- Email: [email protected]
Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children
RESEARCH ARTICLE
Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children D1X XSarah F. Schillie, D2X XMD,1 D3X XLauren Canary, D4X XMPH,1 D5X XAlaya Koneru, D6X XMPH,1 D7X XNoele P. Nelson, D8X XMD,1 D9X XWade Tanico, D10X XBA,2 D1X XHarvey W. Kaufman, D12X XMD,3 D13X XSusan Hariri, D14X XPhD,1 D15X XClaudia J. Vellozzi, D16X XMD1 This activity is available for CME credit. See page A4 for information.
Introduction: Perinatal transmission is an increasingly important mode of hepatitis C virus transmission. The authors characterized U.S. births among hepatitis C virus infected women and evaluated trends in hepatitis C virus testing and positivity in women of childbearing age, pregnant women, and children aged less than 5 years.
Methods: In 2017, National Center for Health Statistics birth certificate data (48 states and District of Columbia) were analyzed to assess the number of hepatitis C virus infected women delivering live births in 2015, and commercial laboratory data were analyzed to assess hepatitis C virus testing and positivity among women of childbearing age, pregnant women, and children aged <5 years from 2011 to 2016. Results: In 2015, a total of 0.38% (n=14,417) of live births were delivered by hepatitis C virus infected women. Births delivered by hepatitis C virus infected women, compared with births overall, occurred more often in women who were aged 20 29 years (60.7% vs 50.9%); white, non-Hispanic (80.2% vs 52.8%); covered by Medicaid or other government insurance (79.2% vs 43.9%); and had rural residence (26.0% vs 14.0%). From 2011 to 2016 laboratory data, among women of childbearing age, hepatitis C virus testing increased by 39%, from 6.1% to 8.4%, and positivity increased by 36%, from 4.4% to 6.0%. Among pregnant women, hepatitis C virus testing increased by 135%, from 5.7% to 13.4%, and positivity increased by 39%, from 2.6% to 3.6%. Among children, hepatitis C virus testing increased by 25%, from 0.47% to 0.59%, and positivity increased by 13%, from 3.6% to 4.0%. Conclusions: The potential for perinatal hepatitis C virus transmission exists. Expanded hepatitis C virus testing guidelines may address the burden of disease in this population. Am J Prev Med 2018;(55):633 641. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
INTRODUCTION
H
epatitis C virus (HCV) infection is the most common blood-borne infection1 and leading indication for liver transplantation in the U.S.2 Approximately 75% 85% of adults who become infected with HCV develop chronic infection and 10% 15% will develop progressive liver fibrosis and cirrhosis.3 HCV transmission occurs most commonly through injection drug use.3,4 The rate of acute HCV infection has more than doubled from 2011 to 2016, from 0.4 to 1.0 cases per 100,000 population.4 The
highest rates of new cases are among people aged 20 29 and 30 39 years. The incidence in males and females is From the 1Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Laboratory Corporation of America, Burlington, North Carolina; and 3Quest Diagnostics, Madison, New Jersey Address correspondence to: Sarah F. Schillie, MD, Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, MS G-37, Atlanta GA 30333. E-mail: [email protected]. 0749-3797/$36.00 https://doi.org/10.1016/j.amepre.2018.05.029
Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
Am J Prev Med 2018;55(5):633 641
633
634
Schillie et al / Am J Prev Med 2018;55(5):633 641
similar (1.1 and 0.9 cases per 100,000 population, respectively).4 Prior to the implementation of universal blood product testing in 1992, HCV in children occurred predominantly as a result of a blood transfusion.5 Perinatal transmission (intrauterine or intrapartum) has become an increasingly important mode of HCV transmission, given the changing epidemiology of HCV infection.5 7 The risk for perinatal transmission is 5.8% for infants born to HCV-infected, HIV-negative mothers and doubles for infants born to mothers co-infected with HIV.6 Nearly 20% of infants with perinatally acquired HCV clear the infection.8 HCV-related liver disease rarely causes complications during childhood. Because fibrosis increases with disease duration, perinatally infected young adults may develop more severe disease.9,10 Existing recommendations for HCV testing during pregnancy relied upon provider identification of at-risk women.11 Universal HCV testing during pregnancy was recently recommended by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.12 The authors analyze data from the Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics (NCHS) and two large commercial laboratories to characterize live births among HCV-infected women and evaluate trends in HCV testing and positivity among women of childbearing age, pregnant women, and children aged less than 5 years to add 1 year of NCHS data and 2 years of commercial laboratory data to the authors’ previously published report.13
METHODS Study Sample Annual birth certificate data are provided to NCHS through cooperative agreements with 57 U.S. vital statistics jurisdictions and compiled into the National Vital Statistics System.14 Maternal HCV infection is recorded on a newborn’s birth certificate if HCV infection (defined as “a positive test for the hepatitis C virus”) is present at the time of pregnancy diagnosis or if a positive HCV test result is obtained during pregnancy. Birth certificate data do not specify whether HCV infection includes only RNA-positive women (some HCV infections recorded on the birth certificate may include women positive for HCV antibody only, which may represent a past infection). The item is a check box with other infectious diseases with these instructions: “Check all boxes that apply. The mother may have more than one infection. If the mother has none of the infections, check ‘none of the above.’”15 Maternal HCV infection status may be obtained from the prenatal record, labor and delivery admission form, admission history and physical examination, or delivery record. Maternal age, race, marital status, education, and insurance (payer type for delivery) as recorded on the birth certificate are included in the NCHS dataset. Level of urbanicity was assigned based on the 2013 NCHS Urban Rural Classification Scheme for Counties. Micropolitan and
non-core urbanicity classifications were considered “rural.” States were grouped by U.S. Census Bureau region. The analysis was limited to women aged 15 44 years and children aged <5 years. Birth certificate data for live births during 2015 and laboratory data for tests performed from 2011 to 2016 were included. Birth certificate data from 48 states and the District of Columbia were included. Connecticut did not report maternal HCV infection, and New Jersey reported infections from a limited number of facilities16; therefore, women residing in and births occurring in these two states were not included in this analysis. Births to non U.S. residents were also excluded. Data were limited to live births and did not include pregnancies resulting in stillbirth, miscarriage, or abortion. Birth certificate records were not restricted to singleton births only; thus, women were counted for each live pregnancy and were included more than once if they had more than one live birth. Because it is not possible to definitively conclude lack of HCV infection during pregnancy based on birth certificate data, these analyses compared “live-births to HCV-infected women” with “all live births” (and not to “live-births to HCV-uninfected women”).
