Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Intrapartum Care
Transmission and Mode of Delivery
(Last updated:9/14/2011)
Panel’s Recommendations:
- Scheduled cesarean delivery at 38 weeks’ gestation is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery, irrespective of administration of antepartum antiretroviral (ARV) drugs, and for women with unknown HIV RNA levels near the time of delivery (AII).
- Scheduled cesarean delivery is not routinely recommended for prevention of perinatal transmission in pregnant women receiving combination ARV drugs with plasma HIV RNA levels <1,000 copies/mL near the time of delivery. Data are insufficient to evaluate the potential benefit of cesarean delivery in this group, and given the low rate of transmission in these patients, it is unclear whether scheduled cesarean delivery would confer additional benefit in reducing transmission. This decision should be individualized based on discussion between the obstetrician and the mother (BII).
- It is not clear whether cesarean delivery after rupture of membranes or onset of labor provides benefit in preventing perinatal transmission. Management of women originally scheduled for cesarean delivery who present with ruptured membranes or in labor must be individualized based on duration of rupture, progress of labor, plasma HIV RNA level, current ARV regimen, and other clinical factors (BII).
- Women should be informed of the risks associated with cesarean delivery; the risks to the woman should be balanced with potential benefits expected for the neonate (AIII).
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Basis for Current Recommendations
Scheduled cesarean delivery, defined as cesarean delivery performed before the onset of labor and before rupture of membranes, is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery and for women with unknown HIV RNA levels [1].
This recommendation is based on findings from a multicenter, randomized clinical trial [2] and from a large individual patient data meta-analysis [3]. These two studies were conducted at a time when the majority of HIV-infected women received no ARV medications or zidovudine as a single drug and before the availability of viral load information. Study results have since been extrapolated to make current recommendations about the mode of delivery in an era when combination ARV regimens during pregnancy are recommended and viral load information is readily available.
In the randomized clinical trial, 1.8% of infants born to women randomized to undergo cesarean delivery were HIV infected compared with 10.5% of infants born to women randomized to vaginal delivery (P <0.001). When adjusted for ARV use in pregnancy (zidovudine alone), scheduled cesarean delivery lowered the risk of HIV transmission by 80%, although the results were no longer statistically significant (odds ratio [OR] 0.2, 95% confidence interval [CI], 0–1.7). When the data were analyzed by the actual mode of delivery, rather than to which group women were allocated, there was still a protective effect of scheduled cesarean delivery (adjusted OR [AOR] 0.3; 95% CI, 0.1–0.8) but not with emergency cesarean delivery (AOR 1.0; 95% CI, 0.3–3.7) [2]. Results from a large meta-analysis of individual patient data from 15 prospective cohort studies also demonstrated the benefit of scheduled cesarean delivery with a 50% reduction in risk [3]. Primarily based on these data, the American College of Obstetricians and Gynecologists has recommended consideration of scheduled cesarean delivery for HIV-infected pregnant women since 1999 [4].
HIV RNA Level of 1,000 copies/mL as a Threshold for Recommendation of Scheduled Cesarean Delivery
The original American College of Obstetricians and Gynecologists committee opinion was updated in 2000 to include further refinements based on HIV RNA levels [1]. Currently, the American College of Obstetricians and Gynecologists [1] recommends that women with HIV RNA >1,000 copies/mL be counseled regarding the potential benefits of scheduled cesarean delivery. Initially, this threshold of 1,000 copies/mL was based largely on data from the Women and Infants Transmission Study (WITS), a large prospective cohort study that reported no HIV transmission among 57 women with HIV RNA levels less than 1,000 copies/mL [5]. Since that time, newer studies have demonstrated that HIV transmission can occurr among infants born to women with low viral loads.
