Secondary Logo

Journal Logo

Original Research

Cost-Effectiveness of Maternal Treatment to Prevent Perinatal Hepatitis B Virus Transmission

Unal, Elizabeth Ramsey MD; Lazenby, Gweneth B. MD; Lintzenich, Anne E. MD; Simpson, Kit N. DrPH; Newman, Roger MD; Goetzl, Laura MD, MPH

Author Information
doi: 10.1097/AOG.0b013e31822ad2c2
  • Free

Hepatitis B virus is a major global health concern, with prevalence rates as high as 10–15% in some regions of the world.1,2 Even in the United States, which overall is a low-prevalence region (less than 2%),2 certain immigrant populations have much higher rates, reflective of their countries of origin.2,3 Perinatal transmission is an important cause of chronic hepatitis B, accounting for 35–50% of the disease in endemic countries.4 Whereas adults infected with hepatitis B virus infections have less than a 5% chance of developing chronic infection, 90% of perinatally infected children become chronic carriers.59 Chronically infected individuals are at high risk for cirrhosis and hepatocellular carcinoma. Approximately 25% of chronic hepatitis B carriers die prematurely as a result of one or both of these complications,2 and this rate may be up to 40% for perinatally infected individuals.10

Currently recommended active-passive immunoprophylaxis for all newborns of women positive for hepatitis B surface antigen is 85–95% effective in preventing perinatal transmission.11 However, multiple studies have shown that women with high levels of viral replication remain at elevated risk. Perinatal transmission rates despite appropriate neonatal prophylaxis in these highest-risk women have been reported to be 13–62.5%,1219 with most estimates between 15% and 30%. The transition point in maternal viral load at which transmission rates begin to rise dramatically is approximately 106–108 copies/mL.12,13,16

A significant proportion of perinatal transmission in women with high viral loads is now believed to be intrauterine.13,14,17,2022 Therefore, studies have been conducted to evaluate the benefit of maternal administration of either lamivudine or hepatitis B immune globulin (HBIG) in the third trimester to decrease transmission rates. Most of these studies have been in Asia, and the results have been promising. In 2010, Shi et al published two meta-analyses on the use of third-trimester maternal lamivudine or HBIG in women with high viral loads.18,19 These meta-analyses found a 69% and 67% reduction in infant hepatitis B surface antigen positivity at age 9–12 months with the use of lamivudine and HBIG, respectively. Despite this evidence, use of these agents to reduce perinatal hepatitis B virus transmission is not standard of care in the United States. Our objective was to estimate the cost-effectiveness of maternal treatment with lamivudine or HBIG.


We created a decision-tree model to estimate the cost-effectiveness of maternal administration of lamivudine or HBIG in the third trimester to prevent perinatal hepatitis B transmission compared with no maternal treatment (Fig. 1). The decision tree was created and run using Microsoft Excel 2008 12.2.3. This project was not submitted to our institutional review board, as all data used were extracted from published studies, and no institutional or individual patient information is included in this analysis. The Medical University of South Carolina Office of Research Integrity states that a study of this kind is not considered to be human subjects research and thus does not require University IRB approval.

Fig. 1
Fig. 1:
Decision tree for maternal treatment with lamivudine or hepatitis B immune globulin to prevent perinatal hepatitis B virus transmission.Fig. 1. Unal. Preventing Perinatal HBV Transmission. Obstet Gynecol 2011.

Our baseline assumptions are outlined in Table 1. The overall perinatal hepatitis B transmission rate without maternal treatment (15.7%) was obtained by averaging the transmission rates in the control groups from two recent meta-analyses, one on lamivudine and the other on HBIG, both by Shi et al.18,19 Both meta-analyses included randomized controlled trials of maternal lamivudine or HBIG compared with no maternal treatment, in English language or Chinese peer-reviewed literature. Transmission rates without treatment stratified by maternal viral load were taken from a study by Yuan et al.12 The odds ratios for perinatal transmission with maternal treatment compared with no treatment (0.31 and 0.33 for lamivudine and HBIG, respectively) were taken from the meta-analyses18,19 and applied to the averaged transmission rate without maternal treatment to obtain transmission rates with treatment (4.9% and 5.2% for lamivudine and HBIG, respectively). These numbers were all based on infant hepatitis B surface antigen positivity at age 9–12 months. We also used the odds ratios for perinatal transmission from the two meta-analyses18,19 and applied those numbers to transmission rates without treatment by maternal viral load to estimate the cost-effectiveness of treatment stratified by maternal viral load.

