Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

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Intrapartum Care

Other Intrapartum Management Considerations

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

Panel's Recommendations Regarding Other Intrapartum Management Considerations
Panel's Recommendations
  • Artificial rupture of membranes (ROM) performed in the setting of antiretroviral therapy (ART) and virologic suppression is not associated with increased risk of perinatal transmission and can be performed for standard obstetric indications (BII)
  • The following should generally be avoided because of a potential increased risk of transmission, unless there are clear obstetric indications:
    • Artificial ROM in the setting of viremia (BIII)
    • Routine use of fetal scalp electrodes for fetal monitoring (BIII)
    • Operative delivery with forceps or a vacuum extractor (BIII)
  • The ART regimen a woman is receiving should be taken into consideration when treating excessive postpartum bleeding resulting from uterine atony:
    • In  women who are receiving a cytochrome P450 (CYP) 3A4 enzyme inhibitor (e.g., a protease inhibitor, cobicistat), methergine should be used only if no alternative treatments for postpartum hemorrhage are available and the need for pharmacologic treatment outweighs the risks. If methergine is used, it should be administered in the lowest effective dose for the shortest possible duration (BIII).
    • In women who are receiving a CYP3A4 enzyme inducer such as nevirapine, efavirenz, or etravirine, additional uterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatment effect (BIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

Data on the association of duration of rupture of membranes (ROM) and perinatal transmission in the era of effective antiretroviral therapy (ART) are reassuring. A prospective cohort study of 707 pregnant women on ART included 493 women with delivery HIV-RNA <1,000 copies/mL with no cases of perinatal transmission with up to 25 hours of membrane rupture; logistic regression found that HIV viral load >10,000 copies/mL was the only independent risk factor for transmission.1 A large prospective, population-based surveillance study in the UK and Ireland included 2,116 pregnancies delivered at term vaginally or by emergency Cesarean delivery in women on ART from 2007 through 2012 with information on duration of ROM. The median duration of ROM was 3 hours 30 minutes (interquartile range, IQR 1–8 hours) and the overall perinatal transmission rate was not significantly different with longer duration of ROM (0.64% with duration of ROM ≥4 hours compared with 0.34% for ROM <4 hours, [OR 1.90, 95% CI, 0.45–7.97]). In those women with a viral load <50 copies/mL, there was no difference in perinatal transmission rates with duration of ROM ≥4 hours, compared with <4 hours (0.14% for ≥4 hours versus 0.12% for <4 hour; OR 1.14, 95% CI, 0.07–18.27). Among infants born preterm, there were no transmissions in 163 deliveries where the maternal viral load was <50 copies/mL.2 If spontaneous ROM occurs before or early during the course of labor, interventions to decrease the interval to delivery (e.g., administration of oxytocin) can be considered based on obstetric considerations in women with HIV with viral suppression. Women with detectable HIV viral loads should not undergo artificial ROM unless there is a clear obstetric indication. 

Obstetric procedures that increase the risk of fetal exposure to maternal blood, such as invasive fetal monitoring, have been implicated in increasing vertical transmission rates by some, but not all, investigators, primarily in studies performed in the pre-ART era.3-6 Data are limited on use of fetal scalp electrodes in labor in women receiving suppressive ART who have undetectable viral loads; routine use of fetal scalp electrodes for fetal monitoring should generally be avoided in the setting of maternal HIV infection.

Similarly, data are limited regarding the potential risk of perinatal transmission of HIV associated with operative vaginal delivery with forceps or the vacuum extractor and/or use of episiotomy4,6 and are mostly from the pre-ART era. A prospective, population-based surveillance study in the UK and Ireland reported 251 operative deliveries (forceps or vacuum) from January 2008 through March 2016; 1 infant delivered operatively is known to have acquired HIV, although there were other significant risk factors that may have contributed to this transmission.7 Although information on HIV-RNA levels was not included in this report, during this time period 80% to 90% of pregnant women living with HIV in the UK achieved viral suppression by the time of delivery.7,8 These procedures should be performed only if there are clear obstetric indications. There are no data in the ART era regarding risk of perinatal HIV transmission with episiotomy or with vaginal or perineal tears, specifically in the absence of maternal viremia; indications for episiotomy should be the same as they are for women without HIV (e.g., need for expedited vaginal delivery, need for operative vaginal delivery, shoulder dystocia). Delayed cord clamping has been associated with improved iron stores in both term and preterm infants as well as a lower incidence of necrotizing enterocolitis and intraventricular hemorrhage in preterm infants born to mothers without HIV infection. The American College of Obstetricians and Gynecologists now recommends this practice in vigorous term and preterm infants, with clamping delayed for at least 30 to 60 seconds after birth.9-11 Even though HIV-specific data on the practice are lacking, there is no reason to modify it in mothers with HIV.

