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
Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants
Teratogenicity
(Last updated:9/14/2011)
Panel’s Recommendations:
• All cases of antiretroviral (ARV) drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Registry (see details at http://www.APRegistry.com) (AIII).
• Efavirenz should not be used in the first trimester and nonpregnant women receiving efavirenz should be counseled to avoid pregnancy (AIII). |
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. Data are limited for antiretroviral (ARV) drugs, particularly when used in combination therapy. 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, long-term animal carcinogenicity, and animal teratogenicity for the Food and Drug Administration (FDA)-approved ARV drugs. Concerns have been raised about the risk of several ARV agents.
In cynomolgus monkeys receiving efavirenz from gestational days 20–150 at a dose resulting in plasma concentrations comparable to systemic human exposure at therapeutic dosage, significant malformations were observed in 3 of 20 infant monkeys [2]. The malformations included anencephaly and unilateral anophthalmia in 1, microphthalmia in another, and cleft palate in the third. In prospectively reported pregnancies with exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2011, birth defects were observed in 2.7% (17 of 623) live births with first-trimester exposure; this proportion is not significantly different from that observed among U.S. births in the general population (2.7%) as reported by the Registry [3]. Defects reported prospectively included 1 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 [3]. In addition, 6 cases of central nervous system (CNS) defects, including myelomeningocele, have been retrospectively detected in infants born to mothers receiving efavirenz during the first trimester [2].
A recent meta-analysis including data from 9 cohorts with prospective reporting on 1,132 first-trimester exposures did not find an increased risk of overall birth defects among infants born to women on efavirenz during the first trimester compared with those on other ARV drugs during the first trimester (relative risk [RR] 0.87; 95% confidence interval [CI], 0.61-1.24) [4]. One neural tube defect occurred among 1,256 live births. Two subsequent smaller studies had conflicting results. A cohort in West Africa found no visible anomalies among 147 infants born after first-trimester exposure to efavirenz, while an analysis of the PACTG 219 database found a significantly increased risk of birth defects among infants born to women after first-trimester exposure to efavirenz (5 of 32; 15.6%), including 1 neural tube defect also included in the retrospective Registry cases [5-6].
Although a causal relationship has not been established between these events and the use of efavirenz, in light of similar findings in primates, efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because of the potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period of fetal organogenesis. Women of childbearing potential should undergo pregnancy testing prior to initiation of efavirenz and should be counseled about the potential risk to the fetus and need to avoid pregnancy. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception. Use after the first trimester can be considered if, after consideration of other alternatives, it is the best choice for an individual woman. If efavirenz is to be continued postpartum, adequate contraception must be ensured.
Tenofovir has not demonstrated teratogenicity in rodents or monkeys. In infant monkeys with in utero exposure to tenfovir 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 2.4% in 1,092 women with first-trimester tenofovir exposure, similar to that in the general population [3]. However, because of the limited data on use in human pregnancy and concern regarding potential fetal bone effects and potential nephrotoxicity, tenofovir is recommended as an alternative rather than a preferred drug for use in pregnancy unless the pregnant woman has HIV/hepatitis B coinfection (see Table 5).
Among cases of first-trimester didanosine exposure reported to the Antiretroviral Pregnancy Registry, defects have been noted in 4.7% (19 of 406), compared with a rate of 4.3% (20 of 460) among those with didanosine exposures later in pregnancy [3]. All defects were reviewed in detail by the Registry, and no pattern of defects was discovered. However, these data do suggest a possible higher risk of birth defects with exposure to didanosine in the first trimester compared with the frequency of birth defects observed in the general population and with the use of other ARV agents, and the Registry continues to follow this.
See Supplement: Safety and Toxicity of Individual Antiretroviral Drugs in Pregnancy to obtain detailed information on individual drugs.
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. 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
Research Park
1011 Ashes Drive
Wilmington, NC 28405
Telephone: 1–800–258–4263
Fax: 1–800–800–1052
http://www.APRegistry.com
References
1. Mills JL. Protecting the embryo from X-rated drugs. N Engl J Med. 1995 Jul 13;333(2):124-125.
2. Bristol-Myers Squibb. Sustiva drug label, 11/30/2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021360s024lbl.pdf.
3. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 – 31 July 2011. Wilmington, NC: Registry coordinating center; 2011. www.apregistry.com
4. Ford N, Mofenson L, Kranzer K, et al. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS. 2010 Jun 19;24(10):1461-1470.
5. Ekouevi DK, Coffie PA, Ouattara E, et al. Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS Databases, Abidjan, Cote d'Ivoire. J Acquir Immune Defic Syndr. 2011 Feb 1;56(2):183-187.
6. 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 Aug;29(8):721-727.