Measures Under separate contractual agreements with CDC, Quest Diagnostics (Quest) and Laboratory Corporation of America (LabCorp) provided HCV antibody, RNA (qualitative and quantitative), and genotype test results for all people tested by their respective laboratories. Quest and LabCorp are two large commercial reference testing laboratories in the U.S. and processed 3.9 million and 3.3 million HCV tests, respectively, in 2015. Test-level data are submitted to CDC quarterly with anonymous patient identifiers (for 80% 95% of records that contain sufficient information to allow for de-duplication of multiple tests performed on individual patients). Patient-level data contain selected demographic, geographic, and clinical characteristics, including age, sex, state, ZIP code (of patient, or provider if patient ZIP code missing), insurance type, and diagnostic codes at the time of testing. The databases provided to CDC also contained an indicator for pregnancy status at the time of HCV testing, as determined by ordering of a concurrent obstetric panel of tests or concurrent record of an ICD-9 or ICD-10 code indicative of current pregnancy (this information was included for all women tested by Quest, irrespective of test result, and for women with a positive result tested by LabCorp). In addition to test- and patient-level data, annual aggregate data for total number of people served, stratified by state and demographic characteristics, are provided to examine population trends overall. ZIP code of patient residence in commercial laboratory data was translated to county and state using the SAS ZIP code file. States were grouped by U.S. Census Bureau region. HCV detection was defined in the laboratory data set as either a reactive HCV antibody result (which may represent only a past infection), detectable RNA via quantitative or qualitative testing, or ascertainment of a valid HCV genotype. HCV detection among children was defined as either a reactive antibody test in a child aged 2 years (to distinguish from detection of maternal antibody), detectable RNA via quantitative or qualitative testing at any age, or ascertainment of a valid HCV genotype at any age. Among women served by the commercial laboratories, HCV detection rates (detection), HCV testing rates (testing), and HCV positivity proportions (positivity) were calculated for women of childbearing age and pregnant women separately and were not mutually exclusive. The denominator used to calculate detection www.ajpmonline.org
Schillie et al / Am J Prev Med 2018;55(5):633 641 and testing was either the number of pregnant women, women of childbearing age, or children served by the commercial laboratories for any tests (not specific to viral hepatitis). Data from both laboratories were combined for all estimates for which numerator and denominator data were available. Among women tested for HCV by LabCorp, pregnancy status was classified only for women with positive results; therefore, Quest-only data were used to calculate HCV testing rates and HCV positivity proportions for pregnant women. Metrics for the commercial laboratory data were stratified by age, gender, pregnancy status, and state of residence, and were calculated on an annual basis as follows: 1. Detection rate=100 £ (number who tested positive for HCV infection/number served by the commercial laboratory for any purpose), 2. Testing rate=100 £ (number who were tested for HCV/number served by the commercial laboratory for any purpose), and 3. Positivity=proportion who tested positive for HCV among all of those tested for HCV.
Statistical Analysis SAS, version 9.3, was used for data analysis, and ArcGIS, version 10.3, was used to create maps with HCV infection and detection rate quintiles. A Cochran Armitage test was used to evaluate the statistical significance in trends of annual detection and testing rates in the commercial laboratory data, with a p-value 0.001 considered statistically significant. This analysis was performed in 2017 and used existing data without identifiers and therefore did not require approval by CDC’s IRB.
RESULTS Among 3,823,723 live births in the U.S. during 2015, a total of 14,417 (0.38%) were delivered by women classified to be HCV-infected (Table 1). Maternal HCV status was missing for 1.7% of birth certificate records overall and is overrepresented by multiple births. A higher proportion of births delivered by women with HCV infection, compared with births among all women, occurred in women who were aged 20 29 years (60.7% vs 50.9%); white, non-Hispanic (80.2% vs 52.8%); American Indian, non-Hispanic (2.9% vs 0.8%); unmarried (74.6% vs 40.5%); not high school graduates (25.5% vs 14.4%); and covered by Medicaid or other government insurance (79.2% vs 43.9%). Births delivered by women with HCV infection, compared with births among all women, occurred more often to women residing in the Northeast (19.7% vs 12.7%), Midwest (24.5% vs 21.8%), and South (42.7% vs 40.4%) and in rural areas (26.0% vs 14.0%; Table 1). According to birth certificate data, in 2015 HCV infection among women with live births was 0.38% overall and varied among states, from a low of 0.07% in Hawaii to a high of 2.78% in West Virginia (Figure 1A, November 2018
635
Appendix Table 1, available online). Likewise, according to the commercial laboratory data, HCV detection among pregnant women served by LabCorp or Quest in 2015 was 0.26% overall and also varied among states, ranging from a low of 0.06% in Wyoming to a high of 2.40% in West Virginia (Figure 1B, Appendix Table 1, available online). Commercial laboratory HCV testing and positivity among women of childbearing age and pregnant women increased most years from 2011 to 2016; testing among pregnant women increased markedly from 2015 to 2016. HCV testing among women of childbearing age increased by 39% (from 6.1% to 8.4%, p<0.001); among pregnant women, the rates increased by 135% (from 5.7% to 13.4%, p<0.001). The greatest increase in testing of pregnant women (39%) occurred from 2015 to 2016. Among women of childbearing age tested for HCV, the proportion with HCV positivity increased by 36% (from 4.4% to 6.0%, p<0.001); among pregnant women tested for HCV, the proportion with HCV positivity increased by 39% (from 2.6% to 3.6%, p<0.001; Figure 2A). Because the denominator for testing rate (i.e., the total number of patients served by the laboratories for any condition) changed <10% over the 6-year period among women of childbearing age, pregnant women, and children aged <5 years (data not shown), increases in testing rates found in this analysis are likely not due to spurious decreases in the number of patients served. Among children aged <5 years, HCV testing and positivity increased from 2011 to 2016. Testing rates increased by 25% (from 0.47% to 0.59%, p<0.001). Among young children tested for HCV, the proportion with HCV positivity increased by 13% (from 3.6% to 4.0%, p<0.001; Figure 2B), which extrapolates to 730 young children with HCV infection in 2016 served by Quest and LabCorp. Although not deemed a positive test result in the analysis for children, it is noteworthy that 64.9% of HCV tests performed among infants aged <1 year were HCV antibody tests and that positive results from HCV antibody testing performed during infancy may reflect maternal (versus infant) HCV antibodies (data not shown).
