Perinatal HIV-1 Transmission and Mode of Delivery

Optimal medical management during pregnancy should include antiretroviral therapy to suppress plasma HIV RNA to undetectable levels. Labor and delivery management of HIV-infected pregnant women should focus on minimizing the risk for both perinatal transmission of HIV-1 and the potential for maternal and neonatal complications. In caring for the HIV-infected pregnant woman, she should be provided with the most complete and current information regarding use of antiretroviral therapy, mode of delivery, and other issues and allowed to make her own decisions. The woman's autonomy in decision making should be respected.

Several studies done before routine viral load testing and combination antiretroviral therapy consistently show that cesarean delivery performed before the onset of labor and rupture of membranes (elective or scheduled cesarean) was associated with a significant decrease in perinatal HIV-1 transmission compared to other types of delivery, with reductions ranging from 55-80%. Pertinent data on transmission rates according to receipt of ZDV or not are summarized in Table 5.

The observational data included individual patient data from 15 prospective cohort studies, including more than 7,800 mother-child pairs, analyzed in a meta-analysis (124). In this meta-analysis, the rate of perinatal HIV-1 transmission in women undergoing elective cesarean delivery was significantly decreased compared to similar women having either non-elective cesarean or vaginal delivery, whether or not they received ZDV. In an international randomized trial of mode of delivery, transmission was 1.8% in women randomized to elective cesarean delivery; many of these women received ZDV (125). While the magnitude of the reduction in transmission after elective cesarean section compared to vaginal delivery among women receiving ZDV in the randomized trial was similar to that seen in untreated women, this was not statistically significant. Additionally, in both studies non-elective cesarean delivery (performed after onset of labor and/or rupture of membranes) was not associated with a significant decrease in transmission compared to vaginal delivery. The American College of Obstetricians and Gynecologists’ (ACOG) Committee on Obstetric Practice, after reviewing the data, has issued a Committee Opinion concerning route of delivery (126).

Transmission, Viral Load, and Combination Antiretroviral Therapy

The studies above report on data from women not receiving combination antiretroviral therapy or undergoing routine viral load testing and which do not differentiate in utero from intrapartum transmission. Whether cesarean delivery offers any benefit to the infants of women receiving highly active combination antiretroviral regimens who have low or undetectable maternal HIV-1 RNA levels is unknown. Studies evaluating vertical transmission rates according to maternal HIV-1 RNA copy number have utilized a variety of assays with different lower limits of detection, and transmission has been reported even when maternal HIV-1 RNA levels were below assay quantification (47, 67, 127, 128). There does not appear to be a threshold of HIV RNA levels below which lack of transmission can be assured. Nevertheless, the upper limits of transmission based on the 95% CI of rates reported among women who have undetectable viral load in late pregnancy are similar to the observed rates of vertical transmission in women who receive ZDV and undergo elective cesarean delivery. Transmissions occurred among one (3.4%) of 29, 0 of 32, 0 of 107, and 0 of 198 women with undetectable viral load (500 copies/mL or less) late in pregnancy, 95% of whom were receiving at least ZDV with almost half receiving two or more antiretroviral agents (70, 71, 129, 130). It is unlikely that scheduled cesarean delivery would further reduce this low transmission rate among treated women with undetectable viral loads nor would it prevent in utero transmission. Given the variability in quantification of HIV RNA levels at low copy numbers, the variety of lower limits of quantification of the tests, and the similarly low levels of perinatal transmission of HIV at levels below 1,000 copies/mL, ACOG has chosen 1,000 copies/mL as the threshold above which to recommend cesarean delivery as an adjunct for prevention of transmission (126).

Similarly low vertical transmission rates have been observed among limited numbers of women receiving combination antiretroviral therapy during pregnancy. A few small published studies have shown transmission among one (6.7%) of 15, 0 of 30, and 0 of 24 women receiving two or more antiretroviral drugs in combination during pregnancy (20, 82, 131). Additional studies in abstract form reported no transmissions among 153 women receiving highly active combination antiretroviral therapy, while others have reported transmission rates of 1% (two of 187) and 5.8% (three of 52 women) in women receiving triple therapy including a protease inhibitor (81, 132, 133). Whether the low transmission rates on combination therapy are due to reduction in HIV-1 RNA to very low or undetectable levels or due to some other mechanism (e.g., transplacental drug passage providing pre-exposure prophylaxis to the infant) is unknown, as HIV-1 RNA levels were not reported. Thus, current data are insufficient to adequately assess whether the impact of combination antiretroviral therapy on vertical transmission is independent from its effect on viral load.

