 hours after delivery was effective in reducing the risk of perinatal HIV transmission.⁷

A randomized, double-blind, placebo-controlled trial of HIV-infected parturients at two hospitals in Thailand assessed an abbreviated ZDV regimen of 300 mg twice daily starting at 36 weeks’ gestation and 300 mg every 3 hours from the onset of labor to delivery.⁸ This regimen resulted in a 50% reduction in the rate of perinatal HIV transmission compared with placebo. All mothers in the trial were provided with infant formula and encouraged not to breastfeed. The authors reported that 80% of the treatment effect was explained by the lower maternal viral loads at delivery.⁸

Finally, a randomized clinical trial in Uganda compared intrapartum and neonatal single-dose nevirapine (Viramune) (200-mg dose at onset of labor, with a 2 mg/kg dose for the neonate within 72 hours after birth) with a ZDV regimen (two 300-mg doses at labor, 300 mg every 3 hours during labor, and 4 mg/kg twice daily for 7 days to the infant) among 626 HIV-positive breastfeeding mothers.⁹ The rate of mother-to-child transmission in the ZDV group was 25.1%, versus 13.1% in the nevirapine group.⁹ Nevirapine has characteristics that make it attractive for wide-scale use in the developing world. It is very effective in rapidly reducing viral load, has a long half-life (approximately 7 days), and does not require repeated dosing. Finally, it is inexpensive: the cost of the entire nevirapine regimen for patients in the trial was roughly equivalent to $4 US.

The cumulative data from these studies support the current clinical practice in the United States of offering an abbreviated ACTG 076 protocol to HIV-infected women who present late for prenatal care, who are in active labor after receiving no prenatal care, or who are identified during the immediate postpartum period. In addition, several effective antiretroviral regimens have been recommended for HIV-infected women in labor who have not received prior therapy. The regimens include:

• Single-dose nevirapine (200 mg) at the onset of labor, followed by a single dose of nevirapine (2 mg/kg) for the newborn at the age of 48 hours
• Oral ZDV and 3TC during labor, followed by 1 week of oral ZDV and lamivudine (3TC) for the newborn
• Intrapartum IV ZDV, followed by 6 weeks of ZDV for the newborn
• The two-dose nevirapine regimen, combined with intrapartum IV ZDV and 6 weeks of ZDV for the newborn.¹⁰

Although ZDV monotherapy is effective in reducing the risk of perinatal HIV transmission, it is not always effective in maximally suppressing maternal viral load. Because the current clinical standard for nonpregnant women is to offer combination antiretroviral therapy for maximum suppression of viral load, an increasing number of HIV-infected women are entering pregnancy on combination therapy. Moreover, more clinicians are prescribing combination therapy to pregnant women in an effort to optimize maternal health. Comprehensive guidelines for antiretroviral therapy in pregnancy have been published by the USPHS that emphasize the importance of including ZDV in any regimen designed to avoid perinatal transmission.¹⁰

SAFETY AND TOXICITY OF THERAPY DURING PREGNANCY

The safety of antiretroviral drugs in pregnancy has not been determined definitively. The toxic effects of antiretroviral agents are thought to be related to mitochondrial dysfunction, and include myopathy, cardiomyopathy, and hepatic dysfunction. In ACTG 076 and three additional placebo-controlled trials, the most common fetal side effect was a reversible anemia that resolved within 12 weeks. Infants enrolled in ACTG 076, who were followed as long as 6 years, revealed no difference between the ZDV and placebo group in growth, immunologic, neurologic, or neurodevelopmental characteristics. In addition, no malignancies have been detected.^11,12 A recent observational study reported a low risk of cardiac abnormalities in HIV-exposed and infected infants who received antiretroviral therapy.¹³

