The world of perinatal HIV prophylaxis seems to have breathed new life into this old surgical adage. Observational data from 15 prospective cohort studies, including more than 7800 mother-infant pairs, were examined in a meta-analysis [The International Perinatal HIV Group. N Engl J Med 1999 Apr 1;340(13):977-87].Women undergoing cesarean delivery before the onset of labor or ruptured membranes had significantly lower perinatal HIV transmission rates compared to those having vaginal delivery or C-section after labor or membrane rupture, regardless of AZT use. Subsequently, a randomized clinical trial of scheduled C-section vs. planned vaginal delivery found a transmission rate of 1.8% in women randomized to planned C-section. While the magnitude of reduction in transmission in women who received AZT and also had scheduled C-section was not statistically significant, it was similar to reductions seen in untreated women [The European Mode of Delivery Collaboration. Lancet 1999 Mar 27;353(9158):1035-9]. Overall, these studies have shown that scheduled cesarean delivery results in reductions in transmission ranging from 55-80% as compared to other types of delivery. Does this mean that planned cesarean delivery should be a routine part of the management of HIV-infected pregnant women? The answer to this question requires a careful review of the weaknesses of these studies and an analysis of other relevant concerns.

Viral Load and Transmission

These studies on mode of delivery were performed before availability or routine use of plasma viral load testing. Other studies have documented an association between plasma viral load close to the time of delivery and risk of transmission [Garcia, et al. N Engl J Med 1999 Aug 5;341(6):394-402; Mofenson, et al. N Engl J Med 1999 Aug 5;341(6):385-93], with overlap between 95% confidence intervals of transmission rates in women with undetectable viral load in late pregnancy and those rates observed in women receiving AZT and undergoing planned C-section. Nevertheless, transmission has been reported even when maternal HIV RNA levels were below the limits of quantification. It has now been shown that genital tract viral load is independently associated with vertical transmission [Chuachoowong, et al. J Infect Dis 2000 Jan;181(1):99-106] and that discordance between plasma and genital tract HIV RNA levels may sometimes occur [Hart, et al. J Infect Dis 1999 Apr;179(4):871-82; Shaheen, et al. J Hum Virol 1999 May-Jun;2(3):154-66].The presence of significant genital tract virus or the presence of other transmission cofactors may account for occasional perinatal transmission in the presence of maximally suppressed plasma viremia.

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HAART and Transmission

The studies described above were also performed before the availability or wide use of combination antiretroviral therapy, specifically highly active antiretroviral therapy (HAART). Clinical trials assessing the efficacy of HAART in preventing perinatal transmission are underway, but results are not yet available. However, several small studies that have been published or presented at conferences report a total of six cases of transmission in 461 women (1.3%) receiving two or more antiretroviral drugs in combination during pregnancy [Lorenzi, et al. AIDS 1998 Dec 24;12(18):F241-7; McGowan, et al. Obstet Gynecol 1999 Nov;94(5 Pt 1):641-6; Clarke, et al. Internat J STD AIDS 2000;11:200; Beckerman, et al. N Engl J Med 1999 Jul 15;341(3):205-6; discussion 206-7; The Women and Infants Transmission Study Investigators. XIII International AIDS Conf 2000, Abstract LBOr4; Helfgott, et al. Soc for Maternal Fetal Medicine Annual Meeting 2000, Abstract 289]. In the PACTG 076 study only 17% of the attributable effect of AZT was due to lowering of plasma viral load. It is therefore possible that antiretroviral therapy with HAART may act to lower risk of transmission through other mechanisms in addition to reduction in plasma viral load, such as providing pre- or post-exposure prophylaxis to the fetus [Sperling, et al. N Engl J Med 1996 Nov 28;335(22):1621-9].

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Maternal Morbidity

It has been clearly established that cesarean delivery is associated with greater risk with respect to both maternal morbidity and maternal mortality when compared with vaginal delivery in the general population. Complications are most common with urgent or emergent C-section or after labor onset or membrane rupture; however, even scheduled cesarean delivery carries risks greater than with vaginal delivery [Roman, et al. Obstet Gynecol 1998 Dec;92(6):945-50; McMahon, et al. N Engl J Med 1996 Sep 5;335(10):689-95]. Other factors that may increase risk of postoperative complications include low socioeconomic status, genital infections, obesity or malnutrition, and smoking, all of which may be more commonly seen in the setting of HIV infection.