Table 1
Table 1:
Model Inputs: Probabilities

We assumed that 90% of infants infected perinatally would become chronic carriers.59 Because perinatal transmission rates are very low in women with low viral loads16 and thus additional treatment with lamivudine or HBIG is most beneficial in patients with high viral activity, we made the assumption that maternal hepatitis B virus DNA viral load would be assessed before initiating third-trimester maternal treatment.

We assumed 100% compliance with current recommendations for active-passive immunoprophylaxis (HBIG and vaccination) for all newborns of women positive for hepatitis B surface antigen. Thus our model applies the current standard of immunoprophylaxis to both groups. We assumed maternal dosing regimens of lamivudine 100 mg orally once daily from 28 weeks of gestation through 4 weeks postdelivery and HBIG 200 international units administered intramuscularly once monthly starting at 28 weeks of gestation, as these have been the most commonly studied regimens. Costs for lamivudine and HBIG were taken from the 2010 Red Book.23 The model also assumes no maternal or fetal risk from third-trimester use of lamivudine or HBIG.

The model was designed to estimate the lifelong medical costs of chronic hepatitis B infection from a health systems perspective. Life expectancy in patients with chronic hepatitis B was taken from 2006–2007 Florida State hospital discharge data, and life expectancy in a general population was taken from 2007 National Vital Statistics data.24,25 The lifelong cost of chronic hepatitis B infection was calculated based on published yearly costs by different hepatitis B health states defined from a health systems perspective,26 using previous studies to determine the number of patients who would progress to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, hepatic transplant, or a combination of these over a lifetime.2734 We assumed that all hepatocellular carcinoma cases arose in the setting of cirrhosis. Because the lifelong natural history of perinatal hepatitis B virus infection is not well described, we derived most of these assumptions from the literature on chronic hepatitis B in general, rather than literature specific to perinatally transmitted chronic hepatitis B. Although serious childhood complications do occur, most perinatally infected children do not experience significant complications until adulthood.35,36 For the model, we made the conservative assumption that no medical complications and therefore no costs accrue until age 20. Cost calculations are outlined in Tables 2 and 3.

Table 2
Table 2:
Model Inputs: Costs
Table 3
Table 3:
Calculation of Lifetime Cost of Hepatitis B Virus Infection

A sensitivity analysis was then performed by varying the estimates for degree of reduction in perinatal transmission with maternal treatment, medical severity of chronic hepatitis B infection, and lifelong cost of chronic hepatitis B. We also varied the percentage of women who would warrant treatment after viral load determination, to evaluate the cost of checking viral loads in all patients to determine need for treatment in some.

Because HBIG and lamivudine are hypothesized to have different mechanisms of action in reducing perinatal hepatitis B transmission, it has been suggested that additive benefit may be expected if both HBIG and lamivudine are administered in combination.20 To our knowledge, this hypothesis has not been evaluated in prospective studies. To evaluate whether this strategy would be cost-effective, we estimated a model using both HBIG and lamivudine in combination, assuming varying levels of additional benefit in reducing perinatal hepatitis B transmission.


Using our base-case estimates, use of either lamivudine or HBIG was not only cost-effective, but also cost-saving, for all situations except lamivudine at a maternal viral load of less than 108 copies/mL. For every 100 pregnant women positive for hepatitis B surface antigen treated with lamivudine, 9.7 cases of chronic hepatitis B virus infections are prevented, with a cost-savings of $5,184 and 1.3 life-years gained per patient treated. For HBIG, 9.5 cases of chronic hepatitis B virus infections are prevented for each 100 pregnant women treated, with a cost savings of $5,887 and 1.2 life-years gained per patient treated. The only instance in which no cost savings was achieved (lamivudine at a maternal viral load of less than 108 copies/mL) had a cost per patient of $390 to prevent two cases of chronic hepatitis B virus infections for each 100 patients treated, well within the limits of what is commonly considered to be cost-effective. For each of the other cases considered, use of lamivudine or HBIG provided a cost savings, in addition to preventing chronic hepatitis B and its sequelae. Detailed results for the base-case estimates are outlined in Table 4.

Table 4
Table 4:
Results of Base-Case Assumptions

One-way and multi-way sensitivity analyses were performed by altering estimates for the percentage of women whose viral load would warrant treatment (ie, the cost of checking viral loads in all women to determine need for maternal treatment in some), the degree of reduction in perinatal transmission with maternal treatment, the medical severity and life expectancy in chronic hepatitis B infection, and lifelong cost of chronic hepatitis B. The results are summarized in Table 5.