Five reverse transcriptase inhibitorsæefavirenz (Sustiva), stavudine (Zerit), didanosine (Videx), ZDV, and 3TCæmay be toxic to the fetus. In March 1998, the US Food and Drug Administration (FDA) issued a safety alert regarding efavirenz based on the results of a study of newborn monkeys whose mothers were exposed to this drug. Of 13 monkeys exposed to efavirenz, 3 had offspring with birth defects: one had a cleft palate, the second had microphthalmia, and the third had anencephaly. The monkeys received doses proportional to those given to humans.¹⁴ Therefore, because of its teratogenic risk, efavirenz should be used with caution during pregnancy, and should not be considered a first-line agentæespecially in the first trimester. Pregnant women who receive this drug should be referred for genetic counseling. They should receive detailed information about potential fetal risk, and all options (including pregnancy termination) should be presented.

In January 2001, the FDA and Bristol Myers Squibb issued a warning that pregnant women may be at increased risk for fatal lactic acidosis when using the combination of stavudine and didanosine with other antiretroviral agents. Severe lactic acidosis is an infrequent but well-described complication of both stavudine and didanosine.¹⁵ This combination should be prescribed for pregnant women only when the potential benefit clearly outweighs the potential risk, and by health care professionals experienced in treating HIV infection. Women who are using this combination drug therapy should be closely monitored for clinical and laboratory signs of lactic acidosis and liver damage. These complications have only been observed in women receiving extended-duration therapy (longer than 3 to 4 months) who continue therapy during pregnancy.

Finally, investigators in France recently reported 8 cases of mitochondrial toxicity in a cohort of 1,754 children with prenatal and neonatal exposure to ZDV or ZDV plus 3TC. Two of the children exposed to both drugs developed progressive neurologic disease at 4 to 5 months, and died at about 1 year of age. Among the other 6 HIV-exposed children, 3 had neurologic symptoms and 3 had biochemical abnormalities.¹⁶ The French report prompted the USPHS to convene a Nucleoside Safety Review Working Group in February 1999. The group carried out a retrospective review of 353 deaths of children in five large, prospective, perinatal US cohorts that included more than 20,000 children born to HIV-infected women. A classification system was used to ascertain possible mitochondrial signs and symptoms leading to death. A review of all deaths yielded no evidence of fatal mitochondrial toxicity in children exposed to antiretroviral therapy. Evaluation of 1,954 living HIV-exposed children did not identify any child exposed to antiretroviral drugs who had symptoms attributed to mitochondrial disease. The Working Group emphasized the importance of long-term follow-up in children exposed to antiretroviral drugs in pregnancy, and plans to conduct future analyses of this important issue.¹⁷

Although a review of current antiretroviral agents for pregnant women has been published,¹⁸ there are limited data on the safety and efficacy of combination therapy during pregnancy. Preliminary data on pregnancy outcome and perinatal transmission rate in 178 pregnant women on combination therapy revealed no documented case of perinatal HIV transmission and no evidence of neonatal or fetal side effects from antiretroviral drug use.^19,20

MATERNAL EVALUATION

All HIV-infected pregnant women should undergo a complete evaluation, including a detailed history and physical examination. In addition to the routine battery of prenatal laboratory tests, each woman should have a viral-load determination, lymphocyte subset determination, screening for other sexually transmitted diseases (STDs), hepatitis B screening, a Papanicolaou smear, and purified protein derivative (PPD) testing for tuberculosis. Clinicians providing prenatal care to infected women should have a detailed discussion with each patient about the risk of perinatal transmission and the risks and benefits of antiretroviral therapy. Two observational studies provide compelling evidence that the amount of serum HIV-RNA in a pregnant woman is the main determinant of the risk of transmission to the baby.^21,22 Viral loads should be monitored at least once per trimester, and antiretroviral therapy adjusted to achieve maximum suppression.