Intrapartum Epidural Use and Pharmacologic Interactions with Antiretroviral Drugs 

Ritonavir inhibition of cytochrome P450 (CYP) 3A4 decreases the elimination of fentanyl by 67%, raising concerns about possible increased risk of respiratory depression, particularly with patient-controlled analgesia during labor, in women receiving ritonavir-containing regimens. However, a pharmacokinetic simulation study suggests that even with maximal clinical dosing regimens of epidural fentanyl over 24 hours, ritonavir-induced CYP3A4 inhibition is unlikely to produce plasma fentanyl concentrations associated with a decrease in minute ventilation.12 This suggests that epidural anesthesia can be used safely regardless of ART regimen. 

Postpartum Hemorrhage, Antiretroviral Drugs, and Methergine Use 

Oral or parenteral methergine or other ergot alkaloids are often used as first-line treatment for postpartum hemorrhage resulting from uterine atony. However, methergine should not be coadministered with drugs that are potent CYP3A4 enzyme inhibitors, including protease inhibitors (PIs). Concomitant use of ergotamines with PIs and/or cobicistat have been associated with exaggerated vasoconstrictive responses.13 When uterine atony results in excessive postpartum bleeding in women receiving PIs or cobicistat, methergine should be used only if alternative treatments such as prostaglandin F2-alpha, misoprostol, or oxytocin are unavailable or are contraindicated. If no alternative medications are available and the need for pharmacologic treatment outweighs the risks, methergine should be used in as low a dose and for as short a period as possible. In contrast, additional uterotonic agents may be needed when other antiretroviral drugs that are CYP3A4 inducers (e.g., nevirapine, efavirenz, etravirine) are used because of the potential for decreased methergine levels and inadequate treatment effect.

References

  1. Cotter AM, Brookfield KF, Duthely LM, Gonzalez Quintero VH, Potter JE, O'Sullivan MJ. Duration of membrane rupture and risk of perinatal transmission of HIV-1 in the era of combination antiretroviral therapy. Am J Obstet Gynecol. 2012;207(6):482 e481-485. Available at http://www.ncbi.nlm.nih.gov/pubmed/23103331.
  2. Peters H, Francis K, Harding K, Tookey PA, Thorne C. Operative vaginal delivery and invasive procedures in pregnancy among women living with HIV. Eur J Obstet Gynecol Reprod Biol. 2016;210:295-299. Available at https://www.ncbi.nlm.nih.gov/pubmed/28092853.
  3. Boyer PJ, Dillon M, Navaie M, et al. Factors predictive of maternal-fetal transmission of HIV-1. Preliminary analysis of zidovudine given during pregnancy and/or delivery. JAMA. 1994;271(24):1925-1930. Available at http://www.ncbi.nlm.nih.gov/pubmed/7911164.
  4. Mandelbrot L, Mayaux MJ, Bongain A, et al. Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group. Am J Obstet Gynecol. 1996;175(3 Pt 1):661-667. Available at http://www.ncbi.nlm.nih.gov/pubmed/8828431.
  5. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. 1999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.
  6. Shapiro DE, Sperling RS, Mandelbrot L, Britto P, Cunningham BE. Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076 Study Group. Obstet Gynecol. 1999;94(6):897-908. Available at http://www.ncbi.nlm.nih.gov/pubmed/10576173.
  7. Peters H, Francis K, Sconza R, et al. UK Mother-to-child HIV transmission rates continue to decline: 2012–2014. Clin Infect Dis. 2017;64(4):527-528. Available at https://www.ncbi.nlm.nih.gov/pubmed/28174911.
  8. Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011. AIDS. 2014;28(7):1049-1057. Available at http://www.ncbi.nlm.nih.gov/pubmed/24566097.
  9. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2013;7:CD004074. Available at http://www.ncbi.nlm.nih.gov/pubmed/23843134.
  10. Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2012;8:CD003248. Available at http://www.ncbi.nlm.nih.gov/pubmed/22895933.
  11. ACOG. Committee Opinion No. 684: Delayed umbilical cord clamping after birth. Obstet Gynecol. 2017;129(1):e5-e10. Available at https://www.ncbi.nlm.nih.gov/pubmed/28002310.
  12. Cambic CR, Avram MJ, Gupta DK, Wong CA. Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation. International Journal of Obstetric Anesthesia. 2014;23(1):45-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/24333052.
  13. Navarro J, Curran A, Burgos J, et al. Acute leg ischaemia in an HIV-infected patient receiving antiretroviral treatment. Antivir Ther. 2017;22(1):89-90. Available at https://www.ncbi.nlm.nih.gov/pubmed/27546463.



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