Table 5
Table 5:
Results of Sensitivity Analysis

Adjustment of parameters related to percentage of chronic hepatitis B patients developing cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma had modest effects on lifetime cost of chronic hepatitis B infection. Altering these parameters yielded a lowest lifetime cost of $72,045 and highest lifetime cost of $74,600. If both life expectancy (ranging from 50 years to 64.9 years) and distribution of chronic hepatitis B health states were altered, the lowest lifetime cost was $64,295 and highest was $74,600.

Altering the proportion of women who would have a viral load drawn, but not warrant maternal treatment, was also evaluated in the sensitivity analysis. The base-case estimates assumed that all women having a third-trimester viral load would be treated with lamivudine or HBIG. Because most experts recommend reserving third-trimester maternal treatment for women at highest risk of perinatal transmission from high viral activity, all women would need to have a viral load drawn to determine need for treatment. The proportion of women with viral loads high enough to warrant treatment would vary by population. Even if only 10% of women qualified for third-trimester maternal treatment based on high viral loads, one-way sensitivity analysis demonstrates that this strategy remains cost-saving for both lamivudine and HBIG.

The parameter most sensitive to changes in baseline estimates was the degree of reduction in perinatal transmission with treatment. One-way sensitivity analysis for lamivudine showed that for a baseline transmission rate without treatment of 15.7%,18 if the risk reduction with treatment is at least 18.5% (ie, from 15.7% to 12.8%), this strategy remains cost-saving. For HBIG, using the baseline transmission rate without treatment of 15.7%, treatment remains cost-saving if the reduction in perinatal transmission is at least 9.6% (ie, from 15.7% to 14.2%). When two-way sensitivity analysis was performed, as long as the degree of risk reduction was at least 39.5% for lamivudine and at least 30.6% for HBIG, treatment remained cost-saving even if only 10% of women tested with a third-trimester viral load warrant treatment.

When combination therapy of HBIG and lamivudine was evaluated using baseline estimates, this strategy remained cost-saving even if the degree of reduction was only 1% more than with either lamivudine or HBIG alone. Assuming a baseline transmission rate without treatment of 15.7%, and a reduction in transmission of 70% (compared with 69% for lamivudine), the cost savings are $2,278 per patient treated. If only 10% of patients in whom a viral load is drawn warrant treatment, using lamivudine and HBIG in combination remains cost-saving with $1,225 saved per patient treated.


Despite evidence of benefit, use of lamivudine or HBIG to reduce perinatal transmission of hepatitis B virus is not common practice in the United States. Our analysis demonstrates that adoption of maternal third-trimester treatment with either agent in women with high viral loads would be not only cost-effective, but also cost-saving.

Perinatal transmission of hepatitis B is uncommon in women with low viral loads, with some series even reporting no cases of transmission in women with viral loads less than 105 copies/mL.12,16 However, the literature is consistent in revealing a dramatic rise in perinatal transmission, despite appropriate neonatal prophylaxis, beginning at maternal viral loads around 106–108 copies/mL.12,13,16 The transmission rates range from 5% to 13% between 106 and 107 copies/mL, and rise to the 40–50% range in women with viral loads of 108 copies/mL or higher.12,13

Our model does have limitations. The model assumes no significant maternal or fetal risk from lamivudine or HBIG. Based on currently available data, this is a reasonable assumption, but potential concerns remain. Studies in both pregnant and nonpregnant patients show that short courses of lamivudine (12–16 weeks) are well tolerated and safe.18,37 Because a strategy of lamivudine to prevent perinatal transmission would not be initiated until the third trimester, birth defects should not be a concern, although data regarding teratogenesis are also reassuring.38 One serious theoretical concern regarding use of lamivudine is development of resistance. Long-term lamivudine use is associated with high rates of resistance: 12.8% after 1 year and 76% with 5 or more years of use.39,40 Resistance has not been reported to be an issue after short-term use of lamivudine in pregnancy for perinatal transmission prevention, but it remains a theoretical concern.

Another potential concern is postpartum flare of disease activity in hepatitis B virus–positive women treated with lamivudine. In one Dutch study,41 against a historical background flare rate of 10–27% per year, 36% of women not treated with lamivudine experienced a flare (3-fold increase in alanine aminotransferase) in the 6 months after delivery. Among women treated with lamivudine, this incidence was 62%. This study was retrospective, and the women in the lamivudine group were at greater risk of postpartum flares by virtue of higher disease activity. Nonetheless, withdrawal flares are known to occur in 17–25% of nonpregnant individuals after cessation of lamivudine therapy,42,43 and this risk will likely need to be evaluated in a prospective fashion in women treated to prevent perinatal transmission. The women in the study described above41 stopped lamivudine immediately after delivery, and the now more common regimen of continuing therapy until 4 weeks postpartum may provide some protection from posttreatment flare.