Women with CD4+ cell counts below 200/mm³ should be offered prophylaxis for Pneumocystis carinii pneumonia with sulfamethoxazole/trimethoprim (Bactrim). Clinical experience has shown that the theoretically increased risk of hyperbilirubinemia in the newborn should not preclude prophylaxis in these at-risk pregnancies. Women with severe immunodeficiency (CD4+ cell count below 50/mm³) should receive Mycobacterium avium complex (MAC) prophylaxis with azithromycin (Zithromax).

MODIFICATION OF OBSTETRIC PRACTICES

The majority of perinatal HIV transmission occurs during the intrapartum period. Therefore, it is important to implement management strategies during labor that will reduce this risk as much as possible. By modifying certain obstetric practices, clinicians can minimize the risk of breaks in the fetal skin that may serve as a portal for viral entry. Evidence suggests that in addition to IV ZDV, there are several other measures that can help to achieve this, including elective cesarean delivery, avoidance of invasive procedures, minimizing infant exposure to maternal blood and secretions, and determination of HIV serostatus in women who present for labor with no prenatal care.

Cesarean delivery prior to rupture of membranes appears to decrease the risk of vertical transmission. A recent meta-analysis from the International Perinatal Group suggests a role for scheduled cesarean delivery in decreasing the risk of maternal-fetal transmission compared with either vaginal or unscheduled cesarean delivery. The meta-analysis of 15 prospective cohort studies concluded that elective cesarean delivery reduced the risk of transmission of HIV-1 from mother to child, and that this benefit was independent of the effects of ZDV treatment. The meta-analysis included 8,533 mother-child pairs of HIV-infected women, and found an approximate 50% reduction in the likelihood of HIV transmission in mothers delivered by elective cesarean section after adjusting for receipt of antiretroviral therapy, maternal disease status, and infant birth weight.²³

The result of the meta-analysis prompted the American College of Obstetricians and Gynecologists to issue a committee opinion supporting prophylactic cesarean section. The opinion contained nine major recommendations:

• HIV-infected parturients with viral loads greater than 1,000 copies/mL should be counseled regarding the benefits of scheduled cesarean section to reduce the risk of transmission
• Neonates of women with high viral loads are most likely to benefit from scheduled cesarean delivery; there are insufficient data to demonstrate a benefit for neonates of women with viral loads of less than 1,000 copies/mL, and there appears to be no reduction in transmission if cesarean delivery is performed after the onset of labor or rupture of membranes
• Patient autonomy should be respected, and clinicians should honor a patient’s informed decision to undergo a trial of labor
• Patients should receive antiretroviral therapy, IV ZDV beginning 3 hours preoperatively, around the time of cesarean delivery (http://www.cdc.gov/hiv/ treatment.htm)
• Prophlyactic antibiotics should be considered because of the increased risk of morbidity
• Scheduled cesarean delivery is recommended at 38 completed weeks’ gestation to reduce the likelihood of labor or rupture of membranes
• The best clinical estimate of gestational age should be used for planning cesarean delivery; amniocentesis to determine fetal lung maturity should be avoided whenever possible
• The patient’s most recent viral load test results should be used to direct counseling regarding mode of delivery
• All women should be clearly informed of the risks associated with cesarean delivery.²⁴

Operative delivery by forceps or vacuum extraction should be used as obstetric indications dictate. Vaginal trauma should be avoided, as this could theoretically increase the risk of perinatal transmission. The routine application of a fetal scalp electrode and fetal scalp puncture for pH determinations should be avoided as well. Because the risk of transmission is increased by exposure to ruptured membranes from 4 to 12 hours, membranes should be kept intact as long as possible in women in labor, and there should be no routine artificial rupture of membranes. Universal body fluid/substance precautions should be implemented for all intrapartum patients. At delivery, the infant’s airway should be cleared by using mechanical (ie, not DeLee) suction.

