C620R9054.rtf

The Role of Cesarean Section in the Prevention of Mother-to-Child Transmission of HIV

H. Minkoff

Departments of Obstetrics and Gynecology at Maimonides Medical Center and at SUNY Downstate, U.S.A.

Introduction

An association between mode of delivery and rate of mother-to-child transmission of infectious agents has been reported for many viruses over the last quarter century. Perhaps most well known is Monif and Amstey’s report in 1974 of a protective effect of cesarean section in the setting of HSV lesions that led to the “four hour rule” for timing of surgery after rupture of membranes in the setting of an active HSV lesion1. Other researchers have performed studies linking cesarean section to protection from transmission of HCV2, HBV3 and HPV4. Thus it is not surprising that since early in the HIV epidemic scientists have speculated about a similar effect in regard to HIV. While several studies have now clarified the extent to which cesarean sections can reduce rates of HIV transmission, obstetricians must be aware of several confounding factors when choosing a route of delivery. For example, the potential benefits of cesarean section may vary with viral load and in all circumstances must be weighed against the risks of surgery to the mother.

Determinants of Transmission: Viral load and therapy

Several determinants of the rate of mother-to-child transmission of HIV have been detailed over the last several years. Perhaps the factors most consistently associated with higher transmission rates are those that relate to the stage of maternal illness, with more advanced disease correlating with higher transmission rates. More advanced disease can be measured clinically (AIDS defining conditions), immunologically (lower CD4 counts or percents) or virologically (maternal p24 antigenemia, or high plasma HIV RNA levels). Other associated factors includeplacental inflammation, and sexually transmitted diseases5,6,7 as well as less consistently reported factors such as preterm birth, maternal illicit drug use, vitamin A deficiency, and female gender of the infant.8-12

Viral factors have been most carefully studied. Studies from both untreated and treated cohorts of pregnant women have consistently demonstrated an association between maternal HIV RNA levels and risk of transmission.14-17 In untreated women, transmission rates increased from about 10% (range 0-22%) among women with HIV RNA levels near delivery of < 1,000 copies/ml, to 17% (range 0-67%) with levels of 1,000-10,000 copies/ml, and to 33% (range 22-64%) with levels above 10,000 copies/ml.18 However,regardless of the viral load antiretroviral medications will reduce transmission rates.19 When loads are reduced to undetectable levels transmission becomes an extremely uncommon event. Inthe original PACTG 076 study, which first highlighted the utility of ZDV in reducing rates of mother-to-child transmission of HIV, among women receiving antiretroviral therapy, predominantly zidovudine monotherapy, transmission rates increased from 1% (range 0-7%) with HIV RNA levels below 1,000 copies/ml, to 6% (range 0-12%) with levels of 1,000 to 10,000 copies/ml, and to 13% (range 9-29%) with levels above 10,000 copies/ml. Treatment lowered the transmission rate among women in each viral load group, even among women with low or undetectable HIV RNA levels, suggesting that the effects of treatment are not all related to decreasing maternal plasma HIV RNA levels, but may also be related to decreasing genital tract HIV levels and pre- and post-exposure prophylaxis of the infant. These same finings have been replicated among women on several agents and among those on HAART.19 While transmission rates are low among women with HIV RNA levels below 1,000 copies/ml, there is not a threshold below which the absence of transmission can be assured.20

More recent observational data suggest that transmission rates are reduced even further, to 2% or lower, by the use of maternal combination antiretroviral therapy.19 Four small studies reported one transmission (0.6%) among a total of 160 infants born to women on two or more antiretrovirals during pregnancy.21-24 Similarly low transmission rates have been reported from the Women and Infants Transmission Study (WITS) which found a transmission rate of 3.8% among 186 women on dual therapy and 1.2% among 250 women on HAART.19 However only 16 of the former and 21 of the latter had HIV-1 RNA levels > 30,000 copies. These data suggest that highly active antiretroviral regimens indicated for HIV-infected women for their own health are also beneficial in reducing the risk of perinatal transmission.

Determinants of Transmission: Obstetrical Factors

Other data demonstrate that obstetrical factors can also play a role in modifying the rate of transmission. Since intrapartum interventions will have no effect on those infections that occur in the antepartum period, the first hint that intrapartum interventions could have utility derived from studies detailing the timing of transmission. While transmission of HIV may occur during the antepartum or postpartum period, in non-breastfeeding populations, only about one-third (20-60%) appears to occur in utero with the remaining two-thirds (40-80%) occurring during labor and delivery.25-28 Several types of evidence have been cited in support of intrapartum transmission including the lag between delivery and the detection of HIV by culture, antigen detection, or DNA in the neonate.27,28 Additionally, newborns have a delayed onset of clinical symptoms,26 and there is a significantly higher transmission rates in first-born compared with second-born twins.29 Several authors have also reported an association of higher transmission rates with increasing duration of ruptured membranes in labor.30-31 These data support the thesis that interventions directed at late pregnancy, delivery, and the neonate may be able substantially reduce transmission.

