Scenario A

Recommendation
Therapy options should be discussed in detail. The woman should be started on antiretroviral therapy including at least the PACTG 076 ZDV regimen. 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 of gestation based on the best available clinical information. When scheduled cesarean section is performed, the woman should receive continuous intravenous ZDV infusion beginning three hours before surgery and her infant should receive six weeks of ZDV therapy after birth. Options for continuing or initiating combination antiretroviral therapy after delivery should be discussed with the woman as soon as her viral load and lymphocyte subset results are available.

Discussion
This woman has characteristics similar to women enrolled to the European randomized trial and those evaluated in the meta-analysis (124, 125). In both studies, the population not on antiretroviral therapy was shown to have a significant reduction in transmission with cesarean section done before labor or membrane rupture. HIV RNA levels were not available in these studies. Without current therapy, it is unlikely that the HIV RNA level will be below 1,000 copies/mL. Even if combination therapy were begun immediately, reduction in plasma HIV RNA to undetectable levels usually takes several weeks, depending on the starting RNA level. ZDV monotherapy could be begun with subsequent antiretroviral therapy decisions after delivery based on the HIV RNA level, CD4+ lymphocyte count, and the woman's preference regarding initiation of long term combination therapy. Scheduled cesarean section and the three part PACTG 076 ZDV regimen would be expected to offer the best chance of preventing perinatal HIV transmission in this setting.

Scenario B

HIV-infected women who initiated prenatal care early in the third trimester, are receiving highly active combination antiretroviral therapy, and have an initial virologic response, but have HIV RNA levels that remain substantially over 1,000 copies/mL at 36 weeks of gestation.

Recommendation
The current combination antiretroviral regimen should be continued as the HIV RNA level is dropping appropriately. The woman should be counseled that although she is responding to the antiretroviral therapy, 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 should also 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 dating parameters, and intravenous ZDV should be begun at least three hours before surgery. Other antiretroviral medications should be continued on schedule as much as possible before and after surgery. The infant should receive oral ZDV for six weeks after birth. The importance of adhering to therapy after delivery for her own health should be emphasized.

Discussion
Current data suggest a rate of vertical transmission of HIV-1 of 1-12% (mean 5.7%) with HIV RNA levels near delivery of 1,000 to 10,000 copies/mL and a rate of 9-29% (mean 12.6%) with an HIV RNA level over 10,000 copies/mL in groups on ZDV therapy with low rates of delivery by scheduled cesarean section (47, 58, 66, 70, 71, 129). Although the woman is currently receiving combination antiretroviral therapy that may be expected to suppress her HIV RNA to undetectable levels with continued use, she is likely to continue to have detectable HIV RNA within the period of expected delivery. Scheduled cesarean section may further reduce the rate of intrapartum HIV transmission and should be recommended to women with HIV RNA levels over 1,000 copies/mL. Although there have been several publications and presentations suggesting low levels of vertical transmission of HIV-1 among pregnant women receiving combination antiretroviral therapy, each has included small numbers of women and has not included adjustment for maternal HIV RNA levels (82, 131, 132, 156). Thus, it is not clear if the impact on transmission is related to the lowering of maternal plasma HIV RNA levels, pre-exposure prophylaxis of the infant, other mechanisms, or some combination. Until further data are available to clarify, women with HIV RNA levels above 1,000 copies/mL should be offered scheduled cesarean section regardless of maternal therapy.

Regardless of mode of delivery, the woman should receive the PACTG 076 intravenous ZDV regimen intrapartum and the infant should receive ZDV for six weeks after birth. Other maternal drugs should be continued on schedule as much as possible to provide maximal effect and minimize the chance of development of viral resistance. Oral medications may be continued pre-operatively with sips of water. Medications requiring food ingestion for absorption could be taken with liquid dietary supplements, but consultation with the attending anesthesiologist should be obtained before administering in the pre-operative period. If maternal antiretroviral therapy must be interrupted temporarily in the peripartum period, all drugs (except for intrapartum intravenous ZDV) should be stopped and re-instituted simultaneously to minimize the chance of resistance developing.