Three retrospective and one prospective case-control studies have suggested an increased risk of perioperative complications among HIV-infected women compared to HIV-uninfected women delivering by C-section, often after labor or ruptured membranes [Semprini, et al. AIDS 1996;9:913; Grubert, et al. Lancet 1999 Nov 6;354(9190):1612-3; Maiques-Montesinos, et al. Acta Obstet Gynecol Scand 1999 Oct;78(9):789-92; Vimercati, et al. Eur J Obstet Gynecol Reprod Biol 2000 May;90(1):73-6]. Complications found to be increased in one or more of these studies included postpartum endometritis, wound infection, and pneumonia. More advanced clinical disease and/or lower CD4 cell count or percentage were associated with the development of complications. Larger cohort studies including only HIV-infected patients have found increased complication rates associated with cesarean delivery compared to vaginal delivery, as expected. However, complications seen with C-section were similar in frequency and magnitude to those reported among HIV-negative women [Watts, et al. Am J Obstet Gynecol 2000;173:100; Read, et al. 6th CROI 1999, Abstract 683; The European Mode of Delivery Collaboration. Lancet 1999 Mar 27;353(9158):1035-9]. A recent retrospective study at Johns Hopkins matched HIV-seronegative patients and HIV-seropositive patients undergoing C-section for other recognized risk factors for postoperative infectious morbidity. There were no significant differences found in postoperative fever or infection [Hanna, et al. Am J Obstet Gynecol 1997;176:59].

In summary, while cesarean delivery is clearly associated with increased risks over vaginal delivery, planned or scheduled C-section before labor or ruptured membranes and use of prophylactic antibiotics should minimize these risks; increased rates of complications seen in some studies comparing HIV-infected with uninfected women may not be due to HIV per se, but rather to confounding risk factors for perioperative morbidity. HIV-infected women with advanced clinical disease or low CD4 cell counts may be at increased risk for morbidity but are also at increased risk for perinatal transmission.

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Other Concerns

• One-quarter to one-third of transmissions between mother and child occur during the antepartum period rather than at the time of labor and delivery. At present there is no way to distinguish which babies have been infected via in utero exposure prior to delivery. Type of delivery, including planned or scheduled cesarean section, would not be expected to provide any protection against infection in these infants.
  
  
• In current American College of Obstetricians and Gynecologists (ACOG) guidelines for HIV-uninfected women needing scheduled cesarean section, it is recommended that C-section be performed at 39 weeks of gestation or with onset of labor, unless fetal lung maturity has been documented with amniocentesis. However, in HIV-infected women undergoing C-section for the prevention of perinatal transmission, ACOG recommends using clinical and first or second trimester ultrasonographic estimates of gestational age and proceeding with delivery at 38 weeks of gestation to minimize the risk of labor or membrane rupture prior to delivery [ACOG Committee Opinion #234, 2000]. This entails a small, but significantly increased, risk of development of infant respiratory distress secondary to lung immaturity. In women known to be HIV-infected who present late in pregnancy, most of whom have uncertain dates, this dilemma will be magnified and requires careful review and discussion, balancing risks of transmission (current antiretroviral therapy, viral load, other risk factors) with those of prematurity.
  
  
• Although the studies cited have not shown a benefit of C-section for reduction of perinatal transmission in women after onset of labor or ruptured membranes, a recent meta-analysis of 15 prospective studies, each with at least 100 mother-infant pairs and no breastfeeding, found that the likelihood of perinatal HIV transmission increased linearly with increasing duration of membrane rupture, after adjusting for mode of delivery, antiretroviral therapy, disease stage, and infant birthweight. Women with clinical AIDS were at greatest risk, with transmission occurring in two percent after two hours of membrane rupture, and increasing to 31% transmission with 24 hours of rupture [Read, et al. 7th CROI 2000, Abstract 659]. The additive risk and the critical time of ruptured membranes in women on antiretroviral therapy with low viral loads, and the potential benefit of cesarean delivery in subgroups of women with ruptured membranes is unknown.
  
