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
Antepartum Care
Monitoring of the Woman and Fetus during Pregnancy
(Last updated:9/14/2011)
Panel’s Recommendations:
• CD4 cell count should be monitored at the initial antenatal visit (AI) and at least every 3 months during pregnancy (BIII). Monitoring of CD4 count may be performed every 6 months in patients on antiretroviral treatment (ART) for more than 2–3 years who are adherent to therapy, clinically stable, and have sustained viral suppression (BIII).
• Plasma HIV RNA levels should be monitored at the initial visit (AI); 2–4 weeks after initiating (or changing) antiretroviral (ARV) drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months during pregnancy (BIII). HIV RNA levels also should be assessed at approximately 34–36 weeks’ gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery) (AIII).
• Genotypic ARV drug-resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >500–1,000 copies/mL, whether they are ARV-naive or currently on therapy (AIII). Repeat testing is indicated following initiation of an ARV regimen in women who have suboptimal viral suppression or who have persistant viral rebound to detectable levels after prior viral suppression on an ARV regimen (AII).
• Monitoring for complications of ARV drugs during pregnancy should be based on what is known about the adverse effects of the drugs a woman is receiving (AIII).
• First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide timing of the procedure (see Transmission and Mode of Delivery) (AII).
• Given the limited data on the effect of combination ARV drugs on the fetus, most experts would recommend second-trimester ultrasound to assess fetal anatomy for women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz (BIII).
• In women on effective combination ARV regimens, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. If amniocentesis is indicated in HIV-infected women, it should be done only after initiation of an effective combination ARV drug regimen and, if possible, when HIV RNA levels are undetectable (BIII). In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. |
In HIV-infected pregnant women CD4 cell count should be monitored at the initial visit and at least every 3 months during pregnancy, similar to recommendations in nonpregnant adults. Monitoring of CD4 counts may be performed every 6 months in patients on ART for more than 2–3 years who are adherent to therapy, clinically stable, and have sustained viral suppression. Viral load should be monitored in HIV-infected pregnant women at the initial visit, 2–4 weeks after initiating or changing ARV regimens, monthly until undetectable, and at least every 3 months thereafter. If adherence is a concern, more frequent monitoring is recommended because of the potential increased risk of perinatal HIV infection associated with detectable HIV viremia during pregnancy. More frequent monitoring of viral load is recommended in pregnant versus nonpregnant individuals because of the urgency to lower viral load as rapidly as possible to reduce the risk of perinatal transmission. Therefore, there is a need to identify pregnant women in whom the decline in viral load is slower than expected. Adult ARV guidelines note that patients should have a decrease in plasma HIV RNA level by at least one log10 copies/mL within 1 month after initiation of potent therapy [1]. Viral suppression generally is achieved in 16–24 weeks in ARV-naive treatment-adherent individuals who do not harbor resistance mutations to the drugs they are receiving but, in rare cases, it may take longer. Viral load also should be assessed at approximately 34–36 weeks’ gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery).
Because of physiologic changes such as hemodilution that are associated with pregnancy, CD4 percentage may be more stable than absolute CD4 count during pregnancy [2-5]. Nevertheless, most clinicians still rely on absolute CD4 count to evaluate immune status during pregnancy because parameters for initiating therapy are based on those values.
ARV drug-resistance testing should be performed in HIV-infected pregnant women before initiation of ARV drugs if HIV RNA levels are above the threshold for resistance testing (e.g., >500–1,000 copies/mL). Testing should also be performed in women with suboptimal viral suppression while receiving an ARV regimen or who have persistant viral rebound to detectable levels after prior viral suppression on an ARV regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Drug-resistance testing in the setting of virologic failure should be performed while patients are receiving ARV drugs or within 4 weeks after discontinuation of drugs. Genotypic testing is preferable to phenotypic testing because it costs less, has a faster turnaround time, and is more sensitive for detection of mixtures of wild-type and resistant virus.