DISCUSSION Birth certificate data from 2015 indicated 0.38% of live births were delivered by HCV-infected women, and commercial laboratory data yielded a corresponding HCV detection rate of 0.26% among pregnant women. These data highlight the concomitant potential for perinatal HCV transmission. Among women of childbearing
636
Schillie et al / Am J Prev Med 2018;55(5):633 641
Table 1. HCV Infection Among Women With Live Births, NCHS NVSS Birth Certificate Data,a U.S., 2015 Maternal characteristics Total Age 15 19 years 20 24 years 25 29 years 30 34 years 35 39 years 40 44 years Race/ethnicity White, non-Hispanic Black, non-Hispanic American Indian, non-Hispanic API, non-Hispanic Hispanic Other, non-Hispanic Unknown Marital status Married Unmarried Education 12th grade or less, no diploma High school graduate or GED completed Some college credit, no degree Associate degree Bachelor’s degree Advanced degree Unknown Insurance type Medicaid and other government Third-party commercial, Champus/Tricare Indian Health Service Self-pay Other/missing/unknown Region/division Midwest Northeast South West Urbanicity of residential county Large central metropolitan Large fringe metropolitan Medium metropolitan Small metropolitan Micropolitan Non-core Missing/unknown
All live births, n (%)
Live births to HCV-infectedb women, n (%)
HCV-positive,%
3,823,723
14,417
0.38
225,057 (5.9) 830,181 (21.7) 1,115,357 (29.2) 1,046,049 (27.4) 501,228 (13.1) 105,851 (2.8)
307 (2.1) 3,435 (23.8) 5,310 (36.8) 3,656 (25.4) 1,455 (10.1) 254 (1.8)
0.14 0.41 0.48 0.35 0.29 0.24
2,017,949 (52.8) 543,852 (14.2) 31,996 (0.8) 237,637 (6.2) 884,797 (23.1) 76,846 (2.0) 30,646 (0.8)
11,560 (80.2) 593 (4.1) 416 (2.9) 200 (1.4) 1,132 (7.9) 359 (2.5) 157 (1.1)
0.57 0.11 1.30 0.08 0.13 0.47 0.51
2,277,128 (59.6) 1,546,595 (40.5)
3,656 (25.4) 10,761 (74.6)
0.16 0.70
549,374 (14.4) 952,533 (24.9) 808,796 (21.2) 309,056 (8.1) 734,713 (19.2) 421,287 (11.0) 47,964 (1.3)
3,677 (25.5) 5,677 (39.4) 3,516 (24.4) 634 (4.4) 492 (3.4) 187 (1.3) 234 (1.6)
0.67 0.60 0.43 0.20 0.07 0.04 0.49
1,677,355 (43.9) 1,884,727 (49.3) 3,653 (0.1) 150,669 (3.9) 107,319 (2.8)
11,419 (79.2) 2,073 (14.4) 54 (0.4) 360 (2.5) 511 (3.5)
0.68 0.11 1.48 0.24 0.48
833,772 (21.8) 485,158 (12.7) 1,543,912 (40.4) 960,881 (25.1)
3,528 (24.5) 2,844 (19.7) 6,162 (42.7) 1,883 (13.1)
0.42 0.59 0.40 0.20
1,272,050 (33.3) 857,867 (22.4) 801,268 (21.0) 355,142 (9.3) 323,262 (8.5) 213,576 (5.6) 558 (0.0)
2,460 (17.1) 3,002 (20.8) 3,557 (24.7) 1,651 (11.5) 2,189 (15.2) 1,557 (10.8) 1 (0.0)
0.19 0.35 0.44 0.46 0.68 0.73 0.18
a
Birth certificate records based on data from 48 states and the District of Columbia. HCV infection present at the time of the pregnancy diagnosis or any positive HCV test during pregnancy. API, Asian/Pacific Islander; GED, General Educational Development test; HCV, hepatitis C virus; NCHS NVSS, National Center for Health Statistics, National Vital Statistics System.
b
www.ajpmonline.org
Schillie et al / Am J Prev Med 2018;55(5):633 641
637
Figure 1. HCV detection rates among (A) U.S. pregnant women with live births by state,a,b NCHS NVSS birth certificate data, 2015; and (B) U.S. pregnant women by state,b commercial laboratory data, 2015. a
Determined by state of mother’s residence. Bold lines represent U.S. Census Bureau regions. HCV, hepatitis C virus; NA, not applicable; NCHS NVSS, National Center for Health Statistics, National Vital Statistics System.
b
November 2018
638
Schillie et al / Am J Prev Med 2018;55(5):633 641
Figure 2. Trends in HCV testinga and positivity among (A) U.S. women of childbearing age and pregnant women and (B) U.S. children aged <5 years, commercial laboratory data, 2011 2016. a
Testing rates for pregnant women from Quest laboratory only. HCV, hepatitis C virus; WCBA, women of childbearing age.
age and pregnant women, testing and positivity increased most years from 2011 to 2016, whereas testing among pregnant women increased markedly from 2015 to 2016. Although this time marked a fluctuating period
in U.S. commercial insurance markets, the observed trends parallel recent epidemics of HCV infection associated with injection drug use among young adults.17 The authors observed that live births to HCV-infected www.ajpmonline.org
639
Schillie et al / Am J Prev Med 2018;55(5):633 641
women disproportionately occurred among white women (representing 0.57% of all births), women residing in rural areas (representing 0.70% of all births), and women with Medicaid or other government insurance (representing 0.68% of all births), in line with demographic characteristics associated with HCV infection in other reports.13,17 Previous analyses utilizing birth certificate data demonstrated the proportion of infants born to HCVinfected mothers increased from 0.19% in 2011 to 0.32% in 2014, with considerable variation between states; Appalachian states, such as Kentucky and Tennessee, are particularly affected.13,18 In comparison to the U.S. population, National Health and Nutrition Examination Survey 2003 2010 data estimate 1.3% of the U.S. population aged 6 years and older had been infected with HCV at some point (HCV antibody positive) and 1% were currently infected (HCV RNA positive).19 CDC and/or the U.S. Preventive Services Task Force recommend HCV testing for people born between 1945 and 1965 (“baby boomers”), those with a history of injection or intranasal drug use, incarcerated individuals, those with unregulated tattoos, and others with medical risks (e.g., receipt of hemodialysis).20 22 These guidelines apply to pregnant women; therefore, any pregnant woman at risk for HCV (e.g., history of injection drug use) should be tested. The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recently recommended universal HCV testing during pregnancy.12 Pregnant women who test positive should be linked to care and treated following pregnancy, and infants born to HCV-infected women should be tested and managed appropriately.20 22 The HCV antibody crosses the placenta and maternal HCV antibody can be detected in infants born to HCV-infected mothers. Antibody testing is therefore not recommended for children aged less than 18 months. HCV RNA can be detected within 1 2 weeks following exposure and is used to identify perinatally infected infants early in life.23,24 However, in this analysis, approximately two thirds of HCV tests performed among children aged less than 1 year were antibody tests. Although a negative antibody test is useful for identifying those infants who are not infected, a positive result does not distinguish between infant infection and passive transfer of the maternal antibody. Perinatal HCV infection has become nationally notifiable in 2018.25 Although HCV treatment has a cure rate of approximately 95%,22 recommendations for pharmacologic agents or other interventions during pregnancy or at delivery for preventing perinatal HCV infection are November 2018
26
largely nonexistent. The safety and efficacy of direct acting antiviral agents during pregnancy have not been established. At least one clinical trial of HCV treatment for pregnant women is in progress27; a registry to document outcomes for women who become pregnant while on HCV therapy can help identify drug-related adverse events. Although treatment for HCV among pregnant women is not yet available, pregnancy is one of the few opportunities for which women in marginalized populations receive routine medical care. Documentation of maternal HCV status prompts appropriate HCV testing of their infant. Women can also be treated for HCV after delivery to reduce risk of transmission in future pregnancies. Although testing during pregnancy allows for the identification of infants requiring testing and for maternal treatment following pregnancy, testing of women prior to pregnancy enables administration of curative maternal therapy and nearly eliminates the risk for perinatal HCV transmission on a pre-pregnancy basis.
Limitations There are potential limitations associated with these analyses. Because universal testing of pregnant women is not currently recommended, these estimates likely do not capture the true burden of HCV infection among this population. However, by accepting HCV antibody alone, the authors overestimated those currently infected and at risk for transmitting infection to others. Greater HCV detection rates in birth certificate data are plausible, as women with known HCV infection may not be retested (and therefore not identified through laboratory testing) but would be classified as HCV-infected on the birth certificate. NCHS data encompassed only pregnancies resulting in live births, whereas laboratory data included pregnancies resulting in miscarriage, abortion, or stillbirth. Medical checkbox items are known to be underreported in birth certificate data, and the completeness of reporting for HCV infection is unknown. Although Quest and LabCorp are two of the largest commercial laboratories in the U.S., laboratory coverage varies by region and patients served by the commercial laboratories may have demographic differences that affect their risk for HCV infection. The authors could not distinguish women who were tested at both laboratories. HCV testing data for pregnant women was only available from Quest. Limitations intrinsic to laboratory tests (e.g., test sensitivity and specificity) also exist.