With regard to HBIG, its safety profile is also good. There has been no reported increase in hepatitis B virus mutation among infected newborns of mothers treated with HBIG.19 However, because HBIG is made from human plasma, there is a small theoretical risk of infectious disease transmission, and anaphylactic reactions are also theoretically possible. Significant adverse effects have not been reported in studies administering HBIG to pregnant women.19

An additional limitation of our model is that the lifelong history of congenitally acquired chronic hepatitis B is not clearly defined in the literature. We therefore used studies of chronic hepatitis B in general to derive our assumptions for prognosis and life expectancy. Because it is believed that perinatal transmission may lead to earlier onset of severe hepatic sequelae, our use of the general literature on chronic hepatitis B would, if anything, lead to more conservative conclusions. Likewise, we also made the conservative assumption that congenitally infected children would not have serious sequelae, and thus not accrue cost, until age 20. In fact, children with chronic hepatitis B do require periodic monitoring of their disease,44 and there can be rare serious sequelae during childhood.35,36 The costs of this surveillance were not included in our analysis. Again, the omission of these costs from our model would only underestimate cost savings from prevention of perinatal hepatitis B virus transmission.

Although our results are subject to the above limitations as well as the inherent limitations of cost-effectiveness analyses, our analysis demonstrates impressive cost savings across a wide range of assumptions. Based on our findings and the current literature demonstrating a consistent rise in perinatal transmission beginning at maternal viral loads around 106 copies/mL despite appropriate neonatal immunoprophylaxis,12,13,16 we recommend screening women positive for hepatitis B surface antigen at 24–28 weeks of gestation and initiating prophylaxis with either lamivudine or HBIG if the viral load is at least 106 copies/mL. Maternal prophylaxis to prevent perinatal hepatitis B virus transmission is both medically beneficial and cost-saving, and this strategy should be strongly considered in the United States.