Personnel in the delivery room and nursery can aid in reducing the risk of HIV transmission from mother to infant by minimizing infant exposure to infected maternal blood and secretions. All maternal body fluids should be carefully removed from the infant’s skin immediately after delivery. The baby’s skin should be carefully cleaned with soap and water as soon as possible. Suctioning of the infant’s upper respiratory tract should be atraumatic to minimize mucous membrane exposure to maternal body fluids. Potentially infected maternal blood and secretions should be removed from the newborn prior to venipuncture, injections, and application of ophthalmic prophylaxis.²⁵

HIV-infected women who have received no prenatal care may not benefit from the advances in intrapartum therapy. Clinicians have proposed that unregistered women presenting in labor be offered HIV testing using the newly available, highly sensitive and specific rapid antibody method, followed by treatment with IV ZDV if they are seropositive.²⁶ A decision analysis model to assess the cost and potential effectiveness of such a program showed that it would be both cost-saving and lead to further reduction of perinatal HIV transmission.²⁷ A voluntary rapid HIV test would allow patients to fully explore their options with regard to testing and treatment, promote earlier follow-up care, and provide both significant health benefits to women and children and economic benefits to the medical system. The logistics and feasibility of rapid HIV testing in the labor and delivery suite will be investigated in the multicentered, CDC-funded Mother Infant Rapid HIV Testing at Delivery study, which began in the fall of 2001.²⁸

POSTPARTUM CARE

HIV-infected women need assistance in the immediate postpartum period in establishing links for long-term medical care for both themselves and their newborns. Every patient should be referred for long-term management to a health care provider with expertise in the management of HIV/AIDS. Unregistered women should have a detailed history and physical examination with a viral load study, lymphocyte subset determination, and PPD test.

Comprehensive care and support services are required for every woman and her family. Prior to discharge, every patient should undergo a careful needs assessment, with emphasis on psychosocial and cultural issues. These assessments should be conducted in a nonjudgmental manner. Maternal medical services during the postpartum period should be coordinated among the obstetrician, gynecologist, and HIV specialist. Appropriate treatment and follow-up for the neonate must be ensured as well. The HIV-exposed newborn should be managed and followed by nursery personnel and a pediatrician experienced in neonatal antiretroviral protocols. Every woman should be advised to avoid breastfeeding. Patients should also be referred for gynecologic evaluation, because HIV-infected women are at increased risk for abnormal Papanicolaou tests and chronic monilial vaginitis. Finally, an appropriate method of contraception should be provided if the patient has not undergone permanent tubal sterilization. Appropriate contraceptive methods include oral contraceptives, depo-progesterone preparations or levonorgestrel implants, diaphragm, and condoms. All HIV-infected women should be encouraged to have their male partners use a condom with every episode of intercourse, as proper and consistent use of condoms affords protection against both HIV and other STDs. Use of the intrauterine device and cervical cap are not recommended because of the increased risk of bleeding and infection.

CONCLUSION

Health care providers for HIV-infected mothers and their HIV-exposed infants have played a major role in the reduction of perinatal transmission in the United States. These committed providers should be applauded for their efforts, but should not rest on their laurels. Women now constitute the subgroup with the fastest rate of increase of HIV/AIDS in this country. Therefore, all pregnant women should be offered HIV antibody testing, and those found to be seropositive should be referred to physicians who have expertise in the management of HIV infection in pregnancy. Because the clinical management of HIV-infected pregnant women is evolving rapidly, clinicians should keep abreast of emerging treatment data. A valuable resource for updated guidelines can be found on the website of the HIV/AIDS Treatment Information Service (http://www.hivatis.org). Only through the concerted efforts of obstetricians and gynecologists and their colleagues will the once seemingly unattainable goal of eliminating perinatal HIV infection be achieved.

Washington Clark Hill, MD, FACOG, is chairman, Department of obstsetrics and gynecology, and director, maternal-fetal medicine, Sarasota Memorial Hospital in Sarasota, Fla. Michael K. Lindsay, MD, MPH, FACOG, is the Luella Klein associate professor and director of the maternal-fetal medicine division in the Department of Gynecology and Obstetrics at Emory University School of Medicine in Atlanta, Ga.

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