CONCLUSIONS These findings highlight the potential for perinatal HCV transmission. Regardless of whether these
640
Schillie et al / Am J Prev Med 2018;55(5):633 641
trends are a result of increased recognition or a true increase in the incidence of HCV among women of childbearing age or pregnant women, the data reported here reveal a burden of HCV disease in these female populations and therefore transmission risk for infants. Access to HCV testing, followed by treatment for HCV-infected women prior to pregnancy, is most effective; however, stronger recommendations (e.g., so that testing is not contingent upon identification of risk factors) for identifying HCV-infected women before and during pregnancy are important to prevent infection in this vulnerable population. In response to increasing HCV infections, Kentucky has adopted mandatory testing and reporting of HCV among pregnant women.13,28,29 Infant testing algorithms can establish absence of infection in the majority of infants, identify the approximately 5% of young children born to HCV-infected mothers who acquired infection and require follow-up, and reduce HCV antibody testing for infants aged younger than 18 months. Testing pregnant women at risk for HCV infection helps to ensure their infants are identified for testing and possible treatment.
ACKNOWLEDGMENTS The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. The two commercial laboratories who contributed data for this analysis have contractual agreements with the Centers for Disease Control and Prevention. Two authors (WT, HK) are employed by these laboratories. No other financial disclosures were reported by the authors.
SUPPLEMENTAL MATERIAL Supplemental materials associated with this article can be found in the online version at https://doi.org/10.1016/j. amepre.2018.05.029.
REFERENCES 1. Allison WE, Chiang W, Rubin A, Oshva L, Carmody E. Knowledge about hepatitis C virus infection and acceptability of testing in the 1945 65 birth cohort (baby boomers) presenting to a large urban emergency department: a pilot study. J Emerg Med. 2016;50(6):825– 831. https://doi.org/10.1016/j.jemermed.2016.02.001. 2. Wertheim JA, Petrowsky H, Saam S, Kupiec-Weglinski JW, Busuttil RW. Major challenges limiting liver transplantation in the United States. Am J Transplant. 2011;11(9):1773–1784. https://doi.org/ 10.1111/j.1600-6143.2011.03587.x. 3. McHutchison JG. Understanding hepatitis C. Am J Manag Care. 2004;10(2 suppl):S21–S29. 4. CDC. Viral hepatitis: Statistics and surveillance. https://www.cdc.gov/ hepatitis/statistics/index.htm. Updated May 17, 2018. Accessed August 30, 2018.
5. Indolfi G, Azzari C, Resti M. Perinatal transmission of hepatitis C virus. J Pediatr. 2013;163(6):1549–1552. https://doi.org/10.1016/j. jpeds.2013.06.077. 6. Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission of hepatitis C virus: systematic review and metaanalysis. Clin Infect Dis. 2014;59(6):763–773. https://doi.org/ 10.1093/cid/ciu447. 7. Boxall E, Baumann K, Price N, et al. Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies. J Clin Virol. 2007;38 (2):91–95. https://doi.org/10.1016/j.jcv.2006.11.012. 8. The European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. Clin Infect Dis. 41(1):45–51. https://doi.org/10.1086/ 430601. 9. Guido M, Rugge M, Jara P, et al. Chronic hepatitis C in children: the pathological and clinical spectrum. Gastroenterology. 1998;115 (6):1525–1529. https://doi.org/10.1016/S0016-5085(98)70032-0. 10. Lee CK, Jonas MM. Hepatitis C: issues in children. Gastroenterol Clin North Am. 2015;44(4):901–909. https://doi.org/10.1016/j.gtc.2015. 07.011. 11. CDC. Recommended testing sequence for identifying current hepatitis C virus (HCV) infection. www.cdc.gov/hepatitis/hcv/pdfs/hcv_flow. pdf. Accessed May 22, 2017 Published 2013. 12. American Association for the Study of Liver Diseases Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Updated May 24, 2018. Accessed June 6, 2018. 13. Koneru A, Nelson N, Hariri S, et al. Increased hepatitis C virus (HCV) detection in women of childbearing age and potential risk for vertical transmission—United States and Kentucky, 2011 2014. MMWR Morb Mortal Wkly Rep. 2016;65(28):705– 710. https://doi.org/10.15585/mmwr.mm6528a2. 14. National Vital Statistics System. Birth data. www.cdc.gov/nchs/nvss/ births.htm. Updated May 30, 2018. Accessed June 6, 2018. 15. National Center for Health Statistics. Guide to completing the facility worksheets for the certificate of live birth and report of fetal death (2003 revision). www.cdc.gov/nchs/data/dvs/GuidetoCompleteFacilityWks.pdf. Updated May 2016. Accessed April 26, 2018. 16. Martin JA, Hamilton BE, Osterman MJ, Driscoll AK, Matthews TJ. Births: final data for 2015. Natl Vital Stat Rep. 2017;66(1):1–70. 17. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related to injection drug use among persons aged 30 years— Kentucky, Tennessee, Virginia, and West Virginia, 2006 2012. MMWR Morb Mortal Wkly Rep. 2015;64(17):453–458. 18. Patrick W, Bauer A, Warren M, Jones T, Wester C. Hepatitis C virus infection among women giving birth—Tennessee and United States, 2009 2014. MMWR Morb Mortal Wkly Rep. 2017;66(18):470–473. https://doi.org/10.15585/mmwr.mm6618a3. 19. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293–300. https://doi.org/10.7326/M13-1133. 20. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945 1965. MMWR Morb Mortal Wkly Rep. 2012;61 (RR 4):1–32. 21. Moyer VA. U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med.159(5):349–357. https://doi. org/10.7326/0003-4819-159-5-201309030-00672. 22. D’Ambrosio R, Degasperi E, Colombo M, Aghemo A. Direct-acting antivirals: the endgame for hepatitis C. Curr Opin Virol. 2017;24:31– 37. https://doi.org/10.1016/j.coviro.2017.03.017. 23. American Academy of Pediatrics. Hepatitis C. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2018-2021 Report of
www.ajpmonline.org
Schillie et al / Am J Prev Med 2018;55(5):633 641 the Committee on Infectious Diseases. 31st ed. Elk Grove Village, IL: American Academy of Pediatrics, 2018:428-434. 24. Mack CL, Gonzalez-Peralta RP, Gupta N, et al. NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr. 2012;54(6):838– 855. https://doi.org/10.1097/MPG.0b013e318258328d. 25. CDC. National Notifiable Diseases Surveillance System (NNDSS): hepatitis C, perinatal infection, 2018 case definition. wwwn.cdc.gov/ nndss/conditions/hepatitis-c-perinatal-infection/case-definition/2018/. Published 2018. Accessed April 26, 2018. 26. Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern
November 2018
641
Med. 2013;158(2):109–113. https://doi.org/10.7326/0003-4819-158-2201301150-00575. 27. U.S. National Library of Medicine. ClinicalTrials.gov. Study of hepatitis C treatment during pregnancy (HIP). www.clinicaltrials.gov/ ct2/show/NCT02683005?term=pregnancy&cond=Hepatitis$C$ Virus$Infection&rank=1. Updated January 19, 2018. Accessed April 26, 2018. 28. Kentucky Legislature. Kentucky reportable disease surveillance. www. lrc.ky.gov/kar/title902.htm. Updated May 31, 2018. Accessed June 6, 2018. 29. Kentucky Legislature. Legislative record online. KRS 214.160. 18 RS BR 379. www.lrc.ky.gov/recorddocuments/bill/18RS/SB250/bill.pdf. Accessed April 26, 2018.