Women with CD4+ lymphocyte counts below 500 cells/mL or HIV RNA levels above 10,000 copies/mL before initiation of combination therapy during pregnancy are most likely to benefit from continued antiretroviral therapy after delivery (14). Discussion regarding plans for antiretroviral therapy use after delivery should be initiated during pregnancy. If the woman elects to continue therapy after delivery, the importance of continued adherence despite the increased responsibilities of newborn care should be emphasized and any support available for the woman should be provided.

Scenario C

HIV-infected women on highly active combination antiretroviral therapy with an undetectable HIV RNA level at 36 weeks of gestation.

Recommendation
The woman should be counseled that her risk of perinatal transmission of HIV-1 with a persistently undetectable HIV RNA level is low, probably 2% or less, even with vaginal delivery. There is currently no information to evaluate whether performing a scheduled cesarean section will lower her risk further. Cesarean section has an increased risk of complications for the woman compared to vaginal delivery, and these risks must be balanced against the uncertain benefit of cesarean section in this case.

Discussion
Scheduled cesarean section has been shown to be beneficial among women on no antiretroviral therapy or on ZDV monotherapy with rates of transmission of HIV-1 of approximately 1-2% (124, 125). Maternal HIV RNA levels were not evaluated in these studies. Similar rates of transmission have been reported among women on antiretroviral therapy with undetectable HIV RNA levels near delivery (70, 71, 130). Data evaluating transmission rates among women with undetectable HIV RNA levels by mode of delivery are not currently available. While a benefit of cesarean section in reducing transmission may be present, it would be of small magnitude given the low risk of transmission among women with HIV RNA levels below 1,000 copies/mL on maternal antiretroviral therapy with vaginal delivery and must be weighed against the known increased risks to the woman with cesarean section. Cesarean section carries with it a several fold increased risk of postpartum infections including uterine infections and pneumonia, anesthesia risks, and surgical complications compared to vaginal delivery. These risks must be balanced against an uncertain benefit in reduction of transmission. However, given no data to indicate lack of benefit, if a woman chooses a scheduled cesarean section, her decision should be respected and cesarean scheduled.

If vaginal delivery is chosen, the duration of ruptured membranes should be minimized as the transmission rate has been shown to increase with longer duration of membrane rupture among predominantly untreated women (127, 151, 152) and among ZDV treated women in some (9, 71) but not all studies (70, 129). Fetal scalp electrodes and operative delivery with forceps or the vacuum extractor may increase the risk of transmission and should be avoided (153, 154). Intravenous ZDV should be given during labor, and maternal drugs should be continued on schedule as much as possible to provide maximal effect and minimize the chance of development of viral resistance, and the infant should be treated with ZDV for six weeks after birth.

Scenario D

Recommendation
Intravenous ZDV should be started immediately since 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 pitocin 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 six weeks of ZDV therapy after birth.

Discussion
No data are available to address the question of whether performing cesarean section soon after membrane rupture to shorten labor and avoid vaginal delivery would decrease the risk of vertical transmission of HIV-1. Most studies have shown the risk of transmission with cesarean section done after labor and membrane rupture for obstetrical indications to be similar to that with vaginal delivery, although the duration of ruptured membranes in these women was often longer than four hours (125, 157). As discussed in scenario #3, in studies showing an effect, the risk of transmission was twice as high among women with ruptured membranes for four or more hours before delivery compared to those with shorter durations of membrane rupture, although the risk increases continuously with increasing duration of rupture.

In the situation where elective cesarean section had been planned and the woman presents with a short duration of ruptured membranes or labor, she should be informed that the benefit of cesarean section under these circumstances is unclear and be allowed to reassess her decision. If the woman presents after four hours of membrane rupture, it is less likely that cesarean section would impact transmission of HIV-1. The woman should be informed that the benefit of cesarean section is unclear and that her risks of perioperative infection increase with increasing duration of ruptured membranes.

If cesarean section is chosen, the loading dose of ZDV should be administered while preparations are made for cesarean delivery and the infusion continued until cord clamping. Prophylactic antibiotics given after cord clamping have been shown to reduce the rate of postpartum infection among women of unknown HIV-status undergoing cesarean section after labor or rupture or membranes and should be used routinely in this setting (150). If vaginal delivery is chosen, intravenous ZDV and other antiretrovirals the woman is currently taking should be administered and invasive procedures such as internal monitoring avoided. Pitocin should be used as needed to expedite delivery.

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