1. World Health Organization. Hepatitis B: fact sheet. Available at: Retrieved March 10, 2011.
2. Centers for Disease Control and Prevention. Hepatitis B information for health professionals. Available at: Retrieved March 5, 2011.
3. Euler GL, Wooten KG, Baughman AL, Williams WW. Hepatitis B surface antigen prevalence among pregnant women in urban areas: implications for testing, reporting, and preventing perinatal transmission. Pediatrics 2003;111(5 pt 2):1192–7.
4. Yao JL. Perinatal transmission of hepatitis B virus infection and vaccination in China. Gut 1996;38(suppl 2):S37–8.
5. Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang SA, et al.; Advisory Committee on Immunization Practices (ACIP). MMWR A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. Centers for Disease Control and Prevention; , 2005. Available at:
6. McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al.. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:599–603.
7. Edmunds WJ, Medley GF, Nokes DJ, Hall AJ, Whittle HC. The influence of age on the development of the hepatitis B carrier state. Proc Biol Sci 1993;253:197–201.
8. Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis 1995;20:992–1000.
9. Beasley RP, Hwang LY, Lee GC, Lan CC, Roan CH, Huang FY, et al.. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983;2:1099–102.
10. Lok AS. Chronic hepatitis B. N Engl J Med 2002;346:1682–3.
11. Andre FE, Zuckerman AJ. Review: protective efficacy of hepatitis B vaccines in neonates. J Med Virol 1994;44:144–51.
12. Yuan J, Lin J, Xu A, Li H, Hu B, Chen J, et al.. Antepartum immunoprophylaxis of three doses of hepatitis B immunoglobulin is not effective: a single-centre randomized study. J Viral Hepat 2006;13:597–604.
13. Li XM, Shi MF, Yang YB, Shi ZJ, Hou HY, Shen HM, et al.. Effect of hepatitis B immunoglobulin on interruption of HBV intrauterine infection. World J Gastroenterol 2004;10:3215–7.
14. Xiao XM, Li AZ, Chen X, Zhu YK, Miao J. Prevention of vertical hepatitis B transmission by hepatitis B immunoglobulin in the third trimester of pregnancy. Int J Gynaecol Obstet 2007;96:167–70.
15. Van Zonnefeld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat 2003;10:294–7.
16. del Canho R, Grosheide PM, Mazel JA, Heijtink RA, Hop WC, Gerards LJ, et al.. Ten-year neonatal hepatitis B vaccination program, The Netherlands, 1982–1992: protective efficacy and long-term immunogenicity. Vaccine 1997;15:1624–30.
17. Xu Q, Xiao L, Lu XB, Zhang YX, Cai X. A randomized controlled clinical trial: Interruption of intrauterine transmission of hepatitis B virus infection with HBIG. World J Gastroenterol 2006;12:3434–7.
18. Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol 2010;116:147–59.
19. Shi Z, Li X, Ma L, Yang Y. Hepatitis B immunoglobulin injection in pregnancy to interrupt hepatitis B virus mother-to-child transmission: a meta-analysis. Int J Infect Dis 2010;14:e622–34.
20. Li XM, Yang YB, Hou HY, Shi ZJ, Shen HM, Teng BQ, et al.. Interruption of HBV intrauterine transmission: a clinical study. World J Gastroenterol 2003;9:1501–3.
21. Zhang SL, Han XB, Yue YF. Relationship between HBV viremia level of pregnant women and intrauterine infection: neated PCR for detection of HBV DNA. World J Gastroenterol 1998;4:61–3.
22. Zhang SL, Yue YF, Bai GQ, Shi L, Jiang H. Mechanism of intrauterine infection of hepatitis B virus. World J Gastroenterol 2004;10:437–8.
23. 2010 Red Book: Pharmacy's Fundamental Reference. Montvale (NJ): Thomson Medical Economics; 2010.
24. Xu JQ, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. National Vital Statistics Reports, vol. 58, no. 19. Hyattsville (MD): National Center for Health Statistics; 2010.
25. HCUP Florida State2006 and 2007 Discharge Data. Available at: Retrieved March 2011.
26. Lee TA, Veenstra DL, Iloeje UH, Sullivan SD. Cost of chronic hepatitis B infection in the United States. J Clin Gastroenterol 2004;38(10 suppl 3):S144–7.
27. Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed [published online ahead of print February 16, 2011]. J Gastroenterol Hepatol doi:10.1111/j.1440-1746.2011.06695.x.
28. Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al.. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology 1995;21:77–82.
29. Fattovich G, Pantalena M, Zagni I, Realdi G, Schalm SW, Christensen E; European Concerted Action on Viral Hepatitis (EUROHEP). Effect of hepatitis B and C virus infection on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol 2002;97:2886–95.
30. Fattovich G. Natural history of hepatitis B. J Hepatol 2003;39(suppl 1):S50–8.
31. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 suppl 1):S35–50.
32. Fattovich G, Olivari N, Pasino M, D'Onofrio M, Martone E, Donato F. Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut 2008;57:84–90.
33. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, et al.. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol 1998;28:930–8.
34. U.S. Department of Health and Human Services. 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999–2008. Rockville (MD): Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; 2009.
35. Marx G, Martin SR, Chicoine JF, Alvarez F. Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins. J Infect Dis 2002;186:295–301.
36. Bortolotti F, Jara P, Crivellaro C, Hierro L, Cadrobbi P, Frauca E, et al.. Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period. J Hepatol 1998;29:184–90.
37. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995;333:1657–61.
38. Antiretroviral Pregnancy Registry Steering Committee. The Antiretroviral Pregnancy Registry Interim Report 1 January 1989 through 31 July 2010. Wilmington (NC): Registry Coordinating Center; 2010. Available at: Retrieved March 12, 2011.
39. Zhao S, Tang L, Fan X, Chen L, Zhou R, Dai X. Comparison of the efficacy of lamivudine and telbivudine in the treatment of chronic hepatitis B: a systematic review. Virol J. 2010;7:211.
40. Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy. Hepatology 2009;49(5 suppl):S174–84.
41. ter Borg MJ, Leemans WF, de Man RA, Janssen HL. Exacerbation of chronic hepatitis B infection after delivery. J Viral Hepat 2008;15:37–41.
42. Honkoop P, de Man RA, Niesters HG, Zondervan PE, Schalm SW. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy. Hepatology 2000;32:635–9.
43. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al.. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–63.
44. Haber BA, Block JM, Jonas MM, Karpen SJ, London WT, McMahon BJ, et al.. Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics 2009;124:e1007–13.
45. United States Department of Labor, Bureau of Labor Statistics. Medical Cost Specific Consumer Price Index. Available at: Retrieved March 5, 2011.
    46. Practice Management Information Corporation (PMIC). Medical Fees in the United States 2008. Los Angeles (CA): PMIC; 2008.
      47. Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver 1989;9:235–41.
        © 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.