  
• In extrapolating findings discussed here, all of which come from studies in developed countries, to the developing world, considerations include availability of a safe blood supply, availability of and access to antiretrovirals and antibiotics, as well as access to locations where cesarean section can be performed and trained personnel are able to perform operative delivery.
  

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Recommendations

Both ACOG and the U.S. Public Health Service have published guidelines to assist clinicians in making decisions about delivery in the setting of HIV infection. The USPHS guidelines are summarized below:

• All HIV-infected pregnant women should be counseled about the issue of mode of delivery, with full discussion of potential benefits and risks, the individual context of the woman's clinical, immunologic, and virologic parameters, as well as other potential individual factors relevant to her specific risk for transmission and/or perioperative morbidity. Current information, which changes rapidly, should be used in counseling.
  
  
• Efforts to maximize the health of the pregnant woman, including provision of HAART, is expected to lower risk of transmission. Effective antiretroviral therapy, with AZT prophylaxis according to the PACTG 076 protocol as a minimum, is recommended. AZT monotherapy should only be used in settings where antiretroviral therapy is otherwise not indicated and is being used only for perinatal prophylaxis - development of AZT resistance is a potential concern.
  
  
• Plasma HIV RNA levels should be monitored in pregnancy according to guidelines for management of HIV-infected adults. The most recently determined viral load value should be used when counseling regarding mode of delivery.
  
  
• Perinatal HIV transmission is reduced by scheduled cesarean section among women on no antiretroviral therapy or on AZT pro-phylaxis alone with unknown viral load levels.
  
  
• Women with HIV RNA levels greater than 1000 c/mL should be counseled regarding the benefit of scheduled cesarean delivery in reducing risk of perinatal transmission. The level of 1000 c/mL has been chosen because of the variability in quantification of HIV RNA at low copy numbers, the variety of lower limits of detection of the tests used in the studies, and the similarly low levels of transmission seen with plasma viral loads below 1000 c/mL.
  
  
• Data are not sufficient to evaluate potential benefit of planned C-section in women with HIV-RNA levels less than 1000 c/mL and treated with antiretroviral therapy. Given the data we have available at this time, scheduled cesarean section is unlikely to result in further reductions in transmission (probably 2% or less). In this author's opinion, the woman on HAART with low viral loads but not necessarily below 1000 c/mL may also be in this category.
  
  
• Data are insufficient to address the issue of C-section after a very short duration of membrane rupture for the purpose of reducing risk of perinatal transmission.
  
  
• If scheduled cesarean delivery is planned, it should be performed at 38 weeks gestation using the best clinical and first or second trimester ultrasonographic estimates of gestational age and avoiding amniocentesis.
  
  
• For scheduled C-section, intravenous AZT should begin three hours prior to surgery, with standard dosing according to the PACTG 076 protocol. Other antiretroviral medications taken during pregnancy should not be interrupted around the time of delivery, regardless of route of delivery.
  
  
• Perioperative antimicrobial prophylaxis should be considered because of the potential increase in maternal infectious morbidity with C-section, although there are no controlled data evaluating the efficacy of this practice in this specific clinical setting.
  
  
• If vaginal delivery is planned, obstetrical procedures increasing the risk of fetal exposure to maternal blood, such as fetal scalp electrodes or other invasive monitoring, should be avoided. Artificial rupture of membranes should also be avoided.
  
  
• If women present in early labor or shortly after rupture of membranes, intravenous AZT should be started immediately and decisions should be made on an individual basis regarding C-section vs. vaginal delivery. Active management of labor with Pitocin to enhance contractions and expedite vaginal delivery may be considered in this scenario.
  
  
• Women should be informed about the risks associated with cesarean delivery, and these risks should be balanced with potential benefits expected for the baby.
  
  
• Women should be counseled about the limitations of current data.
  
  
• The woman's autonomy to make an informed decision about route of delivery should be respected and honored.
  

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