The first direct evidence of a protective effect from elective cesarean section came from two prospective cohort studies, the French Perinatal Cohort32 and the Swiss Neonatal HIV Study Group.33 They both demonstrated reduced rates of perinatal HIV-1 transmission among women who received zidovudine and underwent elective cesarean delivery. The French reported on 872 HIV-infected women who received ZDV, and found that the transmission rate of HIV for mothers delivering by elective cesarean section, emergency cesarean section and vaginal delivery were 0.8%, 11.4% and 6.6%, respectively (P=0.02). The Swiss cohort included 414 children with known infection status, and found that the overall infection rate was 16.2% (95% confidence interval 13.0-18.5%) while the rate among women undergoing elective cesarean section with intact membranes was 6% (odds ratio 0.29; 95% confidence interval 0.12-0.70; P=0.006). In both studies an interaction was found between zidovudine use and cesarean section with the combined use of zidovudine and cesarean section being associated with a significantly lower transmission rate.

Read and her colleagues took advantage of access to individual patient data from 15 cohort studies to reported a meta-analysis that included more than 7,800 mother-child pairs. Her results were similar to those in the studies cited above.34 The rate of perinatal HIV-1 transmission in women undergoing elective cesarean delivery was 8.2% in the group not receiving antiretrovirals and 2% in those receiving ZDV. The rate in both groups were significantly decreased compared those seen among women delivered by either non-elective cesarean or vaginal delivery. The European randomized trial of cesarean section was reported in 1999.35 The results paralleled those that had been found by Read. In that trial HIV-infected women between 34 and 36 weeks of gestation were randomly assigned to undergo an elective cesarean delivery at 38 weeks or to have a vaginal delivery. Three (1.8%) of 170 women born to women assigned cesarean delivery were infected compared with 21 (10.5%) of 200 born to women assigned to vaginal delivery (p<0.001). Seven (3.4%) of 203 infants of women who actually gave birth by cesarean section were infected compared with 15 (10.2%) of 167 born vaginally (p=0.009). Unfortunately the number of participants was not adequate to allow for a separate analysis of the benefit of cesarean section in the setting of antiretroviral therapy. Additionally, HAART use was not reported from the cohort. Despite those limitations, the results suggest that among women who were not optimally treated with HAART, cesarean section could have an important effect on reducing rates of mother-to-child transmission of HIV. In sum, the above cited studies strongly suggest that compared to other types of delivery, cesarean delivery performed prior to the onset of labor and prior to rupture of membranes (elective, or scheduled cesarean) significantly reduces the rate of perinatal HIV-1 transmission.

On the basis of the data reported by Read and of the European Trial, the American College of Obstetricians and Gynecologists published a Committee Opinion in August 1999 that concluded that HIV-infected women should be offered scheduled cesarean section in order to reduce the rate of transmission beyond that which could be achieved with ZDV alone.36 That report also noted that data were insufficient to demonstrate a benefit for women with viral loads less than 1,000 copies per milliliter of plasma, since the rate of transmission was extremely low independent of the mode of delivery. They suggested that scheduled cesarean sections should be performed at 38 weeks of gestation, to minimize the risk of labor and/or ruptured membranes prior to the procedure. They went on to counsel against amniocentesis in order to avoid contamination of the amniotic cavity with viral antigen from maternal blood.

While ACOG felt that there was no proven benefit of cesarean section with low viral loads (<1,000 copies) some data do exist that speak to risks in that particular subgroup. Although, not as compelling as other data cited above, there is some evidence that cesarean section could be beneficial even in the setting of viral loads under 1,000 copies.37 Those data come from a metaanalysis of studies that focused exclusively on women who had viral loads less than 1,000 copies. In those women antiretroviral therapy still played a major role in reducing transmission, dropping rates from approximately 10% to approximately 1%. While cesarean section apparently dropped the rate from 6% to1.5%, there was no control in that analysis for the use of antiretroviral therapy.

Although there are circumstances in which the role of cesarean section is clear, there are other clinical situations in which its utility is less obvious.38 For example, if a patient who had been scheduled for cesarean section ruptures her membranes before delivery the physician must balance the potential benefit of shortening the period between rupture and delivery, against the risks of surgery. The longer the time since the membranes ruptured the greater the percentage of eventual transmissions that will have occurred before a surgical procedure can be undertaken. However, it the interval has been relatively short, and the viral load is high, some advantage probably still accrues to the woman who undergoes cesarean section. Another difficult clinical situation involves the woman with preterm rupture of membranes remote from term. In that circumstance the balance that must be struck is between the risks to the neonate from extreme prematurity and the risk from acquisition of HIV while the mother is managed expectantly. While the former risks can be roughly quantified by reviewing institutional data related to prematurity, there is less empiric data upon which to base estimates of the risk of acquisition of HIV in the setting of prolonged ruptured membranes and HAART. Obviously, the closer the patient is to term the greater the advantage to rapid delivery.

Operative Morbidity

In the European randomized trial of cesarean section, there were few postpartum complications and no serious morbidity was noted in either group.26 However, Grubert and colleagues found marked differences in a report on postoperative complications among 235 HIV-infected women who underwent obstetric and gynecologic procedures and HIV-uninfected, age matched women undergoing the same procedures.39 They reported significantly higher postoperative complication rates after abdominal surgery (OR 3.6, P= 0.001) and noted that the risk of complications was associated with immune status. ACOG’s recommendations for performing elective cesarean section included the suggestion that prophylactic antibiotics be employed because of concerns of heightened risks of postoperative infectious morbidity. Although the data supporting a heightened risk for postoperative morbidity among HIV-infected women undergoing elective surgery is not robust, the evidence that all women undergoing an operative delivery face a greater risk of infectious morbidity is overwhelming. The liberal use of antibiotics in the setting of cesarean section and HIV infection as suggested by AOCG guidelines would therefore seem reasonable.

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