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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
General Principles Regarding Use of Antiretroviral Drugs during Pregnancy
(Last updated: August 6, 2015; last reviewed: August 6, 2015)
All cases of antiretroviral (ARV) drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Registry (see http://www.APRegistry.com) (AIII).
Non-pregnant women of childbearing potential should undergo pregnancy testing before initiation of efavirenz and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on efavirenz-containing regimens (AIII).
Alternate ARV regimens that do not include efavirenz should be considered in women who are planning to become pregnant or are sexually active and not using effective contraception, assuming these alternative regimens are not thought to compromise a woman’s health (BIII).
Efavirenz can be continued in women receiving an efavirenz-based regimen who present for antenatal care in the first trimester, because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy. Pregnancy is rarely recognized before 5 to 6 weeks, and unnecessary changes in ARV drugs during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission. In such situations, fetal ultrasound is recommended at 18 to 20 weeks to assess anatomy (see HIV-Infected Pregnant Women Who are Currently Receiving Antiretroviral Treatment) (CIII).
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
First-Trimester Exposure and Birth Defects
The potential harm to the fetus from maternal ingestion of a specific drug depends not only on the drug itself but also on the dose ingested; the gestational age of the fetus at exposure; the duration of exposure; the interaction with other agents to which the fetus is exposed; and, to an unknown extent, the genetic makeup of mother and fetus.
Information regarding the safety of drugs in pregnancy is derived from animal toxicity data, anecdotal experience, registry data, and clinical trials. Drug choice should be individualized and must be based on discussion with the woman and available data from preclinical and clinical testing of the individual drugs. Preclinical data include results of in vitro and animal in vivo screening tests for carcinogenicity, clastogenicity/mutagenicity, and reproductive and teratogenic effects. However, the predictive value of such tests for adverse effects in humans is unknown. For example, of approximately 1,200 known animal teratogens, only about 30 are known to be teratogenic in humans.1 Limited data exist regarding placental passage, pharmacokinetics and safety in pregnancy, and long-term safety in exposed infants of Food and Drug Administration (FDA)-approved antiretroviral (ARV) drugs (see Supplement: Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy).
In general, reports of birth defects in fetuses/infants of women enrolled in observational studies who receive ARV regimens during pregnancy are reassuring and find no difference in rates of birth defects for first-trimester compared with later exposures.2-5 In the primary analysis by the Antiretroviral Pregnancy Registry of prospective cases of ARV exposure during pregnancy provided by health care providers, prevalence of birth defects was 2.8 per 100 live births among women with a first-trimester exposure to any ARV (203 of 7,135 exposures; 95% confidence interval [CI], 2.5–3.3). The prevalence of defects is not significantly different from that in women with an initial exposure during the second and/or third trimester (2.8 per 100 live births) (prevalence ratio 1.01; 95% CI, 0.84, 1.21).6 In a recent study from France that included 13,124 live births that occurred between 1994 and 2010, 5,388 (42%) had first-trimester exposure to ARV drugs. The authors reported a significant adjusted association between first-trimester zidovudine exposure and congenital heart defects (adjusted odds ratio [AOR] 2.2; 95% CI, 1.3–3.7). Because all infants in this study underwent echocardiography, the clinical significance of the cardiac findings is uncertain.7 The authors also reported significant associations between first-trimester didanosine (AOR 1.44, 1.08–1.92) and indinavir (AOR 1.66, 1.09–2.53) exposure and head and neck defects.8 However, for both these drugs, the absolute numbers of defects in the exposed groups were low, leading to large confidence intervals and reinforcing caution in drawing any conclusions. In the primary analysis, no association was seen between first-trimester efavirenz exposure and birth defects. In an analysis from the Pediatric HIV/AIDS Cohort Study (PHACS) that included 2,580 live births, first-trimester ARV exposure overall was not associated with an increased risk of birth defects.9 In adjusted analyses, the only individual ARV drug for which first-trimester exposure was associated with birth defects was atazanavir (discussed below). In a comparison between 417 HIV- and ARV-exposed, uninfected infants and unexposed controls tested at ages 2 to 7 years, no clinically significant differences were found in echocardiographic parameters of left ventricular function and structure.10
Most studies evaluating a possible association between ARV exposure and birth defects do not evaluate maternal folate use or levels. Folate antagonists (e.g., trimethoprim-sulfamethoxazole), which have been associated with an increased risk of birth defects with first-trimester use in some, but not all, studies, may be prescribed to women with advanced HIV disease.11 Therefore, it may be important to consider the role of folate antagonists as well as folic acid supplementation when evaluating any potential association between ARV drugs and birth defects.12 Maternal tobacco and alcohol use may also serve as confounders.10 However, concerns have been raised about the risk of several ARV agents.
