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Am Fam Physician. 1998;58(1):261-263

The Public Health Service has updated the 1994 guidelines for the use of zidovudine (Retrovir) to reduce the risk for perinatal transmission of human immunodeficiency virus (HIV). The new report is intended to help health care professionals educate pregnant women with HIV infection about the use of zidovudine and other antiretroviral drugs during pregnancy. The report was published in the January 30, 1998, issue of Morbidity and Mortality Weekly Report recommendations and reports series (MMWR Morb Mortal Wkly Rep 1998;[RR-2]:1–30).

The guidelines contain background information; considerations and general principles regarding the use of antiretroviral drugs during pregnancy; recommendations for antiretroviral chemoprophylaxis to reduce perinatal HIV transmission; recommendations for monitoring women and their infants; and a discussion of future research needs. The report also includes four clinical scenarios describing various circumstances that commonly occur in clinical practice (see table) and the factors influencing treatment considerations.

Clinical scenarioRecommendations
HIV-infected pregnant women who have not received prior antiretroviral therapy.HIV-infected pregnant women must receive standard clinical, immunologic and virologic evaluation. Recommendations for initiation and choice of antiretroviral therapy should be based on the same parameters used for persons who are not pregnant, although the known and unknown risks and benefits of such therapy during pregnancy must be considered and discussed.
The three-part ZDV chemoprophylaxis regimen should be recommended for all HIV-infected pregnant women to reduce the risk for perinatal transmission.
The combination of ZDV chemoprophylaxis with additional antiretroviral drugs for treatment of HIV infection should be (a) discussed with the woman; (b) recommended for infected women whose clinical, immunologic and virologic status indicates the need for treatment; and (c) offered to other infected women (although in the latter circumstance, it is not known if the combination of antenatal ZDV chemoprophylaxis with other antiretroviral drugs will provide additional benefits or risks for the infant).
Women who are in the first trimester of pregnancy may consider delaying initiation of therapy until after10 to 12 weeks of gestation.
HIV-infected women receiving antiretroviral therapy during the current pregnancy.HIV-infected women receiving antiretroviral therapy in whom pregnancy is identified after the first trimester should continue therapy.
For women receiving antiretroviral therapy in whom pregnancy is recognized during the first trimester, the woman should be counseled regarding the benefits and potential risks of antiretroviral administration during this period, and continuation of therapy should be considered.
If therapy is discontinued during the first trimester, all drugs should be stopped and reintroduced simultaneously to avoid the development of resistance.
If the current therapeutic regimen does not contain ZDV, the addition of ZDV or substitution of ZDV for another nucleoside analog antiretroviral is recommended after 14 weeks of gestation. ZDV administration is recommended for the pregnant woman during the intrapartum period and for the newborn—regardless of the antepartum antiretroviral regimen.
HIV-infected women in labor who have had no prior therapy.Administration of intrapartum intravenous ZDV should be recommended along with the six-week ZDV regimen for the newborn.
In the immediate postpartum period, the woman should have appropriate assessments (e.g., CD4 cell count and HIV RNA copy number) to determine whether antiretroviral therapy is recommended for her own health.
Infants born to mothers who have received no antiretroviral therapy during pregnancy or intrapartum.The six-week neonatal ZDV component of the ZDV chemoprophylactic regimen should be discussed with the mother and offered for the newborn.
ZDV should be initiated as soon as possible after delivery—preferably within 12 to 24 hours of birth.
Some clinicians may choose to use ZDV in combination with other antiretroviral drugs, particularly if the mother is known or suspected to have ZDV-resistant virus. However, the efficacy of this approach for prevention of transmission is unknown, and appropriate dosing regimens for neonates are incompletely defined.
In the immediate postpartum period, the woman should undergo appropriate assessment (e.g., CD4 cell count and HIV RNA copy number) to determine if antiretroviral therapy is required for her own health.

Background Information

Zidovudine is the only drug that has been shown to reduce the risk of perinatal HIV transmission. In 1994, results from the Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) showed that zidovudine chemoprophylaxis reduced perinatal transmission of HIV by nearly 70 percent. Additional data have since confirmed these results and have proved the efficacy of antiretroviral therapy in women with advanced disease, low CD4 cell counts and prior zidovudine therapy. Advances have also been made in the understanding of the pathogenesis of HIV infection and in the treatment and monitoring of HIV disease, as well as in the understanding of the pathogenesis of perinatal HIV transmission. These advances have resulted in changes in standard antiretroviral therapy for adults with HIV infection. According to the report, pregnancy is not a reason to defer standard therapy; standard antiretroviral therapy should be discussed with and offered to pregnant women with HIV infection. In addition, zidovudine chemoprophylaxis should be incorporated into the antiretroviral regimen.