In an analysis of 957 women with plasma viral loads <1,000 copies/mL, cesarean delivery (scheduled or urgent) reduced the risk of HIV transmission when adjusting for potential confounders including receipt of maternal ARV medications, primarily zidovudine alone as prophylaxis (AOR 0.30; P = 0.022) [6]. Among infants born to 834 women with HIV RNA <1,000 copies/mL receiving ARV medications, 8 (1%) were HIV infected. In a more recent report from a comprehensive national surveillance system in the United Kingdom and Ireland, 3 (0.1%) of 2,309 and 12 (1.2%) of 1,023 infants born to women with HIV RNA of <50 copies/mL and 50–999 copies/mL, respectively, were HIV infected [7].
The recent studies demonstrate that transmission can occur even at very low HIV RNA levels. However, given the low rate of transmission among this group, it is unclear whether scheduled cesarean delivery confers any additional benefit in reducing transmission. Although decisions about mode of delivery for women with HIV RNA levels <1,000 copies/mL should be individualized based on discussion between the obstetrician and the mother, scheduled cesarean delivery is not routinely recommended in this group.
Scheduled Cesarean Delivery in the Highly Active Antiretroviral Therapy Era
In surveillance data from the United Kingdom and Ireland, pregnant women receiving combination ARV regimens (i.e., at least 3 drugs) had transmission rates of about 1%, unadjusted for mode of delivery [7]. Given the low transmission rates achievable with use of maternal combination ARV drug regimens, the benefit of scheduled cesarean delivery is difficult to evaluate. Both the randomized clinical trial [2] and meta-analysis [3] documenting the benefits of cesarean delivery included mostly women who were receiving either no ARVs or zidovudine only. However, other data partially address this issue.
In a report from the European Collaborative Study that included data from 4,525 women, the overall transmission rate among the subset of women on a combination ARV regimen was 11(1.2%) of 918 [8]. Among the subset of 560 women with undetectable HIV RNA levels (<50 to ≤200 copies/mL, depending on site), scheduled cesarean delivery was associated with a significant reduction in perinatal transmission in univariate analysis (OR 0.07; 95% CI, 0.02–0.31; P = 0.0004). However, after adjustment for ARV drug use (none vs. any), the effect was no longer significant (AOR 0.52; 95% CI, 0.14–2.03; P = 0.359). Similarly, data from a European surveillance study did not demonstrate a statistically significant difference in transmission rates between scheduled cesarean delivery and planned vaginal delivery (AOR 1.24; 95% CI, 0.34–4.5) among women on combination ARV drug regimens [7]. The transmission rate among all women who received at least 14 days of ARV medications was 40 (0.8%) of 4,864, regardless of mode of delivery. Therefore, it is not clear whether there is any benefit from scheduled cesarean delivery among women who have been receiving combination ARV medications for several weeks.
Women Presenting Late in Pregnancy
HIV-infected women who present in late pregnancy and are not receiving ARV drugs may not have HIV RNA results available before delivery. Without current therapy, HIV RNA levels are unlikely to be <1,000 copies/mL at baseline. Even if combination ARV medications were begun immediately, reduction in plasma HIV RNA to undetectable levels usually takes several weeks, depending on the kinetics of viral decay for the particular drug regimen [9]. In this instance, scheduled cesarean delivery is likely to provide additional benefit in reducing the risk of perinatal transmission of HIV for women, unless viral suppression can be documented prior to 38 weeks.
Timing of Scheduled Cesarean Delivery
In general, for women without HIV infection, American College of Obstetricians and Gynecologists recommends that scheduled cesarean delivery not be performed before 39 weeks’ gestation because of the risk of iatrogenic prematurity [10-11]. However, in cases of cesarean delivery performed to prevent transmission of HIV, American College of Obstetricians and Gynecologists ACOG recommends scheduling cesarean delivery at 38 weeks’ gestation in order to decrease the likelihood of onset of labor or rupture of membranes before delivery [1]. Among all women undergoing repeat cesarean delivery, the risk of any neonatal adverse event—including neonatal death, respiratory complications, hypoglycemia, newborn sepsis, or admission to the neonatal intensive care unit—is 15.3% at 37 weeks, 11.0% at 38 weeks, and 8.0% at 39 weeks [11]. Gestational age should be determined by last menstrual period and ultrasonography because amniocentesis to document lung maturity should be avoided, when possible, in HIV-infected women.