Monitoring for potential complications of ARV drugs during pregnancy should be based on what is known about the adverse effects of the drugs the woman is receiving. For example, routine hematologic monitoring is recommended for women receiving zidovudine-containing regimens. Liver function should be monitored in all women receiving ARV drugs. Hepatic dysfunction has been observed in pregnant women on protease inhibitors (PIs), and hepatic steatosis and lactic acidosis in pregnancy have been related to nucleoside reverse transcriptase inhibitor (NRTI) use. Women with CD4 counts >250 cells/mm3 are thought to be at particular risk of developing symptomatic, rash-associated, nevirapine-associated hepatotoxicity within the first 18 weeks after initiation of therapy. Data from a 2010 study, however, suggest that abnormal liver transaminase levels at baseline may be more predictive of risk than CD4 cell count [6]. Transaminase levels should be monitored more frequently and carefully in pregnant women initiating therapy with nevirapine, and they should also be watched for clinical symptoms of potential hepatotoxicity (see Nevirapine and Hepatic/Rash Toxicity). The drug can be used cautiously with careful monitoring in women with mildly abnormal liver function tests at the time of ARV drug initiation.
First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide potential timing because such deliveries for prevention of perinatal transmission of HIV should be performed at 38 weeks’ gestation (see Transmission and Mode of Delivery) [7-8]. In patients who are not seen until later in gestation, second-trimester ultrasound can be used for both anatomical scanning and determination of gestational age.
Because less is known about the effect of combination ARV drug regimens on the fetus during pregnancy, some experts consider more intensive fetal assessment for mothers receiving such therapy. Most experts would recommend second-trimester assessment of fetal anatomy with ultrasound in women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz. Furthermore, in addition to standard clinical monitoring, some experts would also recommend ultrasound assessment of fetal growth and well-being during the third trimester in woman who are receiving a combination drug regimen for which there is limited experience with use in pregnancy. The need for additional assessments such as non-stress testing should be determined based on ultrasound findings, any maternal comorbidities, and standard obstetrical indications.
Although data are still somewhat limited, the risk of transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving effective combination ARV drug regimens resulting in viral suppression. This is in contrast to the pre-combination drug regimen era, during which invasive procedures such as amniocentesis and chorionic villus sampling (CVS) were associated with a two- to fourfold increased risk of perinatal transmission of HIV [9-11]. In an evaluation of transmission rates of HIV over time among women with or without amniocentesis, the transmission rate among women undergoing the procedure from 1984 to 1996 (pre-combination drug era) was 30% (3 of 10) compared with 16.2% (40 of 247) in those who did not have amniocentesis [12]. In contrast, no transmissions were noted among 18 women undergoing amniocentesis between 1997 and 2000 who received suppressive combination ARV drug regimens [12].
In an Italian multicenter study that included deliveries between 1997 and 2003, 3.3% (2 of 60) of infants were HIV infected after early invasive diagnostic procedures (CVS, amniocentesis, or cordocentesis) during pregnancy, compared with 1.7% (12 of 712) of infants born to women without invasive procedures (P = 0.30) [13]. No transmissions occurred among 45 women on combination ARV drug regimens during the procedure. One mother of an infected infant had not been diagnosed as HIV infected at the time of amniocentesis and was not receiving ARV prophylaxis; the newborn’s virologic test at birth was negative. The mother of a second infected infant had been receiving zidovudine prophylaxis for 3 weeks and had an HIV RNA level of 10,000 copies/mL at the time of the procedure; the preterm infant had a positive virologic test at birth. In 2 other single-center series, no transmissions occurred in 6 and 9 liveborn infants after amniocentesis in HIV-infected pregnant women on combination ARV drug regimens [14-15]. In the largest series to date, no transmissions were seen among 81 women receiving effective combination ARV drug regimens at the time of amniocentesis [16].