Hepatitis C Virus in Women of Childbearing Age, Pregnant Women, and Children D1X XSarah F. Schillie, D2X XMD,1 D3X XLauren Canary, D4X XMPH,1 D5X XAlaya Koneru, D6X XMPH,1 D7X XNoele P. Nelson, D8X XMD,1 D9X XWade Tanico, D10X XBA,2 D1X XHarvey W. Kaufman, D12X XMD,3 D13X XSusan Hariri, D14X XPhD,1 D15X XClaudia J. Vellozzi, D16X XMD1 This activity is available for CME credit. See page A4 for information.
Introduction: Perinatal transmission is an increasingly important mode of hepatitis C virus transmission. The authors characterized U.S. births among hepatitis C virus infected women and evaluated trends in hepatitis C virus testing and positivity in women of childbearing age, pregnant women, and children aged less than 5 years.
Methods: In 2017, National Center for Health Statistics birth certificate data (48 states and District of Columbia) were analyzed to assess the number of hepatitis C virus infected women delivering live births in 2015, and commercial laboratory data were analyzed to assess hepatitis C virus testing and positivity among women of childbearing age, pregnant women, and children aged <5 years from 2011 to 2016. Results: In 2015, a total of 0.38% (n=14,417) of live births were delivered by hepatitis C virus infected women. Births delivered by hepatitis C virus infected women, compared with births overall, occurred more often in women who were aged 20 29 years (60.7% vs 50.9%); white, non-Hispanic (80.2% vs 52.8%); covered by Medicaid or other government insurance (79.2% vs 43.9%); and had rural residence (26.0% vs 14.0%). From 2011 to 2016 laboratory data, among women of childbearing age, hepatitis C virus testing increased by 39%, from 6.1% to 8.4%, and positivity increased by 36%, from 4.4% to 6.0%. Among pregnant women, hepatitis C virus testing increased by 135%, from 5.7% to 13.4%, and positivity increased by 39%, from 2.6% to 3.6%. Among children, hepatitis C virus testing increased by 25%, from 0.47% to 0.59%, and positivity increased by 13%, from 3.6% to 4.0%. Conclusions: The potential for perinatal hepatitis C virus transmission exists. Expanded hepatitis C virus testing guidelines may address the burden of disease in this population. Am J Prev Med 2018;(55):633 641. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
INTRODUCTION
H
epatitis C virus (HCV) infection is the most common blood-borne infection1 and leading indication for liver transplantation in the U.S.2 Approximately 75% 85% of adults who become infected with HCV develop chronic infection and 10% 15% will develop progressive liver fibrosis and cirrhosis.3 HCV transmission occurs most commonly through injection drug use.3,4 The rate of acute HCV infection has more than doubled from 2011 to 2016, from 0.4 to 1.0 cases per 100,000 population.4 The
highest rates of new cases are among people aged 20 29 and 30 39 years. The incidence in males and females is From the 1Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Laboratory Corporation of America, Burlington, North Carolina; and 3Quest Diagnostics, Madison, New Jersey Address correspondence to: Sarah F. Schillie, MD, Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, MS G-37, Atlanta GA 30333. E-mail: [email protected]. 0749-3797/$36.00 https://doi.org/10.1016/j.amepre.2018.05.029
Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
Am J Prev Med 2018;55(5):633 641
633
634
Schillie et al / Am J Prev Med 2018;55(5):633 641
similar (1.1 and 0.9 cases per 100,000 population, respectively).4 Prior to the implementation of universal blood product testing in 1992, HCV in children occurred predominantly as a result of a blood transfusion.5 Perinatal transmission (intrauterine or intrapartum) has become an increasingly important mode of HCV transmission, given the changing epidemiology of HCV infection.5 7 The risk for perinatal transmission is 5.8% for infants born to HCV-infected, HIV-negative mothers and doubles for infants born to mothers co-infected with HIV.6 Nearly 20% of infants with perinatally acquired HCV clear the infection.8 HCV-related liver disease rarely causes complications during childhood. Because fibrosis increases with disease duration, perinatally infected young adults may develop more severe disease.9,10 Existing recommendations for HCV testing during pregnancy relied upon provider identification of at-risk women.11 Universal HCV testing during pregnancy was recently recommended by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.12 The authors analyze data from the Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics (NCHS) and two large commercial laboratories to characterize live births among HCV-infected women and evaluate trends in HCV testing and positivity among women of childbearing age, pregnant women, and children aged less than 5 years to add 1 year of NCHS data and 2 years of commercial laboratory data to the authors’ previously published report.13
METHODS Study Sample Annual birth certificate data are provided to NCHS through cooperative agreements with 57 U.S. vital statistics jurisdictions and compiled into the National Vital Statistics System.14 Maternal HCV infection is recorded on a newborn’s birth certificate if HCV infection (defined as “a positive test for the hepatitis C virus”) is present at the time of pregnancy diagnosis or if a positive HCV test result is obtained during pregnancy. Birth certificate data do not specify whether HCV infection includes only RNA-positive women (some HCV infections recorded on the birth certificate may include women positive for HCV antibody only, which may represent a past infection). The item is a check box with other infectious diseases with these instructions: “Check all boxes that apply. The mother may have more than one infection. If the mother has none of the infections, check ‘none of the above.’”15 Maternal HCV infection status may be obtained from the prenatal record, labor and delivery admission form, admission history and physical examination, or delivery record. Maternal age, race, marital status, education, and insurance (payer type for delivery) as recorded on the birth certificate are included in the NCHS dataset. Level of urbanicity was assigned based on the 2013 NCHS Urban Rural Classification Scheme for Counties. Micropolitan and
non-core urbanicity classifications were considered “rural.” States were grouped by U.S. Census Bureau region. The analysis was limited to women aged 15 44 years and children aged <5 years. Birth certificate data for live births during 2015 and laboratory data for tests performed from 2011 to 2016 were included. Birth certificate data from 48 states and the District of Columbia were included. Connecticut did not report maternal HCV infection, and New Jersey reported infections from a limited number of facilities16; therefore, women residing in and births occurring in these two states were not included in this analysis. Births to non U.S. residents were also excluded. Data were limited to live births and did not include pregnancies resulting in stillbirth, miscarriage, or abortion. Birth certificate records were not restricted to singleton births only; thus, women were counted for each live pregnancy and were included more than once if they had more than one live birth. Because it is not possible to definitively conclude lack of HCV infection during pregnancy based on birth certificate data, these analyses compared “live-births to HCV-infected women” with “all live births” (and not to “live-births to HCV-uninfected women”).
