It is estimated there are 350–400 million people worldwide chronically infected with HBV. Many of these are women and of reproductive age. As such, they may face therapeutic decisions regarding antiviral therapy and the implication this may have on future or current pregnancies. This article reviews the data of all antivirals licensed for use against hepatitis B infection regarding teratogenicity, carcinogenicity, clinical experience during pregnancy, placental transfer and excretion in breast milk.
CoursagetP., YvonnetB., ChotardJ.Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol1987; 22: 1–5.
3.
McMahonB.J., AlwardW.L., HallD.B.Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis1985; 151: 599–603.
4.
XuW.M., CuiY.T., WangL.Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat2009; 16: 94–103.
5.
FeldJ.J., HoofnagleJ.H.Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature2005; 436: 967–972.
6.
WongD.K., CheungA.M., O'RourkeK., NaylorC.D., DetskyA.S., HeathcoteJ.Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med1993; 119: 312–323.
7.
CooksleyW.G.E., PiratvisuthR., LeeS-D. Peginterferon alfa-2a (40kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat2003; 10: 298–305.
8.
JanssenH.L.A., SenturkH., ZeuzemS.Peginterferon alfa-2b and lamivudine combination therapy compared with peginterferon alfa-2b for chronic HBeAg positive hepatitis B: a randomized trial in 307 patients. Hepatology2003; 38Suppl 1: 246A.
9.
BusterE.H., FlinkH.J., CakalogluY.Sustained HBeAg and HBsAg loss after long-term follow up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology2008; 135: 459–467.
10.
PonsJ.C., LebonP., FrydmanR., DelfraissyJ.F.Pharmacokinetics of interferon-alpha in pregnant women and fetoplacental passage. Fetal Diagn Ther1995; 10: 7–10.
11.
EvansA.T., CarandangG., QuilliganE.J., CesarioT.C.Interferon responses in maternal and fetal mice. Am J Obstet Gynecol1985; 152: 99–102.
12.
HaggstromJ., AdrianssonM., HybbinetteT., HarnbyE., ThorbertG.Two cases of CML treated with alpha-interferon during second and third trimester of pregnancy with analysis of the drug in the new-born immediately postpartum. Eur J Haematol1996; 57: 101–102.
13.
KumarA.R., HaleT.W., MockR.E.Transfer of interferon alfa into human breast milk. J Hum Lact2000; 16: 226–228.
14.
BaerM.R.Normal full-term pregnancy in a patient with chronic myelogenous leukemia treated with alpha-interferon. Am J Hematol1991; 37: 66.
15.
MilanoV., GabrielliS., RizzoN.Successful treatment of essential thrombocythemia in a pregnancy with recombinant interferon-alpha 2a. J Matern Fetal Med1996; 5: 74–78.
16.
MancusoA., ArditaF.V., LeonardiJ., ScuderiM.Interferon alpha-2a therapy and pregnancy. Report of a case of chronic inflammatory demyelinating polyneuropathy. Acta Obstet Gynecol Scand1998; 77: 869–870.
17.
TrotterJ.F., ZygmuntA.J.Conception and pregnancy during interferon-alpha therapy for chronic hepatitis C. J Clin Gastroenterol2001; 32: 76–78.
18.
HiratsukaM., MinakamiH., KoshizukaS., SatoI.Administration of interferon-alpha during pregnancy: effects on fetus. J Perinat Med2000; 28: 372–376.
19.
LabargaP., PinillaJ., CachorroI., RuizY.Infant of 22 months of age with no anomalies born from a HCV-and HIV-infected mother under treatment with pegylated interferon, ribavirin and antiretroviral therapy during the first 16 weeks of pregnancy. Reprod Toxicol2007; 24: 414–416. [Erratum in Reprod Toxicol 2008; 26: 310].
20.
GilesM.L., AudsleyJ., LewinS.R.Lamivudine. In GraysonL., CroweS., MillsJ.. (Editors). Kucers’ the use of antibiotics: a clinical review of antibacterial, antifungal and antiviral drugs.6th Ed.London: Hodder Arnold2010; pp. 2545–2562.
21.
LaiC.L., ChienR.N., LeungN.W.A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med1998; 339: 61–68.
22.
LiawY.F., SungJ.J.Y., ChowW.C.Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med2004; 351: 1521–1531.
23.
LokA.S., LaiC.L., LeungN.Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology2003; 125: 1714–1722.
24.
BloomS.L., DiasK.M., BawdonR.E., GilstrapL.C.III. The maternal-fetal transfer of lamivudine in the ex vivo human placenta. Am J Obstet Gynecol1997; 176: 291–293.
25.
MandelbrotL., PeytavinG., FirtionG., FarinottiR.Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol2001; 184: 153–158.
Antiretroviral Pregnancy Registry Steering Committee.Antiretroviral Pregnancy Registry international report for 1 January 1989 through 31 July 2010. Wilmington, NC: Registry Coordinating Center; 2010. (Updated December 2010. Accessed 27 April 2011.) Available from www.apregistry.com/forms/interim_report.pdf.