Efavirenz use during pregnancy has received increased scrutiny because of the results of a small study in non-human primates. Significant malformations were observed in 3 of 20 infant cynomolgus monkeys receiving efavirenz from gestational days 20 to 150 at a dose resulting in plasma concentrations comparable to systemic human exposure at therapeutic dosage.13 The malformations included anencephaly and unilateral anophthalmia in one, microphthalmia in another, and cleft palate in the third. Among pregnancies prospectively reported to the Antiretroviral Pregnancy Registry through January 2014 that had exposure to efavirenz-based regimens, a 2.3% incidence of overall birth defects was seen with first-trimester exposure, a proportion not significantly different from that observed among U.S. births in the general population.6 Defects reported prospectively included one report of myelomeningocele and a separate report of anophthalmia. The case of anophthalmia included severe oblique facial clefts and amniotic banding that is known to be associated with anophthalmia.6 In addition, six cases of central nervous system defects, including myelomeningocele, have been retrospectively reported in infants born to mothers receiving efavirenz during the first trimester.13 However, retrospective reports can be biased toward reporting of more unusual and severe cases and are less likely to be representative of the general population experience.
A meta-analysis including data from 23 studies reporting on 2,026 first-trimester exposures found no increased risk of overall birth defects in infants born to women on efavirenz during the first trimester compared with those on other ARV drugs during the first trimester (relative risk 0.78; 95% CI, 0.56–1.08). One neural tube defect was observed, giving an incidence of 0.05% (95% CI, <0.01 to 0.28).14 However, the number of reported first-trimester efavirenz exposures still remains insufficient to rule out a 2- to 3-fold increase in low-incidence birth defects (incidence of neural tube defects in the general U.S. population is 0.02% to 0.2%).15
In contrast to the meta-analysis, the Pediatric AIDS Clinical Trials Group (PACTG) protocols 219 and 219C studies reported a higher defect rate in infants with first-trimester exposure to efavirenz compared with those without first-trimester efavirenz exposure (AOR 4.31; 95% CI, 1.56–11.86). However, only 32 infants had efavirenz exposure.16 PACTG protocol P1025 is a companion study of PACTG 219 with considerable overlap in cases enrolled. Although P1025 reports a significant increased risk of congenital anomalies in infants born between 2002 and 2007 with first-trimester exposure to efavirenz,3 there is overlap in the defect cases between the 2 studies and only 41 infants with efavirenz exposure are included in this analysis. In the French study discussed above, first-trimester efavirenz use was not associated with an increase in defects in the primary analysis using the European Surveillance of Congenital Abnormalities birth defect classification system.8 In a secondary analysis using the Metropolitan Atlanta Congenital Defects Program (MACDP) birth defect classification used by the Antiretroviral Pregnancy Registry, an association was found between first-trimester efavirenz exposure and neurologic defects. However, none of the four defects were neural tube defects, and none of the defects had common embryology.7 First-trimester efavirenz exposure was not associated with an increased risk of defects in the PHACS analysis.9 Thus, additional data are needed on first-trimester efavirenz exposures to be able to more conclusively determine whether risk of neural tube defects or other malformations is elevated.
Although a causal relationship has not been established between these events and the use of efavirenz, in light of similar findings in primates the FDA labeling advises that women avoid becoming pregnant while taking efavirenz and that efavirenz not be administered in the first trimester of pregnancy, as fetal harm may occur. Treatment with efavirenz should be avoided during the first 8 weeks of pregnancy (the primary period of fetal organogenesis) whenever possible. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz and should be counseled about the potential risk to the fetus and desirability of avoiding pregnancy while on efavirenz-containing regimens. Alternate combination antiretroviral therapy (cART) regimens that do not include efavirenz should be considered in women who are planning to become pregnant or who are sexually active and not using effective contraception if such alternative regimens are acceptable to the patient and will not compromise her health. However, the Panel now recommends that efavirenz can be continued in women who present for care in the first trimester and are receiving efavirenz-based cART that is effective in suppressing viral replication. This is because the neural tube closes at 36 to 39 days after the last menstrual period; hence, the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (and pregnancy is rarely recognized before 5–6 weeks), and unnecessary changes in ARV drugs during pregnancy may be associated with a loss of virologic control and, thus, increased risk of transmission to the infant.17 In such situations, fetal ultrasound is recommended at 18 to 20 weeks to assess anatomy. For more details, see HIV-Infected Pregnant Women Who are Currently Receiving Antiretroviral Treatment.