Physicians considering the use of antiretroviral drugs in HIV-infected women during pregnancy must consider two issues: (1) antiretroviral treatment of HIV infection for maternal health and (2) antiretroviral chemoprophylaxis to reduce the risk of perinatal HIV transmission. The benefits must be weighed against the risks for adverse effects in the woman, the fetus and the newborn. Combination antiretroviral therapy, generally consisting of two nucleoside analog reverse transcriptase inhibitors and a protease inhibitor, is the currently recommended standard treatment for HIV-infected adults who are not pregnant. Recommendations regarding the choice of antiretroviral drugs for treatment of infected pregnant women are subject to potential changes in dosing requirements resulting from the physiologic changes associated with pregnancy and the potential short- and long-term effects of the antiretroviral drug on the fetus and the newborn, which may not be known for many antiretroviral drugs.

General Principles

The initial evaluation of a pregnant woman with HIV infection should include an assessment of disease status and recommendations regarding antiretroviral treatment or alteration of the woman's current antiretroviral regimen. The assessment should include evaluation of the degree of existing immunodeficiency, the risk for disease progression, a history of prior or current antiretroviral therapy, gestational age and supportive care needs. Decisions regarding the initiation of antiretroviral therapy or continuation of antiretroviral therapy in women currently receiving antiretroviral drugs should take into consideration the potential impact of such therapy on the fetus and the infant. In addition, use of the three-part zidovudine chemoprophylaxis regimen, alone or in combination with other antiretroviral drugs, should be discussed with and offered to all infected pregnant women to reduce the risk for perinatal HIV transmission.

Discussions regarding the use of antiretroviral drugs during pregnancy should include what is known and not known about the effects of such drugs on the fetus and the newborn, what is recommended in terms of treatment for the health of the HIV-infected woman and the efficacy of zidovudine for reduction of perinatal HIV transmission. Women should know that combination therapy may have substantial benefit for their own health but is of unknown benefit to the fetus. The hypothetical risks of these drugs during pregnancy should be placed in perspective to the proven benefits.

The final decision regarding use and choice of antiretroviral drugs is the responsibility of the woman. A decision to refuse treatment should not result in punitive action. Further, use of zidovudine alone should not be denied to a woman who only wants to reduce the risk of HIV transmission to her infant.

A long-term treatment plan should be developed after discussion between the patient and the physician. The patient should be told about the importance of adhering to the drug regimen. Support services, mental health services and drug abuse treatment may be needed. Coordination of services among prenatal care clinicians, primary care clinicians and HIV specialty care clinicians, mental health and drug abuse treatment services and public assistance programs is essential.

Counseling should include information regarding what is known about risk factors for perinatal transmission. Cigarette smoking, illicit drug use and unprotected sexual intercourse with multiple partners during pregnancy have been associated with an increased risk of perinatal HIV transmission. In addition, it is recommended that women with HIV infection refrain from breast-feeding to avoid transmission of HIV to their infants. These recommendations also should be followed by women receiving antiretroviral therapy. It is not known how effective antiretroviral therapy is for the prevention of postnatal transmission of HIV through breast milk or if chronic exposure to antiretroviral drugs excreted through breast milk is toxic.

Physicians should report all cases of prenatal exposure to antiretroviral drugs to the Antiretroviral Pregnancy Registry. The registry allows for the anonymity of patients, and birth outcome follow-up is obtained from the reporting physician. Referral should be directed to Antiretroviral Pregnancy Registry, P.O. Box 13398, Research Triangle Park, N.C. 27709-3398; telephone: 919-483-9437 or 800-722-9292, ext. 38465; fax: 919-315-8981.

Dosing Regimens

The antenatal dosing regimen in PACTG 076 was 100 mg of zidovudine administered orally five times daily. Recent data indicate that administration of zidovudine two or three times daily will maintain intracellular zidovudine triphosphate at levels comparable with those observed with more frequent dosing. Thus, the current zidovudine dosing regimen for adults is 200 mg three times daily, or 300 mg twice daily. Because the mechanism by which zidovudine reduces perinatal transmission is not known, these dosing regimens may not be as effective as that observed in the PACTG 076 trial. However, these two regimens may enhance maternal compliance.

In the PACTG 076 trial, zidovudine was administered intravenously during labor in a one-hour initial dose of 2 mg per kg of body weight followed by continuous infusion of 1 mg per kg of body weight per hour until delivery.

In the PACTG 076 trial, oral zidovudine therapy was administered to the newborn in a dosage of 2 mg per kg of body weight every six hours for the first six weeks of life, beginning eight to 12 hours after birth. Intravenous dosage for infants who cannot tolerate oral intake is 1.5 mg per kg of body weight every six hours. Appropriate dosing for premature infants has not been defined but is being evaluated in a Phase I clinical trial in infants who were born under 34 weeks of gestation. The dosing regimen being studied is 1.5 mg per kg of body weight, administered orally or intravenously every 12 hours for the first two weeks of life; for infants two to six weeks of age, the dosage is increased to 2 mg per kg of body weight every eight hours.

The clinical scenarios are presented in the table. Complete discussions of the scenarios are included in the MMWR document. The Centers for Disease Control and Prevention emphasizes that these scenarios are only recommendations, and flexibility should be exercised according to the patient's individual circumstances.

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Copyright © 1998 by the American Academy of Family Physicians.

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