Measures Under separate contractual agreements with CDC, Quest Diagnostics (Quest) and Laboratory Corporation of America (LabCorp) provided HCV antibody, RNA (qualitative and quantitative), and genotype test results for all people tested by their respective laboratories. Quest and LabCorp are two large commercial reference testing laboratories in the U.S. and processed 3.9 million and 3.3 million HCV tests, respectively, in 2015. Test-level data are submitted to CDC quarterly with anonymous patient identifiers (for 80% 95% of records that contain sufficient information to allow for de-duplication of multiple tests performed on individual patients). Patient-level data contain selected demographic, geographic, and clinical characteristics, including age, sex, state, ZIP code (of patient, or provider if patient ZIP code missing), insurance type, and diagnostic codes at the time of testing. The databases provided to CDC also contained an indicator for pregnancy status at the time of HCV testing, as determined by ordering of a concurrent obstetric panel of tests or concurrent record of an ICD-9 or ICD-10 code indicative of current pregnancy (this information was included for all women tested by Quest, irrespective of test result, and for women with a positive result tested by LabCorp). In addition to test- and patient-level data, annual aggregate data for total number of people served, stratified by state and demographic characteristics, are provided to examine population trends overall. ZIP code of patient residence in commercial laboratory data was translated to county and state using the SAS ZIP code file. States were grouped by U.S. Census Bureau region. HCV detection was defined in the laboratory data set as either a reactive HCV antibody result (which may represent only a past infection), detectable RNA via quantitative or qualitative testing, or ascertainment of a valid HCV genotype. HCV detection among children was defined as either a reactive antibody test in a child aged 2 years (to distinguish from detection of maternal antibody), detectable RNA via quantitative or qualitative testing at any age, or ascertainment of a valid HCV genotype at any age. Among women served by the commercial laboratories, HCV detection rates (detection), HCV testing rates (testing), and HCV positivity proportions (positivity) were calculated for women of childbearing age and pregnant women separately and were not mutually exclusive. The denominator used to calculate detection www.ajpmonline.org
Schillie et al / Am J Prev Med 2018;55(5):633 641 and testing was either the number of pregnant women, women of childbearing age, or children served by the commercial laboratories for any tests (not specific to viral hepatitis). Data from both laboratories were combined for all estimates for which numerator and denominator data were available. Among women tested for HCV by LabCorp, pregnancy status was classified only for women with positive results; therefore, Quest-only data were used to calculate HCV testing rates and HCV positivity proportions for pregnant women. Metrics for the commercial laboratory data were stratified by age, gender, pregnancy status, and state of residence, and were calculated on an annual basis as follows: 1. Detection rate=100 £ (number who tested positive for HCV infection/number served by the commercial laboratory for any purpose), 2. Testing rate=100 £ (number who were tested for HCV/number served by the commercial laboratory for any purpose), and 3. Positivity=proportion who tested positive for HCV among all of those tested for HCV.
Statistical Analysis SAS, version 9.3, was used for data analysis, and ArcGIS, version 10.3, was used to create maps with HCV infection and detection rate quintiles. A Cochran Armitage test was used to evaluate the statistical significance in trends of annual detection and testing rates in the commercial laboratory data, with a p-value 0.001 considered statistically significant. This analysis was performed in 2017 and used existing data without identifiers and therefore did not require approval by CDC’s IRB.
RESULTS Among 3,823,723 live births in the U.S. during 2015, a total of 14,417 (0.38%) were delivered by women classified to be HCV-infected (Table 1). Maternal HCV status was missing for 1.7% of birth certificate records overall and is overrepresented by multiple births. A higher proportion of births delivered by women with HCV infection, compared with births among all women, occurred in women who were aged 20 29 years (60.7% vs 50.9%); white, non-Hispanic (80.2% vs 52.8%); American Indian, non-Hispanic (2.9% vs 0.8%); unmarried (74.6% vs 40.5%); not high school graduates (25.5% vs 14.4%); and covered by Medicaid or other government insurance (79.2% vs 43.9%). Births delivered by women with HCV infection, compared with births among all women, occurred more often to women residing in the Northeast (19.7% vs 12.7%), Midwest (24.5% vs 21.8%), and South (42.7% vs 40.4%) and in rural areas (26.0% vs 14.0%; Table 1). According to birth certificate data, in 2015 HCV infection among women with live births was 0.38% overall and varied among states, from a low of 0.07% in Hawaii to a high of 2.78% in West Virginia (Figure 1A, November 2018
635
Appendix Table 1, available online). Likewise, according to the commercial laboratory data, HCV detection among pregnant women served by LabCorp or Quest in 2015 was 0.26% overall and also varied among states, ranging from a low of 0.06% in Wyoming to a high of 2.40% in West Virginia (Figure 1B, Appendix Table 1, available online). Commercial laboratory HCV testing and positivity among women of childbearing age and pregnant women increased most years from 2011 to 2016; testing among pregnant women increased markedly from 2015 to 2016. HCV testing among women of childbearing age increased by 39% (from 6.1% to 8.4%, p<0.001); among pregnant women, the rates increased by 135% (from 5.7% to 13.4%, p<0.001). The greatest increase in testing of pregnant women (39%) occurred from 2015 to 2016. Among women of childbearing age tested for HCV, the proportion with HCV positivity increased by 36% (from 4.4% to 6.0%, p<0.001); among pregnant women tested for HCV, the proportion with HCV positivity increased by 39% (from 2.6% to 3.6%, p<0.001; Figure 2A). Because the denominator for testing rate (i.e., the total number of patients served by the laboratories for any condition) changed <10% over the 6-year period among women of childbearing age, pregnant women, and children aged <5 years (data not shown), increases in testing rates found in this analysis are likely not due to spurious decreases in the number of patients served. Among children aged <5 years, HCV testing and positivity increased from 2011 to 2016. Testing rates increased by 25% (from 0.47% to 0.59%, p<0.001). Among young children tested for HCV, the proportion with HCV positivity increased by 13% (from 3.6% to 4.0%, p<0.001; Figure 2B), which extrapolates to 730 young children with HCV infection in 2016 served by Quest and LabCorp. Although not deemed a positive test result in the analysis for children, it is noteworthy that 64.9% of HCV tests performed among infants aged <1 year were HCV antibody tests and that positive results from HCV antibody testing performed during infancy may reflect maternal (versus infant) HCV antibodies (data not shown).