Among 1,194 infants born to HIV-infected mothers, 9 (1.6%) infants born vaginally had respiratory distress syndrome (RDS) compared with 18 (4.4%) of infants born by scheduled cesearean delivery (P <0.001). There was no statistically significant association between mode of delivery and infant RDS in an adjusted model that included infant gestational age and birth weight [12]. Clinicians should recognize that newborn complications may be increased in planned early term births <39 weeks’ gestation. However, for HIV-infected women, the benefits of decreasing HIV transmission by planned delivery at 38 weeks are generally thought to outweigh the risks. When cesarean delivery is performed in HIV-infected women for an indication other than decreasing transmission of HIV, cesarean delivery should be scheduled at 38 weeks based on accepted American College of Obstetricians and Gynecologists guidelines.
Risk of Maternal Complications
Because maternal infectious morbidity is increased with cesarean delivery even among women without HIV infection, the administration of perioperative antimicrobial prophylaxis is recommended for all women undergoing cesarean delivery. Most studies have demonstrated that HIV-infected women have increased rates of postoperative complications, mostly infectious, compared with HIV-uninfected women and that the risk of complications is related to the degree of immunosuppression [13-18]. Furthermore, a Cochrane review of six studies of HIV-infected women concluded that urgent cesarean delivery was associated with the highest risk of postpartum morbidity, that scheduled cesarean delivery was intermediate in risk, and that vaginal delivery had the lowest risk of morbidity [19]. Complication rates in most studies [2, 20-24] were within the range reported in populations of HIV-uninfected women with similar risk factors and were not of sufficient frequency or severity to outweigh the potential benefit of reduced transmission. Therefore, HIV-infected women should be counseled regarding the increased risks and potential benefits associated with cesarean delivery based on their HIV RNA levels and current ARV regimen.
Management of Women Who Present in Early Labor or With Ruptured Membranes
Few data are available to address the question of whether performing cesarean delivery after the onset of labor or membrane rupture may decrease the risk of perinatal transmission of HIV. Most studies have shown a similar risk of transmission for cesarean delivery performed after labor and membrane rupture for obstetric indications and for vaginal delivery. In one study, the HIV transmission rate was similar in women undergoing emergency cesarean delivery and those delivering vaginally (1.6% vs. 1.9%, respectively) [7]. A meta-analysis of women, most of whom were on zidovudine as a single drug or receiving no ARV medications, demonstrated a 2% increased transmission risk for every additional hour of ruptured membranes [25]. However, it is not clear how soon after the onset of labor or the rupture of membranes the benefit of cesarean delivery is lost [26]. Therefore, the management of women originally scheduled for cesarean delivery who present with ruptured membranes or in labor must be individualized based on clinical factors such as duration of rupture, progress of labor, plasma RNA level, and current ARV drug regimen status. When membrane rupture occurs before 37 weeks’ gestation, decisions about delivery should be based on gestational age, HIV RNA level, current ARV regimen, and evidence of acute infection such as chorioamnionitis; consultation with an expert is recommended. The ARV drug regimen should be continued and consideration given to initiating intravenous zidovudine if delivery appears imminent. No data exist to suggest that recommendations for administration of steroids to accelerate fetal lung maturity should be altered among HIV-infected women.
Table 7 provides a summary of recommendations regarding mode of delivery for different clinical scenarios.
Table 7. Clinical Scenarios and Recommendations Regarding Mode of Delivery to Reduce Perinatal Transmission of HIV
Clinical Scenario | Recommendations |
| HIV-infected women presenting in late pregnancy (after about 36 weeks’ gestation), known to be HIV infected but not receiving antiretroviral (ARV) medications, and who have HIV RNA level and CD4 cell counts pending but unlikely to be available before delivery. | • Start ARV medications as per Table 6.