Maternal Risks by Mode of Delivery

Maternal morbidity and mortality are greater after cesarean than vaginal delivery among women not infected with HIV. Complications, especially postpartum infections, are approximately five to seven times more common after cesarean section with labor or membrane rupture compared to vaginal delivery (134, 135). Complications after scheduled cesarean delivery are intermediate between those of vaginal delivery and urgent cesarean delivery (136-140). Factors that increase the risk of postoperative complications include low socioeconomic status, genital infections, obesity or malnutrition, smoking, and prolonged labor or membrane rupture.

Complications of cesarean delivery among HIV-infected women are similar in frequency and magnitude to those reported among HIV-uninfected women. In the European mode of delivery randomized trial, there were no major complications in either group (125). However, postpartum fever occurred in two (1.1%) of 183 women who delivered vaginally and 15 (6.7%) of 225 who delivered by cesarean section (p= 0.002). Substantial postpartum bleeding and anemia occurred at similar rates in the two groups. Among the 497 women enrolled to PACTG 185, only endometritis, wound infection, and pneumonia were increased among women delivered by scheduled or urgent cesarean section, compared to vaginal delivery (141). Complication rates were within the range previously reported among similar general obstetric populations. Finally, an analysis among nearly 1,200 women enrolled in the Women and Infants Transmission Study demonstrated a significantly increased rate of postpartum fever without documented source of infection among women undergoing elective cesarean section compared to spontaneous vaginal delivery, but hemorrhage, severe anemia, endometritis or urinary tract infections were not increased (142). In the latter two studies, cesareans without labor and ruptured membranes were done for obstetrical indications such as previous cesarean section or severe pre-eclampsia and not for prevention of HIV transmission, potentially resulting in higher complication rates than might be observed for scheduled cesarean section performed solely to reduce perinatal transmission.

In contrast to the larger cohort studies discussed above, three retrospective and one prospective case-control studies have suggested an increased risk of perioperative complications among HIV-infected compared to uninfected women delivering by cesarean section, often after labor or ruptured membranes (143- 146). In the three retrospective studies, the use of postpartum antibiotics was significantly more frequent among HIV-infected compared to HIV-uninfected women, although postpartum endometritis was significantly increased in only one of the three studies. Wound infection was more common among HIV-infected women in two of the studies. Pneumonia occurred only among HIV-infected women in all of the studies. In all three retrospective studies, complication rates were inversely related to CD4+ lymphocyte count or percentage.

The prospective study of 33 HIV-infected women and 168 matched control women again showed an increase in postpartum pneumonia in HIV-infected women undergoing cesarean delivery, but no increase in postpartum fever or blood transfusion (146). More advanced clinical disease (CDC category B or C), but not CD4+ lymphocyte count (in contrast to the retrospective studies), was associated with development of any postpartum complication.

Considering current data, cesarean section compared to vaginal delivery appears to be associated with a similar magnitude of increase of complications among HIV-infected women as observed in HIV-uninfected women. While pneumonia may be more common among HIV-infected women, most data are retrospective and non-randomized and thus may be influenced by differences in diagnosis and patient populations. Complication rates in most studies are within the range reported in populations of HIV-uninfected women with similar risk factors. Risk factors for postpartum morbidity such as poor nutrition and concomitant genital infections may be especially prevalent in HIV-infected women. HIV-infected women with low CD4+ lymphocyte counts may be more prone to complications after cesarean section but also are more likely to have a reduction in transmission with cesarean section. HIV-infected women should be counseled regarding the increased risks for them associated with cesarean section.

Timing of Scheduled Cesarean Section

If the decision is made to perform a scheduled cesarean delivery to prevent HIV transmission, ACOG recommends that it be done at 38 weeks of gestation using clinical and first or second trimester ultrasonographic estimates of gestational age and avoiding amniocentesis (130). In HIV-uninfected women, current ACOG guidelines for scheduled cesarean section without confirmation of fetal lung maturity are to wait until 39 completed weeks or the onset of labor to reduce the chance of complications in the neonate (147). Cesarean delivery at 38 compared to 39 weeks entails a small absolute but significantly increased risk of development of infant respiratory distress requiring mechanical ventilation (148, 149). This increased risk must be balanced against the potential risk for labor or membrane rupture between 38 and 39 weeks of gestation. Women should be informed of the potential risks and benefits to themselves and their infants in choosing the timing and mode of delivery.