28.
van NunenA.B., de ManR.A., HeijtinkR.A., NeistersH.G., SchalmS.W.Lamivudine in the last 4 weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients. J Hepatol2000; 32: 1040–1041.
29.
KazimS.N., WakilS.M., KhanL.A., HasnainS.E., SarinS.K.Vertical transmission of hepatitis B virus despite maternal lamivudine therapy. Lancet2002; 359: 1488–1489.
30.
van ZonneveldM., van NunenA.B., NiestersH.G., de ManR.A., SchalmS.W., JanssenH.L.Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat2003; 10: 294–297.
31.
ShapiroR.L., HollandD.T., CapparelliE.Antiretroviral concentrations in breastfeeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis2005; 192: 720–727.
32.
MoodleyJ., MoodleyD., PillayK.Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis1998; 178: 1327–1333.
33.
MirochnickM., ThomasT., CapparelliE.Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother2009; 53: 1170–1176.
34.
BenhammouV., WarszawskiJ., BellecS.Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors. AIDS2008; 22: 2165–2177.
35.
MarcellinP., ChangT.T., LimS.G.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med2003; 348: 808–816.
36.
HadziyannisS.J., TassopoulosN.C., HeathcoteE.J.Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med2003; 348: 800–807.
37.
ChenE.Q., WangL.C., LeiJ., XuL., TangH.Meta-analysis: adefovir dipivoxil in combination with lamivudine in patients with lamivudine-resistant hepatitis B virus. Virol J2009; 6: 163.
38.
Hepsera® (adefovir dipivoxil). Product information version 32006. Gilead SciencesFoster City, CA, USA.
39.
ChangT.T., GishR.G., de ManR.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med2006; 354: 1001–1010.
40.
LaiC.L., ShouvalD., LokA.S.Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med2006; 354: 1011–1020.
41.
ChangT.T., LiawY.F., WuS.S.Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology2010; 52: 886–893.
42.
Baraclude® (entecavir monohydrate).Product information2010. Bristol-Myers Squibb.Princeton, NJ, USA.
43.
Viread (tenofovir disoproxil fumarate).Product information2005. Gilead SciencesFoster City, CA, USA.
44.
MarcellinP., HeathcoteE.J., ButiM.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med2008; 359: 2442–2455.
45.
BurchettS.K., BestB., MirochnickM.Tenofovir pharmacokinetics during pregnancy, at delivery and post partum.14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los Angeles, CA, USA. Abstract 738b.
46.
BonoraS., Gonzalez de RequenaD., ChiesaE.Transplacental passage of tenofovir (TDF) and other antiretrovirals (ARVs) at delivery.14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los Angeles, CA, USA. Abstract 738a.
47.
TarantalA.F., CastilloA., EkertJ.E., BischofbergerN., MartinR.B.Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). J Acquir Immune Defic Syndr2002; 29: 207–220.
48.
Van RompayK.K.A., Durand-GasselinL., BrignoloL.L.Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Chemother2008; 52: 3144–3160.
49.
HaberlA., LindeR., ReitterA.Safety and efficacy of tenofovir in pregnant women.15th Conference on Retroviruses and Opportunistic Infections. 3–6 February 2008, Boston, MA, USA. Abstract 627a.
50.
NurutdinovaD., OnenN.F., HayesE., MondyK., OvertonE.T.Adverse effects of tenofovir use in HIV-infected pregnant women and their infants. Ann Pharmacother2008; 42: 1581–1585.
51.
ChidzivaE., ZwalangoE., RussellE.Outcomes in infants born to HIV-infected mothers receiving long-term ART in the DART trial, 2004–2009.17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 924.
52.
LindeR., KonigsC., RusickeE., HaberlA., ReitterA., KreuzW.Tenofovir therapy during pregnancy does not affet renal function in HIV-exposed children.17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 925.
53.
ViganoA., ZuccottiG.V., StucchiS.Exposure during gestation to HAART, including tenofovir, does not impair bone status and metabolism in HIV children born to HIV+ mothers.17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 926.
54.
PurdyJ.B., GafniR.I., ReynoldsJ.C., ZeichnerS., HazraR.Decreased bone mineral density with off-label use of tenofovir in HIV-infected children and adolescents. J Pediatr2008; 152: 582–584.
55.
GafniR.I., HazraR., ReynoldsJ.C.Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children. Pediatrics2006; 118: e711–e718.
56.
KimJ.W., ParkS.H., LouieS.G.Telbivudine: a novel nucleoside analog for chronic hepatitis B. Ann Pharmacother2006; 40: 472–478.
57.
ButD.Y., YuenM., FungJ., LaiC.L.Safety evaluation of telbivudine. Expert Opin Drug Saf2010; 9: 821–829.
58.
LaiC.L., GaneE., LiawY.F.Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med2007; 357: 2576–2588.
59.
LiawY.F., GaneE., LeungN.2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology2009; 136: 486–495.
60.
HanG., ZhaoW., JiangH.A study of the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. Hepatol Int2010; 4: 58.
61.
BridgesE.G., SeldenJ.R., LuoS.Nonclinical safety profile of telbivudine, a novel potent antiviral agent for treatment of hepatitis B. Antimicrob Agents Chemother2008; 52: 2521–2528.