Tenofovir Disoproxil Fumarate
Tenofovir has not demonstrated teratogenicity in rodents or monkeys. In infant monkeys with in utero exposure to tenofovir at maternal doses resulting in levels approximately 25 times those used in humans, low birth weights and reductions in fetal bone porosity were seen. Chronic administration of tenofovir to immature animals of multiple species has resulted in reversible bone abnormalities; these effects were dose-, exposure-, age-, and species-specific. Data from the Antiretroviral Pregnancy Registry show a birth defect incidence of 2.3% in 1,982 women with first-trimester tenofovir exposure, similar to that in the general population.6
As mentioned above, in the PHACS analysis atazanavir exposure (n = 222) in the first trimester was associated with an increased risk of birth defects, with an AOR of 1.93 (P = 0.004), primarily skin and musculoskeletal defects.9 In contrast, no increase in defect rate was detected in the Antiretroviral Pregnancy Registry among 922 births after first-trimester exposure to atazanavir.6
The Antiretroviral Pregnancy Registry includes additional analyses of drugs for which adequate numbers of first-trimester exposures have been reported to warrant separate analyses. For abacavir, atazanavir, darunavir, didanosine, efavirenz, indinavir, and stavudine, sufficient numbers of first-trimester exposures have been monitored to detect at least a 2-fold increase in risk of overall birth defects, and no such increases have been detected to date. For emtricitabine, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, tenofovir, and zidovudine, sufficient numbers of first-trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems. No such increases have been detected to date. A modest (but statistically significant) increase in overall birth defect rates for didanosine and nelfinavir is observed when compared with the U.S. population-based MACDP surveillance data.6 The lower bounds of the CIs for didanosine and nelfinavir (3.0% and 2.9%, respectively) are slightly above the higher bound (2.76%) for the MACDP rate. No specific pattern of defects has been detected with either didanosine or nelfinavir, and the clinical relevance of this statistical finding is unclear. The Antiretroviral Pregnancy Registry will continue to monitor didanosine and nelfinavir for any signal or pattern of birth defects.
Health care providers who are caring for HIV-infected pregnant women and their newborns are strongly advised to report instances of prenatal exposure to ARV drugs (either alone or in combination) to the Antiretroviral Pregnancy Registry as early in pregnancy as possible. This registry is an epidemiologic project to collect observational, nonexperimental data regarding ARV exposure during pregnancy for the purpose of assessing the potential teratogenicity of these drugs. Registry data will be used to supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits of treatment for individual patients. The Antiretroviral Pregnancy Registry is a collaborative project of pharmaceutical manufacturers with an advisory committee of obstetric and pediatric practitioners. The registry does not use patient names, and registry staff obtain birth outcome follow-up information from the reporting physician.
Referrals should be directed to:
Antiretroviral Pregnancy Registry
1011 Ashes Drive
Wilmington, NC 28405
Fax: 1–800–800–1052 http://www.APRegistry.com
Mills JL. Protecting the embryo from X-rated drugs. N Engl J Med. 1995;333(2):124-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/7777019.
Watts DH, Huang S, Culnane M, et al. Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication. J Perinat Med. 2011;39(2):163-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21142844.
Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21983213.
daCosta TP, Machado ES, al e. Malformations among HIV vertically exposed newborns – results from a Brazilian cohort study. Presented at: 6th IAS Conference on HIV Pathogenesis and Treatment and Prevention. 2011. Rome, Italy.
Floridia M, Mastroiacovo P, Tamburrini E, et al. Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011. BJOG. 2013;120(12):1466-1475. Available at http://www.ncbi.nlm.nih.gov/pubmed/23721372.
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989 - 31 July 2014. Wilmington, NC: Registry Coordinating Center. 2014. Available at http://www.APRegistry.com.
Mofenson LM, Watts DH. Safety of pediatric HIV elimination: the growing population of HIV- and antiretroviral-exposed but uninfected infants. PLoS Med. 2014;11(4):e1001636. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781352.
Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781315.
Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):48-55. Available at http://www.ncbi.nlm.nih.gov/pubmed/25383770.
Lipshultz SE, Williams PL, Zeldow B, et al. Cardiac effects of in-utero exposure to antiretroviral therapy in HIV-uninfected children born to HIV-infected mothers. AIDS. 2015;29(1):91-100. Available at http://www.ncbi.nlm.nih.gov/pubmed/25562493.
Ford N, Shubber Z, Jao J, Abrams EJ, Frigati L, Mofenson L. Safety of cotrimoxazole in pregnancy: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2014;66(5):512-521. Available at http://www.ncbi.nlm.nih.gov/pubmed/24853309.
Jungmann EM, Mercey D, DeRuiter A, et al. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect. 2001;77(6):441-443. Available at http://www.ncbi.nlm.nih.gov/pubmed/11714944.
Efavirenz [package insert]. Food and Drug Administration. 2010. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021360s024lbl.pdf. Accessed August 18, 2014.
Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2014;28 Suppl 2:S123-131. Available at http://www.ncbi.nlm.nih.gov/pubmed/24849471.
Watts DH. Teratogenicity risk of antiretroviral therapy in pregnancy. Curr HIV/AIDS Rep. 2007;4(3):135-140. Available at http://www.ncbi.nlm.nih.gov/pubmed/17883999.
Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727. Available at http://www.ncbi.nlm.nih.gov/pubmed/20539252.
Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1 RNA in plasma at end of pregnancy. HIV Clin Trials. 2010;11(6):303-311. Available at http://www.ncbi.nlm.nih.gov/pubmed/21239358.