PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
The limited human data do not allow a prediction as to the risk of amprenavir during pregnancy. The developmental toxicity observed in animals at doses less than the human clinical dose is a potential concern for human pregnancies. However, if indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Amprenavir is an inhibitor of HIV type 1 (HIV-1) protease. Protease is an enzyme that is required for the cleavage of viral polyprotein precursors into active functional proteins found in infectious HIV. Amprenavir, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infections.
In reproduction studies with amprenavir, doses two times the human clinical exposure based on AUC comparisons (HCE) in male and female rats had no effect on fertility or mating (1). During embryo and fetal development, doses 1/2 the HCE produced thymic elongation and incomplete ossification of bones. When administered from day 7 of gestation to day 22 of lactation, a dose two times the HCE was associated with reduced body weights. However, subsequent development of the offspring, including fertility and reproductive performance, was not affected (1). In rabbits, doses up to 1/20th the HCE were associated with abortions and minor skeletal variations resulting from deficient ossification of the femur, humerus trochlea, and humerus (1).
Amprenavir is transferred across rat and rabbit placentas to the fetus (1). In an ex vivo human placental model, the antiviral agent also readily crossed to the fetus but with a clearance index less than abacavir. No accumulation of the drug was measured (2). The placental transfer is consistent with the molecular weight of amprenavir (about 506).
The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2009, prospective data (reported before the outcomes were known) involving 4702 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (3). Congenital defects were noted in 134, a prevalence of 2.8% (95% confidence interval [CI] 2.4–3.4). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (2.5%, 95% CI 2.1–2.9). The prevalence rates for the two periods did not differ significantly. There were 288 infants with birth defects among 10,803 live births with exposure anytime during pregnancy (2.7%, 95% CI 2.4–3.0). The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were 38 outcomes exposed to amprenavir (28 in the 1st trimester and 10 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There was one birth defect among those exposed in the 1st trimester and none in those exposed in the 2nd/3rd trimesters. In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects with efavirenz exposure in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (3). (See Lamivudine for required statement.)
A public health advisory was issued by the FDA on the association between protease inhibitors and diabetes mellitus (4). Because pregnancy is a risk factor for hyperglycemia, there was concern that these antiviral agents would exacerbate this risk. An abstract published in 2000 described the results of a study involving 34 pregnant women treated with protease inhibitors (none with amprenavir) compared with 41 controls that evaluated the association with diabetes (5). No association between protease inhibitors and an increased incidence of gestational diabetes was found.
Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (6,7). The same conclusion was reached in a 2003 review with the added admonishment that therapy must be continuous to prevent emergence of resistant viral strains (8). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected patients continued the recommendation that the therapy, with the exception of efavirenz, should be continued during pregnancy (9). If indicated, therefore, protease inhibitors, including amprenavir, should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. The updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2010 (10). Women receiving antiretroviral therapy during pregnancy should continue the therapy but, regardless of the regimen, zidovudine administration is recommended during the intrapartum period to prevent vertical transmission of HIV to the newborn (10).
No reports describing the use of amprenavir during human lactation have been located. The antiviral agent is excreted into the milk of lactating rats (1). In addition, the molecular weight (about 506) is low enough that excretion into human breast milk should be expected.
Reports on the use of amprenavir during human lactation are unlikely because the antiviral agent is used in the treatment of HIV infections. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (6,7,9,11–13). In developing countries, breastfeeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection in spite of breastfeeding when compared with controls (see Zidovudine).
1.Product information. Agenerase. Glaxo Wellcome, 2000.
2.Bawdon RE. The ex vivo human placental transfer of the anti-HIV nucleoside inhibitor abacavir and the protease inhibitor amprenavir. Infect Dis Obstet Gynecol 1998;6:244–6.
3.Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009. Wilmington, NC: Registry Coordinating Center; 2009. Available at www.apregistry.com. Accessed May 29, 2010.
4.CDC. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR-2.
5.Fassett M, Kramer F, Stek A. Treatment with protease inhibitors in pregnancy is not associated with an increased incidence of gestational diabetes (abstract). Am J Obstet Gynecol 2000;182:S97.
6.Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276;146–54.
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9.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. December 1, 2009:1–161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed September 17, 2010:60, 96–8.
10.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 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. May 24, 2010:1–117. Available at http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed September 17, 2010:30 (Table 5).
11.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
12.De Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7.
13.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.