DISCUSSION Birth certificate data from 2015 indicated 0.38% of live births were delivered by HCV-infected women, and commercial laboratory data yielded a corresponding HCV detection rate of 0.26% among pregnant women. These data highlight the concomitant potential for perinatal HCV transmission. Among women of childbearing
636
Schillie et al / Am J Prev Med 2018;55(5):633 641
Table 1. HCV Infection Among Women With Live Births, NCHS NVSS Birth Certificate Data,a U.S., 2015 Maternal characteristics Total Age 15 19 years 20 24 years 25 29 years 30 34 years 35 39 years 40 44 years Race/ethnicity White, non-Hispanic Black, non-Hispanic American Indian, non-Hispanic API, non-Hispanic Hispanic Other, non-Hispanic Unknown Marital status Married Unmarried Education 12th grade or less, no diploma High school graduate or GED completed Some college credit, no degree Associate degree Bachelor’s degree Advanced degree Unknown Insurance type Medicaid and other government Third-party commercial, Champus/Tricare Indian Health Service Self-pay Other/missing/unknown Region/division Midwest Northeast South West Urbanicity of residential county Large central metropolitan Large fringe metropolitan Medium metropolitan Small metropolitan Micropolitan Non-core Missing/unknown
All live births, n (%)
Live births to HCV-infectedb women, n (%)
HCV-positive,%
3,823,723
14,417
0.38
225,057 (5.9) 830,181 (21.7) 1,115,357 (29.2) 1,046,049 (27.4) 501,228 (13.1) 105,851 (2.8)
307 (2.1) 3,435 (23.8) 5,310 (36.8) 3,656 (25.4) 1,455 (10.1) 254 (1.8)
0.14 0.41 0.48 0.35 0.29 0.24
2,017,949 (52.8) 543,852 (14.2) 31,996 (0.8) 237,637 (6.2) 884,797 (23.1) 76,846 (2.0) 30,646 (0.8)
11,560 (80.2) 593 (4.1) 416 (2.9) 200 (1.4) 1,132 (7.9) 359 (2.5) 157 (1.1)
0.57 0.11 1.30 0.08 0.13 0.47 0.51
2,277,128 (59.6) 1,546,595 (40.5)
3,656 (25.4) 10,761 (74.6)
0.16 0.70
549,374 (14.4) 952,533 (24.9) 808,796 (21.2) 309,056 (8.1) 734,713 (19.2) 421,287 (11.0) 47,964 (1.3)
3,677 (25.5) 5,677 (39.4) 3,516 (24.4) 634 (4.4) 492 (3.4) 187 (1.3) 234 (1.6)
0.67 0.60 0.43 0.20 0.07 0.04 0.49
1,677,355 (43.9) 1,884,727 (49.3) 3,653 (0.1) 150,669 (3.9) 107,319 (2.8)
11,419 (79.2) 2,073 (14.4) 54 (0.4) 360 (2.5) 511 (3.5)
0.68 0.11 1.48 0.24 0.48
833,772 (21.8) 485,158 (12.7) 1,543,912 (40.4) 960,881 (25.1)
3,528 (24.5) 2,844 (19.7) 6,162 (42.7) 1,883 (13.1)
0.42 0.59 0.40 0.20
1,272,050 (33.3) 857,867 (22.4) 801,268 (21.0) 355,142 (9.3) 323,262 (8.5) 213,576 (5.6) 558 (0.0)
2,460 (17.1) 3,002 (20.8) 3,557 (24.7) 1,651 (11.5) 2,189 (15.2) 1,557 (10.8) 1 (0.0)
0.19 0.35 0.44 0.46 0.68 0.73 0.18
a
Birth certificate records based on data from 48 states and the District of Columbia. HCV infection present at the time of the pregnancy diagnosis or any positive HCV test during pregnancy. API, Asian/Pacific Islander; GED, General Educational Development test; HCV, hepatitis C virus; NCHS NVSS, National Center for Health Statistics, National Vital Statistics System.
b
www.ajpmonline.org
Schillie et al / Am J Prev Med 2018;55(5):633 641
637
Figure 1. HCV detection rates among (A) U.S. pregnant women with live births by state,a,b NCHS NVSS birth certificate data, 2015; and (B) U.S. pregnant women by state,b commercial laboratory data, 2015. a
Determined by state of mother’s residence. Bold lines represent U.S. Census Bureau regions. HCV, hepatitis C virus; NA, not applicable; NCHS NVSS, National Center for Health Statistics, National Vital Statistics System.
b
November 2018
638
Schillie et al / Am J Prev Med 2018;55(5):633 641
Figure 2. Trends in HCV testinga and positivity among (A) U.S. women of childbearing age and pregnant women and (B) U.S. children aged <5 years, commercial laboratory data, 2011 2016. a
Testing rates for pregnant women from Quest laboratory only. HCV, hepatitis C virus; WCBA, women of childbearing age.
age and pregnant women, testing and positivity increased most years from 2011 to 2016, whereas testing among pregnant women increased markedly from 2015 to 2016. Although this time marked a fluctuating period
in U.S. commercial insurance markets, the observed trends parallel recent epidemics of HCV infection associated with injection drug use among young adults.17 The authors observed that live births to HCV-infected www.ajpmonline.org
639
Schillie et al / Am J Prev Med 2018;55(5):633 641
women disproportionately occurred among white women (representing 0.57% of all births), women residing in rural areas (representing 0.70% of all births), and women with Medicaid or other government insurance (representing 0.68% of all births), in line with demographic characteristics associated with HCV infection in other reports.13,17 Previous analyses utilizing birth certificate data demonstrated the proportion of infants born to HCVinfected mothers increased from 0.19% in 2011 to 0.32% in 2014, with considerable variation between states; Appalachian states, such as Kentucky and Tennessee, are particularly affected.13,18 In comparison to the U.S. population, National Health and Nutrition Examination Survey 2003 2010 data estimate 1.3% of the U.S. population aged 6 years and older had been infected with HCV at some point (HCV antibody positive) and 1% were currently infected (HCV RNA positive).19 CDC and/or the U.S. Preventive Services Task Force recommend HCV testing for people born between 1945 and 1965 (“baby boomers”), those with a history of injection or intranasal drug use, incarcerated individuals, those with unregulated tattoos, and others with medical risks (e.g., receipt of hemodialysis).20 22 These guidelines apply to pregnant women; therefore, any pregnant woman at risk for HCV (e.g., history of injection drug use) should be tested. The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recently recommended universal HCV testing during pregnancy.12 Pregnant women who test positive should be linked to care and treated following pregnancy, and infants born to HCV-infected women should be tested and managed appropriately.20 22 The HCV antibody crosses the placenta and maternal HCV antibody can be detected in infants born to HCV-infected mothers. Antibody testing is therefore not recommended for children aged less than 18 months. HCV RNA can be detected within 1 2 weeks following exposure and is used to identify perinatally infected infants early in life.23,24 However, in this analysis, approximately two thirds of HCV tests performed among children aged less than 1 year were antibody tests. Although a negative antibody test is useful for identifying those infants who are not infected, a positive result does not distinguish between infant infection and passive transfer of the maternal antibody. Perinatal HCV infection has become nationally notifiable in 2018.25 Although HCV treatment has a cure rate of approximately 95%,22 recommendations for pharmacologic agents or other interventions during pregnancy or at delivery for preventing perinatal HCV infection are November 2018
26
largely nonexistent. The safety and efficacy of direct acting antiviral agents during pregnancy have not been established. At least one clinical trial of HCV treatment for pregnant women is in progress27; a registry to document outcomes for women who become pregnant while on HCV therapy can help identify drug-related adverse events. Although treatment for HCV among pregnant women is not yet available, pregnancy is one of the few opportunities for which women in marginalized populations receive routine medical care. Documentation of maternal HCV status prompts appropriate HCV testing of their infant. Women can also be treated for HCV after delivery to reduce risk of transmission in future pregnancies. Although testing during pregnancy allows for the identification of infants requiring testing and for maternal treatment following pregnancy, testing of women prior to pregnancy enables administration of curative maternal therapy and nearly eliminates the risk for perinatal HCV transmission on a pre-pregnancy basis.
Limitations There are potential limitations associated with these analyses. Because universal testing of pregnant women is not currently recommended, these estimates likely do not capture the true burden of HCV infection among this population. However, by accepting HCV antibody alone, the authors overestimated those currently infected and at risk for transmitting infection to others. Greater HCV detection rates in birth certificate data are plausible, as women with known HCV infection may not be retested (and therefore not identified through laboratory testing) but would be classified as HCV-infected on the birth certificate. NCHS data encompassed only pregnancies resulting in live births, whereas laboratory data included pregnancies resulting in miscarriage, abortion, or stillbirth. Medical checkbox items are known to be underreported in birth certificate data, and the completeness of reporting for HCV infection is unknown. Although Quest and LabCorp are two of the largest commercial laboratories in the U.S., laboratory coverage varies by region and patients served by the commercial laboratories may have demographic differences that affect their risk for HCV infection. The authors could not distinguish women who were tested at both laboratories. HCV testing data for pregnant women was only available from Quest. Limitations intrinsic to laboratory tests (e.g., test sensitivity and specificity) also exist.