Intrapartum Management

For a scheduled cesarean delivery, intravenous ZDV should begin three hours prior to surgery, according to standard dosing (91). Other antiretroviral medications taken during pregnancy should not be interrupted around the time of delivery, regardless of route of delivery. Because maternal infectious morbidity is potentially increased, clinicians may opt to give perioperative antimicrobial prophylaxis. There are no controlled data evaluating the efficacy of antimicrobial prophylaxis specifically in HIV-infected women undergoing scheduled operative delivery (150).

Unanswered questions remain regarding the most appropriate management of labor in cases where vaginal delivery is to be attempted. Increasing duration of membrane rupture has been demonstrated consistently to be a risk factor for perinatal transmission among women who were not receiving any antiretroviral therapy (85, 127, 151, 152). Among women receiving ZDV, some studies have shown an increased risk of transmission with ruptured membranes for four or more hours before delivery (9, 71) but others have not (70, 129). The additive risk and the critical time of ruptured membranes for perinatal HIV-1 transmission in women receiving antiretroviral therapy and with low viral loads is unknown. Obstetrical procedures increasing the risk of fetal exposure to maternal blood, such as amniocentesis and invasive monitoring, have been implicated in increasing vertical transmission rates by some but not all investigators (70, 153-155). If labor is progressing and membranes are intact, artificial rupture of membranes or invasive monitoring should be avoided. These procedures should be considered only when obstetrically indicated and the length of time for ruptured membranes or monitoring is anticipated to be short. If spontaneous rupture of membranes occurs prior to or early during the course of labor, efforts at active management of labor to decrease the interval to delivery may be employed.

In conclusion, the decision regarding mode of delivery for the HIV-infected woman is complex and influenced by many factors. The decision should be made by the woman after discussing the known and potential benefits and risks to her and her infant with her health care provider. The woman¹s decision should be respected and optimal care provided for the chosen delivery mode.

Recommendations

Counseling of HIV-infected pregnant women regarding risks for vertical transmission of HIV to the fetus/neonate, should take into consideration the following:

• Efforts to maximize the health of the pregnant woman, including the provision of highly active combination antiretroviral therapy, can be expected to correlate with both reduction in viral load and low rates of vertical transmission. At a minimum for the reduction of perinatal HIV transmission, ZDV prophylaxis according to the PACTG 076 regimen is recommended unless the woman is intolerant of ZDV.
• Plasma HIV-1 RNA levels should be monitored during pregnancy according to the guidelines for management of HIV-infected adults. The most recently determined viral load value should be used when counseling a woman regarding mode of delivery.
• Perinatal HIV-1 transmission is reduced by scheduled cesarean section among women on no antiretroviral therapy or on ZDV for prophylaxis of perinatal transmission with unknown HIV RNA levels. Plasma HIV RNA levels were not available in these studies to assess the potential benefit among women with low plasma HIV RNA levels.
• Women with HIV-1 RNA levels greater than 1,000 copies/mL should be counseled regarding the benefit of scheduled cesarean delivery in reducing the risk of vertical transmission.
• Data are insufficient to evaluate the potential benefit of cesarean section for neonates of antiretroviral-treated women with plasma HIV-1 RNA levels below 1,000 copies/mL. Given the low rate of transmission among this group, it is unlikely that scheduled cesarean section would confer additional benefit in reduction of transmission.
• Data are insufficient to address the question of whether performing a cesarean section shortly after the onset of labor or after very short duration of membrane rupture to shorten labor and avoid vaginal delivery would decrease the risk of vertical transmission of HIV. Management of women originally scheduled for cesarean section who present with ruptured membranes must be individualized based on duration of rupture, progress of labor, plasma HIV RNA level, current antiretroviral therapy, and other clinical factors.
• Women should be informed of the risks associated with cesarean delivery, and these risks to the woman should be balanced with potential benefits expected for the neonate.
• Women should be counseled regarding the limitations of the current data. The woman's autonomy to make an informed decision regarding route of delivery should be respected and honored.

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