Thus, among 159 cases reported to date of amniocentesis or other invasive diagnostic procedures among women on effective combination ARV drug regimens, no transmissions have occurred, but a small increase in risk cannot be ruled out. HIV-infected women who have indications for invasive testing in pregnancy, such as abnormal ultrasound or aneuploidy screening, should be counseled about the potential risk of transmission of HIV along with other risks of the procedure and allowed to make an informed decision about testing. Some experts consider CVS and cordocentesis too risky to offer to HIV-infected women and they recommend limiting invasive procedures to amniocentesis [14], but existing data on transmission risk associated with these procedures are limited. At a minimum, HIV-infected pregnant women should receive an effective combination ARV drug regimen prior to undergoing any invasive prenatal testing and ideally have an undetectable HIV RNA level at the time of the procedure. In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. These procedures should be done under continuous ultrasound guidance and, if possible, the placenta should be avoided.
References
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
2. Miotti PG, Liomba G, Dallabetta GA, Hoover DR, Chiphangwi JD, Saah AJ. T lymphocyte subsets during and after pregnancy: analysis in human immunodeficiency virus type 1-infected and -uninfected Malawian mothers. J Infect Dis. 1992 Jun;165(6):1116-1119.
3. Tuomala RE, Kalish LA, Zorilla C, et al. Changes in total, CD4+, and CD8+ lymphocytes during pregnancy and 1 year postpartum in human immunodeficiency virus-infected women. The Women and Infants Transmission Study. Obstet Gynecol. 1997 Jun;89(6):967-974.
4. Ekouevi DK, Inwoley A, Tonwe-Gold B, et al. Variation of CD4 count and percentage during pregnancy and after delivery: implications for HAART initiation in resource-limited settings. AIDS Res Hum Retroviruses. 2007 Dec;23(12):1469-1474.
5. Towers CV, Rumney PJ, Ghamsary MG. Longitudinal study of CD4+ cell counts in HIV-negative pregnant patients. J Matern Fetal Neonatal Med. 2010 Oct;23(10):1091-1096.
6. Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count >/=250 cells/muL among women in Zambia, Thailand and Kenya. HIV Med. 2010 Nov;11(10):650-660.
7. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 58. Ultrasonography in pregnancy. Obstet Gynecol. 2004 Dec;104(6):1449-1458.
8. Bennett KA, Crane JM, O'Shea P, Lacelle J, Hutchens D, Copel JA. First trimester ultrasound screening is effective in reducing postterm labor induction rates: a randomized controlled trial. Am J Obstet Gynecol. 2004 Apr;190(4):1077-1081.
9. 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 Sep;175(3 Pt 1):661-667.
10. 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 Dec;94(6):897-908.
11. Tess BH, Rodrigues LC, Newell ML, Dunn DT, Lago TD. Breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil. Sao Paulo Collaborative Study for Vertical Transmission of HIV-1. AIDS. 1998 Mar 26;12(5):513-520.
12. Maiques V, Garcia-Tejedor A, Perales A, Cordoba J, Esteban RJ. HIV detection in amniotic fluid samples. Amniocentesis can be performed in HIV pregnant women? Eur J Obstet Gynecol Reprod Biol. 2003 Jun 10;108(2):137-141.
13. Somigliana E, Bucceri AM, Tibaldi C, et al. Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series. Am J Obstet Gynecol. 2005 Aug;193(2):437-442.
14. Coll O, Suy A, Hernandez S, et al. Prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal anomalies. Am J Obstet Gynecol. 2006 Jan;194(1):192-198.
15. Ekoukou D, Khuong-Josses MA, Ghibaudo N, Mechali D, Rotten D. Amniocentesis in pregnant HIV-infected patients. Absence of mother-to-child viral transmission in a series of selected patients. Eur J Obstet Gynecol Reprod Biol. 2008 Oct;140(2):212-217.
16. Mandelbrot L, Jasseron C, Ekoukou D, et al. Amniocentesis and mother-to-child human immunodeficiency virus transmission in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales French Perinatal Cohort. Am J Obstet Gynecol. 2009 Feb;200(2):160 e161-169.