• Provide counseling on the likelihood that scheduled cesarean delivery will reduce the risk of mother-to-child transmission, if viral suppression cannot be documented prior to 38 weeks. Include information on the increased maternal risks of cesarean delivery, including increased rates of postoperative infection, anesthesia, and other surgical risks.
• When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks’ gestation, as determined by last menstrual period and ultrasonography.
• Administer continuous intravenous zidovudine beginning 3 hours before scheduled cesarean.
• Continue other ARV medications on schedule, as much as possible, before and after surgery.
• Use of prophylactic antibiotics at the time of cesarean delivery is recommended. |
| HIV-infected women who began prenatal care early in the third trimester, are receiving combination ARV drug regimens, and have an initial virologic response but have HIV RNA levels that remain substantially >1,000 copies/mL at 36 weeks’ gestation. | • Continue the current combination ARV regimen because the drop in HIV RNA level is appropriate.
• Provide counseling on the timing of response to ARV medications and the likelihood that maternal HIV RNA levels may not fall below 1,000 copies/mL before delivery. Consider scheduled cesarean delivery if viral load suppression is not achieved by 38 weeks because of the potential additional benefit in preventing intrapartum transmission of HIV. Inform patients about the increased maternal risks associated with cesarean delivery, including risks related to anesthesia and surgery and increased rates of postoperative infection.
• When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks’ gestation, as determined by last menstrual period and ultrasonography.
• When the delivery method selected is scheduled cesarean delivery, administer continuous intravenous zidovudine beginning 3 hours before scheduled cesarean.
• Continue other ARV medications on schedule, as much as possible, before and after surgery.
• Use of prophylactic antibiotics at the time of cesarean delivery is recommended.
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| HIV-infected women on combination ARV drug regimens with undetectable HIV RNA levels at 36 weeks’ gestation. | • Provide counseling on the risk of perinatal transmission of HIV with a persistently undetectable HIV RNA level, which is probably 1% or less, even with vaginal delivery. No evidence currently exists to show that this risk can be lowered further by performing scheduled cesarean delivery.
• Risk of complications is increased with cesarean delivery, compared with vaginal delivery, even in the HIV-uninfected population, and the risks must be balanced against the uncertain benefits of cesarean delivery in women with undetectable viral load.
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| HIV-infected women who have elected scheduled cesarean delivery but present after rupture of membranes at >37 weeks’ gestation. | • Start intravenous zidovudine immediately.
• Individualize the decision regarding mode of delivery, based on clinical factors such as duration of rupture, anticipated progress of labor, plasma RNA level, and current ARV regimen.
• When vaginal delivery is chosen, some clinicians may consider administration of oxytocin, if clinically appropriate, in order to expedite delivery. Scalp electrodes and other invasive monitoring and operative delivery should be avoided, if possible, unless there are clear obstetric indications.
• When cesarean delivery is chosen, administration of the loading dose of intravenous zidovudine ideally should be completed prior to the procedure. However, decisions regarding timing of delivery should be individualized.
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References
1. American College of Obstetricians and Gynecologists. ACOG committee opinion scheduled Cesarean delivery and the prevention of vertical transmission of HIV infection. Number 234, May 2000 (replaces number 219, August 1999). Int J Gynaecol Obstet. 2001 Jun;73(3):279-281.
2. European Mode of Delivery Collaboration. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. The European Mode of Delivery Collaboration. Lancet. 1999 Mar 27;353(9158):1035-1039.
3. International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group. N Engl J Med. 1999 Apr 1;340(13):977-987.
4. American College of Obstetricians and Gynecologists. ACOG committee opinion. Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. Number 219, August 1999. Committee on Obstetric Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 1999 Sep;66(3):305-306.
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18. Vimercati A, Greco P, Loverro G, Lopalco PL, Pansini V, Selvaggi L. Maternal complications after caesarean section in HIV infected women. Eur J Obstet Gynecol Reprod Biol. 2000 May;90(1):73-76.
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