CONCLUSIONS These findings highlight the potential for perinatal HCV transmission. Regardless of whether these
640
Schillie et al / Am J Prev Med 2018;55(5):633 641
trends are a result of increased recognition or a true increase in the incidence of HCV among women of childbearing age or pregnant women, the data reported here reveal a burden of HCV disease in these female populations and therefore transmission risk for infants. Access to HCV testing, followed by treatment for HCV-infected women prior to pregnancy, is most effective; however, stronger recommendations (e.g., so that testing is not contingent upon identification of risk factors) for identifying HCV-infected women before and during pregnancy are important to prevent infection in this vulnerable population. In response to increasing HCV infections, Kentucky has adopted mandatory testing and reporting of HCV among pregnant women.13,28,29 Infant testing algorithms can establish absence of infection in the majority of infants, identify the approximately 5% of young children born to HCV-infected mothers who acquired infection and require follow-up, and reduce HCV antibody testing for infants aged younger than 18 months. Testing pregnant women at risk for HCV infection helps to ensure their infants are identified for testing and possible treatment.
ACKNOWLEDGMENTS The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. The two commercial laboratories who contributed data for this analysis have contractual agreements with the Centers for Disease Control and Prevention. Two authors (WT, HK) are employed by these laboratories. No other financial disclosures were reported by the authors.
SUPPLEMENTAL MATERIAL Supplemental materials associated with this article can be found in the online version at https://doi.org/10.1016/j. amepre.2018.05.029.
REFERENCES 1. Allison WE, Chiang W, Rubin A, Oshva L, Carmody E. Knowledge about hepatitis C virus infection and acceptability of testing in the 1945 65 birth cohort (baby boomers) presenting to a large urban emergency department: a pilot study. J Emerg Med. 2016;50(6):825– 831. https://doi.org/10.1016/j.jemermed.2016.02.001. 2. Wertheim JA, Petrowsky H, Saam S, Kupiec-Weglinski JW, Busuttil RW. Major challenges limiting liver transplantation in the United States. Am J Transplant. 2011;11(9):1773–1784. https://doi.org/ 10.1111/j.1600-6143.2011.03587.x. 3. McHutchison JG. Understanding hepatitis C. Am J Manag Care. 2004;10(2 suppl):S21–S29. 4. CDC. Viral hepatitis: Statistics and surveillance. https://www.cdc.gov/ hepatitis/statistics/index.htm. Updated May 17, 2018. Accessed August 30, 2018.
5. Indolfi G, Azzari C, Resti M. Perinatal transmission of hepatitis C virus. J Pediatr. 2013;163(6):1549–1552. https://doi.org/10.1016/j. jpeds.2013.06.077. 6. Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission of hepatitis C virus: systematic review and metaanalysis. Clin Infect Dis. 2014;59(6):763–773. https://doi.org/ 10.1093/cid/ciu447. 7. Boxall E, Baumann K, Price N, et al. Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies. J Clin Virol. 2007;38 (2):91–95. https://doi.org/10.1016/j.jcv.2006.11.012. 8. The European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. Clin Infect Dis. 41(1):45–51. https://doi.org/10.1086/ 430601. 9. Guido M, Rugge M, Jara P, et al. Chronic hepatitis C in children: the pathological and clinical spectrum. Gastroenterology. 1998;115 (6):1525–1529. https://doi.org/10.1016/S0016-5085(98)70032-0. 10. Lee CK, Jonas MM. Hepatitis C: issues in children. Gastroenterol Clin North Am. 2015;44(4):901–909. https://doi.org/10.1016/j.gtc.2015. 07.011. 11. CDC. Recommended testing sequence for identifying current hepatitis C virus (HCV) infection. www.cdc.gov/hepatitis/hcv/pdfs/hcv_flow. pdf. Accessed May 22, 2017 Published 2013. 12. American Association for the Study of Liver Diseases Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Updated May 24, 2018. Accessed June 6, 2018. 13. Koneru A, Nelson N, Hariri S, et al. Increased hepatitis C virus (HCV) detection in women of childbearing age and potential risk for vertical transmission—United States and Kentucky, 2011 2014. MMWR Morb Mortal Wkly Rep. 2016;65(28):705– 710. https://doi.org/10.15585/mmwr.mm6528a2. 14. National Vital Statistics System. Birth data. www.cdc.gov/nchs/nvss/ births.htm. Updated May 30, 2018. Accessed June 6, 2018. 15. National Center for Health Statistics. Guide to completing the facility worksheets for the certificate of live birth and report of fetal death (2003 revision). www.cdc.gov/nchs/data/dvs/GuidetoCompleteFacilityWks.pdf. Updated May 2016. Accessed April 26, 2018. 16. Martin JA, Hamilton BE, Osterman MJ, Driscoll AK, Matthews TJ. Births: final data for 2015. Natl Vital Stat Rep. 2017;66(1):1–70. 17. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related to injection drug use among persons aged 30 years— Kentucky, Tennessee, Virginia, and West Virginia, 2006 2012. MMWR Morb Mortal Wkly Rep. 2015;64(17):453–458. 18. Patrick W, Bauer A, Warren M, Jones T, Wester C. Hepatitis C virus infection among women giving birth—Tennessee and United States, 2009 2014. MMWR Morb Mortal Wkly Rep. 2017;66(18):470–473. https://doi.org/10.15585/mmwr.mm6618a3. 19. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293–300. https://doi.org/10.7326/M13-1133. 20. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945 1965. MMWR Morb Mortal Wkly Rep. 2012;61 (RR 4):1–32. 21. Moyer VA. U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med.159(5):349–357. https://doi. org/10.7326/0003-4819-159-5-201309030-00672. 22. D’Ambrosio R, Degasperi E, Colombo M, Aghemo A. Direct-acting antivirals: the endgame for hepatitis C. Curr Opin Virol. 2017;24:31– 37. https://doi.org/10.1016/j.coviro.2017.03.017. 23. American Academy of Pediatrics. Hepatitis C. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2018-2021 Report of
www.ajpmonline.org
Schillie et al / Am J Prev Med 2018;55(5):633 641 the Committee on Infectious Diseases. 31st ed. Elk Grove Village, IL: American Academy of Pediatrics, 2018:428-434. 24. Mack CL, Gonzalez-Peralta RP, Gupta N, et al. NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr. 2012;54(6):838– 855. https://doi.org/10.1097/MPG.0b013e318258328d. 25. CDC. National Notifiable Diseases Surveillance System (NNDSS): hepatitis C, perinatal infection, 2018 case definition. wwwn.cdc.gov/ nndss/conditions/hepatitis-c-perinatal-infection/case-definition/2018/. Published 2018. Accessed April 26, 2018. 26. Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern
November 2018
641
Med. 2013;158(2):109–113. https://doi.org/10.7326/0003-4819-158-2201301150-00575. 27. U.S. National Library of Medicine. ClinicalTrials.gov. Study of hepatitis C treatment during pregnancy (HIP). www.clinicaltrials.gov/ ct2/show/NCT02683005?term=pregnancy&cond=Hepatitis$C$ Virus$Infection&rank=1. Updated January 19, 2018. Accessed April 26, 2018. 28. Kentucky Legislature. Kentucky reportable disease surveillance. www. lrc.ky.gov/kar/title902.htm. Updated May 31, 2018. Accessed June 6, 2018. 29. Kentucky Legislature. Legislative record online. KRS 214.160. 18 RS BR 379. www.lrc.ky.gov/recorddocuments/bill/18RS/SB250/bill.pdf. Accessed April 26, 2018.